Poster 1-07 IPMN/MCN - Karger Publishers

321Pancreatology 2004;4:251–414Abstracts

Poster 1-07 IPMN/MCN

P1-07-1

Assessment of Malignancy of IntraductalPapillary Mucinous Tumors of the Pancreasby Imaging Findings and CEA Level inPancreatic JuiceM. Kawai, K. Uchiyama, M. Tani, H. Onishi, H. Kinosita, H. Terasawa, T. Hama, T. Nakase, H. Yamaue

Second Department of Surgery, Wakayama MedicalUniversity, School of Medicine, Wakayama, Japan

The accurate differential diagnosis of malignant intraductal papil-

lary mucinous tumors (IPMT) of the pancreas from benign IPMT still

remains unclear. Because IPMT shows a wide spectrum of histologi-

cal characteristics ranging from hyperplasia to invasive carcinoma.

The aim of the present study was to determine preoperative factors to

be predictive for the early diagnosis of malignant IPMT. Twenty seven

consecutive patients operated with IPMT (11 adenoma, 3 dysplasia, 5

adenocarcinoma, and 8 invasive adenocarcinoma) at Wakayama

Medical University Hospital from January 1999 through December

2003 were retrospectively analyzed in terms of clinicopathological

features as follows: Clinical data, preoperative imaging findings,

cytology and tumor marker level including carcinoembryonic antigen

(CEA) and carbohydrate antigen (CA19-9) in serum and pure pan-

creatic juice. It was clarified that predictive factors for differentiating

benign IPMT from malignant IPMT were tumor size, mural nodule

size, and CEA levels in pure pancreatic juice. In preoperative imag-

ing findings, the mean tumor size in the malignant IPMT group

(81 � 18 mm) was significantly larger than the benign IPMT group

(31 � 4 mm) (p � 0.0023). The mean mural nodule size in the malig-

nant IPMT group (9.8 � 4.4 mm) was significantly larger than the

benign IPMT group (3.3 � 5.7 mm) (p � 0.0025). CEA levels in pure

pancreatic juice in malignant IPMT group (3,051 � 556 ng/ml) was

significantly higher than the benign IPMT group (41 � 80 ng/ml)

(p � 0.0034), although no significant difference in cytology and

CA19-9 levels in pure pancreatic juice was found between two

groups. The optimal cut-off levels for tumor size, mural nodule size,

and CEA in pure pancreatic juice for differentiation between benign

IPMT and malignant IPMT were sought by constructing receiver

operating characteristics (ROC) curve. It was suggested that tumor

size larger than 30 mm, mural nodule larger than 5 mm, and CEA lev-

els higher than 110 ng/ml in pure pancreatic juice were predictive for

the diagnosis of malignant IPMT.

P1-07-2

Differential Diagnosis of IntraductalPapillary Mucinous Tumor (IPMT) of thePancreasH. Uehara1, A. Nakaizumi2, R. Takakura2, H. Iishi1, M. Tatsuta1, H. Eguchi3, H. Ohigashi3, O. Ishikawa3, A. Takenaka4, T. Kasugai5

Departments of 1Gastrointestinal Oncology, 2CancerSurvey, 3Surgery, 4Cytology, and 5Pathology, OsakaMedical Center for Cancer and Cardiovascular Diseases,Osaka, Japan

Background: Intraductal papillary mucinous tumor (IPMT) of

the pancreas is a clinical entity featured by widely opened orifice of

the papilla of Vater, markedly dilatation of the main pancreatic duct

or branch ducts, and abundant mucus secretion, which is distinct from

common carcinoma of the pancreas. The IPMT is classified into

intraductal papillary mucinous adenoma (IPMA) and intraductal pap-

illary mucinous carcinoma (IPMC), and it is difficult to distinguish

IPMC from IPMA preoperatively.

Methods: From 1995 to 2002, 21 patients with IPMT

(18 IPMCs and 3 IPMAs) were diagnosed histologically by surgical

operation and 15 patients with IPMT were diagnosed clinically at

Osaka Medical Center for Cancer and Cardiovascular Diseases. Main

pancreatic duct diameter, size of cyst, and size of tumor were mea-

sured by endoscopic retrograde pancreatography (ERP), endoscopic

ultrasonography (EUS), or intraductal ultrasonography (IDUS).

Pancreatic juice cytology was performed using pancreatic juice col-

lected during ERP after intravenous administration of secretin.

Results: Main pancreatic duct of more than 10 mm in diameter,

cyst of more than 30 mm, and tumor of more than 10 mm suggested

IPMC. Malignant cells were frequently detected in pancreatic juice of

patients with IPMC exclusively.

Conclusion: Endoscopic retrograde pancreatography, EUS,

IDUS, and pancreatic juice cytology was useful for the differential

diagnosis of IPMT.

P1-07-3

Differential Diagnosis of IntraductalPapillary Mucinous Tumor between Benign and Malignant with IntraductalUltrasonographyY. Nakamura, J. Yoshino, K. Inui, K. Okushima, H. Miyoshi,T. Thikaishi, M. Hattori

Department of Internal Medicine, Fujita Health UniversitySchool of Medicine, Second Teaching Hospital, Nagoya,Japan

The efficacy of intraductal ultrasonography (IDUS) was evaluated

to determine therapeutic procedures for intraductal mucinous tumor

of the pancreas (IPMT). In 29 patients with IPMT, including 5 cases

of hyperplasia, 12 intraductal papillary-mucinous adenoma (IPMA),

6 intraductal papillary-mucinous carcinoma (IPMC), and 6 invasive

carcinoma, IDUS was performed by using a miniature ultrasonic

322 Pancreatology 2004;4:251–414 Joint Meeting IAP and JPS

probe with frequency of 20 MHz, developed by Olympus. IDUS find-

ings were compared with pathological findings. IDUS depicted pap-

illary nodules, 1.8 to 12 mm in diameter, at the wall of the pancreatic

duct were depicted in 17 patients. The elevations measured by IDUS

3.8 � 1.3 mm in IPMA was significantly higher than and

8.3 � 3.0 mm in IPMC (p � 0.05). The corresponding heights mea-

sured with pathological examinations were 2.6 � 1.0 and

6.5 � 2.8 mm (p � 0.01), respectively. The height of elevated lesions

were less than 5 mm in 6 of 7 IPMA determined by IDUS. In 3

patients, solid tumors with a mixture of high and low echoes in the

pancreatic parenchyma were depicted. 2 of the 3 patients were diag-

nosed as cancer infiltration to the pancreatic parenchyma affected by

mucous nodules. In the other patient, complicated pancreatitis was

seen. Infiltrated lesions were successfully depicted in 4 of 6 cases of

invasive tumors. In patients with papillary nodule over 5 mm in height

should be treated by surgical treatment. IDUS is capable to reflect

details in pathological findings. IDUS is useful in determining the

therapeutic approach to use for IPMT.

P1-07-4

Branch Duct Type of the IntraductalPapillary Mucinous Tumor of the Pancreas:Usefulness of Endoscopic Ultrasonographyin Differentiation of Benign and MalignantTumorS.-J. Lee1, M.-S. Park2, J.P. Chung1, D.K. Lee1, J.B. Chung1,J.K. Kang1

1Department of Internal Medicine and 2Department ofDiagnostic Radiology, Yonsei University College ofMedicine, Seoul, Korea

Purpose: The purpose of this study was to evaluate the useful-

ness of endoscopic ultrasonography (EUS) in the differential diagno-

sis of benign and malignant the intraductal papillary mucinous tumor

(IPMT) of the pancreas, branch duct type.

Methods: Seven patients with branch duct type of IPMT of the

pancreas, confirmed by surgical resection underwent EUS. After eval-

uation of findings of EUS, these observations were compared with

pathologic findings, and then reevaluated them according to the his-

tologic grade of malignancy.

Results: According to the pathologic specimens, 6 cases of

them were malignant (3 were adenocarcinoma and other 3 were bor-

derline malignancy) remaining one case was benign (adenoma). The

malignant branch duct type of IPMT of the pancreas had several

characteristic findings, compared to the benign branch duct type of

IPMT of the pancreas. The two of malignant tumor involved main

pancreatic duct (MPD) focally. All of malignant tumors showed

larger cystic change (20–35 mm, mean 26.2 mm) than benign tumor

(8 mm). All malignant tumors showed the MPD dilatation (3–9 mm,

mean 4.5 mm), whereas a benign tumor showed no dilatation of the

MPD on EUS. The mural nodules of the malignant tumors (5–15 mm,

mean 8.1 mm) were significantly larger than that of benign tumor

(4.7 mm).

Conclusions: EUS is useful for diagnosing branch duct type of

IPMT of the pancreas, particularly for predicting malignancy. If the

branch duct type of IPMT shows MPD involvement, MPD dilatation,

large cystic change more than 20 mm and large mural nodule more

than 5 mm, these tumors have high malignant potential, so curative

surgical resection was needed.

P1-07-5

Usefulness of Endoscopic Ultrasonographyin the Differential Diagnosis of IntraductalPapillary-Mucinous Tumor (IPMT) of thePancreasY. Takayama1,2, S. Onizawa3, T. Hatori3, K. Shimizu2, F. Toki2, I. Oi2, K. Takasaki3, K. Shiratori2

1Insutitute of Clinical Research, National YokohamaMedical Center, Yokohama, 2Department of Medicine,3Department of Surgery, Institute of Gastroenterology,Tokyo Women’s Medical University, Tokyo, Japan

Preoperative diagnosis of malignant of IPMT is quite important

but often difficult. Among several imaging examination, EUS may be

the most useful procedure for diagnosis of characteristic of IPMT. We

evaluated the usefulness of EUS, US, and CT in comparison to the

pathological findings of IPMT.

Method: In forty patients with IPMT, the size of cystic lesion and

mural nodule of IPMT obtained from the surgically resected speci-

mens was compared with the findings of preoperative EUS, US, and

CT. In addition, pathological malignancy in terms of adenoma or car-

cinoma was also compared to the findings of EUS.

Results: Final diagnosis of IPMT based on the pathological

findings was 21 adenocarcinoma, 16 adenoma, and 3 hyperplasia. In

branch duct-type of IPMT, the accuracies of delineation of the cystic

lesion below 30 mm examined by EUS, US, and CT were 83.3%,

72.7%, and 75.0%, respectively. In the cystic lesions over 30 mm, they

were 82.4%, 87.5%, and 76.5%, respectively. When cut-off sizes of

cystic lesion and mural nodule to differentiate malignant from benign

lesion were 30 mm and 3 mm measured by EUS, the accuracies of

diagnosis of malignant lesion were 64.3% in cystic lesion and 92.9%

in mural nodule, respectively. Therefore, the mural nodule over 3 mm

measured by EUS suggested a high potential of malignant IPMT.

Conclusion: EUS would be strongly recommended to be a use-

ful procedure to diagnose IPMT, particularly malignant potential.

P1-07-6

Usefulness of Pancreatic Juice Cytology inthe Diagnosis of Intraductal PapillaryMucinous Tumor (IPMT) of the PancreasY. Shirai, T. Ishihara, T. Yamaguchi, H. Saisho

Department of Medicine and Clinical Oncology, GraduateSchool of Medicine, Chiba University, Chiba, Japan

Background: Differentiation of benign tumors from malignant

ones is important for the treatment strategy in IPMT of the pancreas

because of its histopathologic variety from hyperplasia to invasive


carcinoma. The aim of this study was to evaluate the usefulness of

pancreatic juice cytology in the diagnosis of IPMT, with special ref-

erence to the utility of pancreatic juice collection under peroral pan-

creatoscopy (POPS).

Methods: 92 patients (63 men, 29 women: mean age 63 years)

were performed pancreatic juice cytology before surgical resection

and the diagnosis of IPMT was confirmed histopathologically. The

histopathological diagnosis was hyperplasia in 7, adenoma in 35, and

carcinoma in 50. Of 60 patients, pancreatic juice was collected during

ERCP examination with a catheter inserted into the main pancreatic

duct sucking with a syringe after intravenous administration of

secretin. Of other 32 patients, it was collected by POPS through a

working channel directly observing the lesion or positioning the tip of

the scope near the lesion.

Results: When we defined the cytologic classification of class

III or more as a malignancy, the sensitivity, specificity, and accuracy

rate were 82%, 45%, and 65% respectively. They were 79%, 47%, and

62% in catheter collecting procedure, while they were 86%, 40%, and

72% in the collection under POPS.

Conclusion: In the diagnosis of IPMT, the diagnostic ability of

pancreatic juice cytology may be improved under POPS.

P1-07-7

Carcinoma in situ with a Minimum InvasiveCarcinoma Occurred at the ResidualPancreas 16 Months Later after MiddlePancreatectomy for Carcinoma in situ at the Pancreatic Body: A Case ReportS. Onizawa1, T. Hatori1, A. Fukuda1, K. Furukawa1, T. Nishino2, F. Toki2, K. Shiratori2, T. Imaizumi3, K. Takasaki1

1Department of Gastroenterological Surgery, 2Departmentof Gastroenterological Internal Medicine, Tokyo Women’sMedical University, Tokyo, 3Department of Surgery, Schoolof Medicine, Tokai University, Isehara, Japan

Background: In spite of the poor prognosis of the pancreatic

cancer, carcinoma in situ of the pancreas is expected to have a favorite

prognosis. However, it is very difficult to find out carcinoma in situ

of the pancreas. We experienced a very interesting case of carcinoma

in situ of the pancreas with a minimum invasive carcinoma.

Case: The patient was a 55-year-old woman who underwent

middle pancreatectomy with distal pancreatico-jejunostomy for the

localized stenosis of the pancreatic body in August 2002. The patho-

logical findings revealed a carcinoma in situ spreading in the main

pancreatic duct and the branches. 8 months later, she was suffered

from acute pancreatitis repeatedly. The stenosis of distal pancreatico-

jejunostomy was suspicious because MRCP showed a dilatation of the

distal pancreatic duct. On the other hand, ERP showed a slight steno-

sis near the stump of the pancreatic head. The cytology of the pan-

creatic juice yielded an adenocarcinoma. However, ultrasonography

and CT-scan couldn’t detect any tumors in the pancreas. It was con-

sidered a possibility of carcinoma in situ of the pancreatic head.

Based on a diagnosis of the pancreatic head cancer and the stenosis of

distal pancreatico-jejunostomy, she underwent duodenum-preserving

pancreatic head resection, resection of the anastomosis of distal

pancreatico-jejunostomy and re-anastomosis 16 months later after the

first operation. The pathological findings revealed a carcinoma in situ

in the branch of the pancreatic duct and a minimum invasive carci-

noma 6 mm in diameter separately. There was seen an inflammatory

change at the stenosis of distal pancreatico-jejunostomy. It was con-

sidered a very interesting case from the viewpoint of carcinogenesis

of the pancreatic cancer.

Poster 1-08 PC Carcinogenesis

P1-08-1

Increased Risk by Smoking for PancreaticCancer in a Japanese Population withInactive Aldehyde Dehydrogenase-2(ALDH2)K. Miyasaka1, T. Kawanami2, H. Shimokata3, S. Ohta4, A. Funakoshi2

1Department of Clinical Physiology, Tokyo MetropolitanInstitute of Gerontology, Tokyo, 2Division of Gastro-enterology, National Kyushu Cancer Center, Fukuoka,3Department of Epidemiology, National Institute forLongevity Sciences, Ohbu, 4Department of Biochemistryand Cell Biology, Institute of Gerontology, Nippon MedicalSchool, Kanagawa, Japan

Although smoking is a well-documented risk factor for the devel-

opment of pancreatic adenocarcinoma, it has not been firmly estab-

lished whether or not alcohol intake is causally related to pancreatic

cancer. Most of the acetaldehyde, a recognized animal carcinogen,

generated during alcohol metabolism is eliminated by liver mito-

chondrial aldehyde dehydrogenase 2 (ALDH2) into acetic acid. More

than 40% of Japanese have the inactive form of ALDH2 and inactive

ALDH2 is a risk factor for multiple cancer of the esophagus as well

as the head and neck cancer. Whether the ALDH2 gene polymor-

phism is associated with pancreatic cancer, and whether smoking

and/or drinking habits are associated with pancreatic cancer, have

been examined in a Japanese population. We investigated 114 patients

with pancreatic cancer, and compared with 2070 control subjects. The

drinking and/and or smoking habits as well as ALDH2 gene poly-

morphism were examined. The frequency of active form of ALDH2

was lower in pancreatic cancer patients than in control subjects

(p � 0.059). The frequency of subjects with both smoking and drink-

ing habits was significantly higher in pancreatic cancer patients than

in control subjects having ALDH2*1/2*1 (p � 0.009, Odds

ratio � 2.31) and ALDH2*1/2*2 (p � 0.0003, Odds ratio � 3.30).

The frequency of smoking habit alone was significantly higher in

pancreatic cancer patients compared with control subjects having

inactive ALDH2, although the difference in subjects having active

ALDH2 was not significant. The drinking habit has not relation to

pancreatic cancer regardless of ALDH2 genotype. In conclusion, the

smoking habit is a positive risk for pancreatic cancer, and the risk is

enhanced in subjects having inactive ALDH2.


P1-08-2

Implantation of Dimethylbenzanthracine in Mice Induces Pancreatic DuctalAdenocarcinomas that Misexpress the Sonic Hedgehog PathwayD.E. Rosow, J.H. Balcom, A.G. Trainor, O. Strobel, B. Antoniu, L. Li, C. Fernandez-del Castillo, A.L. Warshaw,S.P. Thayer

Department of Surgery, Massachusetts General Hospital,Harvard Medical School, Boston, MA, USA

Implantation of dimethylbenzanthracene (DMBA) into the head

of the rat pancreas is an established model of ductal adenocarcinoma.

Following carcinogen exposure, rat pancreata progress from normal

epithelium to carcinoma in situ and adenocarcinoma. We sought to

implement this model in mice and compare the resultant lesions his-

tologically to rat neoplasia. Furthermore, lesions were evaluated for

misexpression of members of the Sonic hedgehog (Shh) signaling

pathway. Shh, an embryonic patterning gene, has recently been char-

acterized as a critical early factor in the initiation of human pancreatic

adenocarcinoma. Following DMBA implantation, mice were sacri-

ficed at different time points, and changes were characterized accord-

ing to the pathologic classification scheme for human pancreatic

ductal lesions. Lesions were tested by immunohistochemistry for

expression of Shh, its receptor Patched (Ptc), the downstream

Hedgehog pathway members Smoothened (Smo) and Gli1, and

BMP4, a foregut mesenchymal marker upregulated in response to

Hedgehog activation. In these mice histologic progression to cancer

was noted post-implantation. Inflammation and reactive atypia

(PanIN-1) were seen by 3 weeks, development of PanIN-2 at 5 weeks,

and carcinoma in situ (PanIN-3) at 6.5 weeks. The Hedgehog pathway

was activated in these lesions, thus recapitulating human disease. The

neoplastic epithelium abnormally expressed Shh, Ptc, Smo, and Gli1,

while the mesenchyme expressed Ptc and BMP4. All were seen early

in the DMBA carcinogenic process, first during the early inflamma-

tory phase and then later within the abnormal tubular complexes of

neoplastic pancreata. These data confirm the early critical role of the

Hedgehog signaling pathway in pancreatic tumorigenesis.

P1-08-3

KiSS-1 Product Metastin and its DerivativesSuppress Migration of Pancreatic CancerCellsR. Doi, T. Masui, T. Mori, E. Toyoda, M. Koizumi, K. Kami,D. Ito, M. Imamura

Department of Surgery and Surgical Basic Science, KyotoUniversity, Kyoto, Japan

Metastin, a post-translationally modified variant of KiSS-1, was

recently identified as an endogenous peptide agonist for a novel G-

protein coupled receptor, hOT7T175 (AXOR12, GPR54). In this

study, we analyzed the role of KiSS-1 and hOT7T175 in both pancre-

atic cancer tissues and pancreatic cancer cell lines. Furthermore we

synthesized novel short variant forms of metastin and tested the

inhibitory effect of those variants on in vitro cell functions that are

relevant to metastasis. Pancreatic cancer tissues showed significantly

lower expression of KiSS-1 mRNA than normal tissues, while cancer

tissues showed significantly higher expression of hOT7T175 mRNA

than normal pancreatic tissues. In human pancreatic cancer cell lines,

KiSS-1 mRNA was highly expressed in 2 out of 6 pancreatic cancer

cell lines, while hOT7T175 mRNA was expressed in all cell lines at

various degrees. PANC-1 cells showed the highest expression of

hOT7T175. Exogenous metastin did not suppress cell proliferation

but significantly reduced the in vitro migration of PANC-1 cells.

Metastin induced activation of ERK1 in PANC-1 and AsPC-1 cells.

Finally, we synthesized 3 novel short variant forms of metastin,

FM053a2TFA, FM059a2TFA and FM052a4TFA. These metastin

variants significantly suppressed the migration of PANC-1 cells, and

activated ERK1. These data suggest that the metastin receptor,

hOT7T175, is one of the promising targets for suppression of meta-

stasis, and that small metastin variants could be an anti-metastatic

agent to pancreatic cancer.

P1-08-4

Reciprocal Distribution of �-smooth MuscleActin� and CD34� Stromal Cells in Non-Neoplastic and Neoplastic Stroma ofthe PancreasS. Ban, Y. Naitoh, Y. Shimizu, T. Mitsuhashi, F. Ogawa, M. Shimizu

Department of Pathology, Saitama Medical School,Saitama, Japan

�-smooth muscle actin (�-SMA)� stromal cells, or so-called

myofibroblasts, emerge in various pathologic situations including

non-neoplastic fibrosis and neoplastic desmoplastic stroma, whereas

CD34� stromal cells are shown to emerge in tissue-damaged areas.

Both of these types of cells are believed to take part in extracellular

matrix production.To find a hint as to their roles in vivo, we per-

formed an immunohistochemical investigation regarding �-SMA and

CD34 in non-neoplastic and neoplastic pancreas tissues obtained

from autopsy and surgical materials. CD34� stromal cells were dis-

tinct from endothelial cells in that they were negative for CD31. In

fibrosis areas of non-neoplastic tissues, �-SMA� and/or CD34�cells were increased, and in this setting, the distribution of �-SMA�cells and CD34� cells seemed to be reciprocal. In the stroma of inva-

sive ductal carcinomas, �-SMA� cells were predominant, but

CD34� cells were also observed focally. The tendency of the recip-

rocal distribution of �-SMA� and CD34� cells was also observed,

although their distribution areas were often overlapped focally.

Immunohistochemical expression of type I procollagen was detected

in a portion of �-SMA� cell areas. The distinct topographic distrib-

ution of �-SMA� cells and CD34� cells suggest that they might

play a different role in both non-neoplastic and neoplastic tissues of

the pancreas.


P1-08-5

Transforming Growth Factor �1 is Expressed in PanINs and PromotesMalignant Transformation in ConditionallyImmortalized Pancreatic Epithelial CellsD. Ito, K. Fujimoto, M. Koizumi, T. Kuhara, K. Kami, T. Mori,E. Toyoda, Y. Kawaguchi, R. Doi, M. Imamura

Department of Surgery and Surgical Basic Science, KyotoUniversity, Kyoto, Japan

Background: Recent studies have demonstrated that TGF-�1

expression is markedly enhanced in invasive ductal pancreatic adeno-

carcinomas, although the precise role of TGF-�1 in pancreatic car-

cinogenesis remains unclear. We analyzed TGF-�1 expression in

PanINs and the effects of chronic TGF-�1 exposure on novel condi-

tionally immortalized pancreatic epithelial (IMPE) cells.

Methods: Sixty-one lesions of PanIN were immunohistochemi-

cally stained with a polyclonal rabbit antibody against TGF-�1.

Growth-inhibitory effect of TGF-�1 was examined in IMPE cells.

IMPE cells resistant to TGF-�1 (IMPE-Tr cells) were generated by

continuous exposure to 1 ng/ml TGF-�1 for more than 50 days.

Phenotypic alterations of IMPE-Tr cells were examined using

Western blot analysis and soft agar and matrigel assay. IMPE and

IMPE-Tr cells were injected subcutaneously into nude mice for in

vivo tumorigenicity assay.

Results: Forty-six percent of PanINs were positive for TGF-�1.

TGF-�1 treatment showed the marked growth-inhibitory effects

(75%) in IMPE cells, whereas its effects were not observed in

IMPE-Tr cells. In soft agar and matrigel, formation of many small

colonies were observed in IMPE-Tr cells, but not in IMPE cells.

Interestingly, the expression of p21WAF1/CIP1 was induced by

TGF-�1 in IMPE cells, whereas the induction was decreased in

IMPE-Tr cells. All of the IMPE-Tr cells-injected mice had sub-

cutaneous tumors, although no tumor was found in the IMPE cells-

injected mice.

Conclusions: TGF-�1 expression in PanINs and neoplastic

transformation of IMPE cells by long-term exposure to TGF-�1 pro-

vide the evidence that TGF-�1 may act as a tumor promoter in early

stage of pancreatic carcinogenesis.

P1-08-6

Different Cell Cycle Protein Expression inAmpulla Vater Cancers and PancreaticCancersM.-C. Chang, Y.-T. Chang, Y.-W. Tien, C.-T. Sun, J.-T. Lin

National Taiwan University Hospital, Taipei, Taiwan

The incidence of periampullary cancers increase gradually in the

world with industalization. Periampullary cancers are still a signifi-

cant challenge for clinicians and basic scientists The role of cell cycle

proteins and tumor suppressor genes in periampullary cancers is wor-

thy to elucidate. Recent studies have revealed that genes and proteins

related to the cell cycle and apoptosis regulation may be involved in

pancreatic carcinogenesis. Cancer tissues obtained from patients with

periampullary cancers who underwent surgery at the National Taiwan

University Hospital without receiving previous chemotherapy or radi-

ation therapy. All periampullary cancers tissues were examined by the

pathologist, who was unaware of the parameters to be investigated. A

total of 68 periampullary cancers (29 ampulla of vater cancers, AVC,

and 39 pancreatic ductal cancers, PDC) including various stages and

histological subtypes were enrolled. Their relevant demographic and

clinicopathological information was obtained from medical records.

Cell cycle proteins, including p16, Rb, cyclin D1, p53 and E2F1

were analyzed by imunohistochemical stains. Among them, signifi-

cant difference of the expression of Cyclin D1 was noted in AVCs and

PDCs. Moreover, relative good survival was noted in AVCs in con-

trast to the poor prognostic role of Cyclin D1 in PDCs (p � 0.05).

There is no obvious statistical difference between above two groups

in the expression of p16, Rb, p53 and E2F1. Different role of the

Cyclin D1 in the carcinogeneiss of AVCs and PDCs was noted.

P1-08-7

Decreased TNF-� Production in Patientswith Pancreatic CancerN. Terakawa, S. Satoi, S. Takai, H. Yanagimoto, K. Takahashi, A.-H. Kwon, Y. Kamiyama

Department of Surgery, Kansai Medical University, Osaka, Japan

Background: Pancreatic cancer has very poor prognosis. Tumor

necrosis factor alpha (TNF-�), which derives from

monocytes/macrophages, has come into recent focus as an indicator

of immune function. The aim of this study is that perioperative

changes of TNF-� production in patients with pancreatic cancer (PC)

are compared with those in patients with hepatocellular carcinoma

(HCC) and benign disease (BD).

Patients and Methods: This study included 15 patients with

PC, 30 patients with HCC, and 13 patients with BD. Peripheral blood

was obtained on the day before surgery and on postoperative days

(POD) 1, 3, 7 and 14. We measured TNF-� levels stimulated by

lipopolysaccharide (LPS) and the proliferation response of T lympho-

cytes (PHA) in patients. The inhibitory index (I.I.) of TNF-� was

defined as the ratio of postoperative to preoperative TNF-� levels.

Results: Preoperative TNF-� levels in PC were significantly

lower than those in HCC and BD (PC 6.6 � 2.9, HCC 9.8 � 3.7, BD

11.5 � 4.5, p � 0.05). The I.I. of TNF-� in PC significantly

decreased on POD1 (p � 0.05) but returned to preoperative levels on

POD3. The decrease in TNF-� on POD1 compared with the rest of

the perioperative period was significantly greater in PC than in HCC

(p � 0.05).

Summary: The results suggest that the immunocompetence of

patients with pancreatic cancer is low, and that surgical stress

depresses TNF-� levels at the early postoperative phase. The avail-

ability of our method to monitor TNF-� production might be more

sensitive than leukocyte counts as a marker of the cytotoxic effects of

surgical procedure and chemotherapy.


P1-08-8

The Link between Obesity and PancreaticCancer is Further Evidence for the Role ofIslets in Pancreatic CarcinogenesisF. Nozawa, M. Yalniz, P.M. Pour

UNMC Eppley Cancer Center, University of NebraskaMedical Center, Omaha, NE, USA

The increasing incidence of obesity in the Western world and the

confirmative epidemiological results linking obesity with some types

of cancer, especially pancreatic cancer (PC), is alarming. Several

experimental studies in the hamster model, which in many aspects

mimics human PC, have shown that islets play a major role in the

development of PC. We have documented that the stimulation of islet

cell hyperplasia promotes pancreatic carcinogenesis, whereas inhibi-

tion of islet cell turnover inhibits it. One of the conditions leading to

islet cell stimulation is peripheral insulin resistance (for example, by

feeding a diet high in unsaturated fat). In the hamster model, periph-

eral insulin resistance is associated with hyperinsulinemia and hyper-

plasia of islet cells, which we believe are the precursor of cancer cells.

The improvement of peripheral insulin resistance, for example by

Metformin, reduces the size of islets, normalized the plasma insulin

level, the number of beta cells and prevents pancreatic cancer induc-

tion. Like in hamsters, obesity is associated with peripheral insulin

resistance, hyper-insulinemia, and islet cell hyperplasia. We, therefore,

believe that the reason for the association between obesity and PC is

the tendency of islet cell proliferation, the suggested tumor progenitor

cells, or the increased production and release of insulin, as a potent

growth factor. If this can be validated by clinical studies, the preven-

tion of pancreatic cancer in the obese population appears a possibility.

Poster 1-09 PC Expression Profiles

P1-09-1

No Apparent Evidence for GermlineMutation of the LKB1/STK11 Gene inFamilial Pancreatic CarcinomaR. Grützmann1, D.K. Bartsch2, C. McFaul3, M. Sina-Frey4,R. Koch5, H.D. Saeger1, C. Pilarsky1

1Department of Visceral, Thoracic and Vascular Surgery,University Hospital Carl Gustav Carus, TechnicalUniversity of Dresden, 2Department of Surgery, Philipps-University Marburg, Marburg, Germany,3University of Liverpool, Liverpool, UK, 4Department ofClinical Genetics, Philipps-University Marburg, Marburg,5Institute of Medical Informatics and Biometrics,Technical University of Dresden, Dresden, Germany

Introduction: As many as 10% of pancreatic cancer cases may

have an inherited component. However, familial pancreatic cancer has

not been linked to defects in any specific gene. Inactivating germline

mutations of the tumor-suppressor gene LKB1/STK11 at 19p13.3

have been shown to cause Peutz-Jeghers syndrome (PJS), an autoso-

mal dominantly inherited disease characterized by a predisposition to

mucocutaneous pigmentations, as well as various benign and malig-

nant neoplasms. It has been assumed, that LKB1/STK11 might play a

role in familiar pancreatic cancer, because PJS patients have a higher

risk in developing pancreatic cancer. To elucidate the role of

LKB1/STK11 in the familial pancreatic cancer, a total of 27 index

patients were analyzed using genomic DNA sequencing of the com-

plete coding region of LKB1/STK11.

Methods: We identified 27 German families in which at least

two first-degree relatives had a histologically confirmed diagnosis of

pancreatic ductal adenocarcinoma. None of the families in our study

met the criteria for the Peutz-Jeghers Syndrome. We sequenced the

complete coding region of LKB1/STK11 using the genomic DNA

isolated from peripheral blood lymphocytes obtained from index

patients to identify germline mutations in LKB1/STK11.

Results: No germline mutation was found within the complete

coding region of LKB1/STK11. However our approach revealed four

intronic polymorphisms, which are two-allelic 1-bp substitution/dele-

tion polymorphisms (IVS2�24, IVS2�49, IVS3�51, IVS7�7).

Conclusion: Our data suggests that germline alterations of

LKB1/STK11 seem to play no role in a subpopulation of families

with familial pancreatic cancer.

P1-09-2

MSX2 Enhances Malignant Phenotype ofHuman Pancreatic Cancer Cell Line BxPC-3K. Satoh, S. Hamada, K. Kimura, T. Shimosegawa

Division of Gastroenterology, Tohoku University GraduateSchool of Medicine, Sendai, Japan

Background and Aim: MSX2, a member of homeobox gene

family, is considered to be downstream target for the Ras and Wnt,

thus, might be involved in tumorigenesis. The aim of this study is to

clarify the correlation of MSX2 expression with the behavior of pan-

creatic cancer cells.

Methods: MSX2 expression in 4 pancreatic cancer cell lines

(AsPC-1, BxPC3, Panc 1 and MIAPaca2) was determined using

reverse transcription-PCR (RT-PCR). Stably MSX2 expressing

BxPC3 cells (BXMS2) or mock cells were generated by G418 selec-

tion after transfection of MSX2 expression vector or empty vector,

respectively. Cell proliferation was examined by BrdU assay. Soft

agar assay and wound healing scratch assay were employed to con-

firm the anchorage independent growth and migration of cells,

respectively. To identify the downstream of MSX2, RT-PCR (for

Snail) and Western blot analyses (for cyclin D1, p21 and E-cadherin)

were performed.

Results: BxPC3, which showed weak MSX2 expression, was

transfected with MSX2 expression vector or empty vector. BXMS2

cells showed 50% induction of cell proliferation (vs. mock cells) and

much more colonies (98 � 3.48) in soft agar than mock cells

(25 � 3.64). BXMS2 cells filled the cell free area within 4-day in

serum-free condition but mock cells did not. RT-PCR and Western

blot revealed the induction of Snail and reduction of E-cadherin by


MSX2 although no significant difference of cyclin D1 and p21 level

was detected.

Conclusion: These results suggest that MSX2 enhanced malig-

nant phenotype of BxPC3 with down-regulation of E-cadherin and

up-regulation of Snail.

P1-09-3

Expression Profiling of MicrodissectedPancreatic Ductal Carcinomas Using High-Density DNA MicroarraysR. Grützmann1, O. Ammerpohl2, J. Lüttges3, H. Kalthoff2, B. Kremer4, H.K. Schackert5, G. Klöppel3, H.D. Saeger1, C. Pilarsky1

1Department of Visceral, Thoracic and Vascular Surgery,University Hospital Carl Gustav Carus, TechnicalUniversity of Dresden, 2Molecular Oncology, Clinic forGeneral and Thoracic Surgery, 3Department of Pathology,4Department of General Surgery, University of Schleswig-Holstein, Campus Kiel, 5Department of Surgical Research,University Hospital Carl Gustav Carus, TechnicalUniversity of Dresden, Dresden, Germany

Introduction: The aim of the study was to search for new mol-

ecular markers of pancreatic ductal adenocarcinoma (PDAC) leading

to novel diagnostic as well as therapeutic targets for this dismal dis-

ease. Despite recent progress in our understanding of the molecular

basis of PDAC further studies are needed to find new molecular

markers for diagnostic and therapeutic purposes.

Methods and Materials: We investigated the mRNA-expres-

sion profile of microdissected cells from 11 normal pancreatic ducts,

from 14 samples of PDAC and of 4 established pancreatic cancer cell

lines. We applied DNA microarray technology with the Affymetrix

U133 GeneChip set representing roughly 33,000 genes. The RNA was

extracted from microdissected samples and cell lines, amplified and

labelled using a repetitive in vitro transcription protocol.

Hybridisation and detection were performed according to Affymetrix

recommendations. Differentially expressed genes were identified

using the SAM (significance analysis of microarrays) program.

Results: We found 616 differentially expressed genes. Within

these, approximately 30% were also identified in other gene expres-

sion profiling experiments and 10% have been associated with pan-

creatic cancer by other analysis techniques, like the Galectins 1 and 3

and the MT-SP2. We have validated the differential expression of sev-

eral genes in PDAC by immunohistochemistry and RT-PCR.

Summary: We present the first whole genome expression study

of microdissected tissue from PDAC, from microdissected normal

ductal pancreatic cells and pancreatic cancer cell lines using high-

density microarrays. Within the panel of genes we identified novel

differentially expressed genes, which have not been associated with

the pathogenesis of PDAC before.

P1-09-4

Survivin Expression in Pancreatic Cancer:Correlation with PrognosisK. Kami1, R. Doi1, M. Koizumi1, E. Toyoda1, T. Mori1, D. Ito1, Y. Kawaguchi1, K. Fujimoto1, M. Wada1, S.-I. Miyatake2, M. Imamura1

1Department of Surgery and Surgical Basic Science,Graduate School of Medicine, Kyoto University,2Department of Neurosurgery, Osaka Medical College, Osaka, Japan

Background: Survivin is a member of the inhibitor of apoptosis

protein family. Survivin is not expressed in normal adult tissues but

highly expressed in several kinds of human cancers. Survivin expres-

sion is expected to be associated with sensitivity to pro-apoptotic

treatments such as radiation. In this study, we assessed survivin

expression in pancreatic cancer specimens from patients who under-

went either pancreatic resection alone, or pancreatic resection plus

post-operative radiation. The aim of the study is to evaluate whether

survivin expression is predictive of sensitivity to radiation therapy

and outcome in pancreatic cancer patients.

Methods: Survivin expression was evaluated by immunohisto-

chemistry for the paraffin sections prepared from 47 pancreatic duc-

tal adenocarcinomas and from 5 normal parts of the pancreas. The

relationship between survivin expression and clinicopathological data

was analyzed.

Results: 68% (32/47) of pancreatic cancer tissues were positive

for survivin expression. Normal pancreatic exocrine tissues were

negative for survivin expression (0/5). Survival of the patients with

positive survivin was significantly shorter than those with negative

survivin (P � 0.02). Survivin was an independent variable that cor-

related with overall survival (P � 0.002). Post-operative radiation

therapy (PORT) showed no impact on mortality in patients who

underwent curative resection for pancreatic cancer. Likely, PORT

showed no impact on survival time in survivin-positive patients

(P � 0.12) as well as in survivin-negative patients (P � 0.95).

Conclusion: The results suggest that survivin protein expres-

sion in pancreatic cancer tissue could be a useful prognostic indicator

in pancreatic cancer patients.


P1-09-5

Why Pancreas Tumor Grows inSubcutaneous Tissue, Pancreas, and Liver, whereas It Does Not Grow in Colon,Stomach, and Uterus?C.Y. Morioka1,3, M.C.C. Machado1, S. Saito2, K. Ohzawa3,R.S. de Godoy1, A.S. Matheus1, J. Jukemura1, T. Bacchella1, L.J. de Souza1, A. Watanabe3

1Department of Surgery, University of São Paulo, São Paulo, Brazil, 2Center for Health Care and HumanSciences, Toyama University, 3Third Department ofInternal Medicine, Toyama Medical and PharmaceuticalUniversity, Toyama, Japan

Paget in 1889 showed that the process of metastasis is not random.

‘Seeds’ are the tumoral and metastatic cells and ‘soil’ is the affinity

for certain organs. This process happens when ‘seed and soil’ are

matched. Pancreas and liver are ‘soil’ organs for pancreatic cancer.

On the other hand, in the clinical picture, direct invasion of colon and

stomach happens, but tumoral cells do not colonize. Rarely, uterus is

a organ of metastasis in this type of tumor.

Aim: The aim of the present study was to verify the possibility

of tumor growth in ‘non soil’ organs such as colon, stomach, and

colon comparing with ‘soil’ organs.

Materials and Methods: HaP-T1, a continuous tissue cultured

cell line derived from BHP-induced pancreatic ductal carcinoma was

used in these experiments. Subcutaneously growing tumors in expo-

nential phase were resected and one piece of graft was implanted

according to the group of study. Hamsters were divided in 6 groups:

1. Subcutaneous implantation (ScI, n � 5), 2. Pancreas implantation

(PI, n � 5), 3. Liver implantation (LI, n � 5), 4. Colon implantation

(CI, n � 5), 5. Stomach implantation (StI, n � 5), and 6. Uterus

implantation (UI, n � 5). Abdominal palpation and monitoring of

weight were done. Survival was studied. After 80 days, living animals

were sacrificed. Necropsy was performed and specimens were sent

for histopathologic study and for detection of K-ras point mutation by

PCR/RFLP analysis.

Results: Pancreatic implanted hamsters survived in average 72

days. All other animals were sacrificed for study. Animals of ScI and

LI groups showed tumor growth and pancreatic metastases were

found in LI group. CI, StI and UI groups did not show local tumor

growth nor metastases. K-ras point mutation was found in implanted

growing tumor of PI, ScI, and LI groups whereas it was not found in

CI, StI and UI groups.

Conclusion: The present study suggests that stomach and

uterus are not ‘soil’ organs for pancreatic ductal cancer. This fact sup-

ports the reasons why pancreatic tumors show direct invasion of these

organs but do not colonize.

P1-09-6

Proteomic Analysis of Pancreatic CancerT.-L. Hwang, Y. Liang

Department of Surgery, Chang Gung Memorial Hospital,Taipei, Taiwan

Purpose: Pancreatic carcinoma is usually advanced by when it

is diagnosed, with an overall five-year survival rate under 5%.

Proteomic study provides an understanding of cellular behavior in

terms of abundance and status of protein. Proteomic analysis of pan-

creatic cancer may find out new biomarkers for the possible further

treatment.

Materials and Methods: Ten tumor specimens from the

patients with pancreatic cancer were analyzed. 2-D electrophoresis

and spot assignment results were condensed in reference gels anno-

tated with description of the spots, linked to established protein data-

base. Via MALDI-MS analysis of tryptic peptides, fast identification

of protein was performed.

Results: The results showed 5 proteins had correlation with the

microarray expression study in our previous study, which are Lectin 1,

Lithostathine, Cathepsin D, Enolase 1, and Phosphoglycerate kinase.

These proteins were then further studied with immunohistochemical

staining to confirm their different expression between tumor and nor-

mal tissues.

Conclusion: Our conclusion is that proteomic study of pancre-

atic cancer can provide some new proteins, which may relate to the

carcinogenesis and helpful for further treatment.

P1-09-7

Phosphoglycerate Kinase is a New ProteinProfile in Pancreatic AdenocarcinomaT.-L. Hwang, Y. Liang, C.-H. Lo

Department of Surgery, Chang Gung Memorial Hospital,Taipei, Taiwan

Purpose: Phosphoglycerate kinase (PGK) was found not only

functions in glycolysis but also is secreted by tumor cells and partic-

ipates in angiogenic process. The role of PGK in pancreatic adeno-

carcinoma was studied.

Materials and Methods: The protein spots were quantified in

10 pancreatic cancers by using quantitative two-dimensional gel elec-

trophoresis analysis. The PGK was chosen as a significant protein. The

PGK protein was further confirmed by Real-time PCR, Western blot-

ting, and immunohistochemical staining. The serum levels of PGK in

13 patients with pancreatic cancer were also checked and compared.

Results: Expression of the PGK protein was significantly dif-

ferent in all the specimens, with 94% showed strong expression, as

tumor-derived with immunohistochemical staining. Western blotting

also confirmed the expression. The serum levels of PGK in patients

with pancreatic cancer showed significantly higher than control. (OD:

0.091 vs 0.069)

Conclusion: Phosphoglycerate kinase is a new biomarker for

pancreatic cancer, which exists in the tumor tissue and elevates its

serum level in patients with pancreatic cancer.


Poster 1-10 PC Signal Pathway

P1-10-1

A Role of Angiotensin II in the Growth andSurvival of AT1-positive Pancreatic CancerCellsT. Ohta, K. Amaya, H. Kitagawa, M. Kayahara, H. Takamura,I. Ninomiya, S. Fushida, T. Fujimura, G.-I. Nishimura, K. Shimizu, K. Miwa

Kanazawa University Hospital, Kanazawa, Japan

More recently, we have reported that tissue angiotensin II concen-

trations in pancreatic ductal cancers are significantly higher than

those of normal pancreas or other solid tumors. However, no report

has focusced on the role of angiotensin II in the growth and survival

of pancreatic cancer cells. This study was designed to examine

angiotensin II type 1 (AT1) receptor expression and the role of

angiotensin II in cell proliferation and survival in human pancreatic

cancer cells. All three pancreatic cancer cell lines studied, from well

to poorly-differentiated types, HPAF-II, AsPC-1, and Panc-1, showed

a strong expression of AT1 receptor. In contrast, HT-29 human colon

cancer cells showed an extremely weak one. Angiotensin II stimulated

the growth of pancreatic cancer cells through MAP kinase activation,

but had no significant effect on proliferation of HT-29 colon cancer

cells. In addition, angiotensin II significantly prevented the cisplatin

(CDDP)-induced apoptosis through NF-�B activation and the subse-

quent production of anti-apoptotic molecules including survivin and

Bcl-XL in pancreatic cancer cells. These findings suggest that

angiotensin II plays a role in the growth and chemoresistance of AT1-

positive pancreatic cancer cells and serves as a potent mitogen and

anti-apoptotic molecule in vitro, functioning as a growth factor.

P1-10-2

Targeting mTOR Signaling for PancreaticCancer TherapyK. Fujimoto, D. Ito, R. Doi, M. Koizumi, E. Toyoda, T. Mori,K. Kami, M. Kawaguchi, M. Imamura

Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto, Japan

The mammalian target of rapamycin (mTOR) plays a central role

in the regulation of cell proliferation, migration and survival.

Dysregulation of mTOR signaling occurs in diverse human tumors,

and can confer higher susceptibility to inhibitors of mTOR. In this

study, we investigated whether or not the mTOR signaling is activated

in 6 pancreatic cancer cell lines and 20 tissue specimens of pancreatic

ductal adenocarcinoma (PDA), and CCI-779 (a mTOR inhibitor,

rapamycin derivative) has antiproliferative effects in in vitro and in

vivo models of pancreatic cancer. Akt, mTOR and p70S6K were

strongly phosphorylated in all of 6 cell lines. PTEN expression was

detected in 4 cell lines except for KMP-3 and KMP-4 cells. In the

tissue specimens, the cytoplasmic expression of p-Akt, p-mTOR and

p-p70S6K was detected in 50%, 55% and 65%, respectively.

Regarding the antiproliferative effects of CCI-779, AsPC-1 and

KMP-3 cells were highly sensitive to the treatment, and BxPC-3 and

Suit-2 cells were slightly resistant. Intriguingly, the combination of

CCI-779 and gemcitabine had additive effects even in the resistant 2

cell lines. Furthermore, CCI-779 induced significant antitumor activ-

ity in 2 in vivo mouse models. In the model by subcutaneous injection

of AsPC-1 cells, tumor volume was 1514 mm3 in control mice and

375 mm3 in CCI-779-treated mice. In another model by intraperi-

toneal injection of Suit-2 cells, median survival time was 16 days in

control mice and 75 days in CCI-779 with gemcitabine-treated mice.

These results demonstrate promising antitumor activity of a mTOR

inhibitor, CCI-779 for pancreatic cancer. Emerging results suggest

that inihibition of mTOR signaling can be exploited as a potential

tumor-selective therapeutic strategy.

P1-10-3

Tumor Growth Suppression of PancreaticCancer by Anti-ras RibozymeH. Kijima1, K. Tobita2, T. Imaizumi2, K.J. Scanlon3, Y. Ueyama1

1Department of Pathology, 2Department of Surgery, Tokai University School of Medicine, Isehara, Kanagawa,Japan, 3Keck Graduate Institute, Claremont, CA, USA

Point mutation in the K-ras gene is observed at a high incidence

in human pancreatic carcinomas. These alterations can be used as

potential targets for specific ribozyme-mediated reversal of the

malignant phenotype. We designed an anti-K-ras ribozyme against

codon 12 of the mutant K-ras gene transcripts (GGT to GTT), and

generated a recombinant adenovirus to express the ribozyme

(rAd/anti-K-ras Rz). We inoculated Canap-1 human pancreatic carci-

noma cells in athymic mice, and made Capan-1 tumor xenografts.

When the Capan-1 tumors in athymic mice became approximately

100 mm3, rAd-anti-K-ras Rz was directly injected into the tumor

xenografts. Fifteen (68%) of 22 tumors injected with rAd/anti-K-ras

Rz showed tumor growth suppression or tumor regression; six of

fifteen tumors were completely regressive, and one tumor was recur-

rent after the tumor regression. By using the recombinant adenovirus

in a mice model system, it was possible to accomplish efficient rever-

sion of the malignant phenotype in human pancreatic tumors with

K-ras gene mutation.


P1-10-4

Suppression of Pancreatic AdenocarcinomaInvasiveness with Antisense OligonucleotideMutation Matched to K-ras Gene in SyrianGolden HamstersR.S. de Godoy1, C.Y. Morioka1,3, M.C.C. Machado1, S. Saito2, Y. Nakada3, A.S. Matheus1, J. Jukemura1, T. Bacchella1, D.P. Filho4, A. Watanabe3

1Department of Surgery, University of São Paulo, São Paulo, Brazil, 2Center for Health Care and Human Sciences, Toyama University, 3Third Departmentof Internal Medicine, 4Second Department of Surgery,Toyama Medical and Pharmaceutical University, Toyama, Japan

Point mutations of K-ras gene are detected in 80% of human

pancreatic cancer. Ras activates a multitude of downstream activities

with roles in cellular processing, including invasion and metastasis.

This has provided opportunities for the development of new thera-

peutics to target a wide range of human diseases. These new drugs

are intended to be highly specific: antisense oligonucleotides (ASO)

are one such class of new drugs. The phosphorothioate antisense

ASO are the current choice for antisense therapy. Hamster pancreatic

experimental cancer resembles to humans immunologically, anatomi-

cally, and genetically. Therefore, for treatment strategies against this

type of cancer, this model may be used for study.

To clarify the anti-invasive activity of ASO specific to K-ras gene

in hamster pancreatic cancer. HaP-T1, a cell culture derived from

BHP-induced hamster pancreatic cancer was used. After liposome-

mediated transfection, cell proliferation was studied by MTT and

MTT-Agarose methods. In vitro chemoinvasion assay with the recon-

stitution of a matrix of basement membrane onto a filter in a Boyden

chamber was used. Migrating cells of the lower chamber were studied

by MTT assay.

ASO strongly inhibit the invasiveness of HaP-T1 in a dose depen-

dent manner. Mutation-mismatched ASO showed not to be effective

in inhibiting the invasion.

The present study suggests that antisense oligonucleotides muta-

tion-matched to K-ras gene may be a new anticancer strategy for pan-

creatic cancer because it could not inhibit only the tumor growth but

also the invasiveness, contributing in the management of the patients

once the process of metastases is multifactorial.

P1-10-5

Is Antisense Oligonucleotides Targeting K-ras Point Mutation a Promise in thePancreatic Cancer Treatment in SyrianGolden Hamsters in vitro and in vivo?C.Y. Morioka1,3, M.C.C. Machado1, S. Saito2, G.I. Yamago4,Y. Nakada3, R.S. de Godoy1, A.S. Matheus1, J. Jukemura1,T. Bacchella1, A. Watanabe3

1Department of Surgery, University of São Paulo, São Paulo, Brazil, 2Center for Health Care and Human Sciences, Toyama University, 3Third Departmentof Internal Medicine, Toyama Medical and PharmaceuticalUniversity, Toyama, 4Department of Cell Biology, OkayamaUniversity Medical School, Okayama, Japan

Pancreas cancer prognosis is still reserved. About 80% of this

type of cancer carries K-ras point mutation, which may play an

important role in tumoral progression. Antisense oligonucleotides

(ASO) targeting this gene may be a therapeutic approach. For this

purpose, our aim was to verify the effectiveness of this gene therapy

in hamster experimental pancreatic model.

HaP-T1, a cell culture derived from BHP-induced hamster pan-

creatic cancer was used. MTT, MTT-Agarose and Western blotting

were performed using ASO specific to K-ras gene. Subcutaneously

implanted tumor in exponential phase of growth was resected and

orthotopic tissue implantation was performed. Animals were divided

in 3 groups: (1) Positive control (PC), (2) Sense treated hamsters

(STH), and (3) Antisense treated hamsters (ATH). Oligonucleotides

were administered for 2 weeks. Follow up was done by abdominal

palpation, ‘general state’, weight, and side effects. Five animals of

each group were sacrificed at Days 10, 17, 24, 31, 38, to study the

local response and metastatic sites. Five animals of each group were

left to study the survival time. Necropsy was performed and speci-

mens were studied histopathologically.

ASO could inhibit the tumoral growth by suppression of K-rasp21 protein synthesis. All tumors were palpable. Positive controls,

STH, and ATH survived in average 72.7, 73.8, and 79.6 days, respec-

tively. Side effects were noted in both oligonucleotide-injected

groups. Tumor sizes were in average smaller in ATH throughout the

study. Lymph node metastases were found from 31 days in ATH

group, while PC and STH groups showed metastases and direct inva-

sion to adjacent organs from 17 days. After death, metastatic sites

were similar in the 3 groups. Liver metastasis showed a higher inci-

dence in PC. Moreover, only PC group showed ascites.

This study suggests that antisense oligonucleotides targeted K-rasgene may be a good choice in the management of pancreatic cancer

because of the suppression of tumor growth in vitro and in vivo.


P1-10-6

Does Methylen Blue Reduce PeritonealCarcinomatosis of Pancreatic Ductal Cancer in Syrian Golden Hamsters?C.Y. Morioka1,3, M.C.C. Machado1, S. Saito2, K.-I. Kita3, R.S. de Godoy1, A.S. Matheus1, M.A.C. Machado1, J. Jukemura1, T. Bacchella1, A. Watanabe1

1Department of Surgery, University of São Paulo, São Paulo, Brazil, 2Center for Health Care and Human Sciences, Toyama University, 3Third Department of Internal Medicine, Toyama Medical and Pharmaceutical University, Toyama, Japan

Background: Methylen blue is known to inhibit the generation

of oxygen radicals. This dye has been tried experimentally to prevent

adhesion formation. However, it has never been reported the preven-

tion of tumoral cell adhesion.

Aim: The goal of the present study was to clarify the effectiveness

of methylen blue to prevent peritoneal tumoral implantation in hamster

pancreatic cancer model.

Materials and Methods: HaP-T1, a cell line derived from

nitrosamine induced tumor was used for these experiments. Tumor cell

suspensions were injected intraperitoneally. Animals were divided into

two groups: 1. only injection (positive control, n � 10) and 2. injection

and administration of methylen blue after the injection (n � 10). They

were observed and weighed until 14 days, when they were sacrificed.

After necropsy, ascites volume was quantified and number of implan-

tations were measured.

Results: Hamsters of Group 1 showed to be more heavy

throughout the experiments. After necropsy, Group 1 had in average

7.4 ml of ascites and generalized peritoneal carcinomatosis including

diaphragm and Group 2 showed in average 2.6 ml of ascites and in

average 9.4 implants located mainly in pelvic region.

Conclusion: The present study showed that methylen blue

decreased the number of pancreatic cancer implants and the volume

of ascites. This substance may be used as an adjuvant therapy to

decrease or even prevent the adhesion of possible metastatic cells in

peritoneal wall.

P1-10-7

Is Farnesyltransferase Inhibitor Effective inthe Neoadjuvant and Adjuvant Treatmentof Pancreatic Cancer in Syrian GoldenHamsters?C.Y. Morioka1,3, M.C.C. Machado1, S. Saito2, K. Ohzawa3, R.S. de Godoy1, A.S. Matheus1, J. Jukemura1, T. Bacchella1, H. Arai4, T. Sakamoto4, A. Watanabe3

1Department of Surgery, University of São Paulo, São Paulo, Brazil, 2Center for Health Care and Human Sciences, Toyama University, 3Third Department of Internal Medicine, 4Second Department of Surgery, Toyama Medical and Pharmaceutical University, Toyama, Japan

Activating oncogenic mutations of the RAS gene are common in

cancer, occurring in 30% of solid tumors in adults. K-ras gene is the

oncogene that is mostly mutated in pancreatic tumors. Farnesyl trans-

ferase inhibitors (FTI) block the main post-translational modification

of the Ras protein, thus interfering with its localization to the inner

surface of the plasma membrane and subsequent activation of down-

stream effectors. We have developed a curative resection model in

Syrian golden hamsters previously.

Aim: To evaluate the effectiveness of FTI (B956) as adjuvant or

neoadjuvant therapy in hamster experimental pancreatic cancer

model.

Materials and Methods: HaPT-1, a cell line derived from

nitrosamine induced pancreatic cancer was used in these experiments.

MTT and MTT-agarose assays were performed. Subcutaneous

implanted tumor was resected in exponential phase and tumor graft was

implanted into the pancreas. At Day 7 or Day 14, partial pancreatec-

tomy and splenectomy were performed. Hamsters were divided in

7 groups: (1) Positive control (PC, n � 5), (2) Only FTI (FT, n � 5),

(3) Neodjuvant therapy after surgical resection at Day 7 (NT-R7,

n � 10), (4) Adjuvant therapy after resection at Day 7 (AT-S7, n � 10),

(5) Neoadjuvant therapy after resection at Day 7 (NT-S14, n � 10),

(6) Adjuvant therapy after resection at Day 14 (AT-S14, n � 10), and

(7) Only surgery at Day 14 (SR, n � 5). FTI was administered for one

week. In FT and NT groups, drug was administered 3 days after ortho-

topic implantation. Body weight and side effects were recorded.

Fourteen days after the surgical resection, sacrifice was done. Four

animals of each group were left to study the survival. After 180 days,

living hamsters were sacrificed. Resected and necropsied specimens

were sent to histopathological analysis.

Results: Successful rate of implantation was 100%. PC, FT,

NT-S7, AT-S7, NT-S14, AT-S14, and SR survived in average 82, 103,

119, 134, 123, 132, and 139 days. Two hamsters of AT-S7 (20%), two

of AT-S14 (20%), and three of SR (60%) were alive until 180 days.

Intra operatory bleeding was higher in NT groups. Loss of body

weight was present in all FTI treated groups.

Conclusion: This study suggests that in contrast to positive

results in chemosensitivity tests in vitro, farnesyltransferase

inhibitor showed not to increase the curative resection rate of ortho-

topically implanted tumors. However, compared to positive control

the administration of the drug alone may be used to increase the sur-

vival time.


Poster 1-11 PC Risk

P1-11-1

Risk Factors of Pancreatic CancerZ. Puchalski, H.R. Hady, J.R. Ladny, J. Dadan, M. Kokoszko, R. Zbucki, W. Serwatka

First Department of General and Endocrinological Surgery,Medical University of Bialystok, Bialystok, Poland

Etiology of malignant neoplasms of pancreas (PC) is still unclear.

However there are several risk factors, which seem to be related to this

disease: smoking, alcohol drinking, coffee, improper diet. Co-existing

PC with some diseases was observed: chronic pancreatitis, diabetes,

gall-stones and partial resection of stomach in the past. In the years

1983 to 2002 at the First Department of General and Endocrinological

Surgery of Medical University of Bialystok 394 patients with cancer

of pancreas were treated. Among them there were 237 males and

157 females of age 26 to 88 (av. 61).

In 14 patients (3.5%) chronic pancreatitis was found, stomach

ulceration in 81 (20.5%), gall-stones in 39 (9.8%), diabetes in 49

(12.5%), stomach resection in the past in 8 (2%), between them in

3 cases resection was performed due to stomach cancer. 194 (49.5%)

patients treated due to pancreatic cancer were smokers (10–40 ciga-

rettes per day during the period of 5 to 30 years), 128 (32.5%) abused

alcohol and 198 (50.2%) used to drink too much coffee (2–5 cups per

day). Etiology and pathogenesis of pancreatic cancer are still unclear

and require further clinical studies. Authors observations and another

observations from the world suggest that pancreatic cancer is related

to some diseases.

P1-11-2

Family History of Diabetes and Pancreatic Cancer RiskN. Egawa, M. Yoshiike, Y. Tu, T. Kamisawa

Department of Internal Medicine, Tokyo MetropolitanKomagome Hospital, Tokyo, Japan

Recent studies have revealed that diabetes mellitus is a predispos-

ing factor for pancreatic cancer. However, it is unclear whether or not

a family history of diabetes is associated with pancreatic cancer. We

reviewed the records of 331 patients with pancreatic ductal cancer and

information about a family history of diabetes in first-degree rela-

tives. They were classified into two groups: patients with a family his-

tory of diabetes (group FH: 43 cases) and those without (group

non-FH: 288 cases), and compared the clinical characteristics, such as

sex, age, histology and anatomical location of the cancer. In addition,

each group was further divided into two subgroups according to the

presence of long-standing diabetes for at least 3 years before pancre-

atic cancer and each two subgroups were also compared. As a result,

group FH was significantly younger at the diagnosis of the pancreatic

cancer (61.33 � 9.00 vs. 65.46 � 10.48 years; p � 0.015) and

showed a significant predilection for cancer of the pancreas body

and/or tail (p � 0.009) compared to group non-FH. In the comparison

of subgroups in group FH, patients with long-standing diabetes more

often had non-tubular type than those without (44% vs. 0%;

p � 0.007). However, no differences were seen between subgroups in

group non-FH. These findings suggest that in some pancreatic cancer

patients a family history of diabetes plays a role in the occurrence of

cancer. In patients with both a family history and long-standing dia-

betes, the pathway for the development of cancer might be different

from that in other patients.

P1-11-3

Differential Diagnosis of Pancreatic Cancer and Focal Pancreatitis UsingEndoscopic Ultrasound Guided Fine Needle Aspiration BiopsyK. Takahashi, K. Okubo, A. Sawaki, N. Mizuno, Y. Okamoto, Y. Shimizu, K. Yamao

Department of Gastroenterology, Aichi Cancer Center Hospital, Aichi, Japan

Background: Despite the current advances in diagnostic imag-

ing techniques, differentiation between pancreatic cancer and focal

pancreatitis can still prove to be difficult. We studied the effectiveness

of endoscopic ultrasound guided-fine needle aspiration biopsy (EUS-

FNAB) in the differential diagnosis between pancreatic cancer and

focal pancreatitis.

Methods: The subjects consisted of sixty two consecutive

patients with pancreatic invasive ductal cancer and fifteen patients

with focal pancreatitis demonstrated as a pancreatic mass lesion by

EUS or computed tomography.

Results: The sensitivity, specificity, positive predictive value

(PPV), and negative predictive value (NPV), of cytological diagnosis

on specimens acquired by EUS-FNAB were 93.5%, 100%, 100%, and

78.9%, respectively, and the sensitivity, specificity, PPV, and NPV,

of histological diagnosis them were 62.9%, 100%, 100%, 39.4%,

respectively. The positive rate for the K-ras point mutation was 74.1%

in pancreatic cancer cases and 0% in focal pancreatitis cases. No

severe complications for EUS-FNAB were observed.

Conclusion: EUS-FNAB is a useful examination method for

differential diagnosis of pancreatic masses caused by pancreatic can-

cer and focal pancreatitis. Analyzing the K-ras point mutation by

EUS-FNAB may enhance the diagnostic accuracy rate in indetermi-

nate cases of positive or negative biopsy results, and will be helpful

for molecular targeting therapy for pancreatic cancer, if developed.


P1-11-4

Pancreatic Cysts: A Sign of High Risk forPancreatic CancerA. Nakaizumi1, S. Tanaka1, T. Ioka1, R. Takakura1, H. Uehara2, H. Eguchi3, H. Ohigashi3, O. Ishikawa3

Departments of 1Cancer Survey, 2GastrointestinalOncology, 3Surgery, Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan

Background: The prognosis of pancreatic ductal adenocarci-

noma remains very poor, but is better in patients with a small tumor

without local infiltration. The identification of the sign of high risk

for pancreatic cancer will lead to early detection and improvement of

the prognosis of this disease. The purpose of this study was to evalu-

ate the pancreatic cyst as a sign of high risk for pancreatic cancer.

Methods: Abdominal ultrasonographic examination was done

after the initial visit to the clinic in total of 1,828 patients with symp-

toms suggesting pancreatic diseases or abnormal findings of ultra-

sonography or serum tumor markers on medical check up. Of those

with abnormal findings, 121 patients eventually were found to have

a malignant tumor including 82 patients with pancreatic cancer.

1,707 patients without the malignant tumor were followed up.

Results: Pancreatic cysts were found in 318 of 1,707 patients

(18.6%). Pancreatic cancer occurred in four of the patients with pan-

creatic cysts over a mean follow-up period of 36 months. On the other

hand, follow-up studies revealed only one pancreatic cancer in 1,389

patients without pancreatic cyst (p � 0.0031).

Conclusion: The pancreatic cyst appear to be a sign of high risk

for pancreatic cancer. The systematic examination of high risk sub-

jects is recommended for the early detection of pancreatic cancer.

P1-11-5

Changes of Serum Neuron-Specific Enolaseas a Good Marker for Small Cell Carcinomaof PancreasY. Nakamura1, T. Tajiri1, E. Uchida1, T. Aimoto1, A. Katsuno1, Z. Naitou2

1First Department of Surgery, 2Second Department ofPathology, Nippon Medical School, Tokyo, Japan

Small cell carcinoma (SCC) of pancreas is a rare disease, which

only 20 cases have been reported in the literature and its prognosis is

extremely poor. Whereas, some cases can be treated successfully with

combined chemotherapy, therefore, it is important to be diagnosed

on earlier stage and exactly evaluated in effect of the treatment.

A 69-year-old woman presented herself with abdominal tumor and

pain. She had been observed for the sensory neuropathy and swelling

of pancreatic head by the referring doctor for ninth months. The

patient was diagnosed as SCC of pancreas after surgery and she had

two course of chemotherapy consisting of cisplatin and etoposide.

Consequently, the tumor completely disappeared by CT, but she died

for recurrence of the diseases three months after chemotherapy. The

patient was monitored the changes of serum neuron-specific enolase

(NSE) level during all progress of the disease. NSE level had already

increased more than normal limit since eighth months before admis-

sion to our hospital and was concurrent with not only tumor growth

but remission or relapse of the disease after treatment. These results

indicated that NSE was a good marker as indicator of diagnosis and

evaluation after treatment for SCC of pancreas.

P1-11-6

Clinical Features and Its Management ofPancreatic Cancer with Bone MetastasesH. Iguchi, M. Yasuda, T. Sumii, A. Funakoshi

Division of Gastroenterology, National Kyushu Cancer Center, Fukuoka, Japan

Prognosis of pancreatic cancer is one of the worst among various

cancers, however, incidense of bone metastasis has been increased even

in pancreatic cancer in recent years. Therefore, we examined clinical

features of pancreatic cancer presenting bone metastases who were

treated in our cancer center, and propose how to manage these patients.

We experienced 13 patients (7.3%) with pancreatic cancer with

bone metastases during 2000–2003. Among these patients, pancreatic

cancer was located at pancreatic body to tail in 10 cases, while it was

located at pancreatic head in 3 cases. Liver metastasis was noted in 7 of

13 cases with bone metastases. Radiographical imagings of bone

lesions revealed osteolytic bone destruction, and serum levels of bone

resorption marker, 1CTP, were elevated in these patients. Stimulation of

osteoclastic bone resorption is a critical step for bone metastasis, thus,

serum levels of cytokines (PTHrP, IL-6, VEGF), which exert a promo-

tive effect on bone resorption, were measured. Serum levels of IL-6 and

VEGF were elevated in most of these patients, while elevation of serum

PTHrP levels was found in 3 of 13 patients with bone metastases.

Survival periods of pancreatic cancer patients with bone metastases was

not long, however, treatment for bone metastases is important in terms

of quality of life (QOL). An earlier diagnosis is essential to prevent

deterioration in the QOL of pancreatic cncer patients presenting bone

metastases. Periodical measurement of serum 1CTP in addition to bone

scintigraphy is helpful for the earlier diagnosis for bone metastases.

P1-11-7

Trends in Pancreatic Cancer Incidence andSurvival with Deprivation – A PopulationBased StudyS.D. Roy1, D.J. Corless1, J.P. Slavin1, M. Deakin2

1Surgical Research Unit, Leighton Hospital, South Cheshire, 2Department of Surgery, UniversityHospital of North Staffordshire, Stoke on Trent, UK

Aim: It is postulated that affluent patients with upper gastro-

intestinal cancer survive better than deprived patients, but demo-

graphic data on pancreatic cancer is lacking. We aimed to analyse the

incidence, mortality and survival trends for pancreatic cancers in

West-Midlands, England (population � 5.3 million) from 1985–2000

in terms of socio economic deprivation.


Methods: Data was collated from regional cancer registry

database. The Townsend Score was employed as a well-validated

measure of deprivation including 4 proxy indicators of socioeco-

nomic status collapsed into quintiles. Individual cases were allocated

one of 5 deprivation categories using the postcode at diagnosis.

Relative survival rates were calculated using stratified actuarial life

tables, regression trends for survival calculated for 1 and 5 years and

p value derived by t-test.

Results: Total number of cancers � 8,820. Preferential increases

in incidence were noted in affluent men (39%, 8.9 to 12.4/100,000)

and women (41%, 5.3 to 7.5/100,000) compared to deprived women

where it fell by 32% (9.6 to 6.5/100,000). This has resulted in affluent:

deprived rate ratios to converge over fifteen years. The affluent groups

had a 3–5% survival advantage over their counterparts but the differ-

ences were not significant at the 95% CI level (p � 0.08 and 0.12 in

men and p � 0.16 and 0.09 in women at 1 and 5 years).

Conclusions: Modest overall decrease in incidence of pancre-

atic cancer over fifteen years masks the preferential increase noted in

the affluent population and decrease in the deprived. The reasons for

these changes are unclear, could be lifestyle related, and warrant fur-

ther examination.

Poster 1-12 PC Chemotherapy Basic

P1-12-1

The Mixture of Gemcitabine and Fibrin Glue is Effective to Inhibit the Growth of Orthotopically Implanted PancreaticCancer in Nude MiceY. Ogura, K. Mizumoto, T. Manabe, E. Nagai, M. Tanaka

Department of Surgery and Oncology, Graduate School ofMedical Sciences, Kyushu University, Fukuoka, Japan

Pancreatic cancer frequently recurs after surgery and leads to dis-

mal prognosis. Strategy to inhibit the growth of residual cancer cells

is important to improve the survival of pancreatic cancer patients.

Fibrin glue (FG) is a biocompatible, restorable, adherent hemostat

that can deliver anticancer drugs to the residual cells at a high con-

centration. The aim of this study is to evaluate the local antitumor

effect of a mixture of FG and gemcitabine (FG-GEM) on pancreatic

cancer cells orthotopically implanted in nude mice. Suit-2 human

pancreatic cells were injected into the pancreas tail of nude mice.

7 days later, groups of mice were treated with 80 mg/kg GEM mixed

with 500 �l fibrin glue (FG-GEM), or 500 �l FG alone. Other

groups of mice also received i.p. injection of 80 mg/kg GEM or PBS

(Control). 21 days after the treatment, tumor volumes of the groups

treated with FG-GEM, GEM, and FG were smaller by 62, 45 and

14%, respectively, than in the controls. In addition, survival of mice

treated with FG-GEM was significantly longer than that of treated

with GEM, FG, or PBS. These results may indicate that the mixture

of gemcitabine and fibrin glue is effective to inhibit the growth of

pancreatic cancer and useful to prevent local recurrence of pancreatic

cancer after surgery.

P1-12-2

Severe Toxicity Related to a SingleNucleotide Polymorphism of the CytidineDeaminase Gene in Japanese CancerPatients Treated with Gemcitabine plusCisplainK. Yonemori1, H. Ueno1, T. Okusaka1, M. Ikeda1, H. Ishii2,J. Huruse2, N. Kaniwa3, S. Ozawa3, N. Saijo4

1Division of Hepatobiliary and Pancreatic Oncology,National Cancer Center Hospital, Tokyo, 2Division ofHepatobiliary and Pancreatic Oncology, National CancerCenter East Hospital, Chiba, 3National Institute of HealthSciences, Tokyo, 4Department of Medical Oncology,National Cancer Center Hospital, Tokyo, Japan

Polymorphisms in genes of drug metabolizing enzymes for anti-

cancer agents may influence drug pharmacokinetics and pharmaco-

dynamics. We investigated a single nucleotide polymorphism (SNP)

of CDA encoding a metabolizing enzyme for gemcitabine to clarify

relationship between the SNP 208G � A and pharmacokinetics or

toxicity in six patients treated with gemcitabine plus cisplatin. Blood

samples were collected for analysis of CDA genotype before treat-

ment. Gemcitabine and its metabolite in plasma collected before the

initiation of infusion, at the end of infusion and at 15, 30, 60, 90,

120, 240 min after the end of infusion on day 1 of the first course

were measured by an HPLC method. A 45-year-old man with pan-

creatic adenocarcinoma experienced severe hematological and non-

hematological toxicity during the first course of chemotherapy. AUC

of gemcitabine in the patient with severe drug toxicity was five times

higher than, and the concentration of the metabolite of gemcitabine

was half of the average concentrations of the other patients. Relative

activity of cytidine deaminase in the patient was one-tenth of average

of that in the other patients. The patient had a variant 208G � A as

homozygote, while the other patients had no such variant. Therefore,

SNP of cytidine deaminase gene, the homozygous 208G � A alter-

ation, might have induced severe drug toxicity in the Japanese cancer

patient treated with gemcitabine.

P1-12-3

Schedule-Dependent Effects of Gemcitabineand 5-fluorouracil in Pancreatic Cancer CellsS. Nakahira, S. Nakamori, M. Tsujie, Y. Takahashi, S. Marubashi, A. Miyamoto, H. Nagano, K. Dono, K. Umeshita, M. Sakon, M. Monden

Department of Surgery and Clinical Oncology, GraduateSchool of Medicine, Osaka University, Osaka, Japan

Background: The systemic administration of gemcitabine has

been accepted as a standard first-line treatment for patients with


advanced pancreatic cancer. The major mediators of gemcitabine

uptake are most probably the equilibrative nucleoside transporter (NT)

which expression is mediated by TS inhibitor such as 5-fluorouracil

(5-FU). The effect of 5-FU on treatment with gemcitabine in pancre-

atic cancer, however, is not well known.

Methods: Seven pancreatic carcinoma cell lines (AsPC1, BxPC3,

MiaPaCa-2, PSN1, Panc1, PCI6, and KMP-7) were treated with 5-FU

either before, simultaneously or following exposure to gemcitabine.

Expression of NT were determined by quantitative mRNA expression

assay using LightCycler. RT-PCR. Anti-proliferative effects on pancre-

atic cancer cells with sequential 5-FU and gemcitabine treatment were

determined by the MTT assay.

Results: A significant increases in NT mRNA levels were

observed after 5-FU treatment in all seven cell lines, while simulta-

neous and following exposure of 5-FU did not increase the NT levels.

Anti-proliferative effects of gemcitabine were enhanced after 5-FU

treatment rather than the following exposure of 5-FU.

Conclusion: Pretreatment with 5-FU seems to enhance anti-

proliferative effect of gemcitabine on pancreatic cancer cells.

P1-12-4

Predictive Factors for Resistance toGemcitabine-Based Chemotherapy inPatients with Pancreatic CancerS. Nagai, T. Okusaka, C. Morizane, H. Ueno, M. Ikeda, Y. Takezako, M. Najima

Hepatobiliary and Pancreatic Oncology Division, National Cancer Center Hospital, Tokyo, Japan

Gemcitabine (GEM) is generally accepted as a standard

chemotherapeutic agent for advanced pancreatic cancer (PC).

Systemic chemotherapy for advanced PC, however, has been of

limited value and a large portion of patients shows rapid disease

progression even after administration of GEM. This study investi-

gated the factors related to resistance to GEM-based chemotherapy

for predicting patients who reap little benefit of chemotherapy for

advanced PC. Ninety-eight consecutive patients with advanced

PC receiving GEM-based regimens including GEM alone, GEM �5-fluorouracil and GEM � Cisplatin, were analyzed retrospectively

to identify predictive factors for resistance to chemotherapy.

‘Resistance to chemotherapy’ was defined as disease progression

within one month after initiation of treatment. Of these 98 patients,

33 (33.7%, 95% confidence interval; range, 24.4% to 43.9%)

showed disease progression within one month. Univariated analysis

revealed that a performance status of 2–3 (P � 0.01), serum

CRP level �2.0 mg/dl (P � 0.01), serum albumin level �3.5 g/dl

(P � 0.017) and two or more organ sites of metastasis (P � 0.02)

were the predictive factors. On multivariated analysis, a performance

status of 2–3 (P � 0.03) and serum CRP level �2.0 mg/dl

(P � 0.037) were independent predictors of ‘resistance to chemo-

therapy’. The findings of this study may be useful in determining

treatment strategies for advanced PC patients. Patients having unfa-

vorable factors may be treated with other experimental approaches or

may be offered only supportive care.

P1-12-5

Our Experience with Gemcitabine Treatmentfor Advanced Pancreatic CancerY. Takeda, R. Sasaki, T. Fujita, M. Takahashi, O. Funato, H. Nitta, H. Kawamura, K. Saito

Department of Surgery 1, Iwate Medical University, Morioka, Japan

Purpose: Gemcitabine is the most promising new agent cur-

rently being tested in pancreatic cancer. The present study was con-

ducted to confirm the tolerability and efficacy of gemcitabine in

Japanese patients with advanced pancreatic cancer.

Methods: 11 patients with locally unresectable pancreatic cancer

were treated with gemcitabine 1,000 mg/m2 over 30 minutes weekly

for three weeks followed by a week of rest (group NR). 8 patients who

underwent resection surgery received 500 mg/m2 or 800 mg/m2 dose as

adjuvant chemotherapy (group R).

Results: 1) In group NR, 1/11 patients had a partial response

(PR), 8 patients had stable disease (SD) and 2 patients progressed dur-

ing treatment. The median survival was 7.0 months. And 1-year sur-

vival rate was 39%. Grade 3–4 toxicities consisted of leucopenia in

36%, anemia in 9%, Anorexia in 9%, nausea/vomiting in 9%, Fatigue

in 9%, and fever in 9% respectively. 2) In group R, with a median

follow-up of 14 months the median disease-free survival and overall

survival was 12.6 and 13.2 months. Grade 3–4 toxicities of 500 mg/m2

consisted of leucopenia in 20%, anemia in 0%, thrombocytopia in 0%

respectively. The non-hematologic toxicities were not recognized.

Grade 3–4 toxicities of 800 mg/m2 consisted of leucopenia in 67%,

anemia in 0%, thrombocytopia in 0%. The non-hematologic toxicities

were not recognized.

Conclusion: Our results indicate that treatment with gemcitabine

is effective, well tolerated and leads to clinical benefit for selected

Japanese patients with advanced pancreatic cancer.

P1-12-6

Effectivity of Gemcitabine in AdvancedPancreatic CancerT. Kohsaki, I. Nishimori, N. Okamoto, K. Morimoto, T. Ishihara, S. Morishita, M. Nishikata, S. Onishi

Department of Gastroenterology and Hepatology, Kochi Medical School, Kochi, Japan

Unresectable adenocarcinoma of the pancreas has very poor prog-

nosis. Various clinical efforts have failed to dramatically improve the

patients’ survival. Recently, a new anti-cancer drug, gemcitabine, has

been shown to be of clinical benefit and to modestly improve the sur-

vival. Here, we report the effectivity of gemcitabine in advanced pan-

creatic cancer. Twenty seven patients (15 males and 12 females) with

a median age of 65 years (50 � 81) were enrolled into the study. All

participants were diagnosed in the advanced stages (9 in stage IVa and

18 in stage IVb). Gemcitabine 1,000 mg/m2 on days 1, 8, and 15 once

every 3 weeks and suspended next 4th week (� one cycle). In cases

showing side effects, gemcitabine was decreased in dose or times per

cycle. No cases with complete response were observed. A partial


response was observed in 18 of 27 patients (67%). Nine patients

(33%) had progressive disease. Median survival time in was 212 days

(69 � 485 days), which was significantly longer than an untreated

patient group in the comparative disease stages (153 days, p � 0.05).

Two patients still survive more than one year. Cancer-induced pain

subsided in nine of 17 patients (53%). Bone marrow suppression and

nausea/vomiting were seen in 59% and 22% of the patients, but no

fetal side effect was observed. These results confirm clinical effec-

tiveness of gemcitabine in patients with advanced adenocarcinoma of

the pancreas.

Poster 1-13 PC Staging

P1-13-1

Usefulness of an Exploratory LaparoscopyFollowing Preoperative Chemoradiation for the Patients with Locally AdvancedPancreatic CancerK. Aiura, T. Hayashida, Y. Itoh, N. Chiba, M. Ueda, M. Kitajima

Department of Surgery, Keio University School of Medicine, Tokyo, Japan

Most of pancreatic cancer are diagnosed in advanced stages of the

disease, and surgery alone is not a curative therapy. Therefore, com-

bined multimodality therapy with radiation and chemotherapy is def-

initely required in order to improve survival. In addition, the

possibility exists that patients with locally advanced tumor may have

occult metastasis at the time of diagnosis, suggesting surgery is not

adequate in these cases. Based on these facts, we planned preoperative

chemoradiation combined with an exploratory laparoscopy per-

formed just before open laparotomy. The patients underwent radiation

at a total dose of 40 Gy and concurrent chemotherapy with 5-FU

(300 mg/body/day, day 1–5/w, 4 w), MMC (4 mg/body/day, day 1,

8, 15, 22), and CDDP (10 mg/body/day, day 2, 9, 16, 23), and received

surgery 1 or 1.5 months after chemoradiation. Three patients under-

went preoperative chemoradiation, and two of three patients under-

went an exploratory laparoscopy and one of them underwent surgical

resection for the present. Serum CA19-9 concentrations were

decreased by 40 to 96% in all patients after chemoradiation. Biopsy

specimen from the pancreatic tumor at the time of operation in case 1

demonstrated necrotic and fibrotic tissue, and resected specimen in

case 3 showed only atypical glands without cancer cells on histologi-

cal evaluation. An exploratory laparoscopy in case 2 avoided unnec-

essary laparotomy due to liver metastasis and peritonitis

carcinomatosa. It is possible that neoadjuvant chemoradiation may be

beneficial for patients with locally advanced cancer. Furthermore, an

exploratory laparoscopy could spare the patients with metastatic dis-

ease an unnecessary laparotomy following chemoradiation.

P1-13-2

Reappraisal of JPS Stage Grouping forPancreatic Head CarcinomaJ. Izai, T. Ebata, H. Nishio, T. Arai, K. Oda, N. Yuasa, M. Nagino, Y. Nimura

Division of Surgical Oncology, Department of Surgery,Graduate School of Medicine, Nagoya University, Nagoya, Japan

Background/Aim: A reliable staging system is useful to evalu-

ate the overall results of anticancer treatments. The aim of present

study was to evaluate the prognostic value of the Japan Pancreas

Society (JPS) staging system, in comparison with the International

Union Against Cancer (UICC) staging system.

Methods: From 1975 to 1997, 77 patients with invasive ductal

carcinoma of the pancreatic head, who underwent macroscopic cura-

tive resection, were enrolled. The patients were classified in accor-

dance with the both stage grouping and the clinicopathologic

variables were also evaluated.

Results: According to the JPS, there were 2 patients in stage

I � II, 16 in stage III, 35 in stage IVa, and 24 in stage IVb. The 1-/2-/

5-year survival rate was 69/31/25% in stage III, 49/26/11% in

stage IVa, and 17/0/0% in stage IVb, respectively. There was a signif-

icant difference among survival curves by the JPS stages, whereas

there was not among those by the UICC stages. Although a macro-

scopic portal vein invasion was a significant prognostic predictor, the

extent of resection had impact on survival. The patients with wedge

resection had similar survival to those without, whereas the patients

with segmental resection had extremely shorter survival.

Conclusion: The JPS staging system may have better prognos-

tic advantage than the UICC staging system. The extent of portal vein

invasion will enhance the JPS staging system to provide more accu-

rate stratification in patients survival.

P1-13-3

Validity of Pancreatectomy for AdvancedPancreatic Carcinoma from Local TumorExtension Factors and Lymph NodeMetastasisH. Ito, F. Kimura, H. Shimizu, A. Togawa, M. Ohtsuka, H. Yoshidome, A. Kato, M. Miyazaki

Department of General Surgery, Graduate School of Medicine, Chiba University, Chiba, Japan

Aim: Prognosis of pancreatic cancer is yet remarkably poor, even

if curative resection was performed by extended tumor abscission,

however, operative resection provides the only chance for cure or

long-term survival. We investigated factors affecting prognosis after

pancreatectomy from the viewpoint of local tumor extension and

lymph node metastases, and assessed validity of pancreatectomy for

carcinoma.

Patients and Methods: 71 cases of invasive pancreatic carci-

noma were analyzed as a local progression factor, pancreatic frontal

serosa invasion (S), retroperitoneal invasion (RP), portal vein or other


major vascular invasion (PV), and extra-pancreatic nerve plexus

invasion (PL). Lymph node metastasis status was classified as N0; no

lymph node metastasis, N1; metastasis to pancreatic neighboring

lymph nodes, N2; metastasis to extra-pancreatic regional lymph

nodes.

Results: Correlation with each factor and postoperative out-

come analyzed by logrank test was S; p � 0.0001, RP; p � 0.016,

PV; p � 0.0003, PL; p � 0.017, and N0/N12; p � 0.0001, N01/N2;

p � 0.0008. Applying a multivariate analysis to these factors, it was

S: p � 0.029, RP: p � 0.37, PV: p � 0.62, PL: p � 0.82 and N0/N12:

p � 0.002. Presence of lymph node metastasis showed the strongest

correlation with poor prognosis.

Conclusion: Considering the validity of operative resection for

panceratic cancer, aggressive panceratectomy would be justified for

the cancer without lymph node metastasis or with only positive in

neighboring lymph node, even if with major vascular involvement.

P1-13-4

Analysis of Long-Term Survivors after Surgical Resection for InvasivePancreatic CancerS. Kure, T. Kaneko, S. Takeda, S. Inoue, A. Nakao

Department of Surgery II, Graduate School of Medicine,Nagoya University, Nagoya, Japan

Pancreatic cancer remains a lethal disease. Although many

authors have reported on survival rates of pancreatic cancer after sur-

gical resection, the clinicopathological characteristics that influence

to over-5-year long-term survival remain controversial.

The clinicopathological characteristics of over 5-years long-term

survivors who underwent radical resection for pancreatic cancer from

the year 1981 to 1997 were retrospectively studied.

There were 182 patients of pancreatic cancer who underwent sur-

gical resection from 1981 to 1997 in our department. Among them,

after 4 patients of IPMT were excluded, there were 8 resected cases of

invasive pancreatic cancer who survived over 5 years after resection.

Surgically R0 resection including 5 combined portal vein resections

(62.5%) had been achieved in all these 8 patients. Negative invasion

of major regional artery (7 of 8, 87.5%), negative invasion to extra-

pancreatic nerve plexus (7 of 8, 87.5%), N0 or N1 lymph node metas-

tasis (7 of 8, 87.5%), and no exposure of carcinoma at the dissected

surface and cut end (7 of 8, 87.5%) were characteristically confirmed

in pathology. Portal vein invasion was seen in 3 of 8 patients (37.5%).

For long-term survival in case of pancreatic cancer, a complete R0

resection should be performed, and negative invasion in major

regional arteries and negative invasion to extrapancreatic plexus of

nerve were necessary. No invasion to portal vein was not necessarily

required, if R0 is achieved by combined resection of the portal vein.

P1-13-5

Short and Long-Term Results ofSimultaneous Resection of the Colon with PancreaticoduodenectomyY. Suzuki, Y. Fujino, Y. Tanioka, T. Sakai, T. Ajiki, T. Ueda, M. Tominaga, Y. Kuroda

Department of Gastroenterological Surgery, Kobe University, Kobe, Japan

Simultaneous resection of the colon is occasionally inevitable to

achieve curable pancreaticoduodenectomy (PD) in patients with a

periampullary tumor involving the mesentery of the colon. However,

there is little information regarding short- and long-term outcomes of

this aggressive surgery. In 95 consecutive patients who underwent PD

for periampullary malignant tumors, 12 received simultaneous resec-

tion of the right side colon (group 1) while 83 underwent PD alone

(group 2). Intraoperative variables, postoperative morbidity and mor-

tality, and periods of hospital stay were comparatively analyzed.

Survival was also compared between the groups in a subset of 36 pan-

creatic adenocarcinoma patients. Group 1 included more patients with

pancreatic adenocarcinoma and was more frequently performed portal

vein resection, which seemed to be associated with the longer operative

time (640 versus 510 minutes) and increased total blood loss (1,965

versus 1,220 ml). However, morbidity and mortality rates did not differ

between the groups (50% and 0%, respectively, in group 1 and 44.6%

and 1.2%, respectively, in group 2). Median periods of hospital stay

were 67 days and 48 days in groups 1 and 2, respectively. Median sur-

vivals of pancreatic adenocarcinoma patients were 14 months in group

1 and 12 months in group 2. There was no statistically significant dif-

ference in survival between the groups. Simultaneous right hemicolec-

tomy with curative intent at the time of PD could be performed safely

and may offer a survival benefit even for advanced pancreatic cancers

with involvement of the transverse mesocolon.

Poster 1-14 PC Surgical Treatment

P1-14-1

Surgical Treatment of Cancer of thePancreas – Own ExperiencesH.R. Hady, Z. Puchalski, J.R. Ladny, J. Dadan, M. Kokoszko, R. Zbucki, W. Serwatka

First Department of General and Endocrinological Surgery, Medical University of Bialystok, Bialystok, Poland

Pancreatic cancer (PC) is malignant neoplasm of digestive system

of the worst prognosis and the highest mortality. Advances in pancre-

atic cancer diagnostics do not change fact, that most of patients arrive

to hospital in the late stadium of disease, when possibility of resection

is rather lower.

The aim of the study is to present own experiences in diagnostic and

surgical treatment of pancreatic cancer. In the years 1983 to 2002 at the


First Department of General and Endocrinological Surgery of Medical

University of Bialystok 394 patients with cancer of extrasecreting part

of pancreas were treated. Among them there were 237 males and

157 females of age 26 to 88 (av. 61). In 267 cases (67%) the primary

cancer focus was localized in the head of pancreas, in 103 (26%) in the

trunk and 24 (6%) in the tail. The diagnosis was based on clinical view,

results of biochemical analysis, neoplasmatic markers level and imag-

ing examinations (ultrasonography, endoscopic ultrasonography,

computer tomography, intraoperative ultrasonography and specular

imaging of bill and pancreatic duct). 386 patients of 394 were operated

on. Surgical management depended on localization and advancing state

of the tumor. Classification UICC (pTNM) was used to show the grade

of neoplasmatic process. In 47 (12%) patients partial or total resection

of pancreas was possible, post-operative chemiotherapy was given to

39. In 226 (58.5%) paliative procedures were performed, and in 113

(29.5%) only laparotomy and biopsy of pancreas was done.

Chemiotherapy was given respectively to 179 and 55 patients.

Basing on observation we found that despite of advances in new

dignostic methods, which allow to detect early stadium of pancreatic

cancer, the possibility of resecting treatment is limited to 10–25% of

the patients. So low percentage of resections in caused mainly by un-

characteristic clinical view in the early stage of disease and lack of

specific screening examination.

P1-14-2

Pancreatic Cancer Resection in ElderlyPatients: Operative Outcome and SurvivalG. Balzano1, A. Zerbi1, P. Veronesi1, F. Scaltrini1, A. Beneduce1, M. Reni2, V. Di Carlo1

Departments of 1Surgery and 2Radiochemotherapy, San Raffaele Hospital, Milan, Italy

Background: Pancreatic cancer resection is considered a high-

risk procedure in patients aged 70 years or older.

Methods: 319 patients with pancreatic adenocarcinoma, who

underwent resection between 1990 and 2002, were reviewed. Data

were prospectively collected in our pancreatic surgery data-base.

Operative outcome and survival of 95 patients aged 70 years or more

were compared with findings in 224 younger patients.

Results: Mortality rate was 2.1% in patients aged 70 years or

more and 2.2% in younger patients; morbility was 44.3% and 49.2%,

respectively (NS). Postoperative pancreatic fistula was less frequent

in elderly patients (9.5% vs 20%, p � 0.05). Median postoperative

stay was 17 days in elderly patients and 16 days in younger patients

(NS). Pathologic prognostic factors were similar between the two

groups (UICC classification, nodal involvement, grading, radicality,

tumour diameter). However, patients aged 70 years or more under-

went less frequently postoperative chemo- and radiotherapy

(p � 0.01) with respect to younger patients. Median postoperative

survival was 15 months in elderly patients and 18 months in the

younger group (log-rank test p � 0.26). Multivariate analysis consid-

ering age, pathologic factors and adjuvant therapies as covariates

demonstrated that tumour diameter, grading and UICC stage were

independent prognostic factors, whereas age was not (p � 0.2).

Conclusion: Patients aged 70 years or more can benefit from

pancreatic cancer resection similarly to younger patients.

P1-14-3

Pancreaticoduodenectomy for SmallPeriampullary Masses Suspected Malignancy in Chinese PatientsL. Sun, X. Fang, Y. Feng, D. Zhang, Z. Zheng

General Surgery Department, China-Japan UnionHospital, Jilin University, Changchun, China

Objective: To evaluate whether pancreaticoduodenectomy (PD)

can be performed on the basis of suspected malignancy when the

tumor is in small size.

Methods: One hundred and forty-five PDs were retrospectively

reviewed , and both preoperative and intraoperative findings were

analyzed. Postoperative pathologic report was considered as the final

diagnosis. Preoperative data between the malignant and benign

lesions were compared.

Results: Altogether 106 of the 145 (73.1%) were performed by

PD without pathologic evidence, and 39 (36.8%) showed the mass

size was less than 3 centimeters. Of the 39 small masses, 33 (84.6%)

were proved to be really malignant, and the other 6 (15.4%) were

benign lesions. No difference was found on preoperative data between

the malignant and benign groups.

Conclusion: Clinical findings are sufficient to diagnose

periampull-ary malignancy even though the tumor is in small size.

P1-14-4

Is Pancreaticoduodenectomy Justified forAdvanced Non-Duodenal GastrointestinalCarcinomaC.-C. Wu1, D.-C. Yeh1, J.-T. Chen1, T.-J. Liu2, F.-K. P’eng1

1Department of Surgery and Pathology, Taichung VeteransGeneral Hospital, Taichung, 2Tao Yuan Veterans Hospital,Taiwan

Pancreaticoduodenectomy (PD) is a standard procedure for peri-

ampullar or duodenal carcinoma. Its role for advanced non-duodenal

gastrointestinal carcinoma remains unclear.

A retrospective review of PD for 33 patients with advanced gas-

tric carcinoma and 9 patients with advanced right coon carcinoma

between 1990 and 2002 was performed. Soft pancreatic parenchyma

and thin main pancreatic duct (diameter � 1 mm) were found in all

patients. Postoperative complication rate was 39.8% and one gastric

cancer patient with solitary liver metastasis (which was also resected)

died after operation (operative mortality 2.2%). All patients were fol-

lowed up until Jan. 2004. The 5-year survival rate for advanced gas-

tric cancer was 23.4% and that for advanced colon cancer was 34.8%.

Patients without advanced lymph node metastasis survived longer,

three patients (one gastric cancer, two colon cancer one with solitary

liver metastasis) survival longer than 10 years. These findings sug-

gested that PD is justified in advanced gastric or colonic carcinoma if

advanced lymph nodes metastasis (such as paraaortic lymph note

metastasis) did not appear.


P1-14-5

Impact of Reconstruction Method onOutcome of Pancreatoduodenectomy in Pancreatic Cancer PatientsR. Doi, E. Toyoda, M. Koizumi, T. Mori, K. Kami, D. Ito, Y. Kawaguchi, K. Fujimoto, M. Imamura


Since the type of recurrence and outcome differ depending on the

type of cancer, these factors should be taken into consideration when

the type of reconstruction is chosen. We compared Billroth I (B-I) and

Billroth-II (B-II) type of reconstruction in terms of post-operative and

long-term morbidity, and the overall prognosis in pancreatic cancer

patients. Fifty-four pancreatoduodenectomies, including 12 pylorus-

preserving pancreatoduodenectomies were performed in patients with

ductal adenocarcinoma of the pancreas from 1994 to 2002. B-I was

performed in 27 consecutive patients before 1999, and thereafter B-II

was employed in another consecutive 27 patients. Clinicopathological

factors, including histology, nodal status, and stage were not different

between the two groups. The time before naso-gastric tube removal

was longer in B-I than B-II patients (P � 0.01). The time before oral

ingestion was longer in B-I than B-II patients (P � 0.01). Seven com-

plications were encountered in B-I patients, whereas 3 complications

occurred in B-II patients. There was no difference in disease-free and

overall survival between the two groups; however, a bypass operation

was required for gastrointestinal obstruction due to recurrence in

6 patients in the B-I, but only 1 patient in the B-II (P � 0.01). PTCD

was performed for biliary obstruction due to recurrence in 6 patients

in the B-I, but only 2 patients in the B-II. Our results suggest that a

B-II type of reconstruction may have some advantages over the B-I

type of reconstruction in terms of post-operative oral ingestion, and

avoiding bypass operation at the time of recurrence.

Poster 1-15 Rare Tumors

P1-15-1

Solid Pseudopapillary Tumor of the Pancreas without Cystic ComponentR. Ito1, J. Sakagami1, T. Motoyoshi1, R. Takada1, D. Kanemitsu1, H. Yasuda1, S. Mitsufuji1, K. Kataoka1, T. Okanoue1, T. Sonoyama2

1Department of Gastroenterology and Hepatology,2Department of Digestive Surgery, Kyoto PrefecturalUniversity of Medicine, Graduate School of MedicalScience, Kyoto, Japan

Solid pseudopapillary tumor of the pancreas is a rare pancreatic

neoplasm of unknown etiology, affecting predominantly to young

women. It is conceived as a low-grade malignant neoplasm that usu-

ally consists of both solid and cystic components. We report two cases

of solid pseudopapillary tumor of the pancreas without cystic compo-

nent, which were incidentally detected by ultrasonography or com-

puted tomography. The first case was a 16-year-old woman with 2 cm

mass in the body of the pancreas and the second was a 21-year-old

woman with 2 cm mass in the body of the pancreas. Angiography and

magnetic resonance image showed that both of these were hypovas-

cular solid tumor lacking cystic component, and had no evidence of

metastasis and invasion of adjacent organ. Laboratory data, including

tumor markers, were normal. The preoperative diagnosis was uncer-

tain. The patients underwent enucleation of the tumors, and their post-

operative course was excellent. Histological examination yielded a

definite diagnosis of solid pseudopapillary tumor of the pancreas.

Solid pseudopapillary tumor has conventionally been considered as a

cystic pancreatic tumor. We treated two cases of entirely solid tumor

of the pancreas, and final diagnosis of solid pseudopapillary tumor

was made. Especially in young women, it is necessary to differentiate

solid speudopapillary tumor from the other neoplasms even if the

tumor has no cystic component.

P1-15-2

Three Cases of Solid-Pseudopapillary Tumor of the PancreasT. Kubozoe, A. Urakami, A. Maeda, K. Iki, H. Matsumoto, T. Tsunoda

Department of Gastroenterological Surgery, Kawasaki Medical School, Kurashiki, Japan

Solid-pseudopapillary tumor (SPT) of the pancreas is a rare benign

or low grade malignant neoplasm that is typically diagnosed in young

women. SPT behaves in benign fashion even if there is invasion in the

surrounding tissue. We report three cases of SPT. Case 1 was a

16-year-old woman. She presented with left abdominal pain. Capsulated

tumor was located in the pancreatic tail. Distal pancreatectomy with

splenectomy was performed. Case 2 was a 27-year-old woman. She

presented with epigastric pain. Capsulated tumor was located in the

pancreatic tail. Distal pancreatectomy with splenectomy was per-

formed. Case 3 was a 30-year-old man. He presented with epigastric

pain. Capsulated tumor was located in the pancreatic head. Pylorus

preserving pancreaticoduodenectomy was performed. All lesions were

pathologically diagnosed as SPT. In SPT, 10 to 20% of them were

reported to have malignant potential, such as capsular invasion, lymph

node metastasis, and liver metastasis. In the case 2, the tumor was

complicated by lymph node metastasis and invasion into the sur-

rounding tissue. However, the patient is still alive and does not show

any sign of tumor recurrence for four years.


P1-15-3

Four Cases of Solid-Pseudopapillary Tumor of the PancreasY. Ito, K. Aiura, N. Chiba, T. Hayashida, S. Kawachi, M. Tanabe, G. Wakabayashi, M. Shimazu, M. Ueda, M. Kitajima

Department of Surgery, Keio University School of Medicine, Tokyo, Japan

Background: Solid-pseudopapillary tumor (SPT) of the

pancreas is a comparatively rare tumor which is mainly recognized for

women. It is characterized by mixture of solid parts and cystic parts,

and the prognosis is made comparatively good.

Patients and Methods: A retrospective review of our experience

with SPT from September 1998 to December 2003 was performed. The

average age of our patients was 30 years (range, 25–36 years). Of these

4 patients, 3 (75%) were women, and 1 (25%) was man.

Results: Two tumors were located in pancreatic head, one in

body, and one in tail. The mean size of the tumors was 36 mm (range,

18–50 mm). Two cases had only solid part without cystic part. Others

had cystic parts and solid parts. Abdominal computed tomography

(CT) and endoscopic ultrasonography (EUS) did not reveal findings

of the invasion to pancreatic parenchyma in all four cases. Pancreatic

tumors were managed by distal pancreatectomies for two cases, pyro-

lus-preserving pancreaticoduodenectomy for one case and tumorec-

tomy for one case. Histopathological examination of tumors showed

the proliferation in a pseudopapillary structure. The capsules were

invaded by the tumor cells in two cases and the pancreatic

parenchyma in one case without capsule was also invaded by tumor

cells. So it was considered that three of four cases had the malignant

potential. None had recurrence after surgery.

Conclusion: It is difficult to diagnose preoperatively whether

they have the malignant potential or not. We need to carefully select

the surgical procedure for SPT.

P1-15-4

A Clinical Study on Solid-PseudopapillaryTumor Experienced in our HospitalG. Ando, M. Kida, H. Moriki, Y. Maesawa, H. Kikuchi, M. Takezawa, M. Araki, M. Watanabe, Y. Kida, H. Imaizumi, K. Saigenji

Kitasato University East Hospital, Sagamihara, Japan

Aim: As the health check has become popular, number of pan-

creas tumor without symptoms has been increasing. Then we investi-

gated the clinical characteristics of solid-pseudopapillary tumor

experienced.

Subjects and Methods: We investigated 6 cases of solid-

pseudopapillary tumor experienced in our hospital on clinical datas

and imaging diagnosis such as US, EUS, CT, and angiography.

Results: Age of cases range from 18 to 56 y/o (average 36.5)

and sex distribution is 2 male (33%) vs 4 female (67%). Chief

complaints is aymptomatic (3 cases, 50%), back pain (2, 33%), and

abdominal pain (1, 17%), respectively. First trigger of diagnosis is

ultrasound in 5 cases and CT in 1 case. There is no apparent abnor-

mal laboratory datas. The location of tumor distributed 2 cases (33%)

in the head, 3 (50%) in the body, and 1 (17%) in the tail. The average

size is 48.8 mm (range 13 to 100) in maximum diameter. All tumor

were revealed rounded tumor with solid and cystic component, and

capsule was detected in 4 cases. CT revealed enhancement in the cap-

sule and septum, however there is no calcification. No connection to

pancreatic duct and compression in 3 cases were shown by ERP.

4 cases were diagnosed solid-pseudopapillary preoperatively. All

cases were diagnosed benign solid-pseudopapillary histologically.

Conclusions: It is important to know the characteristics of pan-

creatic tumor, because many kinds of pancreatic tumors are pointed

out at health check etc.

P1-15-5

Accurate Detection of Tumor Location byMultidetector-Row CT (MDCT) – A CaseReport of an InsulinomaJ. Yamao, S. Satoi, Y. Matsui, S. Takai, J. Fukui, A. Fukuyasu, K. Oishi, A.-H. Kwon, Y. Kamiyama

Department of Surgery, Kansai Medical University, Moriguchi, Japan

Background: The use of multiple detector rows in CT scans

allows faster scanning and thinner collimation, possibly resulting in

true volume acquisition and accurate diagnosis. We report a case of

an insulinoma that was treated with safety after clear imaging of a

small pancreatic tumor by MDCT.

Case Report: seventy-four year-old male who had the typical

Whipple’s triad was admitted to Kansai Medical University. Fasting

blood sugar level was 53 mg/dl. The c-peptide and IRI were 57 �g/day

and 3.4 �U/ml, respectively. Excessive secretion of insulin was

detected on 75 g OGTT and the Fajans score was 0.53 on starvation

test. Consequently, insulinoma was strongly suspected. However,

abdominal ultrasonography, CECT, and MRI failed to show the tumor

location of the insulinoma. Although an arterial stimulation venous

sampling test (ASVS) under tube angiography showed excessive

secretion of insulin in splenic artery, it did not result in tumor detec-

tion. Finally, MDCT vividly showed a small, enhanced tumor 10 mm

in diameter in the pancreas body during the arterial phase. We safely

performed open tumor enucleation but not with a laparoscopic

approach because the tumor seemed very close to the pancreatic

duct. After removing the tumor, the insulin level in the portal

vein rapidly decreased. He was completely relieved of symptoms of

hypoglycemia.

Summary: MDCT provided the accurate location of the pancre-

atic endocrine tumor, which resulted in a safe operation. It is sug-

gested that MDCT could be a useful tool for navigating pancreatic

surgery for benign tumors.


P1-15-6

A Case of Slow Growing AsymptomaticEndocrine Tumor of the PancreasY. Nakamura1, T. Tajiri1, E. Uchida1, T. Aimoto1, A. Katsuno1, Z. Naitou2

1First Department of Surgery and 2Second Departmentof Pathology, Nippon Medical School, Tokyo, Japan

A 38-yr-old female was admitted to our hospital on December 4,

1996, for the treatment of an asymptomatic tumor located in the head

of the pancreas. Distal pancreatectomy for pancreatic endocrinoma

was performed at a different hospital 11 years earlier, and that tumor

of the pancreatic head had been detected 2 years later by CT but left

in situ observed with periodic inspections. The laboratory findings

were within normal limits including tumor markers and hormonal

analysis on admission. Diagnostic images revealed a well-demarcated

tumor measuring 8 4 cm with hypervascularity located in the head

of the pancreas without metastasis. Doubling time of the tumor was

calculated at 1,332 days (3.65 yr) by transition of the size of the tumor

in CT images during 9 years. She was diagnosed as slow growing

endocrine tumor of the pancreas and was performed partial resection

of the pancreas including the tumor. The histopathological diagnosis

was pancreatic endocrinoma with vascular invasion and positivity for

NSE, chromogranin, gastrin, serotonin, and PP. She has not been

recognized the recurrent diseases for 7 years. This tumor might be

malignant because of vascular invasion, but clinically, might expect

good prognosis because of its slow growth.

P1-15-7

Malignant Non-Functioning Endocrine Tumorof the Pancreas with Duodenal InvasionY. Matsumura, M. Suyama,Y. Kuboakawa, J.K. Sai, H. Tadokoro, T. Kamiya, H. Koshikawa, H. Okubo, K. Kato, K. Inami

Department of Gastroenterology, Juntendo University,Tokyo, Japan

A 65 year-old man with malignant non-functioning endocrine

tumor of the pancreas with duodenal invasion is presented. At age

of 64, operations were three times done for prostate cancer, renal can-

cer and thyroid cancer. He was admitted to our hospital with obstruc-

tive jaundice. Abdominal ultrasound showed a low echoic mass in the

head of the pancreas, with high echoic lesion at the center. Enhanced

computed tomography showed a low dense tumor with irregular mar-

gin. Endoscopy revealed a deep ulcerative lesion at the second part of

the duodenum, oral side of the papilla of Vater. Biopsy specimens from

the ulcer revealed poorly differentiated adenocarcinoma. Endscopic

retrograde cholangiopancretography did not show any stenosis of the

main pancreatic duct, showed stenosis of the inferior bile duct.

Angiography showed a hypervascular tumor, and encasement of the

anterior superior pancreaticoduodenal artery, posterior superior pan-

creaticoduodenal artery. The tumor was diagnosed as a cancer of the

pancreas head with duodenal invasion. Pancreatoduodenectomy was

performed. Histopathologic and immunopathologic examination

revealed a malignant non-functioning endocrine tumor of the pancreas

with duodenal invasion.

Poster 2-01 AP Basic

P2-01-1

Effectiveness of Phospholipase A2 (PLA2)Inhibitor in Arresting of Pancreatic AttackN.V. Belyayeva, N.B. Gubergrits, G.M. Lukashevich

Donetsk State Medical University, Donetsk, Ukraine

PLA2 plays an important role in pathogenesis of pancreatitis, but

effectiveness of PLA2 inhibitor for treatment of pancreatic attacks

still not studied.

Aim: To study effectiveness of PLA2 inhibitor tetacin-calcium in

arresting of attacks of chronic pancreatitis (CP).

Materials and Methods: 77 patients with CP were examined.

32 (main group) of them received a traditional treatment (antibacter-

ial drugs, spasmolytics, enzyme preparations) in combination with

tetacin-calcium 10% 10 mL iv. daily N10. 45 patients suffering from

CP (comparison group) received traditional treatment alone. We con-

trolled pancreas excretory function, activity of pancreatic enzymes,

blood level of immunoreactive insulin.

Results: In patients of the main group activity of immunoreac-

tive PLA2 was authentically decreased from 22.4 � 1.4 ng/mL to

14.6 � 3.5 ng/mL ( p � 0.05); the normal level – 7.2 � 1.3 ng/mL.

Treatment with tetacin-calcium led to increase in pancreatic secretion

volume, bicarbonate debit-part, -amylase and tripsin levels, which

were significantly higher in the main group before discharge from our

hospital, than in comparison group. In the main group insulin blood

level increased during the treatment on 0.54 � 0.25 mcU/mL, while

in comparison group it decreased on 0.41 � 0.22 mcU/mL

( p � 0.05). Patients of the main group had more significant reduction

of clinical manifestations of the disease.

Conclusion: It is advisably to include PLA2 inhibitor tetacin-

calcium into complex treatment of CP exacerbation.

P2-01-2

Oxidative Stress, Cytokines, E-Selectin and MODS in Acute PancreatitisI. Bihalskyy, S. Chooklin, A. Perejaslov

Medical University, Lviv, Ukraine

The multiple organ dysfunction syndrome experienced by patients

with acute pancreatitis may be related to reactive oxygen species

(ROS), serum soluble E-selectin and to an overproduction of selective

cytokines such as IL-1� and TNF-.


The ROS, IL-1� and TNF- levels, glutathione peroxidase (GPx)

and superoxide dismutase (SOD) activity were measured on blood

samples in patients with severe and mild pancreatitis.

The blood levels of ROS at baseline were significantly higher in

acute pancreatitis than in controls. Conversely, GPx and SOD activity

at baseline was significantly lower in acute pancreatitis. Serum solu-

ble E-selectin concentrations increased during the first 3 days of

admission. The pattern of increasing serum soluble E-selectin con-

centrations in patients with severe disease is significantly different

from the pattern observed in patients with mild disease. The values of

serum proinflammatory cytokines IL-1� and TNF- were signifi-

cantly higher in acute pancreatitis than in controls. The levels of

serum soluble E-selectin, proinflammatory cytokines and ROS corre-

late with the degree of hemodynamic compromise and organ dys-

function.

Oxygen-derived free radicals may be closely associated with

inflammatory process and the severity of acute pancreatitis. The

dependence of disease severity on the imbalance between oxidants

and natural defences suggests that oxidative stress may have a pivotal

role in the progression of pancreatitis. Antioxidant vitamins are

hypothesized to prevent acute pancreatitis progression by trapping

organic free radicals, deactivating reactive oxygen molecules and

proinflammatory cytokines.

P2-01-3

Effects of Granulocyte Colony-StimulatingFactor on Mice with Severe AcutePancreatitisH. Tuo, M. Sugiyama, N. Abe, Y. Atomi

First Department of Surgery, Kyorin University of Medical School, Tokyo, Japan

Background: Decreased expression levels of opsonin receptors

(CD11b and CD32/16) on peritoneal neutrophils may lead to suscep-

tibility to infection in severe acute pancreatitis. Granulocyte colony-

stimulating factor (G-CSF) increases the expression level of CD11b

on neutrophils and prolongs the neutrophil survival period. Herein,

the effects of G-CSF on CD11b and CD32/16 expression levels were

investigated in severe acute pancreatitis.

Method: Severe acute pancreatitis in mice was induced by

13 hourly subcutaneous injections of caerulein (50 �g/kg body

weight). The mice received subcutaneous G-CSF (120 �g/kg body

weight) before or after the induction of acute pancreatitis. CD11b and

CD32/16 expression levels on circulatory and peritoneal neutrophils

were investigated in acute severe pancreatitis.

Result: In the mice without G-CSF administration 6 and

12 hours after the induction of pancreatitis, the count of circulatory

neutrophils increased and the CD11b and CD32/16 expression levels

on the circulatory neutrophils were also significantly increased when

compared with those in normal mice. The peritoneal neutrophil count

increased, but the CD11b and CD32/16 expression levels on peri-

toneal neutrophils significantly decreased when compared with those

in normal mice. G-CSF, irrespective of administration before or after

pancreatitis induction, significantly increased the counts of circula-

tory and peritoneal neutrophils when compared with those in mice

without G-CSF administration. The CD11b and CD32/16 expression

levels on circulatory and peritoneal neutrophils also increased in the

mice with G-CSF administration.

Conclusion: G-CSF administration may improve the opsonin

receptor expression level on peritoneal neutrophils in severe acute

pancreatitis. Therefore, G-CSF may prevent infectious complications

in severe acute pancreatitis.

P2-01-4

Interleukin-18 in Acute PancreatitisA. Perejaslov, S. Chooklin

Medical University, Lviv, Ukraine

Severe acute pancreatitis characterized by the development of sys-

temic inflammatory response syndrome, which is characterized by the

secretion of proinflammatory cytokines. Interleukin (IL) 18 belongs

to family of IL-1 cytokines and, as a member of this family, has proin-

flammatory properties, primarily because of its ability to induce

IFN-� production in T cells and natural killer cells. The role of IL-18

in the development and progression of acute pancreatitis still poorly

understood.

The plasma levels of IL-18 were studied in 28 patients with acute

pancreatitis. Measurement performed using ELISA technique.

The control group compiled 10 healthy volunteers. According the

Atlanta criterion 15 patients had the severe, and 13 patients had the

mild pancreatitis.

The increased levels of IL-18 were noted in all patients with acute

pancreatitis already at the time of admission. The highest levels of

IL-18 were noted in patients with severe pancreatitis and its levels

clear correlated with the APACHE II score. IL-18 returned to normal

in patients with edematous pancreatitis, whereas concentrations

remained significantly elevated in patients with necrotizing pancre-

atitis. No difference was found between patients who developed pan-

creatic infections compared with those with sterile necrosis.

Thus, the systemic concentration of IL-18 elevated in acute pan-

creatitis and closely correlated with the severity of the disease and

development of pancreatic necrosis.

P2-01-5

Is Octreotide Effective in ReducingCytokines, TAP Levels, and Mortality Rate in Experimental Acute Pancreatitis in Rats?R.S. de Godoy, M.C.C. Machado, C.Y. Morioka, S. Penteado, A.S. Matheus, J. Jukemura, A.M.M. Coelho, S.N. Sampietre, N.A.T. Molan

Department of Surgery, University of São Paulo, São Paulo, Brazil

The systemic effects of acute pancreatites (AP) have been attrib-

uted both to enzymatic activation and cytokines. Elevated tumor

necrosis factor-alpha (TNF-), interleukin-6 (IL-6), and trypsinogen

activation peptide (TAP) are associated with severity of pancreatitis

and high mortality rates. Octreotide inhibits exocrine pancreatic


secretion, although, administration before induction of AP, increases

pancreatic enzyme contents. Octreotide may reduce the release of

cytokines, but the benefit of such effect in AP still remains unclear.

To verify the effect of octreotide pre-treatment on the release of

cytokines (TNF- and IL-6), TAP production, pancreatic histology,

and mortality in necrotizing AP in rats.

AP was induced by retrograde injection of 2.5% or 5% taurocholic

acid into the pancreatic duct of male Wistar rats. Animals were divided

in 4 groups: (A) octreotide � AP group, (B) saline � AP group,

to evaluate the biochemical and histopathological analysis and

(C) AP � octreotide for 48 hours, and (D) AP � saline for 48 hours.

Octreotide (10 �g/kg) or saline solution (NaCl 0.9%) were in a single

dose (Groups A and B), and administered subcutaneously 30 min.

before the induction of AP and twice a day for 48 hours in groups C

and D for late mortality analysis. Animals were followed for 7 days in

these last two groups. Levels of TNF- in ascites, IL-6 in serum, and

TAP in serum, ascites and pancreatic tissue were measured in groups

1 and 2. The cytokines, TAP, and histology were studied two hours

after induction of AP.

Octreotide administration did not reduce TNF- and IL-6 concen-

trations in any group. TAP in pancreatic tissue of group 1 were higher

than group 2 ( p � 0.05). Moreover, there was no difference between

groups A and B concerning the pancreatic histology analysis. No

statistical difference was noted in groups C and D regarding the mor-

tality rates. A higher degree of acinar necrosis was seen in the groups

A and B submitted to 5% taurocholic acid AP (p � 0.05).

Conclusions: This study suggests that octreotide did not reduce

cytokine release, TAP production, histological pancreatic lesions, and

mortality rates in experimental acute pancreatitis.

P2-01-6

A New Proposal for Experimental Model of Acute PancreatitisR.S. de Godoy, C.Y. Morioka, M.C.C. Machado, A.S. Matheus, A.M.M. Coelho, N.A.T. Molan, A.L. Bernardes, A.S. de Alexandre, J. Jukemura, T. Bacchella

Department of Surgery, University of São Paulo, São Paulo, Brazil

Severe acute pancreatitis (AP) continues to be a challenge for

physicians according with the high mortality rates, no specific treat-

ment, and difficulties to clarify the entire pathophysiology of the dis-

ease. Experimental models of AP are an important tool to establish

new concepts in treatments, pathophysiology, and management. Then,

an experimental model that resembles to human pancreas is desirable.

Hamster pancreas is comparable to human pancreas phylogenetically,

topographically, anatomically, and immunologically, in spite of this,

there are no models of acute pancreatitis reported in these animals.

The aim of the present study was to establish a model of acute pan-

creatitis injecting taurocholic acid into the pancreatic duct of Syrian

Golden Hamsters.

The animals were divided in 3 groups: Control (negative control

n � 6), Sham (laparotomy with duodenal manipulation n � 6), and

Intra ductal injection (ID n � 6). Common bile duct was clamped and

taurocholic acid 2.5% was injected into the pancreatic duct. 24 hours

later, animals were sacrificed to evaluate ascites, adhesions, sentinel

loop, and gross appearance of the pancreas, liver, spleen, and lung.

Blood sample was collected for biochemical study. Specimens of the

pancreas, liver, spleen, and lung were sent for pathological study.

Ascites was found in 50% of the cases, adhesions in 66.6%, and

pulmonary changes, such as edema and local eritema in 16.6%.

Concerning pancreas, edema was found in 83.3%, eritema in 83.3%,

and necrosis in 50% of the cases. Increase in aspartate aminotrans-

ferase, alanine aminotransferase, alkaline phosphatase, and total

bilirubin, respectively, were observed. There were no changes in

gamma-glutamyltranspeptidase, amylase, and glicemia levels.

Histopathological examinations showed a extense inflammatory

process, edema, fat necrosis, and hemmorrhagic areas in the pancreas,

as well as, pulmonary edema. No histopathological changes were

found in hepatic and splenic specimens.

The model showed to be easily replicable and effective to produce

AP. It could be used to the development of treatment and pathophys-

iology of AP.

Poster 2-02 AP Clinical

P2-02-1

Strategy for Bacterial Translocation inSevere Acute PancreatitisT. Furuya, K. Takahashi, S. Itoh, T. Soeno

Akita City Hospital, Akita, Japan

Purpose: To clarify whether continuous regional arterial infu-

sion (CRAI), selective digestive decontamination (SDD), jejunal

nutrition with symbiotics (EN) and apheresis prevent bacterial

translocation in severe acute pancreatitis.

Patients and Methods: Mortality and morbidity of 50 succes-

sive severe acute pancreatitis patients from ‘92 were analyzed with or

without following therapy. CRAI: Nafamostat mesilate and imipenem

cilastatin sodium was infused into pancreatic regional artery for 5–7

days. SDD/EN: Vancomycin, amphotericin B, antibiotics-resistant

bifidobacterium followed by special diet containing such as gluta-

mine, dietary fiber or oligosaccharide were given through naso-jeju-

nal tube. Apheresis: Continuous hemodiafiltration and/or direct

hemoperfusion through polymyxin B-immobilized fiber column were

applied to the patients with organ failure.

Results: If the patients underwent this combination treatment

within 1 week after onset of the disease (N � 35), secondary pancreatic

infection (mortality) rate was 2.9 (11.4)% whereas those of patients

without such protocol was 73.8 (26.7)%. Infection rate (mortality) of

patients without CRAI/SDD/EN (N � 14) was 42.9 (21.4)%, whereas

those of 31 patients with CRAI, if it applied within 1 week after onset of

disease with antibiotics was 6.5 (12.9)%. Only one, out of 18 patients,

with both of CRAI, SDD and EN had infection and died (5.6%).

Summary: This strategy prevents BT, and improves outcome of

severe acute pancreatitis patients.


P2-02-2

Intraluminal Administration of OxygenatedPerfluorochemical Counteracts BacterialTranslocation and Renal Failure in theCourse of Severe Acute PancreatitisF. Marotta1, A. Helmy2, C.C. Wu3, J. Bertuccelli4, P. Safran4,Y. Rahman-Shield2, E. Fesce1

1Hepato-Gastroenterology Unit, S. Giuseppe Hospital,Milan, Italy, 2Liver Center, Department of SurgeonMenoufiya University, Giza, Egypt, 3Department of Surgery, Taichung University, Taiwan, 4SFJO and Labs.,Paris, France

The translocation of viable enteric bacteria to the mesenteric

lymph nodes and distant organ is regarded as one of the major

precipitating factors of infected necrosis and kidney failure dur-

ing acute necrotizing pancreatitis (ANP). Oxygenated perfluoro-

chemical (OP) has proved to be of benefit in intestinal

ischemia-reperfusion injury events either when administered

intraperitoneally or intraluminally. The aim of this study was to test

the effect of intraluminally administered OP (as colon instillation

and gastric tube feeding) on bacterial translocation associated with

ANP and renal function. Severe ANP was induced by retrograde

injection of 5% sodium taurocholate into the hepatopancreatic

duct of male Wistar rats and the activity of renal lysosomal

enzymes:Cathepsin B, D, L, Acid Phosphatase, N-acetyl-beta-

D-glucosaminidase, Lipase, Sulfatase, and Beta-D-Galactosidase

was monitored. Haemodynamic monitoring did not show any differ-

ence among the groups. Although mortality rate was not improved

by the treatment, the administration of OP significantly decreased

the incidence of bacterial translocation to the mesenteric lymph

nodes from 69% to 34% 12 hours after development of pancreatitis,

significantly reduced number of bacterial colonies detected after

24 hours while partly limiting the decrease of renal lysosomal

enzymes. Accelerated apoptosis of the intestinal epithelium was

detected histochemically by TUNEL staining and biochemically by

DNA fragmentation ELISA, and the apoptotic changes were signif-

icantly suppressed by the treatment. These results indicate that the

administration of OP inhibits apoptosis of intestinal epithelium and

bacterial translocation induced in severe acute pancreatitis while

contributing to partly spare the associated renal failure.

P2-02-3

Compliance with Acute PancreatitisGuidelines in GermanyP.G. Lankisch1, B. Weber-Dany1, M.M. Lerch2

1Municipal Clinic of Lueneburg, 2Ernst Moritz ArndtUniversity Greifswald, Germany

We asked 192 German gastroenterologists from non-university

hospitals using written questionnaires (response rate 89%), whether

and to what extent they complied with the three most recently pub-

lished guidelines for acute pancreatitis (see Table 1 below).

German hospital gastroenterologists are generally aware of

treatment guidelines for acute pancreatitis. They prefer imaging

techniques to multifactor scoring systems to determine severity and

largely comply with novel treatment recommendations, such as

enteral nutrition and antibiotics, if they are evidence based.

Table 1 for the abstract P2-02-3

Guideline WCG JSAEM IAP This

2002 2002 2003 study

Stratification of APACHE II � � NS 31%

severity CRP � � NS 97%

US/CECT NS NS NS 94/89%

CECT Severe AP � � NS 51%

Prophylactic Necrotizing � � � 45%

antibiotics pancreatitis

ES for biliary AP Cholangitis � � � 84%

Jaundice � � � 80%

Severe AP � � � 42%

Cholecystectomy Same � NS � 21%

for biliary AP hospitalization

Surgery for sterile necrotizing AP rarely rarely rarely No, 79%

FNA to identify infection � � � 65%

Enteral nutrition � � � 71%

Antiproteases – � NS No, 94%

Specialty centers for severe AP � � NS Yes, 40%

WCG: World Congress of Gastroenterology; JSAEM: Japanese Society of Abdominal Emergency Medicine;

IAP: International Association of Pancreatology; NS: not stated; US: ultrasound; CECT: contrast-enhanced

computed tomography; FNA: fine-needle aspiration.


P2-02-4

Evaluation of the Severity of the AcuteBiliary Pancreatitis: Clinical, Morphologicaland Biohumoral CriteriaV. Neri, A. Ambrosi, A. Fersini, N. Tartaglia, T.P. Valentino,L. Petito, C. Santacroce

University of Foggia, Department of Surgical Sciences,Division of General Surgery, Polyclinic of Foggia, Foggia,Italy

Background and Aim: Diagnostic verification of the severity

of the pancreatitis is necessary to program the therapy.

Methods: In the period from 1998 to 2003 were admitted 58

patients with diagnosis of acute pancreatitis. Patients with mild pan-

creatic involvement were enrolled only for the medical therapy: no

abdominal objectivity, isolated iperamylasemia, negative abdominal

US. We have considered 47 patients all of biliary origin and of mod-

erate gravity with compromission of the general state.

Results: In all patients we have found epi-mesogastrium pain;

epigastric contracture: 82%; pancreatic loggia edema (US and/or

CT-scan): 100%; WBC: 16000/mm3; hyperglycemia: mg 1.8%; AST-

ALT: 2; gamma-GT: 3; total bilirubin: mg 2.8%; pancreatic iso-

amylase: 7; CBD dilatation: 2; IL6: 7.5 � 4.99 pg/ml; fibrinogen:

440.75 � 174.47 mg/L; PCR: 50.45 � 41.81 mg/dL; the last three

parameters showed relevant increases of the levels, but not uniform

and not correlated among them and with the clinical pictures, allow-

ing not a standardized use. The research of endotoxin with limulus

test was negative in all cases.

Conclusions: The main evaluation parameter of acute pancre-

atitis is the clinical criterion and it must be integrated by laboratory

data. IL6, C-reactive protein, endotoxin, and fibrinogen seem to be

correlated vaguely with the forms of severe acute pancreatitis. The

elements of the clinical scenario and the data of instrumental and bio-

humoral investigation of biliary and pancreatic involvement are the

fulcrum of diagnosis. In the mild and moderate forms the changes of

IL6 and PCR are almost different and cannot be correlated and uti-

lized for a prognostic judgement.

P2-02-5

Studies of More Available PrognosticFactors in Diagnostic Criteria for Estimatingthe Severity of Acute Pancreatitis in Japan:Clinical Epidemiological Analysis by Settingthe Risk of Death as a Prognostic EndpointM. Otake, A. Noda, E. Ibuki, J. Izumi, K. Hamano, M. Yamamoto, M. Ohta, H. Shida

Division of General Medicine, Department of InternalMedicine, Aichi Medical University School of Medicine,Aichi, Japan

The motality rate of severe acute pancreatitis is about 30% in

Japan. It is generally agreed that the early prediction of the severity of

the disease is very important for reducing its mortality rate. The aim

of this study is to investigate which prognostic factors proposed by

The Welfare-Labor Ministry of Japan are more available for estimat-

ing the risk of death.The data source which we used in this study

came from the report published by The Research Group of Intractable

Pancreatic Diseases in Japan of 1,180 patients, 95 were dead and

1,085 were alive. At first, the risk ratio of death (RR) was calculated,

and then the receiver-operating characteristic (ROC) plot and the

odds-likelihood form of Bayesian analysis were performed in single

or combined form of prognostic factors � and � which consisted of

8 items, respectively. The RR showed that prognostic factors actually

refected the risk of death. The ROC plot revealed the high specificity

and relatively low sensitivity of each prognostic item, and the higher

specificity and the lower sensitivity of combined prognostic items.

The more available prognostic single item or combined items to esti-

mate the risk of death were: (1) BUN/Cr and Base Excess in prog-

nostic factors �, (2) items including prothrombin time or platelet

count in single combination of prognostic factors � and �, or dou-

ble combination of in prognostic factors � and (3) items including

prothrombin time plus calcium or platelet count plus calcium in triple

combination of prognostic factors �.

P2-02-6

A Novel Algorithm Calculated by APACHE-II for Mortality Rate in AcutePancreatitisJ. Sakagami, K. Kataoka, Y. Sogame, D. Kanemitsu, R. Takada, R. Ito, T. Motoyoshi, H. Yasuda, S. Mitsufuji, T. Okanoue

Molecular Gastroenterology and Hepatology, KyotoPrefectural University of Medicine, Graduate School of Medical Science, Kyoto, Japan

Aims: APACHE-II is generally accepted as a classification sys-

tem of severity of diseases. In 1985, Knaus et al., predicted mortality

rates (R%) for various diagnostic categories of acutely ill patients by

using the algorithm:

R% � 100 e 3.517�0.146APACHEII�C�(1 � e 3.517�0.146APACHEII�C)

C value was defined as diagnostic category weight, ranging from

2.108 to 0.891. C value of gastrointestinal disorder was reported to

be 0.501. Acute pancreatitis is regarded as a gastrointestinal disorder,

but no prior study has so far confirmed whether R% of acute pancre-

atitis is consistent with the algorithm. The aims of this study are to

make clear if R% is applicable to observed mortality rate of acute

pancreatitis, and to set up a new algorithm which is more appropriate

for predicting its mortality.

Methods: A total of 896 non-operative patients with acute pan-

creatitis was enrolled in this study. We compared the observed mor-

tality rate with R% for C value at 0.501. Then we obtained an

optimum C value which showed minimum sum of residue vertical to

0.146 ln(R/1-R). Additionally, we made an algorithm more suitable

for the observed mortality.

Results: If we put C value at 0.501 as established by Knaus,

R% was overestimated when APACHE-II was 8 or less. In contrast,

R% was markedly underestimated if APACHE-II was 19 or over. We

obtained an optimum C value at 0.125, which had a best approxima-

tion to cardiovascular failure caused by sepsis (C � 0.113). The most


appropriate algorithm for predicting mortality rate of acute pancreati-

tis was considered as:

R% � 100 e 4.4282�0.2476APACHEII�(1 � e 4.4282�0.2476APACHEII)

(R2 � 0.86).

Conclusions: If we applied Knaus’s R% to acute pancreatitis, it

had a large margin of error. Hence, we developed a novel algorithm

more accurate to predict its mortality. Furthermore, the mortality rate

of acute pancreatitis resembled that of cardiovascular failure caused

by sepsis.

P2-02-7

Scoring System for Predicting InfectiousComplications of Necrotizing PancreatitisT. Ueda1, Y. Takeyama2, N. Matsumura1, H. Sawa1, Y. Kuroda1

1Department of Gastroenterological Surgery, Kobe University Graduate School of Medical Sciences, 2Kobe, Department of Surgery, Kinki University, Osaka,Japan

Background and Aim: In acute necrotizing pancreatitis, infec-

tious complications in the late phase are contributors to mortality. At

the time of admission, it is clinically important to predict the risk of

progression to the infectious complications. We aimed to propose a

scoring system for predicting infectious complications.

Methods: In 65 patients with necrotizing pancreatitis, factors

where statistically significant difference was observed between infec-

tion group and non-infection group were surveyed from the data at the

time of admission. Then, optimum cutoff levels of the factors were

decided by ROC analyses, and scoring system for predicting infec-

tious complications was made.

Results: Serum total bilirubin (T-Bil), lymphocyte count

(Lymph), and fasting blood sugar (FBS) were statistically significant

factors (p � 0.05), and the optimum cutoff levels of T-Bil, Lymph,

and FBS were �2.1 mg/dL, �900/mm3, �230 mg/dl, respectively.

Positive predictive values of T-Bil, Lymph, and FBS at the cutoff lev-

els for prediction of infectious complications were 75.0%, 51.6%, and

57.9%, respectively. The patients were classified by number of posi-

tive factors from 0 to 3 scores. In the cases whose scores were 0 and

1, the incidence of infectious complications was 13.6%. By contrast,

in the cases whose scores were 2 and 3, the incidence of infectious

complications was 72.7%.

Conclusion: These results suggest that this scoring system on

admission is simple and useful for prediction of infectious complica-

tions in patients with necrotizing pancreatitis.

Poster 2-03 CP Clinical

P2-03-1

The Effectiveness of Pancreatic Tube Stentand Timing of its Exchange in the Patientswith Chronic PancreatitisH. Kawamoto, E. Ishida, T. Ogawa, Y. Okamoto, O. Mizuno, T. Nakanishi, J. Kato, H. Okada, Y. Shiratori

Department of Gastroenterology and Hepatology,Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

Objective: The pancreatic tube stent (PS) is effective in the

therapy of chronic pancreatitis with duct stenosis. However, there is

controversy about its exchange timing.

Patients and Methods: During 2003, 14 consecutive patients

(male 12, female 2, averaged age 57 years) with chronic pancreatitis

were enrolled in this study. The size of PS inserted into the patient

was decided according to severity of stenosis. So we inserted 5Fr

(n � 6) or 7Fr (n � 8) PS endoscopically. The PS size was enlarged

stepwisely at its exchange. To prevent the episodes of pancreatitis

induced by PS obstruction, the time of exchange was set as less than

1 month (14–28 days) for the patients inserted with 5Fr PS and was

as 6 months (5–8 months) for the patients inserted with 7Fr PS. At

the exchange, we examined to confirm the PS patency. Then, we

investigated the relation of the symptom and the patency of PS.

Results: The success rate of PS insertion was 100%. After PS

insertion, the symptom and laboratory data of the patients were

improved and no episode of pancreatitis was noted. Ten sessions of PS

exchange were performed. The 5Fr PS was not occluded in all cases

(n � 4) with one-month exchange; however, the 7Fr PS was occluded

in the all cases (n � 6) in spite of no symptom with 6-months

exchange.

Conclusion: Though the PS was occluded, it prevents the symp-

tom of chronic pancreatitis. However, for the patency of PS it may be

changed less than 6 months.

P2-03-2

Oral Litholysis Therapy and its Combinationwith ESWL and Endoscopic Therapy forCalcified or Noncalcified Pancreatic StonesM. Yamamoto, A. Noda, E. Ibuki, J. Izumi, K. Hamano, M. Ohta, H. Shida, M. Otake

Division of General Medicine, Department of InternalMedicine, Aichi Medical University School of Medicine, Aichi, Japan

The aim of the present study was to study the effect of the oral

litholysis therapy (OLT) in patients with calcified or noncalcified pan-

creatic stones. Dimethadione (DMO) can dissolve calcium carbonate


which is a main constituent of pancreatic stones. In this study,

trimethadione (TMO) was given orally as a precursor of DMO to

40 patients with calcified pancreatitis. The 38 patients not treated with

TMO were selected as a control. On plain X-ray films and CT scans

of the abdomen, pancreatic stones significantly diminished in size and

number or disappeared in 26 patients (65.0%) (p � 0.05, vs the con-

trol). During the OLT, the impaired exocrine pancreatic function

returned to normal in 33.3% of the patients examined (p � 0.05, vs the

control), diabetes mellitus was well controlled by either diet therapy

alone or oral hypoglycemic agents in 56.3% of the patients, and

complete relief of pain was attained in 83.3% of the patients (p � 0.05,

vs the control). In another study, a mucolytic expectorant, bromhexine-

hydrochloride 0 application/octet-stream.

P2-03-3

Short-Term Metallic Stenting for Treatmentof Pancreatic Duct Strictures in Patientswith Chronic PancreatitisK. Okushima, K. Inui, J. Yoshino, T. Wakabayashi, H. Miyoshi, Y. Nakamura, T. Chikaishi

Department of Internal Medicine, Fujita Health University, Nagoya, Japan

We inserted a metallic stent into the stricture of the main pancre-

atic duct at the head of the pancreas in 3 patients with calcified

chronic pancreatitis and evaluated the efficacy of the procedures.

They were male and ranged in age from 39 to 59 (mean age 51 years).

The etiology was alcohol-related in 2 patients and idiopathic in a

patient. They were treated with extracorporeal shockwave lithotripsy

(ESWL), but pancreatic stones were recurred in 2 to 5 times. We used

an electronic duodenoscope, TJF-200, developed by Olympus Optical

Co. and a Diamond Stent, developed by Boston Scientific Co., 40 mm

in length and 8 mm or 10 mm in diameter. We inserted the stent into

the main pancreatic duct after treatment of recurrent stones by using

ESWL and/or endoscopic procedures. The stent was successfully

inserted in all cases, and removed 2 to 7 days after insertion. Two

patients suffered from pain, treated by pentazocine or diclofenac

sodium suppository, but the pain was disappeared after removal of the

stent. No other complications were seen. ERP revealed dilatation of

the stricture of the main pancreatic duct after removal of the stent. No

recurrence of pancreatic stones and acute pancreatitis were seen for

15 to 21 months after the treatment. In conclusion, placement of a

metallic stent for a short time may be effective to prevent recurrence

of pancreatic stones in patients with strictures of the main pancreatic

duct.

P2-03-4

Effect of Combination Therapy with Stentand Bromhexine Hydrochloride for ProteinPlug in Alcoholic PancreatitisY. Nakae, M. Imoto, K. Imada, O. Shirai, Y. Ogawa, T. Suzuki

Department of Internal Medicine, Kariya General Hospital, Kariya, Aichi, Japan

Alcohol intake changes the viscosity of pancreatic juice and the

sphincter of Oddi function, which are thought to be associated with

formation of protein plug in the pancreatic duct. We treated two male

patients (47 and 53 years-old) with endoscopic stent placement (7Fr

tube stent) across the major papilla and bromhexine hydrochloride

intake (12 mg/day) for the protein plug in the main pancreatic duct.

They admitted to our hospital diagnosed as alcoholic acute pancreati-

tis, and occurred the second pancreatitis attack as soon as beginning

food intake. ERP showed protein plug in the main pancreatic duct but

no remarkably stricture on the main duct. After treatment, they

showed improvement of clinical symptoms and did not repeat pan-

creatitis. The protein plug disappeared on the ERP when pancreatic

stent removed after three months follow. Patients were followed only

with taking bromhexine hydrochloride after stent removed, but pan-

creatitis did not occur. These results suggest that combination therapy

of stent and bromhexine hydrochloride could be useful for early relief

from symptom and inhibition of formation of protein plug with alco-

holic pancreatitis without stricture on the main pancreatic duct, in

which repeated pancreatitis and protein plug formation are associated

with the high viscosity of pancreatic juice and the sphincter of Oddi

dysfunction.

P2-03-5

The Efficacy of Endoscopic Drainage forChronic and Acute PancreatitisK. Seza, T. Ishihara, T. Yamaguchi, H. Saisho

Department of Medicine and Clinical Oncology, GraduateSchool of Medicine, Chiba University, Chiba, Japan

Aim: The aim of this study was to evaluate the efficacy of endo-

scopic nasopancreatic drainage (ENPD) and endoscopic pancreatic

stenting (EPS) in chronic and acute pancreatitis.

Methods: The medical records of 874 patients (male 588,

female 286) received endoscopic retrograde pancreatography (ERP)

from March 1993 to October 2003 are reviewed. The success rate of

ENPD(5–7F) and EPS(7–10F), inserted duration and adverse event

were evaluated in this study.

Result: We performed ERP 1,774 times in 874 cases. In 98 cases

undergone ENPD and/or EPS, 88 cases are chronic pancreatitis

(72 ductal stenosis, 66 ductal stones, 9 pseudocyst), 9 are acute

pancreatitis (6 pseudocyst, 3 ductal stenosis). Insertion of ENPD was

successful in 80/85 (94%) cases (157 times), EPS was 50/55 (91%)

cases (127 times). Mean inserted duration of ENPD and EPS for

ductal stenosis were 9.2 days, 190.3 days; for pseudocyst 14.2 days,

22.5 days, respectively. In ductal stenosis of 70/75 (95%) cases,


ENPD achieved pain relief. Recurrences of drainage failure were alle-

viated by EPS in 39/45 (87%). Pseudocysts were remitted with ENPD

alone in 9/15 (60%) cases. 6 cases were required further drainage by

EPS, and 4 out of 6 (66%) cases were remitted by EPS. ENPD had no

severe adverse event in our series. Mild pancreatitis was occurred in

4 times and distal dislocation of stent was occurred in 19 times.

Conclusion: ENPD was considered as a primary approach for

pancreatic drainage with little adverse event. EPS was effective in

severe ductal stenosis needs long-term drainage with some adverse

events.

P2-03-6

Long-term Outcome of ExtracorporealShockwave Lithotripsy and EndoscopicTherapy in Patients with Pancreatic StonesH. Tadenuma, T. Ishihara, T. Yamaguchi, H. Saisho

Department of Clinical Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

Aims: To evaluate long-term results of ESWL and endoscopic

treatment in patients with pancreatic stones.

Methods: Between 1991 and 2003, 114 patients with pancreatic

duct stones presented with any symptoms were treated by ESWL

and/or endoscopic therapy in our department. 82 men and 32 women

(mean age 47.4 years) were enrolled in this study. The first line treat-

ment was ESWL and those who were failed to remove the stones were

subjected to endoscopic treatment. Exocrine and endocrine function

was evaluated by urinary PABA recovery and glucose tolerance test,

respectively.

Results: 41 were treated with ESWL alone, 63 with ESWL and

endoscopy, and 10 with endoscopy alone. Complete removal of stones

was made in 69.6%, 52.4%, and 80.0%, respectively, showing no sig-

nificant deferences among them. Pain relief was obtained in all

patients. In over all, complete removal of stones was obtained in 68 of

107 (59.6%). Of 43 patients who were long-term followed up (mean

52.2 months) after complete removal of stones, 16 patients (37.2%)

experienced recurrence of stones. Recurrence was more fequent in

those having stricture of main pancreatic duct than non-stricture

group, however, there was no statistical significance. Stenting of the

pancreatic duct decreased the recurrence without any statistical sig-

nificance. Both exocrine and endocrine function were not improved in

47 patients after long-term follow up (mean 56 months) irrespective

of stone clearance.

Conclusions: ESWL and endoscopic therapy were favorable as

to pain relief. However, exocrine and endocrine function were found

not to improve in long-term follow up.

Poster 2-04 AIP

P2-04-1

Efficacy and Issues Related to Oral Prednisolone (PSL) Therapy of Autoimmune PancreatitisT. Nishino, F. Toki, H. Oyama, I. Oi, K. Shiratori

Tokyo Women’s Medical University, Tokyo, Japan

The present study was undertaken to investigate the clinical man-

ifestations, radiographic findings, and exocrine and endocrine pan-

creatic function of AIP patients before and after oral prednisolone

(PSL) therapy.

Subjects and Methods: Sixteen patients were diagnosed with

AIP on the basis of the following criteria: swelling of the pancreas,

irregular narrowing of the main pancreatic duct, hypergammaglobu-

linemia or presense of autoantibodies, and the histologic findings. We

reviewed the clinical features of 8 cases of autoimmune pancreatitis

that treated with PSL, and whose course it had been possible to fol-

low. PSL was started at 30–40 mg per day, and the dose was subse-

quently tapered.

Results: The pancreatic enlargement and irregular narrowing of

the main pancreatic duct showed improvement to almost their normal

size in every case, however, stricture of the common bile duct per-

sisted in 4 patients (57%, 4/7). The bile duct stricture recurred after

tapering of PSL in one case, but there was no recurrence of the pan-

creatitis. Pancreatic exocrine function improved in 4 cases (67%, 4/6)

according to the results of the secretin test or BT-PABA test, and the

HbA1c values of 3 of the 8 patients with diabetes mellitus improved.

One patient developed Pneumocystis carinii pneumonia during the

course of PSL therapy, but the pneumonia soon responded to adequate

therapy.

Conclusions: Oral PSL therapy is very effective against the

pancreatic lesions of autoimmune pancreatitis, including the morpho-

logic lesions and pancreatic exocrine and endocrine dysfunction. But

since one of the patients developed Pneumocystis carinii pneumonia

and one of the patients experienced recurrence of bile duct stricture

during tapering of PSL, further study is needed to establish a regimen

of maintenance PSL therapy for autoimmune pancreatitis.


P2-04-2

Long-term Prognosis of Duct-NarrowingChronic Pancreatitis: Indications for Steroid TreatmentT. Wakabayashi1, Y. Satomura2, T. Urabe3, H. Watanabe4, Y. Motoo4, N. Sawabu4

1Department of Gastroenterology, Saiseikai KanazawaHospital, 2Department of Internal Medicine, ToyamaPrefectural Hospital, 3Department of Gastroenterology,Public Central Hospital, Matto Ishikawa, 4Departmentof Internal Medicine and Medical Oncology, KanazawaUniversity, Kanazawa, Japan

Aim: To assess the long-term prognosis in patients with duct-

narrowing chronic pancreatitis (DNCP) and determine the indications

for steroid therapy.

Methods: We evaluated clinical and imaging outcomes in

patients with DNCP classified into three groups according to the

treatment given. Group A included 6 patients treated surgically.

Groups B and C included 21 patients treated medically with steroid

and 10 patients without it.

Results: In group A, 2 patients relapsed in the remnant pancreas.

In group B, pancreatic swelling was resolved in all the patients, and

moreover, both the irregular narrowing of the main pancreatic duct

(MPD) and the strictures of the lower common bile duct (CBD)

improved after the initiation of corticosteroid therapy in all but one of

the patients including 5 without immunoserological abnormality.

However, clinical recurrences occurred in 4 patients (19%) during or

after the maintenance therapy. In group C, all the patients showed an

improvement in swelling of the gland, while only 5 showed an

improvement of MPD involvement. Four of the 5 patients did not

show any evidence of abnormal immunoserological findings or bio-

chemical test results suggestive of CBD involvement. In all of the

other 5 patients in whom MPD irregularities did not improve, find-

ings of positive immunoserological test or CBD strictures with

increased levels of serum hepatobiliary enzymes were noted.

Conclusions: Steroid therapy is effective for improving pancre-

atic and bile duct lesions in patients with DNCP irrespective of their

immunoserological results, although some patients have recurrences.

However, other patients who have neither immunoserological abnor-

mality nor biliary tract stricture, show an improvement of MPD

involvement without steroid.

P2-04-3

A Case of Autoimmume Pancreatitis withIgG4-Positive Plasma Cell Infiltration inSalivary Gland and Biliary TractM. Taguchi, G. Aridome, S. Abe, K. Kume, M. Tashiro, M. Yamamoto, Y. Kihara, H. Nakamura, M. Otsuki

The Third Department of Internal Medicine, University of Occupational and Environmental Health,School of Medicine, Kitakyusyu, Japan

A 62-year-old male was referred to the hospital because of liver

dysfunction and diffuse pancreatic swelling. At admission, the patient

was free of pain. On physical examination, enlarged bilateral sub-

mandibular masses were palpable. There was no palpable mass or

organomegaly in the abdomen. The laboratory findings were as fol-

lows: total protein 9.0 g/dl with �-globulin of 37.3% (3.3 g/dl), total

bilirubin 0.4 mg/dl, AST 39 IU/l, ALT 67 IU/l, �-GTP 1647 IU/l,

amylase 135 IU/l. Autoantibodies were all negative, and the values of

tumor markers were almost within the normal range. Level of serum

IgG4 was markedly elevated (1890 mg/dl). A computed tomography

(CT) showed diffuse swelling of the pancreas and dilatation of both

common and intra-hepatic bile ducts. Endoscopic retrograde cholan-

giopancreatography (ERCP) revealed diffuse irregular, narrow main

pancreatic duct and stenosis of lower common bile duct. The biopsy

specimens not only from pancreas, but also from salivary gland and

liver, showed marked periductal fibrosis with IgG4-positive plasma

cell infiltration. We considered this patient to be autoimmne pancre-

atitis with fibrosclerosis of salivary gland and biliary tract. We pre-

scribed prednisolone at an initial dose of 40 mg/day. Three months

later, the laboratory improved almost to normal. Both CT and ERCP

reflected prominent improvement of the pancreatic lesion. Salivary

gland swelling also improved. At present, he is taking 10 mg of pred-

nisolone per day, there has been no recurrence of the pancreatitis.

We present here a case of autoimmune pancreatitis, which showed

no autoantibodies, with fibrosclerosis of salivary gland and biliary

tract.

P2-04-4

Clinical Course of 3 Patients withAutoimmune Pancreatitis, Showed DiffuseNarrowing of the Main Pancreatic Duct Lessthan 1/3 LengthH. Miyoshi, K. Inui, J. Yoshino, T. Wakabayashi, K. Okushima, Y. Nakamura, M. Nagata, T. Chikaishi, M. Hattori

Department of Internal Medicine, Fujita Health University,Second Teaching Hospital, Nagoya, Japan

The diagnostic criteria for autoimmune pancreatitis proposed by

the Japan Pancreas Society (2002) restrict diffuse narrowing of the

main pancreatic duct more than 1/3 length of the entire pancreas. We

treated 3 patients not fulfilled the criteria at the onset, but showed typ-

ical imaging during treatment. The patients were a man and 2 women,

and the mean age was 63 years. Laboratory data demonstrated abnor-

mally elevated levels of serum gamma-globulin and IgG in 2 cases.

Ultrasonography and CT revealed the localized swelling of the body

and/or tail of the pancreas. ERP revealed diffuse narrowing of the

main pancreatic duct less than 1/3 length of the entire pancreas in

2 cases, and obstruction at the tail of the pancreas in 1. We adminis-

trated predonisolone to 2 patients for 4 weeks, and ERP showed

improvement of diffuse narrowing of the main pancreatic duct and

levels of serum gamma-globulin and IgG. In 1 of the 2 patients, ERP

revealed diffuse narrowing of the main pancreatic duct of the entire

pancreas 2 months after stopping of predonisolone. The patient with

obstruction of the main pancreatic duct underwent distal pancrec-

tomy, and histopathological examination showed fibrotic changes

with lymphocyte and plasma cell infiltration. ERP, 45 months after

surgery, revealed diffuse narrowing of the main pancreatic duct and


the lower part of the common bile duct. The levels of serum gamma-

globulin and IgG became high. In conclusions, the item of ‘more than

1/3 length of the entire pancreas’ in diagnostic criteria for autoim-

mune pancreatitis is unnecessary.

P2-04-5

A Case of Autoimmune PancreatitisDeveloped Pancreatic Stones and BiliaryStenosis in the Long-TermM. Hattori, J. Yoshino, K. Inui, T. Wakabayashi, K. Okushima, H. Miyoshi, Y. Nakamura, M. Nagata

Department of Internal Medicine, Fujita Health University,Second Teaching Hospital, Nagoya, Japan

A 60-year-old male with a history of alcohol abuse for 40 years

was admitted to our hospital with complaint of jaundice in January

1998. Laboratory data on admission included the serum level of direct

bilirubin was 14.1 mg/dl; ALT was 163 IU/L; �-GTP was 559 IU/L;

amylase was 294 IU/l. The serum level of gamma-globulin and

IgG were normal. 75 g-OGTT revealed a diabetic pattern.

Ultrasonography revealed low echoic and diffuse swelling of the pan-

creas. Contrast-enhanced CT revealed diffuse swelling and enhance-

ment of the pancreas. ERCP revealed narrowing of the main

pancreatic duct in the head and body of the pancreas, and dilatation

of the branches in the tail of the pancreas. PTCS showed severe stric-

tures of the distal common bile duct, but pathological examinations of

biopsied specimens revealed no malignancy. With administration of

cortico-steroid, pancreatic swelling and pancreatic duct strictures

were improved, but biliary stricture was not improved and biliary

stenting was performed for 32 months. In March 2000, CT revealed

atrophy of the pancreas and pancreatic stones. Serum trans-amynase

elevated in April 2003. Ultrasonography and CT revealed diffuse

swelling of the pancreas. ERCP revealed diffuse narrowing of the

main pancreatic duct, and stricture of the left and right hepatic ducts

and the distal common bile duct. IgG was 3541 mg/dl, IgG4 was

1870 mg/dl and gamma-globulin was 3.13 g/dl. Development of pan-

creatic stones in patients with autoimmune pancreatitis were reported

by some authors, but few reports of patients with chronic calcified

pancreatitis developed to autoimmune pancreatitis were seen.

P2-04-6

A Clinical Study of AutoimmunePancreatitisH. Ishiwatari, H. Maguchi, K. Takahashi, A. Katanuma, T. Matsunaga, F. Itokawa

Center for Gastroenterology, Teine-keijinkai Hospital, Sapporo, Japan

Objective: Aiming to clarify the clinical characteristics of

autoimmune pancreatitis.

Subjects and Methods: The subjects were 12 cases of

duct-narrowing pancreatitis in which involvement of autoimmune

was suspected. We examined in these cases (1) initial symptoms,

(2) biochemical findings by blood test, (3) complications, (4) image

findings, (5) bile duct lesions, (6) treatments and (7) prognoses.

Results: (1) Abdominal pain in 4 cases, jaundice in 4 and

anorexia in 1. (2) Hyperamylasemia in 1 case, high levels of IgG in 8,

positiveness for antinuclear antibody in 5, and positiveness for

rheumatoid factors in 6. (3) Diabetes in 6, Hashimoto disease in 1 and

retroperitoneal fibrosis in 1. (4) By CT, swelling of the pancreas in all

cases, and calcification in 1. By ERP, duct-narrowing of the pancre-

atic duct (PD) in 11 cases, and localized narrowing of PD in the

pancreatic tail in the rest 1 case. (5) Stricture of lower part of the bile

duct in 9 cases; in 2 of them, stricture of hilar bile duct was also

found. (6) Steroid therapy in 10, and follow-up observation without

treatment in 2. (7) Marked improvement by steroid therapy in all

cases. Nine of them had no recurrence.

Conclusion: While most of the cases showed the clinial charac-

teristics which satisfied the diagnostic standard of autoimmune pan-

creatitis proposed by the Japan Pancreas Society, there is a case which

also had swelling or stricture of PD localized in the pancreatic tail.

Also stricture of hilar bile duct, recurrence after withdrawal of steroid

therapy and retroperitoneal fibrosis were seen.

P2-04-7

Pancreatic Regenerative Process duringTreatment with Prednisolone in HumanAutoimmune PancreatitisH. Yoshida1, S. Tanaka1, T. Awai2, T. Saito1, T. Honma1, K. Kitamura1, K. Hanawa1, T. Imamura3, A. Ikegami1, J. Niikawa1, M. Imawari1

1Second Department of Internal Medicine, School of Medicine Showa University, 2Department of Internal Medicine, Tokyu Hospital, 3Department of Gastro-enterology, Toranomon Hospital, Tokyo, Japan

Diagnostic criteria for autoimmune pancreatitis (AIP) was

proposed by the Japan Pancreas Society in 2002. We reported that

CD4� T cells were involved predominantly in pancreatic impairment

in AIP animal model, male aly/aly mice. We observed histological

pancreatic recovery during treatment with prednisolone (PSL) in

human AIP. The aim of the present study was to elucidate the regen-

erative process of pancreas during treatment with PSL in AIP. Eleven

patients were diagnosed with definite AIP (median age: 61.1,

male/female: 7/4, hypergammmaglobulinemia (IgG4 67%), which

fulfilled the criteria, from June 1997 to February 2004. Seven patients

allowed us to obtain their pancreatic tissue by FNAB. We stained

nuclei with anti-Ki-67 antibody to evaluate pancreatic regeneration,

and classified endocrine or exocrine progenitor cells using anti-pan-

creatic/duodenal homeobox-1 (PDX-1) antiserum (kindly provided

from Dr. Yoshitaka Kajimoto, Osaka University Graduate School of

Medicine) to characterize pancreatic cell differentiation in human AIP

during oral treatment with 10 mg/day of PSL. Immunohistochemical

study showed a large number of Ki-67-positive acinar and ductal cells

during treatment although no positive exocrine cells were observed

before treatment. The number of � cells was less than that of cells

during treatment. PDX-1 immunoreactivity was observed on most

� and cells, and it was also seen on most acinar cells of patients


treated with PSL. The present study suggest that differentiation of

pancreatic progenitor cells may be involved in pancreatic regeneration

during treatment with PSL in human AIP, and that exocrine and

endocrine cells presumably arise from common progenitor cells.

Poster 2-05 Physiology

P2-05-1

Xanthine Oxidase-Derived Free RadicalsActivate Rat Pancreatic Stellate Cells in vitroH. Tanioka, T. Mizushima, K. Matsushita, A. Shirahige, T. Shinji, K. Ochi, N. Koide

Labolatory Medicine, Okayama University GraduateSchool of Medicine and Dentistry, Okayama, Japan

Background and Aim: It is generally accepted that pancreatic

stellate cells (PSCs) play an important role in pancreatic fibrosis. We

have previously reported an experimental model of pancreatic fibro-

sis, induced by the intraperitoneal injection of a superoxide dismutase

(SOD) inhibitor, diethyldithiocarbamate (DDC). Although this model

reveals a relationship between fibrosis and free radicals, the mecha-

nisms of pancreatic fibrosis induced by DDC remain to be fully elu-

cidated. Therefore, we investigated how DDC activates rat PSCs in

vitro.

Methods: PSCs were isolated from male Wister rats. Cultured

rat PSCs were incubated with DDC for 48 hours. Intracellular lipid

peroxidation products were examined in DDC treated PSCs.

Activation of PSCs was examined by determining expression of

-smooth muscle actin (-SMA) with immunocytochemistry, the

number of PSCs with using a hemocytometer and type I collagen in

the conditioned media with ELISA. Secretion of transforming growth

factor-�1 (TGF-�1) was evaluated by ELISA. The effects of the

allopurinol, xanthine oxidase (XOD) inhibitor, on PSCs were also

examined.

Results: DDC caused the decrease of SOD activity and the

increase of lipid peroxidation products in PSCs. DDC also activated

PSCs, increasing the number of -SMA positive cells, enchancing

secretion of Type I collagen. Secretion of TGF-�1, which is known to

activate PSCs, was increased by DDC treatment. These alterations

were prevented by allopurinol.

Conclusions: These results suggested that free radicals gener-

ated by XOD may activate PSCs via TGF-�1 pathway in vitro.

P2-05-2

TGF-�1 Enhances Interleukin-1� Expressionand Secretion of Rat Pancreatic StellateCells through Smad3-Dependent Pathway:Possible Autocrine Loop between TGF-�1and Interleukin-1�

H. Ohnishi, K. Hama, H. Aoki, K. Sugano

Department of Gastroenterology, Jichi Medical School, Tochigi, Japan

Interleukin-1� (IL-1�) is assumed to promote chronic pancreati-

tis by activating pancreatic stellate cells (PSCs). However, its origin

and mechanism by which IL-1� modulates PSC function is still

unknown. In this study, we examined the hypothesis that IL-1� may

modulate PSC functions in an autocrine manner. RT-PCR and ELISA

demonstrated IL-1� mRNA expression and peptide secretion of cul-

tured rat PSCs. TGF-�1, a central autocrine activator of PSCs,

enhanced IL-1�1 mRNA expression and peptide secretion of PSCs in

a dose dependent manner when added exogenously in the culture

medium. Adenovirus-mediated expression of dominant-negative

Smad2/3 inhibited both basal and TGF-�1-stimulated IL-1� expres-

sion and secretion of PSCs. In contrast, adenovirus-mediated overex-

pression of Smad3 but not Smad2 markedly increased both basal and

TGF-�1-stimulated IL-1� expression and secretion of PSCs.

Moreover, IL-1� added in the culture medium increased TGF-�1

expression and secretion of PSCs. In addition, IL-1� activated ERK

in PSCs, and failed to increase TGF-�1 secretion when PSCs were

pre-treated with MEK inhibitor PD98059. These results indicate that

TGF-�1 and IL-1� enhance expression and secretion of PSCs each

other through Smad3 and ERK dependent pathways, respectively,

suggesting the existence of autocrine loop between TGF-�1 and IL-1�in PSC activation.

P2-05-3

FGF-2 and IL-17 Synergistically Induce IL-6 Secretion in Human PancreaticMyofibroblastsA. Andoh, S. Bamba, T. Saotome, M. Shimada, O. Inatomi, H. Yasui, Y. Fujiyama

Department of Internal Medicine, Shiga University ofMedical Science, Seta Tukinowa, Otsu, Japan

Interleukin (IL)-6 is a potent inflammatory mediator in patho-

physiology of acute and chronic pancreatitis. We have previously

reported that IL-17, T-cell specific cytokine, plays an important

role in the induction of IL-6 in human pancreatic myofibroblasts

(J. Immunol. 2002;168:861–868). In this paper, we investigated the

effects of FGF-2 in combination with IL-17 on IL-6 secretion in these

cells. Human pancreatic myofibroblasts were isolated by the method

descrived previously (Pancreas 1997; 14: 373–82). IL-6 secretion was

determined by ELISA, and IL-6 mRNA expression was evaluated by

Northern blotting. FGF-2 induced a dose- and time-dependent

increase in IL-6 secretion, and these were also observed at the mRNA


levels. IL-17 also stimulated IL-6 secretion at the mRNA and protein

levels. The effects of FGF-2 and IL-17 were significantly blocked by

the addition of MAP kinase inhibitors (PD98059 and SB203580). The

combination of FGF-2 and IL-17 synergistically induced IL-6 secre-

tion in a dose dependent manner. These results indicate that FGF-2 as

well as IL-17 is involved in the pathogenesis of acute and chronic

pancreatitis via stimulation of IL-6. Part of inflammatory natures of

FGF-2 was demonstrated.

P2-05-4

Apoptosis in Pancreatic IschemiaReperfusion Injury? Impact of Ischemic TimeH.P. Neeff, O. Drognitz, E.F. von Dobschuetz, X. Liu, U.T. Hopt, S.R. Benz

Department of General and Visceral Surgery, University of Freiburg, Freiburg, Germany

Apoptosis leading to cell death is a process which differs funda-

mentally from cell necrosis. As an active energy consuming process

apoptosis occurs only in settings in which cells are still viable. In

order to start the apoptotic process cells need to receive apoptosis pro-

moting signals such as e.g. oxidative stress, cytochrome c release

leading to the formation of effector caspases ultimately resulting in

apoptotic cell death. We investigated the influence of different warm

ischemia times (15, 30 minutes, n � 7 each) in the rat pancreas fol-

lowed by two hours of reperfusion. The quantification of apoptosis

was done using terminal deoxynucleotidyl transferase-mediated

dUTP-biotin in situ nick labelling (TUNEL) staining as well as

caspase-3 ELISA. Simultaneously occurring necrotic cell death was

assessed using a semiquantitative score in HE stained samples. Zero

minute ischemia served as baseline control (n � 5). Apoptosis scores

reached their maximum after 15 minutes of warm ischemia in acinar

cells (1.13 � 0.28 cells/hpf � SEM). 30 minutes of warm ischemia

time resulted in a markedly reduced apoptotic score close to baseline

levels (0.2 � 0.038 vs. 0.15 � 0.023 cell/hpf � SEM). Islets did not

display apoptotic cell death. The results indicate that pancreatic acinar

cells are especially susceptible to cell apoptosis after short periods of

warm ischemia. Necrosis is predominant after longer periods of

ischemia.

P2-05-5

Large Maf Expression in Rat IschemicReperfusion Pancreatic InjuryM. Tsuchiya1, K. Tsuchiya2, A. Niimi1, R. Misaka1, T. Kurihara1, A. Maeda1, M. Shigemoto1, K. Yamashita1

1Insutitute of Geriatorics, Aoyama Hospital, 2Departmentof Medicine IV, Kidney Center, Tokyo Women’s MedicalUniversity, Tokyo, Japan

We performed this study to investigate the expression of target

genes in rat pancreas in acute ischemic reperfusion (I/R) model. The

target genes were genes encoding the large maf family, CD2-associated

protein (CD2AP), nephrin, and hypoxia-inducible factors which are

speculated to encode transcription factors, structural proteins, or func-

tional proteins, however, their roles in the pancreas have not been

clearly identified.

Method: The expression of genes and transcription factors was

monitored and compared in rats subjected to pancreatic injury by

40-minute of ischemia followed by reperfusion until 72 hours and

controls. mRNA and protein expression was quantitated by real-time

PCR and Western blotting, respectively. Immunohistochemical stain-

ing with specific antibodies was performed to identify the localiza-

tion of each protein.

Results: Expression of large maf, CD2AP and nephrin was iden-

tified in the control pancreas. Immunohistchemical analysis with

antibody showed staining of CD2AP in the membranes of acinar

cells, and of maf in the islet cells. Expression of CD2AP was signifi-

cantly induced by I/R injury, whereas nephrin expression slightly

increased. Real-time PCR showed expression of mafA, mafB and

c-maf was induced by I/R injury.

Conclusion: Expression of the structural protein was increased

by I/R pancreatic injury, and that of the transcription factor large maf

was also induced but each large maf exhibited a different response

and seemed to have a somewhat different expression pattern. The

results of the present study suggested that there might be cross-talk

between the islet cells and acinar or ductal cells, which are likely to

play important roles in I/R pancreatic injury.

P2-05-6

Signal Transduction of Cerulein-InducedCytokine Expression in Pancreatic AcinarCellsJ.H. Suh1, J.B. Chung2, S.Y. Song2, B.K. Park2, H. Kim3, M.G. Lee3

1Department of Internal Medicine, NHIC Ilsan Hospital,2Department of Internal Medicine, Institute ofGastroenterology, 3Department of Pharmacology, College of Medicine, Yonsei University, Seoul, Korea

The signaling pathways mediating cytokine production in pancre-

atic acinar cells have not been fully understood. Recent studies indi-

cated that cytokine expression requires activation of NF-�B and AP-1

as well as activation of the MAP kinases. However, the precise rela-

tionship between transcription factor and MAP kinase remains

unclear. We examined the requirements of ras, MAP kinases, NF-�B,

and AP-1 for cerulein-induced cytokine expresssion in pancreatic aci-

nar AR42J cells. Cerulein was treated to the wild-type cells and the

transfected cells with control vector (pcDNA), I�B mutant gene (I�B

mt), H-ras mutant gene (Ras N-17), or c-jun dominant negative gene

(TAM67). In addition, to investigate the role for MAP kinases, three

subtypes of MAP kinases were measured in the cerulein-treated

AR42J cells, and we used pharmacological inhibitors to attenuate

signaling via these kinases. As a result, (1) cerulein (10–8M) induced

production of the inflammatory IL-6, IL-1, and TNF-mRNA and pro-

tein expression in AR42J cell. (2) Inhibition of ras, NF-�B, and AP-1

using transfected cell with Ras N-17, I�B mutant, and TAM67

decreased the cytokine gene expression induced bycerulein (10–8M)

as compared to pcDNA cells and the wild-type cells. (3) Cerulein


induced NF-�B activation with biphasic kinetics. That is, NF-�B was

strongly activated within 30 min after the stimulation and a second

phase of NF-�B activation was prominent at 46 h. Transfection of Ras

N-17 or TAM67 in AR42J cells reduced cerulein-induced NF-�B

activation. (4) Cerulein induced the activation of AP-1 within 30 min

after stimulation and AP-1 activation was sustained continuously until

6 h. Transfection of Ras N-17 but not I�B mutant reduced cerulein-

induced AP-1 activation. (5) Three subtypes of MAP kinases (ERK,

JNK, and p38 MAPK) activities were elevated rapidly by cerulein in

AR42J cells. (6) Inhibition of MEK activity resulted in a reduction of

NF-�B and AP-1 activations, and cytokine expressions whereas the

inhibition of p38 MAPK did not. In conclustion, cytokine gene

expression by cerulein in AR42J cells was mediated via the activation

of the ras, MAP kinases, NF-�B, and AP-1. Ras functioned as com-

mon upstream activators of both NF-�B and AP-1 pathway, and AP-1

might be required for activation of NF-�B. AP-1 and/or NF-�B tran-

scription factors were potential downstream mediators of MAP

kinases, especially ERK in the cerulein-induced cytokine expression

in AR42J cell. It was believed that inhibition of signal transduction

pathway such as ras, MAP kinases, NF-�B, and AP-1 might alleviate

the inflammatory response in pancreatic acinar cells by suppressing

cytokine gene expression.

P2-05-7

Detection of ppENK Hypermethylation inPure Pancreatic Juice for Diagnosis ofPancreatic CarcinomaK. Ohtsubo, H. Watanabe, Y. Yamaguchi, H. Mouri, Y. Motoo, N. Sawabu

Department of Internal Medicine and Medical Oncology,Cancer Research Institute, Kanazawa University,Kanazawa, Japan

Aberrant methylation of CpG islands is a common mechanism for

tumor suppressor genes in a variety of human malignancies. The

ppENK gene encodes a native opioid peptide met-enkephalin, which

is known to a potent regulator of development, cell proliferation,

and angiogenesis. ppENK hypermethylation is recognized in 90% in

pancreatic carcinoma (PC), but not normal pancreas tissues. We

analyzed ppENK hypermethylation in pure pancreatic juice (PPJ) in

patients with PC and chronic pancreatitis (CP), and elucidated the use-

fulness for diagnosis of PC. PPJ was collected endoscopically from

18 patients with PC and 9 patients with CP. DNA was extracted from

the supernatant and the sediment of PPJ. Methylation specific PCR

(MSP) was performed for hypermethylation analyses with the DNA

extracted from these samples. In addition, single-strand conformation

polymorphism (SSCP) was performed simultaneously for analyses of

p53 mutations. The incidence of ppENK hypermethylation in the

supernatant or the sediment was 50% (9 of 18) in patients with PC.

Although the results of the supernatant is agreement with the sediment

in almost cases, ppENK hypermethylation were found only in the

supernatant in one case, and vice versa. In contrast, none of 9 cases

presented hypermethylation in patients with CP ( p � 0.046). In addi-

tion, we investivated p53 mutations in 2 PC cases with ppENK hyper-

methylation. p53 mutation was observed in one of two cases. These

results suggest that ppENK hypermethylation in pure pancreatic juice

would be specific for cancer and the combination assay with p53 could

enhance the genetic diagnosis of pancreatic carcinoma.

Poster 2-06 Regeneration

P2-06-1

In vivo Excellent Function of Islets Isolated from the Pancreas Preserved by the Two-Layer MethodK. Kakinoki, Y. Fujino, Y. Suzuki, T. Goto, S. Li, T. Yoshikawa, T. Tanaka, T. Sakai, Y. Tanioka, Y. Kuroda

Division of Gastroenterological Surgery, Kobe University Graduate School of Medicine, Kobe, Japan

Background: It is considered that the pancreas preservation

technique plays a very important role in subsequent success in islet

isolation. Previously we have reported that the two-layer cold storage

method (TLM) improved yield and in vitro function of isolated islets

from long-term preserved pancreas.

Objective: In this study we performed in vivo more accurate

functional analyses of islets isolated from the pancreas preserved by

TLM.

Method: We used Lewis rats and Balb-c nude mice for donors

and recipients, respectively. Rat islets were isolated immediately after

harvesting (Fresh group), and after 24 hrs pancreas preservation

by TLM (TL group) or conventional cold storage in UW solution

(UW group), 200 isolated islets in each group were transplanted

under the renal capsule of Streptozotocin induced diabetic nude mice.

We monitored recipient blood sugar levels, and performed intra peri-

toneal glucose tolerance testing (IPGTT) at day 21 posttransplant.

Results: Islet yields in each group were 916, 613, and 289 IEQ/rat

in Fresh, TL, and UW groups, respectively. Graft survival rates were

100%, 80%, and 0% in Fresh, TL, and UW groups, respectively. IPGTT

showed the blood sugar curve of TL group was comparable to that of

Fresh group.

Conclusion: The function of the islets isolated from the pan-

creas preserved by TLM for 24 hours is excellent comparably to

freshly isolated islets and significantly better than that preserved by

conventional UW solution. The TLM is an excellent preservation

technique to isolate islets with great viability.


P2-06-2

PVA Hydrogel Macroencapsulation for the Bioartificial PancreasM. Qi, Y. Gu, N. Sakata, D. Kim, Y. Shirouzu, C. Yamamoto, A. Hiura, S. Sumi, K. Inoue

Department of Organ Reconstruction, Institute forFrontier Medical Sciences, Kyoto University, Kyoto, Japan

We newly developed a sheet-type macroencapsulation device

entrapping rat islets from 3% PVA dissolved in Euro-Collins solution

containing 10% FBS and 5% DMSO (PVA � EC) using a

freezing/thawing technique. The same encapsulation technique but

with 3% PVA dissolved only in double-distilled water (PVA) and a

culture of free islets were served as controls. After 14-day culture in

the CMRL-1066 medium, the islet recovery rate, morphological

changes, insulin content, and insulin secretion were evaluated in vitro

to prove the feasibility of this method of encapsulation. We also xeno-

transplanted the device into the peritoneal cavity of diabetic C57BL/6

mice to check its function in vivo. After 1-day culture, the islet recov-

ery rate and insulin content in the PVA group were significantly lower

than that in the PVA � EC and free islet groups. After 14-day culture,

only the islets in the PVA � EC group maintained a normal mor-

phology and effective insulin secretory response to high glucose

while the response was not observed in the PVA group after 1-day

culture and no longer observed in the free islets after 7-day culture.

After transplantation of rat islets encapsulated in the PVA � EC

device to diabetic C57BL/6 mice, nonfasting blood glucose levels

showed a rapid decrease from high glucose levels of pre-transplanta-

tion, maintaining significantly lower glucose levels during the whole

course of study in comparison with the sham-operated group. Our

results indicated that this freezing/thawing macroencapsulation tech-

nique using 3% PVA � EC was effective for xenotransplantation of

islet cells.

P2-06-3

Differentiation of Duct and Endocrine Cells in Embryonic Pancreas is Induced byAll-Trans-Retinoic Acid via Mesenchymal/Epithelial InteractionsR. Doi, S.S. Tulachan, M. Koizumi, E. Toyoda, T. Mori, D. Ito, K. Kami, Y. Kawaguchi, K. Fujimoto, M. Imamura


During embryonic period, retinoids (RA) act as mesenchymal

inducer in many organs including kidney, lung, central nervous system

and gut. RA demonstrates insulinotropic effects in adult pancreas, but

only a limited study has elucidated its role in pancreatic organogene-

sis. In this study, we have analyzed the existence of RA-signaling

machinery in embryonic pancreas and evaluated its role using in vitro

tissue culture experiments. We show the presence of endogenous

RALDH2, the most effective RA-synthesizing enzyme, RA-binding

proteins and RA-Receptors in embryonic pancreatic tissue. To note,

RALDH2 is expressed exclusively in the mesenchyme. Exogenously

added all-trans RA (atRA) in tissue culture experiments stimulated dif-

ferentiation of endocrine and duct cells, and promoted apoptotic cell

death of acinar tissue. Furthermore we demonstrate that atRA upregu-

lates the PDX-1 expression. Taken together, our data suggests that

atRA-mediated mesencyhmal/epithelial interactions play an important

role in determining the cell fate of epithelial cells via regulation of

PDX-1 gene, leading to the proper formation of endocrine versus

exocrine component during pancreatic organogenesis.

P2-06-4

A Treatment Effect of Leukemia Inhibitory Factor to the Embryoid Body for Differentiation of Insulin-Producing Cells from Embryonic Stem CellD. Kim, M. Qi, S. Sumi, K. Inoue

Department of Organ Reconstruction, Institute forFrontier Medical Sciences, Kyoto University, Kyoto, Japan

To induce pancreatic differentiation of mouse embryonic stem

(mES) cells, various culture protocols have been previously devel-

oped and all of them require the formation of embryoid bodies (EBs),

and a treatment with both basic fibroblast growth factor (bFGF) and

leukemia inhibitory factor (LIF). It is unclear whether requirement of

LIF depends on its inhibitory effects, supporting the derivation and

expansion or its stimulatory effects on ES cell survival and prolifera-

tion. Here, we performed a histological study to investigate whether

or not differentiation of insulin-producing cells (IPC) can also occur

in the absence of either LIF, or bFGF. In the control experiment, the

protocol consisting of a 4-day culture in serum-containing DMEM

followed by continuous exposure to the LIF and bFGF in DMEM

drove a vast majority of ES cells to generate EBs whereas IPC differ-

entiation and EB formation can not be achieved without LIF treat-

ment to EBs. On the other hand, bFGF did not induce additional

differentiation of ES cells, but rather they significantly improved the

proliferation of already differentiated cells.

Our analyses show that adjustment of culture conditions by

adding or withdrawing growth factors, cytokines or serum enable us

to selectively and specifically alter the survival, proliferation, and

differentiation dynamics of the two subpopulations thus effectively

controlling population of outputs. Our findings therefore have impor-

tant applications in engineering stem cell culture systems to pre-

dictably generate desired stem cells or their derivatives for various

regenerative therapies.


P2-06-5

Development of Exocrine Pancreas of Rats during Neonatal TermT. Inagaki1, T. Tajiri2, T. Enosawa1, N. Ohike3, M. Kojima1, K. Saito1, T. Kunimura1, T. Morohoshi1

1First Department of Pathology, Showa University Schoolof Medicine, Tokyo, 2Department of Pathology, ShowaUniversity Fujigaoka Hospital, 3Department of Pathology,Showa University Northern Yokohama City Hospital,Yokohama, Japan

Purpose: Exocrine pancreas shows rapid development in neona-

tal term with conflicting reaction consisting of both proliferation and

apotosis. To clarify those complex reactions, the following examina-

tion was performed.

Material and Methods: Sequential pancreatic tissue samples

were obtained from fetal and neonatal rats and examined for light and

electron microscopic study as well as immunohitochemistric study.

Results: Electronmicroscopically, fetal type of acinar cells (FA)

in prenatal term included zymogen granules diffusely scattered in

cytoplasm, while adult type of acinar cells (AA) in postnatal term

included zymogen granules in the apical region of the cytoplasm with

abundunt organelles. In 3 days before birth, FA and peripheral duct

epitheliulm showed strong proliferative activity with high positivity

for proliferating cell nuclear antigen by immunohistochemical study.

Interestingly, the proliferative activity of both acinar and peripheral

duct cells was decreased before birth and increased again in 2 days

after birth with frequent apoptosis evaluated by positive staining for

TUNEL method. At the same time, peripheral duct cells and cen-

troacinar cells showed strongly positive for bcl-2.

Conclusion: FA seems to be immediately eliminated by apopto-

sis and exchanged to AA transformed from pancreatic stem cells that

presented at peripheral duct epithelium in the neonatal term.

P2-06-6

Insulin Producing Cells Delived fromPancreatic Duct CellsR. Morita1, M. Sunamura1, N. Omura1, T. Furukawa2, K. Matuda1, K. Tuchihara1, H. Abe1, N. Fukuyama1, S. Egawa1, K. Takeda1, S. Matuno1

1First Department of Surgery, 2Molecular Pathology,Tohoku University, Sendai, Japan

Introduction: Insulin gene expression is under specific control

mechanisms mediated by specific transcription factors. Pancreatic

and duodenal homeobox gene1 (PDX-1) play central role in regulat-

ing pancreatic development and glucose homeostasis. Most studies

have shown there is limited in vitro cell growth of adult islet cells, but

several recent reports have found that adult pancreatic duct cells have

the capacity to expand and differentiate into islet cells.

Aims and Methodology: Immortal epithelial cell lines were

previously established after transduction of the HPV16-E6E7

genes into primary cultures of normal human pancreatic duct epithe-

lial cells (HPDEC). Adenoviral vectors were generated to express

PDX-1(AdV-pdx-1), in addition to enhanced green fluorescence

protein. AdV-pdx-1was infected to HPDEC to induce the differentia-

tion of insulin producing cells. Insulin production was evaluated by

immunohistochemical analysis, RT-PCR, insulin secretion test, and

insulin content.

Result: HPDEC are not tumorigenic in SCID mice and have the

flexibility in various culture systems with some growth factors. In

matrigel, infected HPDEC by AdV-pdx-1 formed clusters of islet like

structures. PDX-1 expression was confirmed by RT-PCR analysis.

Though, RT-PCR and western blotting analysis showed they have the

not enough function to produce insulin.

Conclusion: HPDEC have the possibility to behave as pancreatic

endocrine stem cells in special conditions.

PDX-1 gene delivary mediated by AdV-pdx-1 can induce multi-

potential ability of HPDEC.

Poster 2-07 Regeneration

P2-07-1

Experimental Study on the Role of thePancreas to Liver Regeneration afterSimultaneous Resection of the Liver and the PancreasM. Yoshida, H. Hoshino, M. Katori, K. Furuta, K. Shimada,T. Takahashi, K. Sato, M. Watanabe

Department of Surgery, Kitasato University, School ofMedicine, Kanagawa, Japan

Background and Purpose: As a radical treatment for hepato-

biliary carcinomas, patients sometimes undergo simultaneous hepate-

ctomy and pancreatectomy. However, the clinical outcome of this

treatment is extremely poor, presumably due to the excessive physio-

logical stress induced by this surgical procedure. In this study, we per-

formed hepatectomy with pancreatectomy to assess the physiological

contribution of the pancreas, especially in terms of endocrine function

to hepatic regeneration.

Material and Method: Twenty-three dogs were divided into the

following four groups, group 1 dogs underwent 70% hepatectomy

alone, group 2 dogs underwent 70% hepatectomy with 66% pancrea-

tectomy, group 3 dogs underwent 70% hepatectomy with 80% pan-

createctomy. group 4 dogs underwent 70% hepatectomy with 95%

pancreatectomy. Arterial and portal blood samples were collected by

a portal puncture and arterial puncture from animals (group 1–3) 1, 3,

7, 14, 28 days after surgery for the biochemical and endocrine func-

tion tests, respectively. After 4 weeks survival, the liver was removed

and the rate of liver regeneration was calculated on a wet weight basis

by Fishback’s formula.

Results: While 4 week survival rate of the group 1 was 100%, the

survival rate decreased significantly in group 2–4. The liver regenera-

tion rate in group 2 and group 3 were also lower than those in group 1.

Changes on pancreatic hormones, such as insulin and glucagon, in a


portal blood after the simultaneous resection of the liver and the pan-

creas depended on the size of the resected pancreas. Glucagon levels

in the portal blood were especially increased in the group of hepatec-

tomy with pancreatectomy.

Conclusions: These results show that the pancreatic hormones

affect the liver regeneration after the simultaneous resection of the

liver and the pancreas. In clinical practice, large scale simultaneous

hepatectomy and pancreatectomy carries a high risk of postoperative

hepatic insufficiency. Our present findings may contribute to estab-

lishing prophylactic administration of glucagon and insulin to help

stimulate the hepatic regeneration after evisceration.

P2-07-2

Contribution of Bone Marrow Cells toPancreatic Islet Regeneration Induced byChemical Damage of Islets or by PartialPancreatectomyK. Ohtake, T. Gunji, S. Asawa, T. Saito, M. Gotoh

Department of Surgery I, Fukushima Medical University,Fukushima, Japan

To clarify possible roles of bone marrow cells in repair or regen-

erative process of pancreatic islet tissue, the experiment was under-

taken under GFP-expressing bone marrow chimera.

Materials and Methods: C57BL/6N mice given 1 106 bone

marrow cells from GFP-transgenic mice after 12 Gy irradiation were

subjected to two different protocols (1) streptozotocin (200 mg/kg)

injection or (2) 60% partial pancreatectomy. Regeneration was assessed

either by B cell mass or number of PCNA positive cells.

Results: For protocol (1) some animals received an insulin

implant to maintain non-fasting blood glucose levels under 250 mg/dl,

which led to significant larger size of B cell mass as compared to

animals without insulin treatment. GFP positive cells suggesting

inflammatory cells were found within the islets on days 1–3 post-STZ

injection, however, GFP positive cells were hardly found later on. For

protocol (2) numbers of PCNA positive cells within the islets were

increased 4 weeks after partial pancreatectomy as compared to con-

trol. However, GFP positive cells were not found within the islets,

although some were found around the islets.

Conclusion: Both chemical damage of islets and partial pancre-

atectomy induce repair or regeneration of pancreatic islets. In both

models a participation of bone marrow cells were noted, however, its

significant role on constitution of endocrine components was negligi-

ble at least under the conditions studied here.

P2-07-3

Influence of Microcirculatory Derangementon the Morphological Changes of PancreaticRegeneration in PancreatitisM. Sugimoto, T. Takada

Teikyo University School of Medicine, Tokyo, Japan

To demonstrate the process of progressing severity of acute pan-

creatitis and its transition to pancreatic regeneration after pancreatitis,

we investigate the influence of tissue microcirculation derangement on

the morphological changes of pancreatitis. We developed a new model

of reversible acute pancreatitis, as an incomplete closed duodenal loop

(ICDL) model in rats. The duodenum was ligated over half its cir-

cumference at 2 cm either side of the duodenal entry of the bilio-

pancreatic duct. We investigated histological progression and its tissue

blood flow by laser Doppler flowmetry, compared between CDL,

ICDL, and sham. Pancreatic histology in the CDL and ICDL consisted

of edema, parenchymal necrosis. From two to three weeks onward,

periductal and interlobular fibrosis and tubular complex spread to the

parenchyma in ICDL only, presenting pancreatic regeneration after

pancreatitis. Duodenal histology appeared degenerative change at 24 h

in CDL and stable in ICDL. Tissue blood flow in the pancreas and

duodenal loop decreased over time after model preparation, and the

decline in ICDL occurred and remained at a plateau in chronic

pancreatitis phase. Duodenal blood flow was under detective value

immediately after producing CDL. These results suggest that the

involvement of pancreatic microcirculation hemodynamics in the

progression of pancreatitis was thus demonstrated by comparison of

ICDL with conventional CDL, and significant influence of microcir-

culation impairment was observed on morphological changes of pan-

creatitis. Regeneration of reversible pancreatitis is induced by

maintenance of microcirculation. The predictable nature in which the

regeneration are occured may stimulate novel approaches to disease

treatment.

P2-07-4

Expression of CCK2i4sv Receptor TransgeneEnhances Pancreatic Regeneration FollowingPartial PancreatectomyM. Ishihara, H. Watanabe, B.M. Evers, M.R. Hellmich

Department of Surgery, University of Texas MedicalBranch, Galveston, TX, USA

The peptide hormone gastrin stimulates pancreatic cell growth

and differentiation. The effects of gastrin are mediated by the chole-

cystokinin2/gastrin (CCK2) receptor. Three splice variants of the

CCK2 receptor have been identified: CCK2short, CCK2long and the

novel CCK2i4sv variant. Transgenic mice expressing CCK2short

show increase pancreatic growth following ligation injury. The role of

CCK2i4sv in pancreatic growth is unknown. The aim of this study

was to test whether forced expression of CCK2i4sv in a transgenic

mouse model would enhance pancreatic growth following partial pan-

createctomy (Px).


Methods: Transgenic mice expressing either CCK2i4sv or

CCK2short under the control of the elastase promoter were generated.

Receptor expression was confirmed in transgenic mice by RT-PCR.

Eight month-old transgenic mice and non-transgenic litter mates

(control) where divided into 2 groups. One group received a sham

operation and the other received 70% Px. Each group was further

subdivided into 2 groups and treated either with the CCK2 receptor

agonist, pentagastrin (5,000 �g/kg/day) or vehicle (saline) for 14 days

post-operation. On day 14, the pancreas of each mouse was harvested,

wet weight determined and analyzed for DNA and protein content.

Results: The wet weight, protein and DNA content were

significantly increased in Px mice expressing either CCK2short or

CCK2i4sv when treated with pentagastrin. In the absence of penta-

gastrin, no significant differences in wet weight, protein or DNA

content were detected in any of the groups. A forced expression of

either CCK2short or CCK2i4sv enhances pancreatic regeneration

following Px in an agonist-dependent manner.

Poster 2-08 PC Cell Cycle

P2-08-1

Enhanced Expression of 14-3-3sigma in Pancreatic Cancer and its Role in Cell Cycle Regulation and ApoptosisJ. Kleeff1, A. Guweidhi1, N. Giese1, K. Ketterer1,2, M.W. Büchler1, M. Korc2, H. Friess1

1Department of General Surgery, University of Heidelberg,Heidelberg, Germany, 2Departments of Medicine andPharmacology and Toxicology, Dartmouth HitchcockMedical Center, Dartmouth Medical School, Lebanon, NH, USA

Background: 14-3-3sigma belongs to the 14-3-3 family of pro-

teins, which are involved in the modulation of diverse signal trans-

duction pathways. Loss of 14-3-3sigma expression has been observed

in a number of human cancers, suggesting that it may have a role as a

tumor suppressor gene.

Aim: To investigate the expression and the functional role of

14-3-3sigma in pancreatic ductal adenocarcinoma.

Methods: Expression of 14-3-3sigma was analyzed using laser

capture microdissection, real-time quantitative PCR, immunohisto-

chemistry, and Western blot analysis. The role of 14-3-3sigma in

apoptosis and cell cycle regulation was evaluated by Western blotting,

immunoprecipitation, and FACS analysis.

Results: 14-3-3sigma mRNA levels were 54-fold increased in

pancreatic adenocarcinoma in comparison to normal pancreatic sam-

ples and localized in pancreatic cancer cells. In pancreatic cancer

cells, the degree of 14-3-3sigma expression was not decisive for the

maintenance of G2/M cell cycle checkpoint or induction of apoptosis.

Responses to radiation or apoptosis-inducing agents were neither

accompanying by a significant 14-3-3sigma accumulation nor by a

change in association of 14-3-3sigma with cdc2, bad and bax.

Conclusion: The marked overexpression of 14-3-3sigma in

PDAC together with multiple known alterations of potential

14-3-3sigma interacting partners suggests an important role of aber-

rant 14-3-3sigma downstream signaling in pancreatic cancer.

P2-08-2

Role of Akt in Resistance of PancreaticCancer Cells to TRAIL-Induced ApoptosisT. Mori, R. Doi, M. Koizumi, E. Toyoda, D. Ito, K. Kami, T. Kuhara, K. Fujimoto, Y. Kawaguchi, M. Imamura


Akt/protein kinase B is known to have an important role in the cell

survival. Recent studies have reported that Akt protects cancer cells

from apoptosis that is induced by anticancer therapies. We investi-

gated the role of Akt activity in the resistance of pancreatic cancer

cells to TRAIL-induced apoptosis.

Methods: (1) Six human pancreatic cancer cell lines were

treated with TRAIL at various concentrations. After 2 days, the

number of viable cells was evaluated. (2) Basal levels of Akt activity

and the expression of XIAP, FLICE-inhibitory protein (FLIP), Bcl-2,

Bcl-xl, Bax in six pancreatic cancer cells were analyzed by Western

blotting. (3) Effects of PI3K inhibitor ly294002, a novel selective Akt

inhibitor, on TRAIL-induced apoptosis, caspase activity and FLIP

expression in TRAIL-resistant cells were evaluated.

Results: (1) Six pancreatic cancer cell lines exhibited various

sensitivities to TRAIL treatment. (2) No correlation was found

between expression of XIAP, Bcl-2, Bcl-xl, Bax and the sensitivity

to TRAIL. TRAIL-resistant cells exhibited a high expression of

phospho-Akt and FLIPs as compared to sensitive cells. (3) Inhibition

of Akt markedly augmented TRAIL-induced apoptosis and caspase

activity in resistant cells. Expression of FLIPs was decreased by inhi-

bition of Akt activity in resistant cells.

Conclusion: The results suggest that Akt activity promotes

pancreatic cancer cell survival against TRAIL-induced apoptosis by

regulating FLIPs. Selective Akt pharmacological inhibitors might

be useful to overcome the resistance of pancreatic cancer cells to anti-

cancer therapies.

P2-08-3

Role of Smac/DIABLO in TRAIL-InducedApoptosis of Pancreatic Cancer CellsT. Mori, R. Doi, M. Koizumi, E. Toyoda, D. Ito, K. Kami, T. Kuhara, K. Fujimoto, Y. Kawaguchi, M. Imamura


Smac/DIABLO was recently identified to promote caspase acti-

vation by neutralizing the IAPs. We investigated the role of Smac in

regulation of apoptosis by TRAIL.


Methods: (1) Six human pancreatic cancer cell lines were

treated with TRAIL at various concentrations. After 2 days, the num-

ber of viable cells was evaluated. (2) Expression of four types of

TRAIL receptor in five pancreatic cancer cell lines was analyzed by

RT-PCR. (3) Localization of Smac and the activity of caspase-3, -8,

and -9 before and after exposure to TRAIL were analyzed by Western

blotting. (4) Smac-tat peptide was synthesized and PANC-1 cells were

treated with TRAIL in the absence or presence of Smac-tat peptides

for 48 hours. Cell viability and DNA fragmentation was evaluated.

Results: (1) Six pancreatic cancer cells exhibited various sensi-

tivities to TRAIL treatment. (2) No correlation was found between

expression of DR4, DR5, DcR1 and the sensitivity to TRAIL.

Resistant cells exhibited a high expression of DcR2 when compared

to the sensitive cells. (3) In TRAIL-sensitive cells but not in resistance

cells, treatement of TRAIL caused a redistribution of Smac from

mitochondria to cytosol. The redistribution was associated with down

regulation of XIAP and activity caspase-3, -9. (4) Smac peptides

markedly enhanced TRAIL-induced apoptosis in PANC-1 cells.

Conclusion: The results indicate that Smac plays an important

role in TRAIL-induced apoptosis of pancreatic cancer cells. The com-

bination of Smac peptide and TRAIL may be an effective approach to

pancreatic cancer that is resistant to pro-apoptotic treatment.

P2-08-4

Significance of Focal Adhesion KinaseExpression in Human Pancreatic CarcinomaK. Furuyama, R. Doi, T. Mori, E. Toyoda, M. Koizumi, D. Ito, K. Kami, Y. Kawaguchi, K. Fujimoto, M. Imamura


Focal adhesion kinase (FAK) is a non-receptor, cytoplasmic

protein tyrosine kinase, which is involved in the regulation of cellu-

lar signaling, migration, apoptosis and cell cycle progression.

Previous reports have shown that FAK is expressed in various kinds

of cancer tissues and cancer cell lines; however, no information is

available about the human pancreatic carcinoma specimens. The

purpose of this study was to investigate the relationship between

FAK expression and clinicopathological factors in human pancreatic

carcinoma.

Methods: Formalin-fixed paraffin-embedded tissue specimens

were obtained from 63 patients who underwent pancreatic resection

for pancreatic invasive ductal carcinoma at our institute from 1996 to

2002. Immunohistochemical staining of FAK was performed by the

standard streptavidin-biotin method. Seven human pancreatic cancer

cell lines (AsPC-1, BxPC-3, CFPAC-1, HPAC, MIAPaCa-2, PANC-1,

Suit-2) were used in reverse transcription PCR analysis and Western

blot analysis for FAK and phosphorylated FAK.

Results: FAK expression was detected in 28 of 63 cases (44.4%).

There was a statistically significant correlation between FAK expres-

sion and tumor size (P � 0.001), although FAK expression did not

significantly correlate with other factors such as tumor histological

grade, lymph node metastasis, distant metastasis, histological stage

and overall survival. Reverse transcription PCR analysis and Western

blot analysis showed that FAK was expressed in all 7 pancreatic cancer

cell lines.

Conclusion: FAK expression was not related to clinicopatho-

logical factors except tumor size in pancreatic carcinoma. FAK

expression may not be a prognostic marker for pancreatic cancer

patients.

P2-08-5

Glial Cell Line-Derived Neurotrophic Factor(GDNF) Enhances Nuclear Factor-�B Activityand Invasive Potential in Human PancreaticCancer CellsH. Takahashi, Y. Matsuo, M. Sakamoto, H. Funahashi, H. Sawai, M. Yamamoto, Y. Okada, T. Hayakawa, M. Tanaka, H. Takeyama, T. Manabe

Department of Gastroenterological Surgery, Nagoya CityUniversity Graduate School of Medical Sciences, Nagoya,Japan

We have previously reported that the invasive potential of human

pancreatic cancer cells is increased by Glial Cell Line-Derived

Neurotrophic Factor (GDNF). In the present study, we examined

whether the signaling pathway activated by GDNF is correlate to tran-

scription factor NF-�B in human pancreatic cancer cells.

BxPC-3 cells were transfected with a mutated I�B (I�BM),

which blocks NF-�B activity. To quantify the invasive ability, we

performed in vitro invasion assay. GDNF-stimulated control cells

migrated at about 2-fold the rate for non-GDNF-stimulated cells. On

the other hand, I�BM transfected cells migrated at only one-third

the rate of the control cells and the invasion cell number did not

increase even on exposure to GDNF. To quantify NF-�B dependent

gene expression, dual luciferase reporter assay was performed. The

relative luciferase activity of control cells increased in the presence

of GDNF, but the reduced basal NF-�B activity of I�BM trans-

fected cells remained unchanged by GDNF. Next, we used protea-

some inhibitor (MG132) for pharmacological NF-�B inhibitor. The

results were almost similar to experimental findings with I�BM

transfection.

These results indicate that GDNF promotes NF-�B activation and

that the latter is involved in the invasive ability of human pancreatic

cancer cells.

P2-08-6

The Role of Notch Signaling Pathway inPancreatic Cancer CellsK. Kimura, K. Satoh, S. Hamada, T. Shimosegawa

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

Background and Aim: Truncated, constitutively active forms

of Notch have a crucial role in neoplastic pathway in various cell

types. However, the precise role of Notch signaling pathway in

pancreatic cancer is still largely unknown. In this study, we aimed to

clarify the role of Notch signaling pathway in pancreatic cancer.


Methods: Three human pancreatic cancer cell lines, BxPC-3,

MiaPaca-2 and Panc-1 were used in this study. All cell lines were

cultured in condition media containing ATRA, known as a differenti-

ation promoting factor in pancreatic cancer cell lines, or �-secretase

inhibitor, DAPT, a potent inhibitor of Notch signaling pathway.

Cell growth was evaluated by MTT assay. The expression of

Notch1, Hes1, Nestin, cyclinD1, carbonic anhydrase II (CAII) and

Cytokeratin 19 (CK19) was examined by RT-PCR and Western blot

analysis.

Results: Significant growth inhibition was observed in BxPC-3

by ATRTA and DAPT treatment. Cell growth of MiaPaCa-2 and

Panc-1 was also inhibited but not statistically significant. The

cyclinD1 expression was inhibited in BxPC-3 by both ATRA and

DAPT. Notch1 and Hes1 were expressed in all cell lines. Notch1

expression was inhibited by ATRA treatment but not affected by

DAPT treatment as expected. All cell lines expressed Nestin, known

as a marker of undifferentiated pancreatic epithelial cells. The expres-

sion of Hes1 and Nestin was inhibited by ATRA and DAPT treatment

in BxPC-3. Conversely, CA II and CK19 expressions were enhanced

by both treatment. These findings indicate that the block of Notch sig-

naling induces not only growth inhibition but also differentiation in

certain type of pancreatic caner cell.

Conclusions: It is suggested that wild type Notch regulates cell

growth and malignant potential in pancreatic cancer cells. Our data

also suggests that Notch pathway can be a novel target in pancreatic

cancer.

P2-08-7

Cyclin D1, P27 and Bax – Impact on Survival after DuodenopancreatectomyA. Tomazic, A. Pleskovic, D. Stanisavljevic

Department of Abdominal Surgery, University Medical Center Ljubljana, Slovenia, Europe

Background: The outcome of patients undergoing pancreato-

duodenectomy for periampullary adenocarcinoma is influenced by

various clinicopathological factors, chemo/radiotherapy and expres-

sion of various oncogenes, tumor supressor genes, growth factors and

factors controlling apoptosis. The aim of this study was to define clin-

icopathological predictors of survival in periampullary adenocarci-

noma, and to determine the prognostic significance of cyclin D1,

p27KIP1 and bax expression in these tumors.

Methodology: Prospectively, we collected clinicopathological

data for patients operated on between January 1995 and December

1998. Cyclin D1, p27KIP1 and bax expression was assessed immuno-

histochemically. The potential influence of clinicopathological factors

and cyclin D1, p27KIP1 and bax expression on survival was investi-

gated. Univariate analyses were performed using the Kaplan-Meier

method and log-rank test. For multivariate analysis Cox proportional

hazards regression was used.

Results: Fifty-five patients were included in the study. The actu-

arial 5-year survival was 30%: 11% for pancreatic adenocarcinoma

and 46% for distal bile duct/papillary adenocarcinoma. Univariate

analysis identified diabetes mellitus, blood transfusion, diameter of

the tumor, histological type of the tumor, lymphatic invasion, neural

invasion, lymph node metastasis, overexpression of cyclin D1 and

lower expression of bax and p27KIP1 as factors that significantly

decrease survival rates. In multivariate analysis, the histological type

of the tumor (p � 0.001), lymph node involvement (p � 0.03) and

overexpression of cyclin D1 (p � 0.02) independently influenced sur-

vival, whereas decreased expression of bax nearly reached statistical

significance (p � 0.054).

Conclusion: Our findings confirm the association between

cyclin D1 and bax expression and aggressive biological behavior of

periampullary adenocarcinomas. Moreover, these parameters were

indentified as independent prognostic indicators in these tumors.

Poster 2-09 PC Cell Biology

P2-09-1

Invasive Mechanisms of Pancreatic CancerCells: the Signal of Glial-cell-line-DerivedNeurotrophic Factor (GDNF) Transmits toIntegrins through NF-�BH. Funahashi, H. Sawai, H. Takahashi, Y. Matsuo, T. Wakasugi, M. Yamamoto, Y. Okada, T. Hayakawa, M. Tanaka, H. Takeyama, T. Manabe

Gastroenterological Surgery, Nagoya City UniversityGraduated School of Medical Sciences, Nagoya, Japan

The presence of neural invasion in the pancreatic cancer is con-

sidered to be a poor prognostic sign. The invasive mechanisms form

by multiple steps in the pancreatic cancer, but it has not cleared yet.

We investigated the alteration of integrins by glial cell line-derived

neurotrophic factor (GDNF) and the role of NF-�B as signal trans-

mission. In this study, we use four human pancreatic cancer cells

(MIA PaCa-2, SW1990, Capan-2 and BxPC-3). We confirmed to

express the RET and GFR-1 receptor for GDNF. In the invasion

assay, all human pancreatic cancer cells stimulated by GDNF

increased the invasive and the adhesive ability for Extra Cellular

Matrix. Therefore, their invasive ability were inhibited by anti-RET

antibody and anti-GFR-1 antibody. In the flow-cytometric analysis,

the integrin subunit 2, 3, 5, 6 and �1 expressed in the all pan-

creatic carcinoma cell lines. In the cellular enzyme-linked

immunosorbent assay, the integrin subunit of all pancreatic cancer

cells expressed strongly under stimulating by GDNF. NF-�B, which

manages the signaling pathway, moving into the nuclear was

enhanced in the all pancreatic cancer cells stimulated by GDNF.

Similarly, after blocking the NF-�B, all cell lines showed a decreased

ability to invade through the ECM proteins. In the all pancreatic can-

cer cells, the invasive ability appeared to increase under stimulating

by GDNF and the signal of GDNF is transmitted through NF-�B. We

conclude that GDNF, NF-�B and integrins have very important role

for the invasive and metastatic systems of pancreatic cancer cells.


P2-09-2

Is the Sensitivity Higher by Using PCR/RFLP Analysis in the Detection of Early Metastasis in Hamster ExperimentalPancreatic Cancer Model?C.Y. Morioka1,3, M.C.C. Machado1, S. Saito2, A.S. Matheus1, R.S. de Godoy1, J. Jukemura1, M.S. Kubrusly1, T. Bacchella1, K.-I. Kita3, A. Watanabe3

1Department of Surgery, University of São Paulo, São Paulo, Brazil, 2Center for Health Care and HumanSciences, Toyama University, 3Third Department ofInternal Medicine, Toyama Medical and PharmaceuticalUniversity, Toyama, Japan

We have previously established a curative resection model in ham-

ster experimental pancreatic cancer. However, the pathological exam-

ination should be enriched by sensitive methods to detect residual

disease. Thus, a method of early diagnosis would be helpful for better

follow-up. K-ras mutation has a relationship higher than 80% with

pancreatic cancer. The purpose of this study was to elucidate whether

the sensitivity of histopathological and molecular study differs in the

diagnosis of metastatic sites.

HaP-T1, a cell line derived from BHP induced pancreatic cancer

was used in these experiments. A tissue derived from subcutaneously

implanted cancer cells was implanted orthotopically. Partial pancrea-

tectomy and splenectomy were done. Hamsters were divided in

3 groups: (1) Positive control (n � 33), (2) Surgery performed at Day 7

(n � 30), and (3) Surgery performed at Day 14 (n � 27). Three ani-

mals of each group were sacrificed every 7 days until Day 77 and

necropsy was performed. Surgically-resected and necropsied speci-

mens such as pancreas, liver, lung, kidney, testis, and ovary were sent

for histopathological study and for detection of K-ras point mutation

by PCR/RFLP analysis.

Positive controls showed metastases in the histopathology starting

from Day 35 in 13 cases (39.4%) and in the molecular level starting

from Day 21 in 22 cases (66.6%). Groups 2 and 3 showed free

margins in the surgically-resected specimens. In Group 2, tumoral

recurrence was detected from Day 42 in one case (3.3%) in the

histopathological findings and in 2 cases (6.6%) in the molecular

level. In Group 3, metastases were detected from Day 35 in one ani-

mal (3.3%) in the histopathology and micrometastases in 2 cases

(6.6%).

This study suggests that PCR/RFLP analysis sensitivity rate was

higher when compared with histopathological findings. These experi-

ments showed the importance of possible use of this method for better

staging and follow up of pancreatic cancer.

P2-09-3

Sperm Associated Antigen 1 (SPAG-1)a Novel Protein Overexpressed in Pancreatic CancerA. Neesse1, T. Crnogorac-Jurcevic1, R. Gangeswaran1, V. Bhakta1, E. Costello2, J.P. Neoptolemos2, N.R. Lemoine1

1Cancer Research UK Molecular Oncology Unit, Imperial College of London, Faculty of Medicine,Hammersmith Campus, London, 2Department of Surgery, University of Liverpool, Liverpool, UK

SPAG-1 (sperm associated antigen 1) was identified in a rare form

of infertility where anti SPAG-1 antibodies derived from an infertile

woman were reported to cause sperm agglutination and/or immobili-

sation. The SPAG-1 mRNA (AF311312) is 3818bp in length and

encodes a protein of 926 amino acids which has been reported to be

located at the cell surface. The protein contains 3 tetratricopeptide

(TPR) motifs, an ATP/GTP binding site and putative phosphorylation

sites for PKC, CK2 and cAMP/cGMP-dependent kinases. In a previ-

ous microarray analysis, we identified SPAG-1 as one of the most

highly up-regulated genes in pancreatic cancer as compared to the

normal pancreas. We extended our results and studied the expression

profile of SPAG-1 in pancreatic cancer in more detail. Using RT-PCR

and QRT-PCR we could confirm the overexpression of SPAG-1 in

13 out of 18 pancreatic tumour tissues and 9 out of 10 panceratic can-

cer cell lines, whereas SPAG-1 was expressed only at very low levels

in chronic pancreatitis (9 cases) as compared to the normal pancreas.

Using a custom made monoclonal anti SPAG-1 antibody for

immunodetection, we analysed SPAG-1 protein expression in a panel

of pancreatic tissues. 30 out of 31 pancreatic cancer cases showed

immunoreactivity for SPAG-1 in malignant ducts and surrounding

acinar cells, whereas the stromal compartments were completely

devoid of detectable SPAG-1 expression. Normal pancreas (5 cases)

and chronic pancreatitis (5 cases) revealed only low or no SPAG-1

expression. Therefore, we conclude that SPAG-1 might play a role in

the pathogenesis of pancreatic tumours with potential diagnostic and

therapeutic implications.

P2-09-4

The �2-chain of Laminin-5 (LN5) Indicates the Invasiveness and Metastatic Potency of Pancreatic CarcinomasA. Jimi1, M. Katayama2, T. Sumii3, A. Funakoshi3

1Department of Pathology, Kurume University School ofMedicine, 2Diagnostic Department, Tsukuba ResearchLaboratory, Eisai Company Limited, 3Department ofGastroenterology, National Kyushu Cancer Center, Japan

The �2-chain, a component of the laminin-5 (LN5) heterotrimer,

has been shown to be expressed prominently in the invasive front of

malignant epithelial tumors. Here, we investigated whether the

LN5�2-chain N-terminal fragment (G2F) was present in the human

circulation and if it was increased appreciably in patients with


pancreatic carcinomas. The circulating levels of G2F in 185 patients

with digestive diseases were determined by a monoclonal antibody-

based immunoassay. The G2F levels in 22 patients with pancreatic

carcinoma with liver metastases were significantly elevated

(mean � SE; 183.3 � 37.2 ng/ml; P � 0.0001), as compared with

those in 33 patients with pancreatic carcinoma with no liver metas-

tases (55.0 � 4.6). The G2F levels in patients with benign pancreatic

tumors (pancreatic cysts and intraductal papillary-mucinous tumors)

were found to be slightly lower (30.8 � 5.7 and 29.6 � 2.7, respec-

tively) than those in 8 patients with diabetes mellitus (41.8 � 4.1).

The circulating levels of G2Fs correlated moderately (R � 0.408;

P � 0.001) with those of CA19-9, the well-established clinical tumor

marker. Immunohistochemical studies showed that pancreatic cancer

cells including their metastatic foci were positive for G2F, whereas

normal pancreatic tissues and benign pancreatic tumors were

negative. The elevation of this new circulating tumor indicator, G2F,

may suggest the invasiveness and metastatic potency of pancreatic

carcinomas.

P2-09-5

Analysis of HMGA2 Expression Level inPancreatic CancerN. Abe, Y. Suzuki, N. Matsumoto, M. Sugiyama, Y. Atomi

Department of Surgery, Kyorin University School of Medicine, Tokyo, Japan

Background and Aim: The altered form of the High Mobility

Group A2 [HMGA2] gene is related to the generation of human

benign and malignant tumors of mesenchymal origin. In this study,

we examined the HMGA2 expression level in pancreatic cancer, and

investigated whether alterations in the HMGA2 expression level are

associated with a malignant phenotype in pancreatic tissue.

Methods: HMGA2 mRNA and protein expression was deter-

mined in eight surgically resected specimens of non-neoplastic tissue

(six specimens of normal pancreatic tissue and two of chronic pan-

creatitis tissue) and 27 pancreatic cancers by highly sensitive RT-PCR

techniques and immunohistochemical staining, respectively.

Results: RT-PCR analysis revealed the expression of the

HMGA2 gene in non-neoplastic pancreatic tissue, although its

expression level was significantly lower than that in cancer.

Immunohistochemical analysis indicated that the presence of the

HMGA2 gene in non-neoplastic pancreatic tissue observed in

RT-PCR reflects its abundant expression in islet cells together with its

focal expression in duct epithelial cells. Intense and multifocal or

diffuse HMGA2 immunoreactivity was noted in all the pancreatic

cancer examined.

Conclusions: Based on these findings, we propose that an

increased expression level of the HMGA2 protein is closely associ-

ated with the malignant phenotype in the pancreatic exocrine system,

and accordingly, HMGA2 could serve as a potential diagnostic mole-

cular marker for cancer.

P2-09-6

Enhanced Angiogenesis Due to InflammatoryCytokines from Pancreatic Cancer Cell Linesand Relation to Metastatic PotentialY. Matsuo, H. Sawai, H. Funahashi, H. Takahashi, M. Sakamoto, M. Yamamoto, Y. Okada, M. Tanaka, T. Manabe

Department of Gastroenterological Surgery, Nagoya CityUniversity Graduate School of Medical Sciences, Nagoya,Japan

Purpose: To investigate the mechanisms of metastasis forma-

tion in human pancreatic carcinoma, we examined the angiogenic

capabilities of human pancreatic cancer cell lines with different

metastatic potentials and the roles of tumor-cell derived inflammatory

cytokines.

Methods: Interleukin (IL)-8 secretion by human pancreatic can-

cer cells stimulated with IL-1 or IL-1 receptor antagonist (IL-1ra)

was measured by enzyme-linked immunosorbent assay (ELISA). We

then examined how cancer cells with different metastatic potentials

influenced the proliferation and tube formation of human umbilical

vein endothelial cells (HUVECs) using the 3-(4,5-dimethylthiazol-

2-yl)-2,5-diphenyltetrazolium bromide dye reduction method (MTT-

assay) and an angiogenesis assay, respectively. We also examined the

role of tumor-cell derived inflammatory cytokines in the relationship

between tumor metastatic potential and angiogenesis.

Results: IL-8 secretion levels by pancreatic cancer cells were

regulated by IL-1 and correlated with metastatic potential. Both

HUVEC proliferation and tube formation were strongly enhanced by

co-culture with metastatic pancreatic cancer cells and were enhanced

to a similar extent by culture in the presence of IL-1 and IL-8. In

contrast, blockade of IL-1 or IL-8 inhibited HUVEC proliferation

and angiogenesis.

Conclusions: The tumor-cell derived inflammatory cytokines

IL-1 and IL-8 may have an important role in metastasis via vascular

endothelial cell proliferation and angiogenesis.

P2-09-7

Upregulation of Amino Acid TransporterLAT1 in Pancreatic Tumor Cells and its Role in Pancreatic Tumor Cell GrowthN. Matsumoto1, N. Abe1, O. Yanagida1, T. Masaki1, T. Mori1, M. Sugiyama1, Y. Atomi1, Y. Kanai2, H. Endou2

1Department of Surgery, 2Department of Pharmacology,Kyorin University, Tokyo, Japan

Background and Aim: LAT1(L-type amino acid trans-

porter 1) which transports neutral amino acids including several

essential amino acids, is considered to play an important role in tumor

cell growth. Its expression, however, has never been examined in pan-

creatic cancer. To test the possibility of using LAT1 as a diagnostic

marker and a molecular target for pancreatic tumor therapeutics, we

investigated LAT1 expression in pancreatic cancer and its role in

tumor cell growth.


Method: LAT1 expression was determined in five surgically

resected specimens of non-neoplastic tissue and 16 specimens of

invasive ductal carcinoma of the pancreas by immunohistochemical

staining using antibodies specific for LAT1. Furthermore, to inves-

tigate whether LAT1 is essential in supporting tumor growth, we

examined the effect of BCH (2-Aminobicyclo-(2,2,1)-heptane-

2-carboxylic), which has been known as a LAT1 inhibitor, on human

pancreatic cancer cells. To this end, a human pancreatic carcinoma

cell line (MIA PaCa-2) was exposed to BCH for three days and cell

growth rate was determined. The cancer cells were inoculated into a

nude mouse, and three days after BCH was injected into the subcuta-

neously inoculated tumor. The tumor volume was finally measured.

Result: LAT1 was expressed at high levels in all specimens of

pancreatic cancer, whereas the non-neoplastic tissue did not express

LAT1. BCH inhibited pancreatic tumor cell growth in a concentration-

dependent manner in vitro and also suppressed the growth of tumors

in vivo.

Conclusion: These findings suggest that LAT1 may serve as a

potential diagnostic marker. LAT1 inhibition may be a new rationale

to pancreatic tumor therapeutics.

Poster 2-10 PC Biotherapy

P2-10-1

Prognostic Role of Angiogenesis and its Correlation with ThymidinePhosphorylase Expression in Invasive Ductal Adenocarcinoma of the PancreasJ. Ma, W. Kimura, I. Hirai, F. Sakurai, T. Moriya, M. Mizutani

First Department of Surgery, Yamagata University School of Medicine, Yamagata, Japan

Aims: Thymidine phosphorylase (dThdPase), a member of the

pyrimidine nucleoside phosphorylase family, catalyzes the metabo-

lism of thymidine and is essential for DNA synthesis. Recently, it has

been shown that dThdpase is identical to Platelet-derived endothelial

cell growth factor and possess potent angiogenic activity in vivo.

Currently, little information is available regarding the prognostic role

of angiogenesis and its correlations with dThdPase expression in duc-

tal adenocarcinoma of the pancreas. In the present study, we aimed to

clarify the correlations between tumor angiogenesis, dThdPase

expression and clinicopathological factors, to evaluate whether tumor

angiogenesis, dThdPase expression correlate with prognosis in

patients after radical surgical treatment for ductal adenocacinoma of

the pancreas.

P2-10-2

Midkine Promoter-Based ConditionallyReplicative Adenovirus for Gene Therapy of Pancreatic CancerE. Toyoda1, R. Doi1, M. Wada2, M. Tagawa3, K. Hamada4,K. Fujimoto1, Y. Kawaguchi1, M. Imamura1

1Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto, 2Kobe City General Hospital,Kobe, 3Division of Pathology, Chiba Cancer CenterResearch Institute, Chiba, 4Department of Obstetrics and Gynecolory, Ehime University, Ehime, Japan

Midkine (MK) is a heparin-binding growth factor as a product of

a retinoic acid-responsive gene. MK is highly expressed in various

types of human cancer including pancreatic cancer. In contrast, the

expression of MK in human adult normal tissues is low and strictly

limited. Therefore, MK promoter can be a potential candidate for sui-

cide gene therapy. In this study, we have examined the expression of

MK in human pancreatic cancer cells and tissues. Furthermore, we

assessed the efficacy of conditionally replicative adenovirus on pan-

creatic cancer cells, in which expression of the essential E1 gene is

driven by MK promoter (AdMK). Seven human pancreatic cell lines

except one expressed the MK gene in various levels. The expression

level of human pancreatic cancer tissues is significantly higher than

that of non-cancerous regions. To investigate the selectivity of this

adenovirus, Western blot analyses were performed using anti-

adenovirus E1A antibodies after infection to MK-positive or negative

cell lines. E1A protein was detected in only MK-positive cells. The

extent of the antiproliferative effect was determined by comparing the

cell count of MK-positive or negative cells after infection. Cell

growth of MK-positive cells was strongly inhibited, wheares AdMK

had minimum effect on MK-negative cells. These results suggest that

the use of oncolytic adenoviruses using MK promoter can be a good

tool for the therapy of human pancreatic cancer.

P2-10-3

Treatment of Human Pancreatic Cancer by a Conditionally Replication-CompetentHSV-1 Vector using Survivin PromoterK. Kami1, R. Doi1, M. Koizumi1, E. Toyoda1, T. Mori1, D. Ito1, Y. Kawaguchi1, K. Fujimoto1, M. Wada1, S.-I. Miyatake2, M. Imamura1

1Department of Surgery and Surgical Basic Science, Kyoto University, Kyoto, 2Department of Neurosurgery,Osaka Medical College, Osaka, Japan

In this study, we constructed an oncolytic HSV-1 vector

(d120.survE) in which the survivin promoter drives expression of ICP4,

a major trans-activating factor for viral genes, so that replication of the

vector is restricted to survivin expressing cells. We assessed the ability

of d120.survE to inhibit growth of pancreatic cancer cells in vitro.

Methods: A 397bp survivin promoter was characterized using

luciferase reporter assays, and was cloned into the thymidine kinase (tk)


gene of mutant HSV-1 d120, deleted for both copies of the ICP4

gene. ICP4 protein expression in the cells infected by d120.survE

was examined by Western blot analysis. The ability of d120.survE to

replicate specifically in survivin expressing cells was examined by

a viral single-step growth experiment in three human pancreatic

cancer cell lines (PANC-1, AsPC-1, BxPC-3). The in vitro cyto-

toxic activity of d120.survE was examined by infecting the same

cell lines with d120.survE at a low multiplicity of infection (MOI:

0.001 to 10).

Results: ICP4 protein was expressed in pancreatic cancer cells

infected by d120.survE. The ability of d120.survE to replicate and the

cytotoxic activity of d120.survE were correlated with survivin pro-

moter activity of the host cells. There were 60% and 10% cells sur-

viving respectively in PANC-1 (low expression of survivin) and

AsPC-1 (high expression of survivin) cells infected by d120.survE at

an MOI of 0.01 on days 7 post-infection compared to those of mock-

infected cells.

Conclusion: A conditional replication-competent HSV-1 vector

regulated by the survivin promoter may be a new therapeutic strategy

for treatment of pancreatic cancer.

P2-10-4

Gene Therapy for Pancreatic Cancer byFiber-Modified Oncolytic Replication-Selective AdenovirusN. Omura1, M. Sunamura1, F. Motoi1, H. Hamada2, S. Ottomo1, Y. Saito1, H. Abe1, S. Fukuyama1, S. Egawa1, K. Takeda1, S. Matsuno1

1Department of Gastroenterological Surgery, TohokuUniversity, Sendai, 2Department of Molecular Medicine, Sapporo Medical University, Sapporo, Japan

Background and Aim: We constructed a double-mutant,

replication-selective adenovirus (AxdAdB-3) containing a mutation

in the RB-binding motif of the E1A region and a deletion of large

E1B-55 kDa. AxdAdB-3 swiftly induced cancer cell death in vitro and

showed a potent antitumor effect in vivo. In order to increase the

infectivity and therapeutic efficacy, we modified the fiber of

AxdAdB3 and evaluate the usefulness of this novel strategy.

Methods: Wild type fiber adenovirus (AxCAZ3-F/wt) and

mutant fiber adenovirus (AxCAZ3-F/RGD) and AxdAdB3-F/RGD,

oncolytic replication-selective adenovirus with mutant RGD fiber

motif were constructed. Coxacky adenovirus receptor (CAR) and

V�5 integrin on pancreatic cancer cells were analyzed by

Flowcytometry. In vitro therapeutic effect was evaluated using MTS

cytopathic assay. AxdAdB3-F/RGD was administered into tumor

xenotransplantation mice.

Result: In several pancreatic cancer cell lines, the expression of

CAR was decreased but the expression of V�5 was preserved. The

fiber-mutant AxCAZ3-F/RGD has higher infectivity in such cells

than the wild type AxCAZ3-F/wt. AxdAdB3-F/RGD showed strong

cytopathic effect, furthermore the combined use of anti-tumor drug

enhanced its cytopathic effect in vitro and in vivo.

Conclusion: Use of fiber-mutant adenovirus enhances the

infectivity in CAR negative cancer cells, suggesting that expression

of integrin V�5 might have helped the infection. These results

strongly suggested that AxdAdB3-F/RGD is a promising tool for gene

therapy against this intractable disease.

P2-10-5

A New Oncolytic Virus for Pancreatic CancerT. Asano1, Y. Shino2, K. Sunouchi2, K. Suzuki2, H. Yamamoto1, M. Nagata1, N. Takiguchi1, H. Soda1, K. Watanabe1, H. Shirasawa2

1Digestive Surgery, Chiba Cancer Center, Molecular Virology, 2Gradutate School of Medicine, Chiba University, Chiba, Japan

Viruses have potential cytopathetic effect to certain specific cells

and make them cell death. Certain viruses also infect specific cancer

cells and make them oncolysis. Adeno, Herpes, Reovirus etc., are well

known as Oncolytic viruses. We have investigated oncolytic effect of

Reovirus and found that it oncolyse specifically RAS activated pan-

creatic cancer cells in vitro and vivo without impair the normal cells

and tissues. We have found also RAS pathway JNK is a specific tar-

get of Reovirus and make pancreatic cells apoptosis. From our

oncolytic virus studies we have found a new oncolytic virus; Sindbis

virus which is RNA virus belong to Alphaviruses. Oncolytic function

on Sindbis virus is effect to pancreatic cancer cell line with or without

RAS activation, and various kinds of cancer cell line, but not to nor-

mal cells, in vitro and in vivo experiments. We will report oncolytic

effects of Sindbis and Reovirus, and talk on their mechanisms.

P2-10-6

Targeting Delivery of Gemcitabine byCationic Liposomes Efficiently Suppressesthe Local Growth and Liver Metastasis ofHuman Pancreatic Cancer Cells in vivoC.M. Lee, T. Kitagawa, Y.-K. Kim, T. Ito, H. Matsuda

Department of Surgery, Osaka University, Osaka, Japan

In our institute, radical resections for advanced pancreatic cancer

have been performed. Although their prognosis has not been pro-

longed because of frequent metastasis to the liver. So novel strategy is

required to control the liver metastasis of pancreatic cancer.

Significant increases in CS were reported in a variety of epithelial

neoplasms including pancreatic cancer. Indeed, the expression of CS

in pancreatic cancer that clinically resected in our institute was sig-

nificantly higher than normal tissue and gastric cancer.

In previous study, CS expressed on highly metastatic tumor cells

(LM8G5: murine osteosarcoma) were used as a target for the selec-

tive delivery of anti-cancer drugs by polyethylene glycol-coated lipo-

somes that contained a new cationic lipid (TRX-20). Cisplatin-loaded

TRX-20 liposomes significantly suppressed the local growth and

liver metastasis of LM8G5 cells comparing with cisplatin-loaded

plain liposomes or free cisplatin in vivo.


So we investigated the effectiveness of gemcitabine-loaded TRX-20

liposomes (Gem-TRX-20L) on human pancreatic cancer cells. Gem-

TRX-20L killed the CS-expressing tumor cells (CFPAC-1) in vitro

cytotoxicity assay under the experimental condition of co-culture with

each drug for only 90 minutes, whereas gemcitabine-loaded plain lipo-

somes lacking TRX-20 were totally ineffective. Therapeutic experi-

ments in mice bearing CFPAC-1 tumor revealed that Gem-TRX-20L

were significantly more effective in reducing the local tumor growth

and liver metastasis than free gemcitabine or gemcitabine-loaded plain

liposomes.

These data suggest that the CS-targeted delivery of gemcitabine

by our liposomes represents a potentially useful strategy to prevent

the local growth and liver metastasis of human pancreatic cancer cells

that have enhanced expression of CS.

P2-10-7

Induction of c-Met Expression by All-transRetinoic Acid (atRA) in Pancreatic CancerCell LinesK. Leelawat1, K. Mizumoto2, E. Nagai2, H.R.H.P.C. Mahidol3, M. Tanaka2

1Chulabhorn Cancer Center, Chulabhorn ResearchInstitute, Bangkok, Thailand, 2Department of Surgery andOncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan, 3Chulabhorn Research Institue, Bangkok, Thailand

Purpose: Many lines of evidences showed that retinoic acid can

inhibit growth and modulate differentiation of pancreatic cancer cell

lines through activation of gene transcription via the nuclear retinoic-

acid receptors (RAR) and retinoid-X receptors (RXR). Increasing

numbers of studies have revealed that retinoic acid also augments the

transcription of various genes by increase the binding activity of Sp1

to their gene promoters. Recently, c-Met (hepatocyte growth factor

receptor) which plays a major role in the process of cancer progression

including proliferation, invasion and angiogenesis through the interac-

tion of HGF/c-Met signal pathway, was found to be up-regulated by

Sp1 binding at its promoter. In this study, we investigated the effects of

atRA on expression of the c-Met gene in pancreatic cancer cell lines.

Methods: Panc-1, Capan-1 and Suit-2 pancreatic cancer cell

lines and HeLa S3 cell line treated with or without atRA, were inves-

tigated for their growth proliferation and the changes in expression

levels of c-Met were evaluated by real time PCR.

Results: All pancreatic cancer cell lines demonstrated a minor

growth inhibitory effect after treatment with atRA while the prolifer-

ation rate of atRA treated HeLa S3 cells was obviously inhibited.

Although the levels of c-Met transcripts in atRA treated Panc-1 were

not different from the control, in Capan-1 and Suit-2 cells, the levels

of c-Met transcripts were increased by atRA in a dose-dependent

manner and the maximum level was found at 48 hours after treatment.

For HeLa S3 cells, the levels of c-Met mRNA were declined after

atRA treatment.

Conclusions: atRA induced the expression of c-Met gene in

Capan-1 and Suit-2 pancreatic cancer cell lines. These findings may

indicate the undesirable effects of using retinoic acid as cancer thera-

peutic drug.

P2-10-8

A Promising Effective Alternative Therapyfor Pancreatic CancerF. Nozawa, M. Yalniz, P.M. Pour

UNMC Eppley Cancer Center, University of NebraskaMedical Center, Omaha, NE, USA

Despite advances in pancreatic cancer (PC) research, the outlook

for the disease has remained dismal. The disappointing therapeutic

approaches opened the door for the use of alternative medicine. Based

on a report on the favorable effect of porcine pancreatic enzyme prepa-

ration (PPE) on survival of PC patients, we tested the effect of PPE on

two experimental PC models. Feeding the nude mice with orthotopi-

cally transplanted human PC cells with PPE significantly prolonged the

survival, although cancer cells destroyed most of their pancreas as

extensively as in the control mice. Moreover, tumors in the PPE group

grew slower than in the control. Encouraged by this finding, we then

examined the efficacy of PPE in the hamster model, which in many

clinical, pathological and biological aspects mimics the human disease.

Two groups of hamsters were used. One group received PPE at a dose

of 1 g/kg bw in drinking water (PPE), and the other received tap water

(Control). One week later, all hamsters were treated with a single sub-

cutaneous injection of N-nitrosobis-(2-oxopropyl)amine (BOP) at a

dose of 40 mg/kg bw. The experiment was terminated 43 weeks after

the PPE treatment. Some biological parameters were assayed. The size,

multiplicity and histological type of pancreatic lesions were recorded.

The incidence of pancreatic adenocarcinoma and the frequency of

steatorrhea were significantly lower in the PPE group than in the con-

trol. These data suggest that PPE also inhibit the growth of PC in the

hamster model and may be of value in the treatment of PC patients.

Poster 2-11 Image Diagnosis

P2-11-1

Usefulness of Contrast EnhancedUltrasonography on Evaluation of TreatmentEffect in Patients with UnresectablePancreatic Carcinoma: Correlative Studywith Intratumoral Microvessel Density forCD34 ImmunostainingM. Nishida1, K. Koito2, N. Hirokawa2, T. Ichimura2, Y. Kawai2, T. Satou2, T. Shounai2, M. Someya2, K. Nakata2,N. Yama2, H. Hyodo2, M. Hareyama2

1Radiation Oncology, Imaging and Diagnosis, GraduateSchool of Medicine, 2Department of Radiology, School ofMedicine, Sapporo Medical University, Sapporo, Japan

Objective: The evaluation of chemoradiation therapy on pan-

creatic tumor viability has been difficult by conventional CT and US.


Currently, intratumoral microvessel density (IMD), provides a reliable

assessment of angiogenic activity. We investigated the hemodynamic

response to treatment, as shown by contrast enhanced ultrasonogra-

phy (EU).

Patients and Methods: In ten patients with unresectable Stage

IVa/IVb pancreatic adenocarcinoma. EU was performed before and

after chemoradiation. Intratumoral enhancement patterns were evalu-

ated and compared to IMD and AVD (average of microvessel diame-

ter) calculated from biopsy specimens immunostained for CD34.

Results: As measured on CT, one case responded completely

(CR) to therapy, five responded partially (PR), and four were

unchanged (NC). All tumors showed intratumoral enhancement pat-

terns pre-radiotherapy (IMD 20.6). Five (2PR, 3NC) developed

increasing enhancement patterns within 11 days post-radiotherapy

(IMD 12.0, AVD increased). Five (CR, PR) exhibited diminished

enhancement patterns more than 12 days post-radiotherapy

(IMD 2.1). Three (NC) showed no change or increased enhancement

pattern (IMD 8.0).

Discussion: NC implied hypovascularity, PR and CR showed

tumor hypervascularity pre-treatment and might indicate a high

sensitivity to treatment. Increased intratumoral enhancement patterns

within 11 days post-radiotherapy probably represents dilatation of

AVD secondary to tumor necrosis and granulomatous change. In PR,

decreased enhancement pattern results from fibrotic change, whereas

in NC, continuous vascular enhancement pattern suggests continued

tumor viability.

Conclusion: EU can demonstrate vascular alterations induced

by chemoradiation in pancreatic carcinomas.

P2-11-2

Dynamic Imaging of Pancreatic Diseases:Value of Contrast-Enhanced Coded Phase-Inversion Harmonic UltrasonographyM. Kitano, M. Kudo, K. Maekawa, H. Sakamoto, Y. Suetomi, R. Nakaoka, N. Fukuta, T. Kawasaki

Department of Gastroenterology and Hepatology, Kinki University, Osaka, Japan

Background: Coded phase-inversion harmonic ultrasonogra-

phy, a newly available sonographic technique, enables the visualiza-

tion of slow flow in minute vessels in a real-time fashion with the use

of a monosaccharide-containing sonographic contrast agent. Our

purpose is to employ this novel technique to observe microvessels in

pancreatic tumors.

Subjects and Methods: Sixty-five patients with suspicious

pancreatic tumors received contrast-enhanced coded phase-inversion

harmonic ultrasonography, contrast-enhanced computed tomography

and endosonography. Final diagnoses based on histological findings

were pancreatic ductal carcinomas in 49 patients, inflammatory

pseudotumors with chronic pancreatitis in 7 and endocrine tumors

in 9. For the contrast-enhanced coded harmonic ultrasonography,

Levovist®, a contrast agent, was injected intravenously as a bolus.

When the first microbubble signal appeared in the pancreas, images of

the ideal scanning plane were displayed in a real-time continuous fash-

ion (vessel images). Subsequently, interval-delay scanning (perfusion

images) was taken to demonstrate parenchymal flow. On the basis of

patterns of the two images, the tumor vascularity was evaluated.

Sensitivities for depicting pancreatic tumors were compared among

three examinations.

Results: Contrast-enhanced ultrasonography demonstrated

tumour vessels in 67% of pancreatic ductal carcinomas, although most

of them were relatively hypovascular compared to the surrounding

pancreatic tissue. The vascular patterns of tumors obtained by contrast-

enhanced ultrasonography was closely correlated with those obtained

by contrast-enhanced computed tomography. Values for sensitivity in

depicting pancreatic tumors of 2 cm or less in size were 68% on

contrast-enhanced computed tomography, 97% on endosonography

and 95% on contrast-enhanced ultrasonography.

Conclusion: Contrast-enhanced coded phase-inversion harmonic

ultrasonography successfully visualized fine vessels in pancreatic

tumors and may play a pivotal role in the depiction and differential

diagnosis of pancreatic tumors.

P2-11-3

Usefulness of Contrast-EnhancedUltrasonography in the Diagnosis of Pancreatic TumorsT. Fukuhara, M. Shirai, M. Hatano, M. Morimoto, Y. Ono, K. Honda, N. Kobayashi

The First Department of Surgery, Ehime University School of Medicine, Ehime, Japan

Background: Aim of this study was to evaluate the usefulness

of contrast-enhanced ultrasonography in the diagnosis of pancreatic

tumorous lesion.

Methods: From September 2000 to February 2003, 11 patients

(5 males and 6 females, average age 72, range 60–80) were submitted

to contrast-enhanced ultrasonography. There were 10 pancreatic duc-

tal carcinoma and 1 tumor-forming pancreatitis. All 11 patients were

examined with contrast-enhanced coded harmonic angio (CHA) in

conjunction with a galactose-based microbubble contrast agent

(SHU 508A). Prior to injection of the contrast agent, a scanning plane

displaying both the tumor and some surrounding pancreatic

parenchyma was chosen. Images in the ideal scanning plane were dis-

played in a real-time fashion. Immediately after real-time continuous

imaging of the tumor vessels for about 60 seconds (Vessel Image),

interval scanning or manual flash imaging was performed to demon-

strate tumor parenchymal flow (Perfusion Image). All the data were

recorded continuously on digital video.

Results: At the Vessel Image, spotty or linear enhancement in

the mass was shown on CHA in 6 of 9 carcinomas. At the Perfusion

Image, pancreatic parenchymal enhancement was obtained in 8 of 10.

In 7 pancreatic carcinoma, the mass revealed hypovascular pattern

compared with adjacent pancreatic tissue. In the tumor-forming pan-

creatitis, the mass showed diffuse enhancement and isovasucular

pattern.

Conclusion: Contrast-enhanced ultrasonography is useful tech-

nique in the differential diagnosis of pancreatic tumors.


P2-11-4

Is it Possible to Diagnose the Grade ofHistological Differentiation of PancreaticCarcinoma of TS1 Stage using UltrasoundContrast Imaging?A. Sofuni, T. Itoi, D. Nakayama, K. Nakamura, H. Iijima, F. Moriyasu

The Fourth Department of Internal Medicine, TokyoMedical University, Tokyo, Japan

We have reported that it is possible to diagnose the grade of his-

tological differentiation of pancreatic carcinoma using CE-US with

the contrast agent. The aim of our study is to evaluate whether the

enhancement patterns can diagnose the grade of histological differen-

tiation of pancreatic carcinoma of TS1 stage or not. The subjects were

10 pancreatic carcinomas of TS1 stage. And all subjects were diag-

nosed histologically by operation and biopsy.

The 8 cases of 10 pancreatic carcinomas of TS1 stage showed

hypo imaging. The 2 cases were iso imaging. The grade of histologi-

cal differentiation of the 7 cases of 10 cases were well�moderately

differentiated adenocarcinoma. The enhancement pattern by CE-US

was hypo imaging. The 3 cases were poorly differentiated adeno-

carcinoma, and then they were divided into 1 scirrhous type and

2 medullary type. The enhancement pattern was hypo in scirrhous

type and iso in medullary type.

In conclusion, this study suggested that it may also useful for

CE-US to differentiate the histological diagnosis of pancreatic carci-

noma of TS1 stage.

P2-11-5

Comparison with Histropathology andFindings of Enhanced Power DopplerUltrasonography in Patients with Pancreatic CancerS. Suzuki, N. Harada, M. Suzuki, F. Hanyu

Hachioji Digestive Disease Hospital, Tokyo, Japan

Recently vascular image and perfusion image by enhanced power

doppler ultrasonography (EPDU) has been evaluated. EPDU using

mixure of GalactosePalmic acid was evaluated in the patients with

pancreatic cancer. A few report that comparison with findings of

EPDU and resected specimen of pancreatic cancer was published

until now 8 patients, who had curative operation for pancreatic cancer

and had EPDU preoperatively, were selected for this study. Device

of ultrasonography were SSD-5500 produced by Aloka and Aplio

50 produced by TOSHIBA. 7 ml of mixure of GalactosePalmic acid in

300 mg/ml was injected from vein of forearm at 7 seconds 3 types in

image of EPDU were classified: diffuse enhanced type, partial

enhanced type, no enhanced type 5 patients showed no enhancement,

and 2 patients showed patrial, 1 patient showed diffuse. Angiography

demonstrated no enhancement in the all patients. But computed

tomography revealed same findings as EPDU. All patients had tubular

adenocarcinomas. Partial and diffuse type had recognized a diffusely

infiltrating pattern of growth characterized by an indistinct border.

Cancer-stroma relationship had a tendency to tumors containing

abundant stroma on partial and diffuse type 3 patients, who had par-

tial and diffuse type in EPDU, showed poorly or moderately differen-

tiated adenocarcinoma in histological findings. EPDU can predict

cancer-stroma relationship, histological findings, and growth patterns

of tumors infiltrating surrounding tissue.

P2-11-6

Size of Main Pancreatic Duct (MPD) inMagnetic Resonance Pancreatography(MRP): A Preliminary Investigation forNormal ValuesY. Kitagawa1, M. Ogawa2, N. Hayakawa3, H. Yamamoto3, Y. Katono3, T. Matsunaga2, S. Fukata1, J. Kamiya4, K. Oda4,Y. Nimura4

1Department of Surgery, National Center for Geriatricsand Gerontology, Obu, 2Department of Radiology,3Department of Surgery, KKR Tokai Hospital, Division of Surgical Oncology, 4Department of Surgery, NagoyaUniversity Graduate School of Medicine, Nagoya, Japan

Purpose: Limited studies were focused on the size of main pan-

creatic duct (MPD) in Magnetic Resonance Pancreatography (MRP).

MRP provides 3D image and cross section of the ducts. 3D images pro-

vide accurate estimation for the diagnosis of dilatation of the duct. Aim

of this study is to elucidate the size of the MPD using this modality.

Methods and Materials: MRP images of consecutive

58 patients with normal pancreas and papilla were collected by 1.5-T

MR system using 3D-T2 image of half-Fourier acquired single-shot

turbo spin-echo sequence, prospectively. The provided image voxel

was 1.0 by 0.9 by 1.0 mm. The area and diameter of MPD and com-

mon bile duct (CBD) were measured. These parameters and methods

were used in the daily clinical practice basis. The measurements were

performed at the CBD on upper boarder of pancreas (A), MPD in the

head of the pancreas (B), and MPD in the body of the pancreas

(C) using Vessel View software.

Results: Only 11 of the 58 cases (19.0%) were appropriate for

measurement. Area of the ducts (mm2) were 30.5 � 12.8 in A,

10.7 � 2.9 in B and 8.7 � 2.8 in C, respectively. The ratio of areas of

A to B was 1:0.35, A to C was 1:0.29 and B to C was 1:0.81.

Conclusion: MRP was less invasive to define normal values of

main pancreatic duct. However, these data would be measured only

for dilated ducts. Smaller voxel size and breath-holding one-shot

method would be mandate for measurement of normal MPD.


P2-11-7

Growth Rate of Pancreatic AdenocarcinomaH. Furukawa1, N. Moriyama2

1Division of Diagnostic Radiology, Shizuoka Cancer Center Hospital, 2Department of Diagnostic Radiology,National Cancer Center Hospital, Japan

A better understanding of the growth rate of pancreatic carcinoma

is important in determining its natural course and in evaluating the

effects of treatment or prognosis. We investigated the growth rate of

pancreatic carcinoma and the relationship between its tumor volume

doubling time (TVDT) and host survival. Nine cases of pancreatic

carcinoma, in which serial examinations by helical computed tomog-

raphy (CT) without anticancer treatment during the observation

period were collected and the TVDT were calculated by measuring

the tumor size on helical CT. The initial mean tumor diameter ranged

from 1.3 to 3.2 cm (mean 1.9 cm). At the end of the observation, the

mean tumor diameter ranged from 1.5 to 4.7 (mean 3.0 cm). The

observation period ranged from 99 to 642 (mean 300 days). The mean

TVDT of the 9 primary lesions of pancreatic carcinoma was

159 � 67 days (median 144 days), and the range was 64 to 255 days.

There was a significant positive correlation between TVDT and

survival time (r � 0.793, p � 0.011). This preliminary study suggests

that examination of TVDT may be useful in clinical evaluation of

the prognosis for patients with pancreatic carcinoma in selected

situations.

Poster 2-12 PC Chemoradiation

P2-12-1

A Phase I Trial of Chemoradiation Therapywith Concurrent Full Dose Gemcitabine forUnresectable Locally Advanced PancreaticAdenocarcinomaT. Ioka1, S. Tanaka1, R. Takakura1, A. Nakaizumi1, H. Iishi2,K. Nishiyama3, M. Tatsuta2

1Department of Hepatobilliary and Pancreatic Oncologyand Screening, 2Department of Gastroenterology,3Department of Radiation Oncology, Osaka MedicalCenter for Cancer and CVD, Osaka, Japan

Purpose: The primary objective of this study is to assess the

toxicity of radiotherapy with concurrent full dose Gemcitabine

(GEM) for unresectable locally advanced pancreatic cancer.

Patients and Methods: Between 04/01 and 06/02, twelve

patients were entered to this trial. GEM was planned to be administered

at a dose of 1,000 mg/m2 weekly for 3 weeks during RT. The starting RT

dose was 30 Gy in 2.0 Gy fractions. Escalation was achieved by increas-

ing the duration in 5 fractions increments, keeping the fraction size in

2.0 Gy. DLT was defined as grade 4 thrombocytopenia, grade 4 neu-

tropenia, or grade 3 nonhematologic toxicity. RT was directed at tumor

volume with a conformal technique with inclusion of regional nodes.

Every twelve patients were evaluated for response with RECIST crite-

ria by an extramural radiologist, Dr. Natsuo OHYA (Kyoto University

Department of Radiation Oncology).

Results: Treatment was well tolerated; twelve patients com-

pleted all protocol therapy. No patient experienced DLT. We experi-

enced six patients (50%) of grade 3 neutropenia, two patients (17%)

of grade 2 thrombocytopenia and six patients (50%) of grade 2 non-

hematologic toxicity. Six patients (50%) had evidence of a local anti-

cancer effect. Five of these six patients (41.5%) had a complete or

partial response to therapy. The median survival for the entire group

was 16.5 months. The 1-year and 2-year survival rate for patients was

58.3% and 25.0%.

Conclusion: The Chemoradiation therapy with concurrent full

dose GEM can be delivered safely for unresectable locally advanced

pancreatic cancer.

P2-12-2

Phase II Study of Twice-Weekly Gemcitabineplus Intraoperative Radiation Therapy andExternal-Beam Radiation Therapy in Patientswith Unresectable Pancreatic CancerM. Wada1, R. Hosotani1, S. Okabe2, T. Kajiwara1

1Department of Surgery, 2Department of Gastroenterology, Kobe City General Hospital, Kobe, Japan

Chemoradiation therapy including gemcitabine has a significant

impact on the survival and quality of life in patients with locally

advanced pancreatic cancer. Twice-weekly gemcitabine administra-

tion has reported to result in an enhanced radiation sensitizing effect.

Our aim was to examine the feasibility and effectiveness of electron-

beam intraoperative radiation therapy (IORT) and concurrent external

beam radiation therapy (EBRT) with gemcitabine as a radiosensitizer.

Three patients with stage IVa disease (JPS5) and eight patients with

stage IVb disease have completed the treatment from October 2001 to

January 2004. Gemcitabine treatment (600 mg/m2) by 30-minute

intravenous infusion was performed 24 hours prior to IORT. IORT

was administered at a dose of 24–28 Gy, and directed to the pancre-

atic tumor and regional lymph nodes. Eight days after IORT, patients

were treated with 27 Gy EBRT (1.8 Gy/fraction 15 fractions) con-

current twice-weekly gemcitabine (40 mg/m2; 80 mg/m2/week) for

three weeks. After the completion of concomitant therapy, patients

without disease progression received a weekly gemcitabine treatment

(1,000 mg/m2) on days 1, 8, 15 followed by a week rest. Grade 3

hematological toxicity of anemia occurred in 3 patients. One patient

had a complete response, two had partial responses, and eight

remained in stable disease. With a median follow-up of 9.5 months,

five patients are alive without radiographic evidences of disease

progression. The preliminary results suggest that twice-weekly

gemcitabine plus IORT and EBRT is feasible, and could be more

beneficial in patients with locally advanced unresectable pancreatic

cancer.


P2-12-3

Hypofractionated Radiation TherapyCombined with Sequential GemcitabineChemotherapy in Patients with LocallyAdvanced Pancreatic CancerM. Nagase, J. Furuse, H. Ishii, M. Kawashima, M. Yoshino

National Cancer Center Hospital East, Kashiwa, Japan

Purpose: We conducted a pilot study of hypofractionated radia-

tion therapy (HRT) followed by full-dose gemcitabine (GEM)

chemotherapy to evaluate the feasibility and effectiveness of this

sequential chemoradiotherapy.

Methods: The treatment consists of HRT (total dose, 45 Gy,

3 Gy/day) followed by gemcitabine (1 g/m2) on days 1, 8 and 15 of a

28 day cycle. Chemotherapy was initiated at least one week after com-

pletion of HRT, and after hematological toxicities had recovered to

Grade 1. Eligibility criteria were presence of pathologically proven

adenocarcinoma, no distant metastases on computed tomography

staging, KPS 50–100, adequate hematological, renal and liver func-

tions, control of pain and jaundice before inclusion, and written

informed consent. Median follow-up time was 12 months.

Results: Eighteen patients were enrolled (M8 F10) with a

median age of 63 years (range 45–78). One patient refused further

HRT at 9 Gy because of malaise, but the other 17 completed HRT.

Fifteen received a total of 89 cycles of GEM (median 5, range 1–15)

except one patient who committed suicide after HRT and another

patient moved to other hospital. Severe toxicities (Grade 3–4)

included GI bleeding (n � 7), neutropenia (n � 3), thrombocytopenia

(n � 2), and nausea/vomiting (n � 4). Response data in 15 evaluable

patients indicate 4 PR (27%) and 9 SD (60%). One- and two-year

overall survival rate was 53.6 and 8.9%, respectively. Overall median

survival was 12.2 months and median progression free survival was

12.0 months.

Conclusion: HRT with sequential GEM had moderate activity

but it has high rate of GI bleeding.

P2-12-4

Evaluation of Predictive Factors for AcuteIntestinal Toxicity in Patients Treated withConcurrent Weekly Gemcitabine andRadiotherapy for Locally AdvancedPancreatic CancerY. Ito1, T. Okusaka2, Y. Kagami1, H. Ueno2, M. Ikeda2, M. Sumi1, A. Imai1, N. Fujimoto1, H. Ikeda1

1Radiation Oncology Division, 2Hepatobiliary andPancreatic Oncology Division, National Cancer CenterHospital, Tokyo, Japan

Treatment of concurrent gemcitabine and radiotherapy for pan-

creatic cancer was reported to have a higher rate of severe acute

intestinal toxicity. The purpose of this study is to evaluate the predic-

tive factors for the acute intestinal toxicity in patients treated with

gemcitabine-based chemoradiotherapy. Forty two patients were enrolled

in a phase II trial of concurrent weekly gemcitabine and radiotherapy

for unresectable locally advanced pancreatic cancer. The total dose

was 50.4 Gy in 28 fractions. Gemcitabine was administered weekly at

a dose of 250 mg/m2 for 6 weeks. The dose planning of all cases was

performed by the 3D dose radiotherapy planning system. Clinical tar-

get volume (CTV) included the gross tumor volume and regional

lymph nodes and planning target volume (PTV) was defined as CTV

plus 5–10 mm. Dose-volume histogram was generated for the normal

tissues and PTV. Acute intestinal toxicity was defined as any toxicity

that could be related to the small bowel, which included nausea, vom-

iting, anorexia, diarrhea and fatigue. Correlation between the acute

intestinal toxicity and the patient- and treatment factors were evalu-

ated. Grade 3 and 4 (according to NCI-CTC) acute intestinal toxici-

ties were observed in twelve (29%) and fourteen (33%) patients.

There was a significant association between the acute intestinal toxi-

city and the volume of the PTV (P � 0.021). Univariate analysis

revealed no other significant predictors of severe acute intestinal tox-

icity. Reducing the treated volume such as omission of elective nodal

irradiation seems to be able to decrease the severe acute intestinal tox-

icity when treated with concurrent gemcitabine-based chemoradio-

therapy.

P2-12-5

Chemoradiation Treatment withGemcitabine for Locally AdvancedPancreatic CancerT. Sumii, M. Yasuda, H. Iguchi, A. Funakoshi

Department of Gastroenterology, National Kyushu Cancer Center, Fukuoka, Japan

Background: Chemoradiation treatment (CRT) has been per-

formed for locally advanced pancreatic cancer as a standard treat-

ment. After CRT 5-fluorouracil (5-FU) has been used for maintenance

chemotherapy until gemcitabine (GEM) appeared. Our aim is to com-

pare the effects of 5-FU with that of GEM as the maintenance agent.

Patients and Methods: Between 1991 and 2004, 34 patients

with locally advanced pancreatic cancer received CRT treatment. CRT

was performed according to standard-fractionation method (total dose:

50.4 Gy) and concurrent chemotherapy with 5-FU or cisplatin. As the

maintenance agent after CRT, 5-FU was given to 26 patients and GEM

was given to 8 patients.

Results: In 2 patients of GEM group, metastatic liver lesions

were detected soon after CRT. The median survival time of GEM

group (467.0 � 103.8 days, M � SE) was longer than that of 5-FU

group (368.8 � 47.0), but there was no significant difference between

two groups. One year survival rate were 75.0% in GEM group and

42.3% in 5-FU group.

Conclusion: As for the chemotherapy after CRT, GEM is rec-

ommended than 5-FU. Recently we use GEM not only as the mainte-

nance agent but also as radiosensitizer (250 mg/m2 per week). This

result will be reported together.


P2-12-6

Chemoradiotherapy using Daily Low DoseCisplatin and Continuous 5-fluorouracilInfusion for Unresectable PancreaticCarcinomaK. Sudo1, T. Yamaguchi1, T. Ishihara1, K. Nakamura1, K. Asano1, T. Baba1, H. Kawakami2, T. Uno2, H. Saisho1

1Department of Clinical Oncology, 2Department ofRadiation Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan

Backgrounds: Cisplatin and 5-fluorouracil (5FU) in combination

with radiotherapy (RT) has already proved its efficacy in head-and-

neck cancer, esophageal cancer, cervical cancer. The combination ther-

apy of daily low dose cisplatin and continuous 5FU infusion with RT

for unresectable pancreatic carcinoma was performed to assess its

effectiveness and toxicity.

Methods: Between 2001 and 2004, 15 patients with unresectable

pancreatic cartinoma (12 patients with locally advanced disease and

3 patients with metastatic desease) were received 3 � 5 mg/m2

cisplatin 30 minutes infusion and 2003 � 0 mg/m2 5FU continuous

infusion during RT period. RT dose was 50 Gy in 25 fractions. The

gross tumor volume (GTV) was the primary tumor, regional lymphn-

odes detected by CT. Planning target volume (PTV) was defined as the

GTV plus 15–20 mm. No prophylactic nodal irradiation was given.

Results: Overall, 3 patients achieved objective response (2 com-

plete response and 1 partial response). The median survival and 1 year

survival rate was 12.0 months and 44.4%, respectively. The 2 patients

who achieved complete response remain alive without evidence of

disease more than 18 months. Grade III/IV hematological toxicities

(NCI-CTC) were observed in 3/0 patients and grade III/IV non-

hematological toxicities were observed in 4/0 patients, respectively.

Conclusions: This combination therapy was well tolerated and

showed moderate activity in terms of local control. Further evaluation

of this therapy in patients with locally advanced pancreatic carcinoma

is warranted.

P2-12-7

Chemoradiotherapy for Locally AdvancedPancreatic Carcinoma in Elderly PatientsC. Morizane1, T. Okusaka1, Y. Ito2, Y. Kagami2, H. Ikeda2, H. Ueno1, M. Ikeda1, Y. Takesako1

1Hepatobiliary and Pancreatic Oncology Division,2Radiation Oncology Division, National Cancer CenterHospital, Tokyo, Japan

Background: Chemoradiotherapy, which is one of the standard

treatments for locally advanced pancreatic carcinoma, is considered a

high-risk procedure in elderly patients.

Objective: This study investigated the outcome and tolerability

of this treatment for elderly patients.

Methods: We reviewed our database from November 1993 to

March 2003, and retrospectively examined the clinical data of

patients with histologically confirmed exocrine pancreatic carcinoma

that was nonresectable but confined to the pancreatic region, who

were treated with protracted 5-fluorouracil (5-FU) infusion

(200 mg/m2/day) and concurrent radiotherapy (50.4 grays [Gy] in 28

fractions over 5.5 weeks). We compared the outcome of the patients

70 years or older to those younger than 70 years.

Results: There were 19 patients 70 years of age or older and

39 patients less than 70 years of age. On pretreatment evaluation,

elderly patients showed lower serum albumin levels, lower transami-

nase levels, better ECOG performance status (PS), more frequent

body weight loss, and less frequent abdominal and/or back pain with

administration of morphine than the younger patients. There were no

significant differences in the frequency of severe toxicity. Neither the

response rate nor the incidence of treatment discontinuation differed

significantly between the two groups. The median survival time was

longer in elderly patients than that in younger patients (12.3 vs.

10.2 months, p � 0.04).

Conclusion: With careful patient selection, chemoradiotherapy

can be one of the treatment options for locally advanced pancreatic

carcinoma in elderly patients.

Poster 2-13 PC AdjuvantChemotherapy

P2-13-1

Adjuvant Chemotherapy using Gemcitabinein Pancreatic CancerA. Togawa, H. Itoh, F. Kimura, H. Shimizu, S. Ambiru, M. Ohtsuka, H. Yoshidome, A. Katoh, M. Miyazaki

Department of General Surgery, Chiba UniversityGraduate School of Medicine, Chiba, Japan

Post-operative adjuvant chemotherapy using gemcitabine has

been performed for 35 patients who underwent pancreatectomy at our

department. All patients were administrated intravenously gemc-

itabine (1,000 mg/m2 weekly 7 followed by 1 week of rest, then

weekly 3 every 4 weeks thereafter as outpatients). Grade 1 or 2 leu-

copenia was found in twenty-six patients (73.4%). Thirteen patients

complained of appetite loss and/or nausea. All toxicities were grade 1

or 2, and then no patient needed admission for its side effect. Median

survival was 16.2 months. There was no significant difference of total

gemcitabine doses and survival rates between residual tumor 0

patients (n � 25) and 1 (n � 6). In contrast, macroscopically non-

curative patients (n � 4) had low doses of gemcitabine and short sur-

vival, compare with microscopically curative patients. In conclusion,

gemcitabine as adjuvant chemotherapy could be administrated safely

in outpatients with post-operative pancreatic cancer.


P2-13-2

Clinical Benefit and Feasibility ofGemcitabine after Surgical Resection for Pancreatic CancerT. Aimoto, E. Uchida, Y. Nakamura, A. Katsuno, T. Tajiri

Surgery for Organ Function and Biological Regulation,Nippon Medical School, Graduate School of Medicine,Tokyo, Japan

Gemcitabine (GEM) is an active agent in patients with locally

advanced pancreatic cancer. GEM has shown promising activity in

the first-line treatment in terms of clinical benefit response (CBR)

and survival, although response rate being modest. However, there

have been a few reports about the adjuvant setting with GEM. The

purpose of this study is to evaluate the feasibility and CBR of post-

operative administration of GEM in pancreatic cancer. From January

2000 to December 2003, 14 patients were enrolled (6 patients were

resectable and 8 patients were unresectable). All patients were treated

with GEM 1,000 mg/m2 i.v. 30 minutes weekly for 3 weeks out of

every 4. Among the unresectable patients, one patient achieved PR

while 5 patients had NC, 2 patients had PD. A CBR was achieved in

4 patients (50%). As side effects, grade 3 neutropenia and grade 3

nausea were observed each in one patient and therapy was discontin-

ued. However, six patients (75%) completed the full treatment. In the

adjuvant setting with GEM, 4 of 6 patients (67%) discontinued the

treatment within 2 cycles because of grade 4 vomitting and severe

fatigue, in spite of dose reduction. In these patients, the median sur-

vival was 11 months. Two of 6 patients achieved the entire treatment

and were free of disease after a follow-up of 17 months. In conclu-

sion, GEM monotherapy in patients with locally advanced pancreatic

cancer is well tolerated and offers good palliation, but postoperative

administration of GEM resulted in poor clinical benefit on quality

of life.

P2-13-3

The Indications for Adjuvant Chemotherapyin Pancreatic Cancer, 5-fluorouracil vs. GemcitabineS. Takeda, S. Inoue, T. Kaneko, A. Nakao

Department of Surgery II, Nagoya University School of Medicine, Nagoya, Japan

Background/Aim: It was reported that adjuvant treatment itself

was beneficial in pancreatic cancer. Since 2001, Gemcitabine (GEM)

has been used as adjuvant first line. We used 5-fluorouracil (5FU)

continuously via portal vein (so-called liver perfusion chemotherapy

(LPC)) for only 3 weeks just after surgery before 2001. To clarify the

reliable indications for adjuvant 5FU in pancreatic cancer patients, we

assessed the effect of 5FU or Gemcitabine depending TS expression

and DPD expression immunohistochemically in resected pancreatic

cancer tissues.

Methods: Between 1988 and 2001 from patients with advanced

pancreatic cancer 78 resected specimens (IIA 21 cases, IIB 34 cases,

IV 23 cases) were obtained. Formalin-fixed paraffin-embedded

tissues were immunostained with polyclonal anti-TS antibody and

anti-DPD antibody. The relation between intratumoral TS, DPD

expression and the prognoses of the pancreatic cancer patients was

investigated retrospectively.

Results: Of the 67 tumors studied, 46 carcinomas (70%) were

TS(�) and 21 (30%) were TS( ). In the TS(�) group, the LPC(�)

subgroup showed a significantly higher survival rate than the no LPC

subgroup (median survival, 16.4 vs. 8.3 months), whereas in the

TS( ) group, the median survival was 10.1 months with LPC(�), 7.4

months with LPC( ).

Of the 70 tumors studied, 31 carcinomas (47%) were DPD(�) and

39 (53%) were DPD( ). In the DPD(�) group, the median survival

was 14.0 months with LPC(�), 5.5 months with LPC( ), whereas in

the DPD( ) group the LPC(�) subgroup showed a significantly

higher survival rate than the LPC( ) subgroup (median survival, 17.8

vs. 8.3 months). Moreover, in the LPC(�) group, overall survival in

the TS(�) DPD( ) subgroup was significantly better than in the

TS( )DPD(�) or TS(�)DPD( ) subgroup.

Conclusion: In the TS(�)DPD( ) subgroup, 5FU via the

portal vein is an effective adjuvant reagent for pancreatic cancer. In

the TS( )DPD(�) subgroup, GEM might be effective to prolong

survival.

P2-13-4

Adjuvant Chemotherapy using Gemcitabinefor the Pancreatic CancerK. Kato, T. Takada, H. Yasuda, I. Nagashima, H. Amono, M. Yosida, F. Miura, T. Isaka, N. Toyota, K. Takagi, M. Sugimoto

Department of Surgery, Teikyo University School of Medicine, Tokyo, Japan

Although operation is the only curative treatment for the pancre-

atic cancer, patients undergoing complete resection frequently

develop liver metastasis, local recurrence, and peritoneal metastasis.

We examined adjuvant chemotherapy using gemcitabine (GEM) for

the pancreatic cancer. Between January 2001 and December 2003,

53 patients received adjuvant chemotherapy using GEM for the

pancreatic cancer. Nine of these 53 patients underwent pancreatico-

duodenectomy (PD), eighteen had pylorus preserving pancreatico-

duodenectomy (PPPD), seven had distal pancreatectomy (DP), one

had total pancreatectomy (TP) and eighteen had bypass operation.

GEM 1000 mg/m2 was administered once a week, continued as much

as possible. These 39 patients treated GEM and cisplatin (CDDP).

Average of first administer day was 17 post operative days (2–73).

Grade 3 or more of National Cancer Institute Common Toxicity

Criteria (NCI-CTC) appeared 15 cases (28%). 3 cases of these were

appetite loss, 12 cases were neutropenia. Since GEM is convenient to

administer, and does not diminish a patient’s quality of life (QOL). In

conclusion, adjuvant chemotherapy using gemcitabine for the pancre-

atic cancer may be beneficial for patients. And GEM is currently a

first-line therapeutic agent of adjuvant chemotherapy of the pancre-

atic cancer.


P2-13-5

Distal Pancreatectomy for Patients with Invasive Ductal Carcinoma of the Pancreas and the Usefulness of Adjuvant ChemotherapyH. Terasawa, M. Tani, M. Kawai, T. Hama, T. Nakase, H. Kinoshita, H. Onishi, M. Ueno, T. Shimamoto, K. Uchiyama, H. Yamaue


We have performed distal pancreatectomy for 33 patients from

1987 through 2002. The patients with surgical stage I, II, III and IV

accounted for 6.1%, 6.1%, 3.0% and 84.8%, respectively. Median sur-

vival time of stage IVb was poor (221 days) compared with that of

stage I, II, III (589 days) and also stage IVa (480 days, p � 0.05).

Forty-five percent of patients were microscopic positive for malignant

cells around the resectional margin of the pancreas and their median

survival time was poor (248 days) compared with that of negative

patients (313 days, p � 0.001). Lymphnode metastases were found

45.2% of patients and their median survival time was also poor (220

days) compared with that of another patients (318 days, p � 0.001).

Tumor involvement of large vessels did not have an influence on the

survival time. On the other hands, the ratio of portal invasion of tumor

was significantly higher in stage IVb patients (p � 0.05) and they were

considered as the high risk group of liver metastasis. To prevent liver

metastasis, we put the reserver catheter in hepatic artery of 13 patients

and infuse 160 mg/m2 of 5FU biweekly. However, there was no signif-

icant difference in the survival time between the adjuvant chemother-

apy group (289 days) and no adjuvant group (222 days). Therefore, the

extended surgery and the effective adjuvant systemic chemotherapy in

addition to the hepatic arterial chemotherapy are necessary for the

treatment of patients with carcinoma of distal pancreas.

P2-13-6

Secondary Leukemia Induced by Hepatic Arterial Infusion Chemotherapy for Liver Metastasis of Common Bile Duct Carcinoma after Pylorus-PreservingPancreaticoduodenectomy – Report of a CaseK. Amikura, H. Sakamoto, Y. Tanaka

Department of Gastroenterological Surgery, SaitamaCancer Center, Saitama, Japan

A 68-year-old man was admitted with pancytopenia (WBC

3,300/mm3, RBC 2.26 104/mm3, Hb 7.6 g/dl, Plt 4.7 104/mm3)

after 20 months complete regression of liver metastases of common

bile duct carcinoma by hepatic arterial infusion chemotherapy (HAI).

Multiple liver metastases were detected by abdominal CT scan

6 months after pylorus-preserving pancreticoduodenectomy. HAI

with 5FU 400 mg, MMC 16 mg, and Epirubicin 48 mg bolus injection/

20 minutes was performed with minimum side effect. Liver metas-

tases were regressed completely in abdominal CT scan and level of

CA 19-9 was normalized after three times (two months interval) of

HAI. On admission, any bleeding spot could not be seen by gas-

troscopy or colonoscopy. Abdominal CT scan revealed no sign of

varix or aneurysm. Bone scintigram showed no matastasis. Bone mar-

row aspiration resulted in acute myeloid leukemia. Chromosomal

mutation was classified as type I secondary leukemia, which is often

induced by alkylating agents. Chromosomal mutation induced by

chemotherapeutic agents may cause second malignancies.

Poster 2-14 Anomalies

P2-14-1

Unusual Clinical Presentation of AnnularPancreas in the AdultJ.E.M. Cunha1, M.S. de Lima1, J. Jukemura1, S. Penteado1,R. Jureidini1, R.A. Patzina2, S.A.C. Siqueira2

1Department of Gastroenterology – Surgical Division,2Department of Pathology, São Paulo University Medical School, São Paulo, Brazil

Annular pancreas (AP) is a rare congenital anomaly usually pre-

sent in childhood with symptoms due to duodenal obstruction; how-

ever, this condition can manifest in adulthood with abdominal pain,

pancreatitis and pancreatic head mass. The authors present a case of

AP observed in a 22 year-old patient that presented an unusual dual

phase clinical manifestation, of duodenal obstruction in infancy that

was treated by a duodenojejunostomy and abdominal pain due to

chronic pancreatitis in the adult age. MRI with cholangiopancreato-

graphy played a decisive role in achieving the correct diagnosis. The

patient was treated by a pylorus preserving Whipple procedure, with

resection of the previous duodenojejunostomy. A marked bilio-

pancreatic ductal anomaly not previously described in the literature

was demonstrated by radiologic examination of the surgical speci-

men. The pathogenesis of AP, the importance of its association with

benign and malignant pancreatic disease and the treatment alterna-

tives are discussed by the authors.

P2-14-2

Bifid PancreasM. Tanikawa, T. Kumada, S. Kiriyama, Y. Sone, Y. Hisanaga,H. Toyoda

Department of Gastroenterology, Ogaki MunicipalHospital, Ogaki, Japan

Pancreatic divisum and the ectopic pancreas are well-known

anatomic anomalies. However, the bifid pancreatic duct is less

common and is still poorly understood. The present case report shows


this anatomic variant. We observed a bifid pancreatic duct in a nonal-

coholic man with gallstones in both gallbladder and common bile

duct.

Case Report: A 56-year-old man was admitted to our hospital

complaining of epigastric pain. Laboratory evaluation on admission

was as follows: AST was 833 IU/l, ALT 460 IU/l, total bilirubin

1.1 mg/dl, alkaline phosphatase 308 IU/l, P-amylase 32 IU/l, and CRP

0.11 mg/dl. An abdominal ultrasound showed the gallstones in both

GB and CBD. The pancreatic duct was not dilated. In order to manage

the choledocholithiasis, an ERCP was performed. The ERCP demon-

strated a bifid main pancreatic duct in the body of the pancreas. CBD

stones were removed after the EPBD procedure. A CT did not demon-

strate pancreatic abnormality. In the literature, bifid pancreas may be

an additional cause of idiopathic pancreatitis. But, the relationship

between this anomaly and cholelithasis in this case is unclear.

P2-14-3

Choledochal Cyst and PancreaticobiliaryMaljunction (Undilated Type) are Based on Pancreatic AnomaliesH. Tadokoro, M. Suyama, Y. Kubokawa, J.K. Sai, H. Koshikawa, T. Kamiya, H. Matsumura, K. Inami, N. Sato


Background: Pancreaticobiliary maljunction (PBMJ) can be

classified into two categories, which are common bile duct dilatation

(choledochal cyst) and undilatated (UD type). The etiology of these

conditions is unknown.

Methods: Five pancreases from patients who had choledochal

cyst (CC) or the UD type were examined macroscopically. To clarify

the pattern of fusion between the ventral and dorsal parts of the pan-

creas, we also examined each pancreas by immunohistochemical

staining for pancreatic polypeptide (PP).

Results: CC: The pancreatic head was fairly thick in the

dorsoventral direction, while the inferior part of the head was unde-

tectable. The dorsal portion of the head was formed by the ventral

pancreas macroscopically, and it was divided into PP-rich and

PP-poor portions immunohistochemically. UD type: The inferior part

of the head was small and the neck of the pancreas was slender. The

PP-rich portion (ventral pancreas) was situated obliquely dorsal to the

PP-poor portion (dorsal pancreas).

Conclusions: CC: The PP-rich and PP-poor portions of the

ventral pancreas may be derived from the right and left parts of the

ventral primordia, respectively. CC may occur when the remnant of

the left part of the ventral primordium prevents normal recanalization

of the common bile duct, resulting in dilatation of the duct. UD type:

This type may be caused by abnormal fusion between the ventral and

dorsal primordia.

P2-14-4

A Rare Case of Pancreas Divism: TheAccessory Pancreatic Duct does notConnect with the Main Pancreatic DuctS. Koide1, M. Kikuyama1, Y. Sasada1, M. Haruki1, S. Iwamoto1, H. Murakami1, Y. Kobayashi2

1Department of Gastroenterology, Hamamatsu RosaiHospital, 2Second Department of Internal Medicine,Hamamatsu University School of Medicine, Hamamatsu,Japan

A 58-year-old female was admitted with upper abdominal pain,

which had been intermittently recurring for a month. Laboratory

data were normal and endoscopic examination revealed no abnormal-

ities. On ultrasonography, atrophy of the pancreas was recognized

which suggested chronic pancreatitis. Endoscopic Retrograde

Pancreatography (ERP) revealed mild dilatatin of the main pancreatic

duct with a irregular wall, but the accessory pancreatic duct was not

recognized. ERP via the minor papilla, which was reddish and swollen,

revealed a short pancreatic duct, which did not connect with the main

pancreatic duct and was neither irregular nor dilated. A biopsy from

the minor papilla showed adenoma. Without oral intake, the symptom

subsided gradually and disappeared several days after admission, and

did not recur after oral intake resumed. We think this case is a type of

pancreatic divism with adenoma of the minor papilla. This case is con-

sistant with Warshaw’s classification of pancreas divism ‘Without duct

of Santrini’ (Am J Surg 1990;159:59–66), with the exception that in

this case the accessory pancreatic duct is present. This case is consid-

ered to be a rare type of pancreas divism and is available for discussion

about the development of pancreas.

P2-14-5

Complete Pancreatic Encasement of thePortal Vein – Surgical Implications of anExtremely Rare AnomalyS. Benz, R. Obermaier, U.T. Hopt

Department of Surgery, University of Freiburg, Freiburg , Germany

Pancreatic anatomy can be very variable. In pancreatic surgery it

is important to recognise such anomalies and adjust the surgical pro-

cedure accordingly in order to minimise postoperative morbidity.

Here we present an extremely rare case of pancreatic encasement of

the portal vein encountered during a multivisceral resection.

A 64 year old European woman was admitted for unclear outlet

obstruction of the stomach. On CT-scan a thickening of the stomach

wall was seen. Biopsies of the Stomach didn’t show malignant dis-

ease. The patient was operated and a large carcinoma of the distal

antrum with infiltration of the mesocolon and the pancreatic head was

found. The tumor was completely resected with a subtotal gastrec-

tomy, pancreatic head resection and a right hemicolectomy. At the

stage of transecting the mesopancreas along the superior mesenteric

artery it was evident that the parenchyma of the uncinate process

communicated with the pancreatic body behind the portal vein. The


communication was about 3 cm wide and about 1 cm thick. The

communication was divided using a GIA stapler device and oversewn.

The pancreato-jejunostomyto was performed in typical fashion ante-

rior to the portal vein. Pancreatic parenchyma was verified on histol-

ogy at the cutting surface of the communication.

This case represents the second in the literature with this anomaly.

Surgical closure of the abnormal communication seemed important in

order to prevent pancreatic fistula. This case shows that even very rare

anomalies should be recognised in order to reduce morbidity after

pancreatic surgery.

P2-14-6

Acute Pancreatitis Probably Caused byCirculatory Impairment Associated withAmyloidosis Secondary to RheumatoidArthritis: Case ReportM. Shiozaki, Y. Yamada, Y. Arisaka, T. Inoue, Y. Hongo, K.-I. Katsu

Second Department of Internal Medicine, Osaka Medical College, Osaka, Japan

The patient was a 67-year-old woman. Since the age of 55 years,

she had suffered from rheumatoid arthritis complicated by secondary

amyloidosis-induced hypertrophic cardiomyopathy and chronic renal

failure. She had no history of alcohol intake. She was admitted with

left-sided abdominal pain and bruising of the left flank. The serum

amylase level was increased to 384 U/L, and there was peripancreatic

inflammation as well as a pancreatic psudocyst and left pleural effu-

sion, meeting the diagnostic criteria for severe acute pancreatitis.

Despite treatment of her pancreatitis, renal failure progressed and ini-

tiation of dialysis was necessary. Her general condition deteriorated

and disseminated intravascular coagulation developed, leading to

death on the 56th hospital day. An autopsy was performed. Congo

Red staining as well as hematoxylin-eosin staining was on sections of

the pancreas. The small intrapancreatic arteries showed luminal

stenosis and occlusion due to amyloid deposits and fibrous intimal

hypertrophy. Around these lesions, there were autolysis-induced foci

of fatty necrosis. At the sites of advanced intravascular amyloid depo-

sition, extensive amyloid deposits were also seen in the nearby foci of

fatty necrosis. These findings suggests that pancreatic ischemia due

to circulatory impairment in the small intrapancreatic arteries was the

origin of her acute pancreatitits and that oxygen-derived free radicals

may have been involved in its development at the acinar cell level.

P2-14-7

Torsion of Wandering Spleen and DistalPancreas Accompanied by AcutePancreatitisH. Yoshida, H. Naito, M. Takahashi, A. Kanno, T. Ueno, W. Takahashi

Department of Surgery, South Miyagi Medical Center, Miyagi , Japan

A 14-year-old woman visited our hospital complaining of sudden

lt. upper quadrant pain and nausea. A fist-sized elastic firm mass with

strong tenderness was palpable, along with high WBC (17,400),

amylase (346) and lipase (588). She was admitted to the hospital sus-

pecting of acute pancreatitis. A CT scan demonstrated stenosis of the

splenic artery and delayed splenic enhancement associated with a

sphere soft tissue at splenic hilum, and substantial ascites. Celiac

angiography showed kink of the splenic artery along with pooling

contrast media in the spleen. She was diagnosed as torsion of the

spleen and underwent emergency operation. The exploration revealed

that the spleen and the distal pancreas were not anchored to retroperi-

toneum, and the pancreatic tail was twisted with the spleen, resulting

in hemorrhagic distal pancreatitis and splenic congestion. She under-

went distal pancreatectomy and splenectomy because of potent pan-

creatic necrosis. Pathologic report showed diffuse sinus hyperplasia in

the spleen and acute pancreatic necrosis with extreme edema and

hemorrhage. She suffered from postoperative acute general dermati-

tis with pustules and wound infection, but was restored from the com-

plication. She was discharged from the hospital 44 days after

operation.

Torsion of distal pancreas accompanied by acute pancreatitis is

very rare disease, but demonstrates specific radiological diagnostic

images. We should consider the disease when we come across sudden

onset acute pancreatitis.

Poster 3-01 AP Basic

P3-01-1

Treatment with a Neurokinin-1 ReceptorAntagonist Protects Mice against AcutePancreatitis and Associated Lung InjuryM. Bhatia, H.Y. Lau, F.L. Wong

National University of Singapore, Singapore

Preprotachykinin-A (PPT-A) gene products substance P and

neurokinin-A (NKA) have been shown to play an important role

in neurogenic inflammation. Substance P acts primarily via the

neurokinin-1 (NK1) receptor. NKA acts primarily via the

neurokinin-2 (NK2) receptor. Earlier work has shown that knockout

mice deficient in NK1 receptors and in the PPT-A gene are protected


against acute pancreatitis and the associated lung injury. In this study,

we have investigated the effect of pharmacological administration of

CP-96345, an NK1 receptor antagonist, on acute pancreatitis and

associated lung injury. Acute pancreatitis was induced in mice by

hourly intraperitoneal injections of caerulein. Substance P was

extracted from plasma, pancreas and lungs and levels were deter-

mined by ELISA. CP-96345 was administered either thirty minutes

before or one hour after starting caerulein injections and pancreatic

inflammation and lung injury were assessed. Induction of acute pan-

creatitis resulted in an increase in pancreatic, lung, as well as circu-

lating levels of substance P. Treatment with CP-96345 protected mice

significantly from acute pancreatitis as evident by significantly atten-

uated plasma amylase, pancreatic myeloperoxidase (MPO) activity,

and histological evidence of pancreatic injury. There was even more

significant protection against acute pancreatitis associated lung

injury, evident by attenuated lung MPO activity and pulmonary

microvascular permeability and histological evidence of lung injury.

Treatment with CP-96345 protects mice against acute pancreatitis

and associated lung injury. NK1 receptor antagonists may potentially

be of use for the treatment of acute pancreatitis and its systemic

complications.

P3-01-2

Rat Experimental Model of ContinuousRegional Arterial Infusion of ProteaseInhibitor and its Effects on Rat SevereAcute PancreatitisY. Mikami, K. Takeda, K. Matsuda, S. Fukuyama, S. Egawa, M. Sunamura, S. Matsuno

Division of Gastroenterological Surgery, Tohoku UniversityGraduate School of Medicine, Sendai, Japan

Introduction: Rat experimental model of continuous regional

arterial infusion of protease inhibitor (CRAI) on acute pancreatitis

has not completely established yet.

Aim: To establish the rat experimental model of CRAI and to

evaluate the effects of the synthetic protease inhibitor nafamostat

mesilate (FUT) on rat severe acute pancreatitis through different

routes of administration.

Methodology: FUT was infused to rats through the internal

jugular vein or the celiac artery for one-hour and the concentrations

of FUT in the blood, lung and pancreas were measured. After the

induction of severe acute pancreatitis, rats received intravenous or

regional intra-arterial infusion of FUT for one-hour, and then,

trypsinogen activated peptide (TAP), histological findings of the

pancreas, serum IL-6 were examined. Ninety-six hours survival was

evaluated.

Results: CRAI led to the higher concentration of FUT in the

pancreas than that infused intravenously, but on the contrary, the

intravenous infusion of FUT led to the higher concentration of FUT

in the lung than that infused intra-arterially. The intravenous infusion

of FUT significantly reduced the level of serum IL-6 and the mortal-

ity rate. Only CRAI significantly reduced the level of TAP and the

pancreatic histological score. Moreover, the level of serum IL-6 and

the mortality rate were significantly reduced after CRAI compared

with the intravenous infusion of FUT.

Conclusion: We established the rat experimental model of

CRAI on acute pancreatitis. The concentration of the FUT in the pan-

creas and lung and the effects of FUT depend on the route of the

administration.

P3-01-3

Hypertonic Solution (NaCl 7.5%) ReducesMortality in Experimental PancreatitisM.C.C. Machado1, A.M.M. Coelho1, V. Pontieri2, S.N. Sampietre1, N.A.T. Molan1, A.S. Matheus1, F.G. Soriano2, I.T. Velasco2

1Departments of Surgery and 2Internal Medicine, School of Medicine, University of São Paulo, São Paulo,Brazil

Background: In spite of advances in the understanding of the

pathophysiologic mechanisms of acute pancreatitis (AP), the thera-

peutic interventions have not significantly changed clinical evolution

and mortality. Previous studies have demonstrated that treatment of

hemorrhagic shock with hypertonic saline solutions significantly

reduces mortality through a improvement in the hemodynamic condi-

tions and possible by a anti-inflammatory effect. Therefore hypertonic

solutions could be effective in AP. The aim of this study was to eval-

uate the effects of hypertonic solution treatment on rats with acute

pancreatitis.

Methods: We used 31 male Wistar rats weighing 230–270 g.

The left femoral artery and vein were canulated 24 hours prior to AP

induction by the injection of 2.5% sodium taurocholate into the pan-

creatic duct. The animals were divided in two groups: NS (n � 17)-

received 34 ml/Kg of normal saline solution (NaCl 0.9%) i.v.; and HS

(n � 14)-received 4 ml/Kg of hypertonic saline solution (NaCl 7.5%)

i.v. The solutions were administrated 1 hour after AP induction in both

groups. Arterial blood pressure and cardiac rate were recorded before

(baseline), 24 and 48 hours after AP. In the mortality study the ani-

mals were followed for 4 days.

Results: In the animals of group NS it was observed a signifi-

cant decrease of mean arterial blood (MAP) 48 h after AP

(91 � 3 mmHg) compared to baseline (105 � 2 mmHg) (p � 0.05).

An significant decrease of MAP was observed in animals of group

HS in the first 24 h after AP (101 � 2 mmHg) compared to baseline

(102 � 2 mmHg) (p � 0.05) and remained stable in the next 24 h

(102 � 2 mmHg) (p � 0.05). Hypotension observed 48 h after AP in

group NS was higher than in animals of group HS (p � 0.05).

Cardiac rate (CR) not show significant differences in animals of

group NS (baseline: 381 � 11 bpm, 24 h after AP: 366 � 9 bpm, 48 h

after AP: 377 � 10 bpm) and animals groups HS (baseline: 398 � 14

bpm, 24 h after AP: 375 � 27 bpm, 48 h after AP: 360 � 28 bpm)

(p � 0.05). A significant reduction on mortality was observed in HS

(0/14) compared to NS (6/17–35%) (�2, p � 0.013).

Conclusion: Administration of HS attenuates the hemodynamic

insults in experimental acute pancreatitis reducing the mortality rate.

However many others known effects of hypertonic saline solution

administration need to be evaluated in this model. Hypertonic solu-

tions may represent a novel therapeutic strategic in the treatment of

acute pancreatitis.


P3-01-4

Effect of Hyperthermia on ExperimentalAcute PancreatitisJ.L. Almeida, J. Jukemura, R.A. Patzina, S.N. Sampietre,J.E.M. Cunha, M.C.C. Machado

Department of Gastroenterology, School of Medicine,University of São Paulo, São Paulo, Brazil

Background and Aim: Recent studies indicate that hyperther-

mia can change inflammatories mechanisms and protects experi-

mental animals from deleterious effects of secretagogue induced

pancreatitis. The mechanisms responsible for this protective effect are

not known. This present study was designed to evaluated the effects

of hyperthermia post-treatment on cerulein-induced acute pancreati-

tis in rats.

Materials and Methods: Acute pancreatitis (AP) was induced

in Wistar rats by the administration of two cerulein injections

(20 �g/Kg SC followed by another 20 �g/Kg IV one hour later). After

the induction of AP the animals were heated in a cage with two 100 W

lamps. Body temperature was increased to 39�C (during 15 minutes)

and maintained at that level for 45 minutes. Animals temperature was

monitored with a rectal thermometer. Control group animals were

also submitted to AP but kept at room temperature thereafter. The rats

were killed by exsanguination after the ending of the hyperthermia

process. Serum amylase levels were determined and pancreatic edema

formation was analyzed through pancreatic wet weight ratio and

Evans’ Blue dye extravasation. Pancreatic biopsies were taken for his-

tology study.

Results: Hyperthermia post-treatment ameliorated the pancre-

atic edema, whereas the morphologic damage and the serum amylase

level remain unaltered. Control animals had typical edema, serum

amylase activity and morphologic changes of this acute pancreatitis

model.

Conclusion: The findings suggest a beneficial effect of the

thermal stress on the inflammatoy edema in the cerulein-induced

model of experimental AP.

Supported by Grant: CNPq.

P3-01-5

Reduction of the Bacterial Translocation inExperimental Acute Pancreatitis usingPentoxifyllineA.S. Matheus, C.Y. Morioka, A.M.M. Coelho, S.N. Sampietre, R.S. de Godoy, J. Jukemura, J.E.M. Cunha, M.C.C. Machado

Department of Surgery, School of Medicine, University of São Paulo, São Paulo, Brazil

Background: Pancreatic necrosis develops in 10–20% of all

cases of acute pancreatitis, and in 30–50% of these patients, pancre-

atic infection occurs. Sepsis and septic complications are the major

cause of deaths in this disease. Bacterial translocation (BT) has been

implicated in the development of multiple organ failure and is one of

the major causes of pancreatic infection in patients with severe acute

pancreatitis. Pentoxifylline (PTX) is a derivative of methyl xanthine

and has a several beneficial effects in sepsis. The purpose of this

study was to determinate if the BT can be reduced in severe AP after

pentoxifylline administration.

Methods: An experimental model of severe AP by injection of

0.5 ml of 2.5% sodium taurocholate into the pancreatic duct was uti-

lized. Thirty male wistar rats were divided in 3 groups: Sham (surgi-

cal procedure without AP induction), Pancreatitis (AP induction), and

Pentoxifylline (AP induction plus intraperitoneally administration of

25 mg/kg Pentoxifylline). We analyzed the occurrence of BT to the

pancreas, mesenteric lymph nodes, liver, blood, and peritoneal cavity,

BT was evaluated with bacterial cultures performed 24 h after the AP

induction. The numbers of organisms were expressed in colony form-

ing units (CFU) per gram.

Results: Bacterial translocation was not observed in the Sham

group. We observed bacterial translocation and a higher bacterial

accumulation in the pancreas, mesenteric lymph nodes, blood, and

peritoneal cavity in Pancreatitis group (p � 0.05). The Pentoxifylline

group had a statistically significant reduction of BT in all analyzed

tissues (p � 0.05).

Conclusions: Severe AP increased BT. BT in AP is a complex

process and involves many variables as a hematogenic, lymphatic, and

transperitoneal bacterial dissemination. The administration of

Pentoxifylline reduces bacterial translocation in this acute pancreati-

tis experimental model. These findings provide a possible improve-

ment in treatment of acute pancreatitis.

Supported by Grant: FAPESP 02/03773-6.

P3-01-6

Suppression of Interleukin 6 and Interleukin 10 in an Experimental AcutePancreatitis Model using IndomethacinA.S. Matheus, C.Y. Morioka, R.S. de Godoy, A.M.M. Coelho, S.N. Sampietre, J. Jukemura, J.E.M. Cunha, M.C.C. Machado

Department of Surgery, School of Medicine, University of São Paulo, São Paulo, Brazil

The clinical manifestations of acute pancreatitis are determined

by actions of inflammatory mediators, including TNF-, interleukins,

PAF, and ICAM-1. These inflammatory mediators play a key role in

acute pancreatitis and result in multiple organ dysfunction, which is

the primary cause of death in this condition. Recent studies have

confirmed the critical role played by inflammatory mediators such

interleukin 6 (IL-6) and interleukin 10 (IL-10). Severe cases of acute

pancreatitis are related with high levels of IL-6 and IL-10. The pur-

pose of this study was to determinate the effect of indomethacin

administration on interleukin levels in an experimental acute pancre-

atitis model.

Methods: An experimental model of severe AP by injection

of 0.5 ml of 2.5% sodium taurocholate into the pancreatic duct was

utilized. Twenty-four male wistar rats were divided in 3 groups: Sham

(surgical procedure without AP induction), Pancreatitis (AP induction),

and Indomethacin (AP induction plus intraperitoneally administration


of 3 mg/kg Indomethacin). We analyzed the blood levels of IL-6 and

IL-10 two hours after the acute pancreatitis induction. Student’s t test

was used to analysis.

Results: Production of IL-6 and IL-10 was lower in the

Indomethacin group compared with the pancreatitis group

(p � 0.05).

Conclusions: The administration of Indomethacin reduces IL-6

and IL-10 in this acute pancreatitis experimental model. These find-

ings provide a possible improvement in treatment of acute pancreatitis.

Supported by Grant: FAPESP 02/03773-6.

Poster 3-02 AP Clinical

P3-02-1

Pancreatic Pseudocyst: Diagnosis and TreatmentS. Neagu1, R. Costea1, N.O. Zarnescu1, A. Stamatoiu1, V. Badea1, C. Dumitrescu1, S. Gradinaru1, R. Vladescu2, M. Pelmus3, G. Iana2

1Second Department of Surgery, 2Radiology Department,3Pathology Department, University Hospital Bucharest,Bucharest, Romania

Background: The aim of this study is to present our experience

concerning pancreatic pseudocyst.

Methodology: We reviewed data of fourteen patients with pan-

creatic pseudocyst, which have been admitted in our department from

1999–2003.

Results: There were five females with an average age of 53 and

nine males with an average age of 49. The diagnosis was established

by ultrasound and CT scan. The aetiology of pancreatic pseudocyst

was necrotic acute pancreatis (alcoholic in six cases, biliary in two

cases and ERCP induced pancreatitis in one case) and alcoholic

chronic pancreatitis in one case. The management was surgical

approach in ten cases and conservatory in four cases. Indications for

surgical intervention were: pseudocyst diameter above 5 cm (six

cases), abdominal pain (one case) and persistence of pseudocyst more

than three months (three cases). We performed two surgical

approaches: external drainage (three cases) and interal drainage

(gastric in five cases and jejunal in two cases). The postoperative

evolution was favourable for all patients.

Conclusions: Pancreatic pseudocyst represents a complication

in evolution of some patients with necrotic acute pancreatitis or

chronic pancreatitis. Correct diagnosis and surgical intervention for

selected cases are essential steps in management of pancreatic

pseudocyst.

P3-02-2

Laparoscopic Management ofPsudopancreatic CystS. Chaube, S.K. Jain

Department of Surgery, St. Jude’s Hospital, Sipri, Jhansi, India

Psudopancreatic cyst usually present after 4 to 6 weeks after the

onset of acute pancreatitis. cysts of more than 6 cm. persisting more

than 6 weeks needs surgical intervention. To pass the benefits of min-

imally invasive surgery to the patients of pseudo cyst of pancreas,

intraluminal cystogastrostomy was performed.

In this procedure anterior gastrostomy is avoided and adequate

stoma can be created with the help of bipolar electrosurgical genera-

tor to avoid recurrence.

Postoperative morbidity is insignificant and patients can be dis-

charged within 72 hours.

P3-02-3

Safe Endoscopic Therapy for BiliaryPancreatitis; Usefulness of ProphylacticEndoscopic Main Pancreatic Duct StentingH. Kutsumi, K. Nishida, S. Ikezawa, E. Fukiya, H. Shiomi, H. Nakamura, K. Hata, Y. Okuyama, H. Kimura, N. Yagi, S. Fujimoto

Digestive Disease Center of Kyoto First Red CrossHospital, Kyoto, Japan

It’s recognized that endoscopic retrograde cholangiopancreatogra-

phy (ERCP) is a contra-indicative procedure for the patient with acute

pancreatitis. The other hand, the necessity and effectiveness of urgent

endoscopic sphincterotomy (ES) for biliary pancreatitis is well

known. However, ES is not usually carried out successfully. If ES is

achieved insufficiently or unsuccessfully, present pancreatitis may

grow worse and may be able to become fatal state. Especially, endo-

scopic papillary dilatation (EPD) on such patient is more risky of get-

ting worse of pancreatitis. Pancreatitis in these cases seems to be

caused by obstruction of the outflow of pancreatic juice, so pancreatic

duct stenting and drainage may be effective for this condition. Then,

we’ve performed endoscopic main pancreatic duct stenting (EPS)

before ES or EPD to prevent from aggravation of pancreatitis on 16

patients with severe biliary pancreatitis, all with high level of serum

amylase value more than 2,000 U/L, maximum of 7,385 U/L. In all

patients, EPS and following ES or EPD were successfully carried out.

The serum amylase levels were immediately decreased, in average of

66% at the next day. We used 5-Fr plastic stent as a drainage catheter

and removed it endoscopicaly 7or 14 days after. The symptoms were

improved in all patients and no procedure-related complications were

observed. These suggest that temporary EPS may not only prevent

postprocedual pancreatitis but also improve obstructive pancreatitis.


P3-02-4

Early Laparoscopic Cholecystectomy forAcute Biliary Pancreatitis – A Comparisonwith Elective and Acute LaparoscopicCholecystectomy for Gallstone DiseaseJ. Zoumaras, R.T.A. Padbury, J. Toouli, T.G. Wilson, L. Kow, D.I. Watson, J.R. Bessell, J.W.C. Chen

Department of Surgery, Flinders Medical Centre, Flinders University, Adelaide, South Australia, Australia

Aim: To evaluate the safety of cholecystectomy in the setting of

acute biliary pancreatitis (ABP), by comparing it with those patients

undergoing acute and elective cholecystectomy.

Methods: Of 268 patients admitted with acute pancreatitis

between 1st January 2000 and 31st May 2003, 129 with first episode

ABP at Flinders Medical Centre were compared with 94 patients

(31st January and May 31st 2003) undergoing acute (ALC, n � 47)

and elective (ELC, n � 47) laparoscopic cholecystectomy for acute

cholecystitis and cholelithiasis respectively. The parameters analysed

include interval to operation, type of operation, operation duration,

conversion rate, post-operative stay, operative and post-operative

complications and mortality. Statistical analysis using SPSS® soft-

ware version 11.

Results: Of the 129 patients admitted with ABP, 80 received a

cholecystectomy during same admission. The median time to opera-

tion for ABP, ELC and ALC are 5 (0–45), 0 (0–5) and 2 (0–19) days

respectively (P � 0.001). The operative complication (ABP) rate was

3.8% (including one operative cardiac death), compared to 4.2% for

both ELC and ALC. The median operative duration was longer in ABP

(86 minutes) compared to 63 mins for ELC and 75 minutes in ALC

(P � 0.005). The median post-operative stay for ABP, ELC and ALC

was 3 (0–63), 1(1–7), and 2(0–31) days (P � 0.02). The conversion

rate in ABP was 10% compared to 8.5% in ALC and 0% in ELC.

Conclusions: Early laparoscopic cholecystectomy for ABP

although longer to perform has similar operative complication rate as

either ELC or ALC. Early laparaoscopic cholecystectomy can be per-

formed safely in ABP.

P3-02-5

Management of Visceral PseudoaneurysmBleeding in Patients with PancreatitisK.-H. Liu, J.-T. Hsu, H.-M. Chen, T.-L. Hwang, Y.-Y. Jan, M.-F. Chen

Departments of General Surgery, Chang Gung MemorialHospital, Taipei, Taiwan

Background: Bleeding pseudoaneurysms are an infrequent but

potentially lethal complication in patients with pancreatitis. It carries

a high mortality rate and management of bleeding pseudoaneurysm is

still a challenging for clinicians.

Methods: A retrospective analysis of ten patients with bleeding

pseudoaneurysm in acute and chronic pancreatitis between August

1992 and July 2003 was conducted.

Results: Eight patients had chronic pancreatitis and 2 had acute

pancreatitis. The splenic artery was involved in 5 cases, pancreatico-

duodenal artery in 3, gastroduodenal in 1, and the middle colic artery

in 1. Eight patients underwent celiac angiography preoperatively and

all were diagnosed. Eight patients initially underwent operative ther-

apy emergently or electively with or without the impression of bleed-

ing pseudoaneurysm. Of the 8 patients, definite management during

operation was performed in 7. One was treated successfully by the

following embolization. Embolization was performed in two patients

initially with rebleeding later. Total 10 surgical interventions and

6 arterial embolizations were conducted in treating bleeding pseudoa-

neurysm and interventional morbidity. The mean time of follow-up

was 26.6 months, ranging from 3 to 75 months. Rebleeding was

detected in three patients. One patient died form the complication of

angiography with overall mortality of 20% (2/10).

Conclusion: Mesenteric angiography is valuable in localizing

bleeding pseudoaneurysms and can provide temporary hemostasis in

a critically ill patient. Subsequent surgery is often needed. Surgery

should be reserved for active bleeding, hemodynamically unstable

patient, for failed embolization, and other secondary complications

such as pseudocyst formation.

P3-02-6

Deep Vein Thrombosis Associated withSevere Acute PancreatitisY. Takeyama1, T. Ueda2, N. Matsumura2, H. Sawa2, C. Yasuda1, Y. Kuroda2

1Department of Surgery, Kinki University School ofMedicine, 2Department of Gastroenterological Surgery,Kobe University Graduate School of Medicine, Kobe, Japan

In this paper, we report 2 cases of deep vein thrombosis (DVT)

associated with severe acute pancreatitis. As hemoconcentration, acti-

vation of coagulation system, and immobilization due to systemic

condition are inevitable in severe acute pancreatitis, severe acute pan-

creatitis is assumed to be of high risk for DVT. However, significance

of DVT in acute pancreatitis has not been well recognized. The first

case was 52-year-old female of post-ERCP pancreatitis. CT scan on

the 2nd day exhibited necrotizing pancreatitis with portal thrombus.

2 months later, retroperitoneal abscess was treated by percutaneous

drainage, and DVT on the right femoral vein was noticed. CT scan

revealed thrombus reaching beyond the level of renal veins. Although

she was treated with anticoagulant, bleeding occurred from retroperi-

toneal drainage. Eventually, she died of DIC 9 months after onset. The

second case was 55-year-old male of idiopathic pancreatitis. CT scan

exhibited DVT on the bilateral lower extremities and pulmonary

embolism 2 weeks after onset. Anticoagulation therapy with insertion

of IVC filter was performed successfully. In both cases, continuous

regional arterial infusion therapy was performed through catheters

from femoral arteries for 5 days, and intravenous catheters were

inserted though femoral veins before the onsets of DVT. We can

assume these treatments, which brought immobilization and vascular

injury, promoted DVT in these cases. We should note that severe acute

pancreatitis is of high risk for DVT, and a squeezing device of lower

extremities should be used in severe acute pancreatitis for prevent-

ing DVT.


P3-02-7

Incidence of Pancreatic Diseases – A Retrospective StudyJ. Chaube, R.C. Jain, A. Khatri, P. Augusta, S. Chaube

Department. of Radiology, Medicine, Peadiatrics, andSurgery, St. Jude’s Hospital, Jhansi, India

Objective: to study the spectrum of pancreatic diseases in a

urban hospital set up located in the Central India.

A retospective analysis of hospital records from Jan 93 to Dec 94

was performed to evaluate the spectrum of pancreatic diseases. Out of

total admission in the above period from 1/1/03 to 31/1/04, 262 cases

of pancreatic diseases were recorded in the hospital.

Acute pancretitis was most common presentation (64%). Biliary

calculus were present in 66% cases of acute pancretitis. Tumour was

present in only 21 cases.

Biliary litheasis is the most common cause of acute pancreatitis in

this region of India. Alcohol induced pancretitis has low incidence.

Poster 3-03 CP Clinical

P3-03-1

Up-to-date Possibilities of PatientRehabilitation in Chronic Pancreatitis (CP)N.B. Gubergrits, V.Y. Kolkina

Donetsk State Medical University, Donetsk, Ukraine

Patients suffering from CP with severe pancreatic insufficiency

need a continuous intake of enzyme preparations. For patients with

moderate to mild pancreatic insufficiency it could be avoided using

antihomotoxic therapy, which contributes to optimization of proper

pancreatic excretory function.

Aim: to prove efficacy of antihomotoxic therapy for rehabilita-

tion of CP patients.

Materials and Methods: 60 CP patients were observed in our

clinic. 30 of them (main group) received antihomotoxic drug

Momordica compositum and Lymphomyosot; another 30 patients

(comparison group) received enzymatic drugs. We studied results of

direct probe test of excretory pancreatic function (aminophyllin-cal-

cium test) and coproscopy.

Results: Patients of the comparison group had steatorrhea in

20.0% before the treatment and in 10.0% 1 month after it. The same

for the main group was 16.7% and 13.3% correspondingly. But in the

main group steatorrhea pattern was changed: there were more cases

of mild steatorrhea and less of moderate to severe one. So antihomo-

toxic preparations promotes optimization of own pancreas function.

This was proved with higher lipase debit-part after treatment in

patients of the main group –110,860 � 2,250 U/L�h (in comparison

group –90,140 � 2,380 U/L�h); in healthy –120,800 � 4,640 U/L�h.

Conclusion: Antihomotoxic therapy of CP promotes rehabilita-

tion of patients and recovery of own pancreas excretory function.

P3-03-2

The Psychological Status of the Patientswith Chronic Alcoholic and ChronicRecurrent PancreatitisN.V. Shirinskaya, E.A. Roslyakov, V.A. Akhmedov

Omsk State Medical Academy, Emergency Hospital 2,Omsk, Russia

Aim: To estimate the psychological status of the patients with

chronic pancreatitis.

Methods: 32 patients with chronic alcoholic pancreatitis,

80-chronic recurrent pancreatitis were studied. The estimation of a

psychological condition was carried out on a technique 16PF (form A).

Results: The patients with chronic alcoholic pancreatitis differ

with greater propensity to a leaving in the world of the imaginations

and ideas. They also had the feeling of fault, bad emotional condi-

tions, suspiciousness, reduced responsibility.

These features of the patients with chronic alcoholic pancreatitis

caused by alcohol consumption and euphoria.The patients with

chronic recurrent pancreatitis were characterized by responsible and

punctual performance of the instructions of doctor.

The patients with this form of chronic pancreatitis were inclined

to transfer of the responsibility and initiative in realization of treat-

ment in hands of doctors.

Conclusions: These results revealed that the efficiency of med-

ical process at the patients with chronic alcoholic pancreatitis

depends on the established trust between the doctor and patient and

formation at the patient the feeling of trust in curative properties of

the ordered method of treatment.

A high incidence of inspire of the patients with chronic recurrent

pancreatitis can give the opportunity to use this group as placebo.

P3-03-3

Hereditary Pancreatitis – Experience of a Surgical Department from RomaniaN.O. Zarnescu1, S. Neagu1, R. Costea1, V. Dinca2, A. Stamatoiu1, M. Sajin3

1Second Department of Surgery, 2Intensive Care Unit,Pathology Department, 3University Hospital Bucharest,Bucharest, Romania

We present the cases of members of two families with hereditary

pancreatitis. The first family is represented by three brothers

(a woman and two men) with recurrent attacks of necrotic acute

pancreatitis. All patients have presented the first episode of acute

pancreatitis around age of 35. We couldn’t identify the etiology of

these episodes of acute pancreatitis (biliary stones, alcohol, trauma,

drugs, lipid disorders). Two of them have diabetes mellitus controlled


through insulin treatment. The genetic testing for trypsinogen muta-

tions or SPINK1 mutations for the youngest member of this family

was negative. In addition two members of this family presented recur-

rent attacks of abdominal pain without any biochemical or imagistic

signs of acute pancreatitis. Recently we have identified another fam-

ily represented by members of three generations. The grandfather

died by pancreatic disease, father (47 years old) was diagnosed with

idiopathic chronic pancreatitis at age of 42 and son (18 years old) has

recurrent idiopathic acute pancreatitis with first episode at age of ten.

After our knowledge these are the first Romanian families reported

with hereditary pancreatitis.

P3-03-4

The Nutritional State and Measured Resting Energy Expenditure in Patients with Decompensated Stage of ChronicPancreatitisM. Yanagimachi1, Y. Tando1, Y. Matsuhashi1, H. Tanaka1, E. Shizuno1, A. Matsumoto1, T. Suda1, T. Nakamura2

1Third Department of Internal Medicine, 2Department ofHealth Science, Hirosaki University School of Medicine,Hirosaki, Japan

The measured resting energy expenditure (REE) can be predicted

from Harris-Benedict formula in healthy person. But resting energy

metabolism is changed in ill patients, and the measured REE can be

more useful than the information from the formula in view of treat-

ment for ill patients. We investigated REE, nutritional state and blood

glucose profile in 7 patients with decompensated stage of chronic

pancreatitis (DCP) (5 males, 2 females) before and one month after

insulin and pancreatic enzyme replacement therapy. The REE was

measured using indirect calorimetry and predicted from Harris-

Benedict formula. The measured REE was compared to the predicted

energy expenditure (PEE). Nutritional state was assessed by serum

nutritional parameter (albumin, prealbumin, total cholesterol and

hemoglobin) and BMI. Blood glucose profile was assessed by fasting

blood glucose levels and HbA1c. Before treatment, they had hyper-

glycemia and malnutrition. Their measured REE was higher than PEE

(REE/PEE � 1.2 � 0.2). One month after treatment, their nutritional

state and blood glucose profile improved. Their REE were decreased

but still 10 percent higher than PEE (REE/PEE � 1.1 � 0.2). The

REE increased in malnutrition due to pancreatic insufficiency which

affects glucose and lipid utilization. Insulin and pancreatic enzyme

replacement therapy decreased REE through the improvement of glu-

cose and lipid utilization. Their REE were still 10 percent higher than

PEE. The increase of speciffic dynamic action in the convalescent

phase of malnutrition might be related with this discrepancy.

P3-03-5

Experience of Frey’s Operation –Perioperative and Short Term ResultsY. Takeyama1, S. Kishi2, T. Ueda2, N. Matsumura2, H. Sawa2, Y. Kuroda2

1Department of Surgery, Kinki University School ofMedicine, 2Department of Gastroenterological Surgery,Kobe University Graduate School of Medicine, Kobe, Japan

In this paper, we summarized the perioperative and short-term

results of Frey’s operation in 15 cases with chronic pancreatitis. All

patients were male, and aged from 11 to 66 years old. Twelve cases

were alcoholic, and the others idiopathic. Diameter of main pancreatic

duct ranged from 4 to 12 mm, and calcification in pancreas head was

noted in all cases. Cholecystectomy and intraoperative choledochogra-

phy were done in two cases. Duration of operation ranged from 4.1 to

8.8 h (mean: 5.3 h), and blood loss was from 220 to 2823 g (mean:

865 g). Particularly, in 12 cases without previous operation for pancre-

atitis, averages of these parameters were 5.1 h and 560 g, respectively.

Hospital mortality and morbidity rates were 0% and 6.7% (1 cases),

respectively. In one case, bile leakage from Luschka’s duct after chole-

cystectomy was complicated. In all cases, oral intake restarted within

6 days after operation. Observation periods for postoperative outcome

ranged from 8 months to 3 years, and pain relief and occupational or

educational rehabilitation were completely achieved. As for endocrine

function, required dose of insulin were reduced in two cases, and pro-

gression of diabetes was not noted in any case. Exocrine function eval-

uated by BT-PABA test was improved in 9 cases. Although long-term

follow-up is necessary, we can conclude that Frey’s operation is safe

and less invasive, and that it brings adequate pain relief and social

rehabilitation with preserving pancreatic functions.

P3-03-6

Immediate and Medium-Term Resultsof Pancreatoduodenectomy for ChronicPancreatitisJ.-T. Hsu, H.-M. Chen, T.-L. Hwang, Y.-Y. Jan, M.-F. Chen

Departments of General Surgery, Chang Gung Memorial Hospital, Taipei, Taiwan

Purpose: To analyze the efficacy of Pancreatoduodenectomy

(PD) with or without pylorus preservation for chronic pancreatitis in

term of pain relief, control of complications arising from adjacent

organs and pancreatic function

Methods: From April 1997 to 2002, a retrospective analysis of

24 consecutive patients with final diagnosis of chronic pancreatitis

underwent PD were enrolled in this investigation. The main indica-

tions for surgery were recurrent intractable pain, local complications,

and suspicion of malignancy. The mean duration of follow-up in 22

patients was 41 months ranging from 14 to 90 months.

Results: There were 21 men and 3 women. The age of these

patients ranged from 21 to 73 years with a mean age of 44 years.

The etiology was predominantly alcohol abuse in 14 patients.

Surgical indications include inflammatory mass in pancreatic head


and stenosis of pancreatic duct in 15 patients, biliary obstruction in 9,

duodenal obstruction in 4 and left-sided portal hypertension in 1.

Surgical mortality was zero and morbidity rate was 17%, with four

patients having 5 complications. At the 3rd month after surgery,

excellent and good pain relief was achieved in 87.5% patients. Three

patients developed diabetes mellitus and pancreatic exocrine insuffi-

ciency occurred in 10 patients. The pain recurred in 5 (21%) patients

at the postoperative one year and all are related with the alcohol

reabuse. Other medium-term consequences were found in three

patients, including CBD stones (2) and pancreatic duct stenosis (1).

Conclusion: In selected patients with chronic pancreatitis, pan-

creatoduodenectomy is a safe procedure and effective in relieving

pain and control of local complications. Deterioration of pancreatic

endocrine function after PD was mainly related to the disease pro-

gression and resumption of alcohol. Pancreatic resection plays an

important role on the impact of the pancreatic exocrine insufficiency.

Poster 3-04 Physiology

P3-04-1

Dynamic Magnetic ResonanceCholangiopancreatography with SecretinInjection is Useful for Functional Analysis of Pancreaticobiliary MaljunctionS. Ohhigashi1, F. Watanabe2

1Department of Surgery, 2Department of Radiology, St. Luke’s International Hospital, Tokyo, Japan

Purpose: In the case of choledochal cyst with pancreaticobiliary

maljunction (PBM), surgical resection of the dilated extra-hepatic

bile duct is the principle. But, surgical strategy for the non-dilated bile

duct type of PBM is still controversial. It is important to analyze the

individual function of PMB to perform the appropriate surgical pro-

cedure. The purpose of this study is to verify the utility of dynamic

magnetic resonance cholangiopancreatography (MRCP) with secretin

injection for the functional analysis of PBM.

Patients and Methods: Thirteen cases of PBM were analyzed

by MRCP with secretin. These cases were classified into 3 types

according to the shapes of extra-hepatic bile duct; a cystic type in

8 cases, a columnar type in 3 cases, and a non-dilated type in 2 cases.

Dynamic MRCP images were obtained serially at interval of 60 sec-

onds for 15 minutes after secretin injection. Images were analyzed on

the total intensity calculated by tracing the contour line of the indi-

vidual images of extra-hepatic bile duct, duodenum and gallbladder.

Results: In the cystic type, intensity of the extra-hepatic bile

duct increased gradually following secretin injection and remained

high after duodenal intensity increased. In the columnar type, no

remarkable change was observed on bile duct intensity in 2 cases. The

bile duct intensity increased and decreased alternately and this change

was inversely correlative to duodenal intensity in one case. In the non-

dilated type, intensity of bile duct was stable and early increase of

duodenal intensity was observed. Intensity of gallbladder was almost

stable in all cases of PBM.

Conclusion: Dynamic MRCP with secretin makes clear verifi-

cation of dynamics of bile and pancreatic juice possible. Thus, it is use-

ful for functional analysis of PBM and helpful for surgical strategy.

P3-04-2

Endocrine Function of Pancreas afterPancreatectomyY. Ishikawa1, T. Asano2, T. Kenmochi3, H. Miyauchi1, N. Hashimoto4, T. Ochiai1

1Department of Academic Surgery, Graduated School of Medicine, Chiba University, Chiba, 2Department ofSurgery, Chiba Prefecture Cancer Center, 3Department of Surgery, National Sakura Hospital, 4Department ofInternal Medicine, Asahi Chuo Hospital, Japan

After pancreatectomy diabetes is a frequent complication. It is

thought that diabetes is caused by the fibrosis of the pancreas, the

high pressure of the pancreatic duct, and the decrease of insulin due

to pancreas resection. The aim of this study was to evaluate the

change of pancreatic endocrine function after pancreatectomy, and to

investigate the causes of diabetes. 425 patients underwent pancreate-

ctomy from January 1965 to February 2002. We evaluated only 56

patients (30 pancreaticoduodenectomy, 16 dorsal pancreatectomy, and

10 partial pancreatectomy) except for the patients who had diabetes

before the operation, underwent hepatectomy or, whose tumor was

endocrinoma. The 56 patients were classified with amount of resec-

tion (�50% vs �50%) and part of the resected pancreas (head vs

tail), and were compared among preoperative data, postoperative data,

and 1 year’s data after the operation. The homeostasis model insulin

resistance index (HOMA-R), and the homeostasis model insulin

secretion index (HOMA-�) were used for the analysis of pancreatic

endocrine function. In the cases of �50% resection pancreatic

endocrine function was not affected by operation. In the cases of

�50% and head resection HOMA-� decreased, and in the cases of

�50% and tail resection HOMA-R rose. Reduction of HOMA-� was

based on the decrease of � cells and the deterioration of b cells’ func-

tion due to the complications of pancreaticointestinal anastomosis.

On the other hand, one of the reasons why HOMA-R rose might be a

participation of lowering response to insulin in the remnant pancreas.


P3-04-3

Relationship between Morphology ofPancreatic Ductal System andPancreaticobiliary DiseasesB.K. Park, S. Bang, J.H. Suh, J.H. Lee, S.W. Park, S.Y. Song, J.B. Chung, J.K. Kang

Department of Internal Medicine, Institute ofGastroenterology, Yonsei University College of Medicine, Seoul, Korea

The purpose of this study was to identify the morphological diver-

sities and anatomical variations of pancreatic duct (PD) and to clarify

the relationship between PD types and pancreaticobiliary diseases.

Five hundred and eighty-two consecutive patients, in whom both PD

and common bile duct (CBD) were clearly visualized by ERCP, were

included. PD types were categorized into four types according to the

relationship between CBD and PD as follows; type A [main duct

(MD): Wirsung duct (WD), Santorini duct (SD): open to minor

papilla], type B [MD: WD, SD: not open to minor papilla], type C

[MD: SD, SD: open to minor papilla], type D [others]. The PD types

were classified into type A in 84.4%, type B in 9.6%, type C in 3.4%,

and type D in 2.6%. The PD anomalies were noted in 51 patients,

which were comprised of 19 (3.3%) fusion anomalies (12 complete

pancreas divisum, 7 incomplete pancreas divisum) and 32 (5.5%)

duplication anomalies (5 number variations, 27 form variations). No

significant relationships between various PD morphologies and

pancreaticobiliary diseases were found. Post-ERCP hyperamylasemia

was more frequently complicated in type C (41.7%) and D (50%) than

in type A and B. In conclusion, various PD types were not related with

pancreaticobiliary diseases. However, the understanding of anatomi-

cal variations of PD may aid in more accurate interpretation and pre-

diction of a complication such as pancreatitis.

P3-04-4

Detection of Mesothelin mRNA in thePancreatic Juice from the Patients withVarious Pancreatic DiseasesH. Watanabe, G. Okada, K. Ohtsubo, Y. Yamaguchi, H. Mouri, Y. Motoo, N. Sawabu

Department of Internal Medicine and Medical Oncology, Cancer Research Institute, KanazawaUniversity, Kanazawa, Japan

With serial analysis of gene expression (SAGE) by Ryu et al., the

tag for the mesothelin mRNA (Mm) transcript was present in SAGE

libraries derived from pancreatic carcinoma (PCa) but not in those

derived from normal duct epithelial cell. Mm expression was con-

firmed by in situ hybridization in 4 of 4 resected primary PCa and by

RT-PCR in 18 of 20 PCa cell lines. Furthermore, mesothelin protein

expression was confirmed by immunohistochemistry in all

60 resected primary PCa tissues by Argani et al. We evaluated Mm

expression in pure pancreatic juices (PPJ) obtained endoscopically

from 30 patients with PCa, 27 with chronic pancreatitis (CP), and 11

intraductal papillary mucinous tumor (IPMT) by reverse-transcription

PCR (RT-PCR). PCR products were analyzed by agarose gel elec-

trophoresis. PPJ samples from 7 PCa and 5 CP patients were deleted

because of inadequate amount of RNA. Two products of which the

size was 308 and 226 bp were obtained by RT-PCR and RT-PCR prod-

uct of the 308 bp was confirmed as that derived from genomic DNA

by direct DNA sequencing. Mm expression was found out by RT-PCR

in 11 (52%) of 21 with PCa, 5 (45%) of 11 with IPMT, and 3 (14%)

of 22 with CP. Moreover, RT-PCR band (226 bp) of Mm in PPJ

samples from PCa was stronger than that in PPJ samples from IPMT

or CP. Expression of Mm in PPJ from the patients with PCa was not

correlated with the size and location of PCa, and clinical staging of

the patients with PCa. These results suggest that expression of

mesothelin mRNA is not strictly specific to PCa. However, quantita-

tive detection of mesothelin mRNA in the PPJ by real-time PCR may

have potential diagnostic implication for pancreatic tumor.

P3-04-5

Effect of Chronic Exercise on the ExocrinePancreas in Zucker Fatty RatK. Minato1, Y. Shiroya1, H. Matsuzaki1, T. Kondo2

1Wayo Women’s University, 2Nagoya University, Nagoya,Japan

Introduction: Daily physical exercise affects the exocrine

pancreas. We have found that chronic exercise increases pancreatic

weight, protein content, and enzyme activity with hypertrophy of aci-

nar cells in rat. The purpose of this study was to investigate whether

these fact occur in Zucker Fatty rat.

Methods: Male Zucker Lean rats (age, 6 weeks) were used as

control (LC; n � 5). Male Zucker Fatty rats (age, 6 weeks) were

divided into an obese (OB; n � 5), a diet restriction (DR; n � 5), and

an exercise (EX; n � 5) group. LC and OB rats had free access to

food, DR and EX rats had food intake restricted to 71% and 78% of

OB group level, respectively. EX rats were exercised voluntarily on

the wheel ergometer with a load of 30% on their body weight every

day. After 6 weeks, the pancreas were excised and weighed. Protein

content and amylase activity in pancreatic tissue were measured.

Pancreatic tissues were prepared for transmission electron

microscopy.

Results: Zucker Fatty rats ate a large number of food and

became to have heavy body weight, obviously. However, total pancre-

atic weight, protein content, and amylase activity were reduced with

atorophy of acinar cells. Increases of these parameters occurred in

EX rats.

Conclusion: Chronic exercise may improve function of the

exocrine pancreas in Zucker Fatty rats.


P3-04-6

Expiration Tests were Useful to Evaluate the Digestive and Absorptive Function of Either Fat or Carbohydrate in Patientswith Pancreatic InsufficiencyH. Tanaka1, T. Nakamura2, T. Watanabe3, E. Shizuno1, A. Matsumoto1, Y. Matsuhashi1, M. Yanagimachi1, Y. Tando1, Y. Ogawa1, T. Suda1

1Third Department of Internal Medicine, 2Department ofHealth Science, 3Hirosaki University School of Medicine,Watanabe Hospital, Hirosaki, Japan

Background: Patients with pancreatic insufficiency often suf-

fered from steatorrhea and/or carbohydrate malabsorption by the

deteriorated secretion of lipase and/or amylase. It is important to eval-

uate the digestive and absorptive function in such patients, because

these dysfunction might induce various complication such as

advanced malnutrition, infectious disease, and unexpected hypo-

glycemia with pancreatic diabetes.

Aims: We investigated if expiration tests would be useful to

assess the digestive and absorptive function as compared with the mea-

surements of excreted fat in feces. Subjects and methods: Healthy sub-

jects (n � 20) and patients with pancreatic insufficiency (n � 10) were

examined. Either 13CO2 analysis in expiration after taking 13C-labelled

mixed triglyceride or hydrogen analysis in expiration was performed to

evaluate the digestion and absorption of fat or carbohydrate.

Result and Discussion: 13CO2 analysis in expiration was use-

ful to diagnose the patients with pancreatic steatorrhea more than 10 g

fat a day. And hydrogen analysis in expiration could detect 60% of

patients who had pancreatic insufficiency with carbohydrate malab-

sorption. The expiratory hydrogen concentration was not significantly

correlated with the amount of excreted fecal fat in patients with pan-

creatic insufficiency, which suggested that the grade of the deteriora-

tion in lipase secretion and amylase secretion was not always

synchronized.

Conclusion: These expiration tests might be useful to evaluate

the digestive and absorptive function in the patients with decompen-

sated chronic pancreatitis more easily.

P3-04-7

Does the Pancreas Really Produce Much More Lipase than Required for Fat Digestion?P. Grandval1, P. Gregory3, C. Renou1, F. Hennigues3, F. Carrière2, R. Laugier1

1Gastroenterology Department, CHU la Timone,2Laboratoire de Lipolyse Enzymatique du CNRS UPR9025, Marseilles, France, 3SOLVAY PharmaceuticalsGmbH, Hannover, Germany

It is known for very long time that fibrosis of the pancreas, such

as developed in the late stage of chronic calcifying pancreatitis (CCP)

is associated with chronic diarrhoea and malnutrition. Later, malnu-

trition was explained by the pancreatic exocrine insufficiency (PEI)

and, more specifically, steatorrhea was found in patients presenting a

dramatic decrease of lipase secretion.

In 1973, Di Magno et al., reported that there was no linear rela-

tionship between the amounts of secreted lipase persisting in severe

CCP and the presence (and quantitative importance) of steatorrhea

(1), the latter being considered to appear when more than 90% of the

pancreatic secretory capacity had gone away. When pancreatic

extracts (PE) were not able to treat correctly steatorrhea in CCP

patients, the maximum attention was payed towards destruction of

added lipase or disturbance in the synchronism of lipase and meal

delivery, rather than low levels of lipase.

1. In recent years, we noted that the inhibitory level of both gas-

tric and pancreatic lipases by the lipase inhibitor Orlistat was almost

linearly correlated with the amount of excreted fats.

2. In minipigs and in dogs with experimentally – induced PEI, the

amount of PE needed for compensating completely fat maldigestion

represented much more than 10% of the lipase secretory rate

observed in normal animals.

3. The very high specific activity of lipase is usually measured in

experimental conditions far away from physiology: with such data,

the duration of fat digestion in vivo would be of a few minutes only!

In fact, lipase specific activity on meal triglycerides is much lower

(3 orders of magnitude!). One understands better why more lipase is

needed than expected, why fat digestion lasts for more than a few

minutes and finally why there is not such spared secretory capacity

for lipase as thought before!

4. In patients without steatorrhea but almost no residual lipase

secretion, the presence and action of gastric lipase has to be taken into

account for explaining this apparent discrepancy.

Reference

1. Di Magno, et al: Relations between pancreatic enzyme outputs and mal-

absorption in severe pancreatic insufficiency. N Engl J Med 1973;288:

813–815.


P3-05-1

The Prognosis of Pancreatic IPMTS.-J. Sheng, Y.-Y. Jan, M.-F. Chen, T.-L. Hwang

Department of Surgery, Chang Gung Mem. Hospital,Taipei, Taiwan

Purpose: Intraductal Papillary-Mucinous Tumor (IPMT) of the

pancreas is a rare type of neoplasm that grows papillary in the large

pancreatic duct and is considered to be a rather low-grade malig-

nancy. The prognosis of IPMT was retrospectively analyzed.

Materials and Methods: In the past 5 years, there were 15

cases of IPMT, 6 males and 9 females, diagnosed in our hospital.

Most patients manifested with epigastralgia, four had repeated attack

of pancreatitis, and three had jaundice. They were diagnosed with

sonogram, CT, ERCP & MRCP.


Results: Three patients were performed with Whipple opera-

tion, 6 patients received subtotal pancreatectomy, and two patients

underwent bypass procedures, and one patient received near total

pancreatectomy. Eight patients were found to have malignant

changes, half of them had preoperative elevation of CEA or CA19-9.

The others almost had borderline or dysplasia changes of their IPMT

by pathological examination. Only one patient died one and half year

after operation, and the others were well until now.

Conclusion: We conclude that adequate resection of IPMT

results in good recovery and prognosis. Preoperative elevation of

tumor markers has high possibility of malignant changes.

P3-05-2

Cystic Tumors of the Pancreas – Radical or Organ-Preserving Resection?M. Siech, S. Thumerer, D. Henne-Bruus, H. Beger

Department of General Surgery, Ostalb-Klinikum,Germany

Cystic tumors are only 1% of all pancreatic tumors. These tumors

divide into other tumor entities, some of them benign, some of them

borderline or malignant. The kind of therapy is presently under dis-

cussion. Between 1986 and 2003 we treated 97 patients with cystic

tumors of the pancreas, evaluated the data retrospectively and fol-

lowed the patients up 67% were treated by radical resection and 32%

were treated by organ-preserving resection. None of our patients died

in the hospital. Recurrence of the tumor was seen only in mucinous

entities and occurred in 9% after extensive and 13% after organ-pre-

serving resection (n.s.). Postoperative ‘new’ diabetes mellitus was

with 41% significantly higher after radical resections than after

organ-preserving resections (24%, p � 0.01). Long time survival was

worst after mucinous cystadenocarcinoma (59% after 36 months), all

other patients lived in 90% longer than 36 months. We conclude that

organ-preserving resection should be considered in all serous cystic

tumors and solid pseudo-papillary tumor of the pancreas. All muci-

nous cystic tumors are of malignant or borderline nature and should

be treated as such by radical resection.

P3-05-3

Surgical Treatment for Intraductal Papillary-Mucinous Neoplasm (IPMN) andMucinous Cystic Neoplasm (MCN) of thePancreas according to the MorphologicalCharacteristicsT. Hatori, A. Fukuda, S. Onizawa, K. Furukawa, K. Takasaki

Department of Surgery, Institute of Gastroenterology,Tokyo Women’s Medical University, Tokyo, Japan

Background: Intraductal papillary-mucinous neoplasm (IPMN)

and mucinous cystic neoplasm (MCN) of the pancreas are a unique

neoplasm which has a favorite prognosis. Various kind of operation

can be chosen for these neoplasms. The aim of this study is to

evaluate surgical treatment for IPMN and MCN of the pancreas

according to the morphological characteristics.

Methods: We investigated 228 patients who underwent pancre-

atectomy for IPMN and MCN between 1981 and 2003 retrospectively.

IPMN was much seen in the elderly (average 64.6 year), men (65%)

and pancreatic head (69%). On the other hand, MCN was much seen

in middle aged (average 48.1 year), women (96%) and pancreatic

body and tail (100%).

Results: (1) IPMN: The average size and the height of the tuber-

cles in a lesion of the adenoma and carcinoma were more than 3 cm,

more than 3 mm, respectively. The carcinoma was much seen in the

elevated type (tubercles in a lesion more than 3 mm) than in the flat

type (tubercles in a lesion less than 3 mm). Lymph node metastasis

was seen with 43% in only elevated type with invasive carcinoma, but

there was no lymph node metastasis in the flat type. The 5-year sur-

vival rate was 38% in the patients with invasive carcinoma, but the

others were around 95%. (2) MCN: The average size of the neoplasm

was around 8 cm. The ovarian-type stroma was seen except one male

case. The carcinoma was much seen in the elevated type than in the

flat type. Lymph node metastasis was seen in only elevated type with

invasive carcinoma. The prognosis was good except the invasive

carcinoma.

Conclusion: The pancreatectomy with lymphadenectomy

should be done for the elevated type with invasive carcinoma.

However, the minimized pancreatectomy could be done for the ele-

vated type without invasive carcinoma and the flat type.

P3-05-4

Surgical Strategy for Intraductal PapillaryMucinous Tumor of the PancreasT. Ishikawa, T. Kaneko, T. Fujii, K. Koshikawa, H. Sugimoto,S. Nomoto, S. Inoue, S. Takeda, A. Nakao

Department of Surgery II, Nagoya University GraduateSchool of Medicine, Nagoya, Japan

The aim of this study was to evaluate the diagnostic and surgical

strategy for intraductal papillary mucinous tumor (IPMT) of the pan-

creas. Fifty-six patients (40 men and 16 women) who underwent

surgery for IPMT between 1991 and 2003 in Nagoya University

Hospital, the clinicopathological features and surgical outcomes were

investigated retrospectively. Forty patients had benign IPMT, 6 had

invasive carcinoma, and 10 had non-invasive carcinoma. Of the

benign IPMTs, 9 tumors were the MPD type and 32 were the branch

duct type in their principle location. Of the malignant IPMTs, on the

other hand, 8 were the MPD type and 7 were the branch duct type. The

mean MPD diameter was 6.2 mm in benign tumors and 8.9 mm in

malignant tumors. Mural nodules were seen in 19 of 40 cases with

benign tumors and in all cases with malignant tumors. IPMT is a slow

glowing tumor but, if it progresses to invasive carcinoma, the prog-

nosis is poor. The accurate preoperative diagnosis is very important

for suitable treatment. In cases with invasion, radical operation with

dissection of lymph nodes is necessary. But in cases of benign IPMTs

or non-invasive tumors, an operation that preserves pancreatic and

digestive function is recommended.


P3-05-5

Acinar Cell Carcinoma of the PancreasMimicking Intraductal Papillary-MucinousNeoplasmsK. Uesaka, H. Kanemoto, A. Maeda, K. Matsunaga, J. Izai, T. Ebata

Division of Hepato-Biliary-Pancreatic Surgery, ShizuokaCancer Center, Shizuoka, Japan

Acinar cell carcinoma (ACC) of the pancreas is usually found as

a bulky mass on imaging diagnosis. We report a rare case of ACC pro-

liferating within the main pancreatic duct like intraductal papillary-

mucinous neoplasms of the pancreas. To our knowledge, this is the

second report of ACC in the world, spreading mainly in the main pan-

creatic duct. The patient is a 63-year-old woman with recurrent

episodes of acute pancreatitis over a 3-year period. Computed tomog-

raphy and magnetic resonance imaging revealed a mass filling the

dilated main pancreatic duct thus making the pancreatic parenchyma

very thin. A splenic vein tumor thrombus was also visualized.

Endoscopy demonstrated the swollen ampulla and dilated orifice with

whitish exudate. Endoscopic retrograde pancreatography revealed a

lot of filling defects in the dilated main pancreatic duct. Her tumor

marker values including CEA and CA19-9 were normal. In February

2003, she underwent total pancreatectomy, splenectomy, and com-

bined resection and reconstruction of the portal vein, based on the

preoperative imaging diagnosis of intraductal papillary-mucinous

carcinoma. Cut surface of the resected specimen showed whitish

tumor in the main pancreatic duct as well as splenic vein, and

markedly compressed parenchyma of the pancreas. Histopathologic

examination demonstrated proliferation of eosinophilic atypical cells

in solid, trabecular, and acinar arrangements. Immunohistochemical

staining was positive for �1-antitrypsin, but negative for chromo-

granin A and synaptophysin. Electron microscopic examination

revealed zymogen granules. These findings were compatible with the

diagnosis of ACC of the pancreas. Eleven months after the surgery,

she is still alive despite multiple liver metastases.

P3-05-6

Intraductal Papillary Mucinous Tumor of the Pancreas Growing from One Branchof the Pancreatic Duct, with SolidFormationM. Sugaya, M. Ryu, M. Izumi, W. Takayama, T. Okada, S. Kobayashi, N. Hanari, T. Oshima

Surgery, Chiba Prefecture Sawara Hospital, Chiba, Japan

We will present a case of huge intraductal papillary mucinous can-

cer derived from one pancreatic duct. The tumor showed solid and

hypervascular findings. Patient is a 67-year old Japanese man who

presented at our hospital with a complaint of epigastralgia. US, plain

CT findings showed solid mass lesion in head of the pancreas and

dilatation of main pancreatic duct. Angiography demonstrated rela-

tively hypervascular lesion. It seems like a ductal invasive carcinoma

or islet cell tumor. Dynamic CT showed water dense lesion in edge of

the tumor. Angio CT demonstrated that peripancreatic artery was

mainly enhanced. MRCP showed multiple cystic lesion in head of the

pancreas. Endoscopy showed fish-egg-like appearance of Papilla of

Vater Preoperative diagnosis of IPMT was established. Intraoperative

ultrasound showed solid mass in head of the pancreas. We performed

intraoperative pancreatoscopy and there was no malignant lesion in

residual pancreatic duct. We performed pylorus preserving pancreati-

coduodenectomy. Macroscopic findings, round and clearly demar-

cated tumor was seen in head of the pancreas. Papillary cancer is not

seen in another all of the small branch of head of the pancreas. Main

tumor is extending to the papilla of Vater through the main pancreatic

duct. A part of main tumor had invaded to the pancreas parenchyma

slightly. Microscopic findings showed papillary cancer which is filled

inside the marked dilated pancreatic duct. The main tumor was grow-

ing papillary within one branch of pancreatic duct. There were blood

vessels in the wall of the pancreatic duct. No remarkable mucin was

seen. Final diagnosis is intraductal papillary mucinous cancer. The

patient is doing well for 24 months now.

P3-05-7

Combined Minimally Invasive SurgicalProcedures for Intraductal PapillaryMucinous Tumor (IPMT) of the Body of the Pancreas and Early Gastric Cancer –Special Reference to the Significance ofSpleen Preserving Distal Pancreatectomy for Blood Supply for the Remnant StomachI. Hirai, A. Suzuki, J. Ma, T. Moriya, A. Fuse, W. Kimura

Gastrointestinal and General Surgery Division, YamagataUniversity School of Medicine, Yamagata, Japan

We present the significance of minimally invasive surgery for

intraductal papillary mucinous tumor (IPMT) of the body of the pan-

creas and early gastric cancer of the stomach.

Case Report: A 79-year-old man was diagnosed as IPMT and

followed up during 10 years, because he did not want surgical treat-

ment. However, early gastric cancer was found in 2003, he was

referred to our department for surgery. Gastric endoscopes revealed

2c type cancer in the body of the stomach. Preoperative ERP and EUS

examination showed cystic tumor with 7 mm height elevated lesion in

the body of the pancreas. Since there were no findings of invasion to

surrounding tissue, spleen preserving distal pancreatectomy was per-

formed. Intraoperative pancreatoscopy showed fish-egg like appear-

ance in the distal side of the pancreatic duct, but no abnormal findings

in the head of the pancreas. There was no IPMT in the cut margin of

the pancreas with frozen section study. Pathologically, although there

existed very limited lesion of the CIS, most of the tumor was con-

sisted of benign adenoma. Moreover, because there was no regional

lymph node metastasis, pylorus-preserving gastrectomy was also per-

formed. In spite of the high aged patient, he discharged on 21 days

after surgery, and doing well.

Conclusion: When left sided pancreatectomy is scheduled, even

in a case combined with gastric cancer, spleen preserving distal pan-

createctomy can avoid total gastrectomy, because remnant stomach

will be supplied through the short gastric artery which originates from

the splenic artery.



P3-06-1

Four Cases of Intraductal Papillary-Mucinous Tumors of the Pancreas Operated for Preoperatively DiagnosedParenchymal InvasionD. Kudo1, M. Kobari1, T. Tsuchiya1, K. Ito2, T. Kobayashi2, N. Fujita2, Y. Mikami3

1Department of Surgery and 2Department ofGastroenterology, Sendai Open Hospital, 3Department ofDigestive Surgery, Tohoku University, Sendai, Japan

Major pancreatectomies were undergone in four patients with

intraductal papillary mucinous tumor (IPMT) of the pancreas for pre-

operatively diagnosed parenchymal invasion. Patient 1, 2 and 3 were

diagnosed as having branch duct type of IPMT and followed every 6

months. Tumors invading common bile duct were found in endo-

scopic retrograde cholangiopancreatography (ERCP) in patient 1 and

2 after 4 and 1.5 years after diagnosis of IPMT. Pancreato-

duodenectomy and total pancreatectomy were undergone respectively.

Tumor invading pancreatic body was found in abdominal CT in

patient 3 after 15 years of follow up period under diagnosis of IPMT.

Total pancreatectomy accomplished with total resection of gastric

remnant was done. Main duct type of IPMT invading pancreatic head

was diagnosed in ERCP in patient 4. Pylorus preserving total pancre-

atectomy was performed without follow up period. Histologically all

of four tumors were diagnosed as invasive carcinoma derived from

IPMT. It is generally accepted that IPMT grows slowly even when it

progresses to carcinoma, and the prognosis is relatively good. Even

though, it should be noticed invasive carcinoma with rapid progres-

sion can be derived from benign IPMT. In patients diagnosed as hav-

ing benign IPMT which can be followed, not only IPMT local but also

whole pancreas and neighboring organs should be carefully checked.

P3-06-2

A Case of Invasive PanceaticAdenocarcinoma Derived from Intraductal Papillary Mucinous TumorY. Okamoto1, A. Sawaki1, K. Okubo1, N. Mizuno1, T. Nakamura1, R. Ashida1, M. Katsurahara1, T. Isaka1, H. Imaoka1, Y. Shimizu2, K. Yamao1

1Department of Gastroenterology, 2Department ofGastroenterological Surgery, Aichi Cancer CenterHospital, Aichi, Japan

We report a rare case of pancreatic adenocarcinoma derived from

intraductal papillary mucinous tumor (IPMT). A 78-years old

Japanese woman was admitted to our hospital for examination of pan-

creatic mass. Preoperative abdominal ultrasonography discovered a

low echoic lesion with dilatation of the distal part of main pancreatic

duct and anechoic area in the body of the pancreas. Computed tomog-

raphy (CT) showed the lesion mild enhancement by contrast medium.

Endoscopic retrograde pancreatography displayed obstruction of

main pancreatic duct at the pancreas body. Endoscopic ultrasonogra-

phy (EUS) revealed a cystic lesion with mural nodule and hypoechoic

mass in pancreatic parenchyma. We diagnosed the tumor as a

resectable pancreatic tumor without arterial invasion and performed

distal pancreatectomy with splenectomy in December 2003.

Microscopic finding showed carcinomatous invasion of the pancre-

atic parenchyma accompanied with atypical columnar epithelium

which forms papillary proliferations in the dilated duct. The tumor

was histopathologically diagnosed as invasive adenocarcinoma

derived from IPMT. The mild enhancement tumor with cystic lesion

includes various pancreatic tumors: islet cell tumor, acinar cell tumor,

solid pseudopapillary tumor, and IPMT. Since EUS could detect

small elevation in the cystic lesion and solid mass in pancreatic

parenchyma, we might diagnosis invasive adenocarcinoma derived

from IPMT. EUS is thought to be one of the most useful modality for

diagnosis of pancreatic tumors.

P3-06-3

Intraductal Papillary-Mucinous Tumor withLarge Mural NoduleM. Shirai1, T. Fukuhara1, M. Hatano1, M. Morimoto1, Y. Ono1, K. Honda1, N. Kobayashi1, H. Hasegawa2, S. Fujita2

1The First Department of Surgery, 2The First Departmentof Internal Medicine, Ehime University School ofMedicine, Ehime, Japan

Intraductal papillary-mucinous tumor (IPMT) is defined as a syn-

drome consisting of dilatation of the main pancreatic duct and/or

branch ducts associated with mucin overproduction. Differential

diagnosis among hyperplasia, adenoma or adenocarcinoma is clini-

cally important in the decision of therapeutic strategy. Recent reports

suggest that the larger diameter or cyst, nodule, or main pancreatic

duct in branched-type IPMTs is more likely to be adenocarcinomas

than the smaller ones. We report a rare case of adenoma that reveals

large cyst and large mural nodule.

A 68-year-old woman with chief complaint of left lower abdomi-

nal pain was admitted to our hospital. Serum levels of CEA, CA19-9,

DUPAN-2 and SPAN1 were within normal limit respectively.

Ultrasonography showed a cystic lesion with mural nodule at the pan-

creatic head, and contrast-enhanced ultrasongraphy revealed an

arborescent enhancement effect in the nodule. Computed tomography

showed the nodule was effectively enhanced since early phase.

Duodenal endoscopy revealed mucin secretion through an enlarged

papilla of Vater. Endoscopic retrograde cholangiopacreatography

demonstrated that the diameter of main pancreatic duct (MPD) was

dilated as 12 mm, and the MPD communicated with the cyst.

Endoscopic ultrasonography showed that size of cyst was 70 mm and

that of nodule in the cyst was 29 mm. Intraductal papillary-mucinous

carcinoma was suspected and a pylorus-preserving pancreatoduo-

denectomy was performed. Histopathologically mucinous epithelium

proliferated and formed papillary shape in the branched-dilated pan-

creatic duct, and the tumor still remained adenoma.


P3-06-4

Anaplastic Carcinoma Recurring from aBorderline-Type Mucinous Cystic Tumor of the Pancreas: A Case ReportK. Hakamada1, Y. Toyoki1, S. Narumi1, S. Yoshihara1, M. Sasaki1, N. Yajima2, S. Yagihashi2

1Department of Surgery II, 2Department of Pathology I,Hirosaki University, Hirosaki, Japan

Anaplastic carcinoma of the pancreas is rare variants of ductal

adenocarcinoma, occurring more commonly in men, usually after

50 years of age. We report an unusual case of anaplastic carcinoma

occurring one year after the resection of a mucinous cystic tumor,

borderline-type, in 38-year-old pregnant woman. A large retroperi-

toneal cystic mass, 11 cm in maximum dimension, was pointed out by

the routine ultrasonography in the first pregnancy in October 2000.

A probable diagnosis of a mucinous cystic neoplasm was made, but

she rejected surgery. In the second trimester of the second pregnancy,

she presented hematemesis and tarry stool, causing severe anemia.

Emergent distal pancreatectomy was performed on November 28,

2001 and a diagnosis of mucinous cystic tumor, borderline-type, was

made. She recovered well and delivered second baby on April 8, 2003.

A follow-up CT showed a recurrent mass near the left adrenal gland

on August 29, 2003, which was subsequently resected on October 16.

Pathology revealed a 30 mm cystic mass adjacent to the pancreatic

stump, showing a character of anaplastic carcinoma with sarcomatous

components and osteoclastoid giant cells with positive cytokeratin,

vimentin, and p53. She survived four months after the second surgery

under the close monitoring for tumor recurrence.

P3-06-5

A Case of Mucinous Cystadenocarcinoma of the PancreasN. Ito1, Y. Owa1, H. Inagaki1, K. Suzumura1, K. Takahashi2,T. Hashimoto2, T. Nonami1

1Department of Gastroenterological Surgery, 2Gastroenterology, Aichi Medical University, Aichi, Japan

A 63-year-old woman was admitted to our hospital for an abdom-

inal tumor. CT scan showed multiple cystic tumor in the left epigas-

trium. MRCP showed that the chief pancreatic duct was intact.

Angiography showed that the pancreas was being pressed by the

tumor. The diagnosis was mucinous cystic tumor of the pancreas,

which was suspected to be cancer. We conducted distal pancreatec-

tomy. The pathological finding was invasive mucinous cystadenocarci-

noma of the pancreas, stage 2 by TMN classification. UFT-E was

taken. After four months, CA19-9 level was found to be increasing.

CT scan showed a solitary liver tumor. Positoron emission tomography

showed no other metastasis. We performed partial hepatectomy with

cholecystectomy. The pathological diagnosis was metastasis of muci-

nous cystadenocarcinoma of the pancreas. Gemcitabine was adminis-

tered. CA19-9 level decreased to within the normal limits. There were

no remarkable findings of recurrence for seven months after the sec-

ond surgery. Patient with invasive mucinous cystadenocarcinoma of

the pancreas have a poor prognosis and often develop pancreatic inva-

sive ductal cancer. Multiple liver metastasis often result from invasive

mucinous cystadenocarcinoma. It is rare that solitary liver metastasis

can be excised. We report a case of a solitary liver metastasis of muci-

nous cystadenocarcinoma of the pancreas in which surgical treatment

was possible, and also present a review of the literature.

P3-06-6

A Case of Chronic Pancreatitis that wasDifficult to Distinguish from IPMTK. Yanagi, T. Kodama, H. Kinoshita, S. Aoyagi

Department of Surgery, Kurume University School ofMedicine, Kurume, Japan

A 68 year-old man admitted for hyperamylasemia was found by

abdominal US and CT to have a dilatation of the main pancreatic duct

and a cystic area in the pancreatic head. The cystic area was about

3.5 cm in size. Endoscopy showed dilatation of the orifice of the pan-

creatic duct. ERP showed a dilatation of the main pancreatic duct.

Pancreatic juice was mucilaginous but there was no mucus plug.

EUS and IDUS findings showed a multilocular cystic area. A

15 � 10 mm low echoic area protruded into part of the lumen.

IPMT was suspected, and an operation (PpPD) was performed

after obtaining sufficient informed consent.

The pathology showed dilatation of the ductus pancreaticus which

extended to the pancreatic head, along with epithelial hyperplasia

without atypical change.

The findings included invasion by inflammatory cells, inflamma-

tory granulation and deciduation of pancreatic acinus cells, and indi-

cated chronic pancreatitis.

There were no malignant findings or neoplastic lesions.

We report here a case we experienced of chronic pancreatitis

which was difficult to differentiate from IPMT.

Poster 3-07 PC Pathology

P3-07-1

Histopathologic Study on IntraductalComponents (Carcinoma in situ andCancerization of the Ducts) in PancreaticCancerB. Nobukawa, K. Suda, K. Kume, S. Yamasaki, S. Shiono,M. Takase, Y. Fukumura, H. Tanase, H. Sonoue

Department of Pathology (I), Juntendo University Schoolof Medicine, Tokyo, Japan

Intraductal components (ICs) are often observed inside and out-

side of pancreatic cancers (PCs). These intraductal lesions include


both carcinoma in situ (CIS) and cancerization of the ducts (intraduc-

tal invasion of PCs). In order to clarify characteristics of precursors of

PCs, we analyzed the histology of ICs in PCs. Thirteen cases of PCs

obtained after the publication of 5th edition of classification of

pancreatic carcinoma by Japan Pancreas Society in 2002 were stud-

ied. ICs were identified by confirmation of mural elastic fibers of the

ducts and classified into three histologic patterns such as low papil-

lary, flat, and tubular (including solid and cribriform). Numbers of

foci of ICs were observed in all 13 cases (100%). Cancerization of the

ducts were seen in all 13 cases (100%). CISs were found in 12 cases

(92%). CISs were less atypical than invasive components/canceriza-

tions of the ducts. Intraductal spreads of CISs were seen in 10 cases

(77%). Most CISs with disruption of pancreatic ducts inside of PCs

morphologically shiftted to more atypical invasive cancer. In contrast,

some CISs spread intraductally to peripheral pancreatic ducts without

invasion were mostly low papillary and partly flat. Most invasive

components/cancerizations of the ducts involving to pancreatic ducts

were more atypical and showed tubular or flat patterns. These results

suggest that less atypical low papillary ICs inside of PCs are CISs,

developing to PCs with intraductal spread.

P3-07-2

Histopathologic Study on Invasive Ductal Carcinomas (IDCs) of the Pancreaswithout Cancerous Occlusion of the MainPancreatic DuctY. Naito1,2,3, K. Suda1, B. Nobukawa1, H. Abe1, H. Kinoshita2, M. Kojiro3

1Department of Pathology (I), Juntendo University Schoolof Medicine, 2Department of Surgery, 3Department ofPathology, Kurume University School of Medicine,Kurume, Japan

Most IDCs of the pancreas are thought to be that they grow

involving the main pancreatic duct (MPD). The aims of this study

were to clarify characteristics and histopathologic differences

between both IDCs with and without cancerous occlusion of the

MPD. We analyzed 59 IDCs (56 cases of IDCs in Kurume University

Hospital and 3 cases of IDCs in Juntendo University Hospital)

histopathologically. Fourteen cases of IDCs with cancerous occlusion

of the MPD were selected to be compared with IDCs without it.

Hematoxylin-eosin, elastic van Gieson (EVG), and Ki-67-stain were

performed. The MPD was confirmed by EVG-stain to visualized

mural elastic fiber of the pancreatic ducts. IDCs without cancerous

occlusion of the MPD were 4 cases (approximately 3%). They all

were located in the pancreatic head. Compared to IDCs without and

with cancerous occlusion of the MPD, mean age were 66 and 65

years, and male-female ratio were 2/2 and 7/6, respectively. There

were no differences in tumor histology (well/moderately/poorly/

adenosquamous): 0/2/1/1, 2/10/0/1, respectively. Intraductal compo-

nents in IDCs and Ki-67 index were average 0.5 and 4.3 each cases,

and 12% and 31%, respectively. Although there were no significant

differences in such as age, sex and tumor histology among them,

number of intraductal components and Ki-67 index in IDCs without

it were less than that in IDCs with it.

P3-07-3

Histopathologic Features of IntraductalSpread and Invasion in Invasive DuctalCarcinoma of the PancreasH. Tanase, K. Suda, S. Yamasaki, B. Nobukawa

Department of Pathology, Juntendo University School of Medicine, Tokyo, Japan

Aim: To attempt discrimination between carcinoma in situ (CIS)

and the intraductal invasion/cancerization of invasive ductal carci-

noma (IDC) of the pancreas, by means of comparing the histology of

the intraductal components and venous invasion.

Method and Results: Thirty cases of IDC were examined

histopathologically. Intraductal components and blood vessel invasion

in IDC were estimated by specimens stained with hematoxylin-eosin

and elastica van Gieson (EVG). Intraductal components of IDC were

found in 261 ducts in 28 out of the 30 cases, and in 2.3 ducts per one

section of one case on average. The intraductal components of IDC

were divided into three histological patterns, as follows: low papillary

(including flat), tubular (including solid and cribriform) and mixed

(low papillary plus tubular). The incidences of the low papillary, tubu-

lar and mixed patterns were 39% (102 ducts), 56% (145 ducts), and

5% (14 ducts), out of the 261 ducts, respectively. The histological pat-

tern of venous invasion was tubular in all cases, except in one case

with a few low papillary patterns.

Conclusion: A tubular pattern of intraductal components in

IDC of the pancreas indicates intraductal invasion, while a low papil-

lary pattern indicates carcinoma in situ or in the location to which it

has spread.

P3-07-4

Immunohistochemical Expression ofReceptor-Tyrosine Kinase c-kit Protein in Human Pancreatic CancerJ. Ma, I. Hirai, T. Moriya, M. Mizutani, F. Sakurai, W. Kimura

First Department of Surgery, Yamagata University Schoolof Medcine, Yamagata, Japan

Aim: The proto-oncogene c-kit encodes a trans-membrane tyro-

sine-kinase receptor, which is related to the platelet-derived growth-

factor/CSF-1 receptor subfamily. The oncogenic potential of c-kit has

been demonstrated through its expression in NIH 3T3 mouse fibrob-

lasts. After activation of the receptor, enhanced cell proliferation rate

and increased capacity of colony formation in soft agar were

observed. Recently, a selective c-kit inhibitor Glivec (STI571) has

been introduced into the chemotherapy of GIST, and showed promi-

nent effects against c-kit (�) GIST.

Materials and Methods: The expression of c-kit in pancreatic

tumor and in normal pancreatic tissue will be detected by immuno-

histochemistry staining. Primary antibody against c-kit (Poly; A4502,

Dako, Japan, 1:50 dilution) will be used. c-kit expression in pan-

creatic tumor and normal pancreatic tissue will be quantified by


counting at least 1,000 cells in each sample. Immunohistochemical

findings is scored positive when at least 5% of the neoplastic cells or

normal pancreatic tissue is immunoreactive.

Results: The expression of c-kit in 45 pancreatic cancers,

16 IPMT, 3 MCT and in 5 normal pancreatic tissue will be studied in

this study. In fact, twenty cases of pancreatic cancer have been

immunostained and 16 cases were identified as positive cases. The

relationship between expression of c-kit and clinicopathological

factors, and impact of c-kit expression on survival of patients with

pancreatic cancer will also evaluated in this study. All of the results

and conclusions will be finished and re-submitted soon.

P3-07-5

Acinar Cell Carcinoma Mimicking DuodenalSubmucosal Tumor: A Case ReportH. Kanemoto, K. Uesaka, A. Maeda, T. Ebata,K. Matsunaga, J. Izai

Division of Hepato-Biliary-Pancreatic Surgery, ShizuokaCancer Center, Shizuoka, Japan

Although acinar cell carcinoma (ACC) usually forms a solid

mass, we present an usual type of ACC mainly located in the submu-

cosal layer of the duodenum.

A 66 year-old man was admitted to our hospital for surgical treat-

ment of sigmoid colon carcinoma. Preoperative computed tomogra-

phy incidentally showed a duodenal tumor with invasion to the head

of the pancreas. Endoscopic examination revealed a Borrmann type II

tumor in the duodenum, involving the minor papilla. The round wall

of the tumor was coved by non-cancerous duodenal mucosa.

Pathologic examination of the biopsy specimen revealed suspicious of

neuroendocrine tumor. Magnetic resonance pancreatography showed

dilatation of the pancreatic duct with a filling-defect. Our preopera-

tive diagnosis was submucosal tumor of the duodenum with invasion

to the pancreas. The patient underwent pancreaticoduodenectomy and

sigmoidectomy. On the cut surface of the specimen, a whitish mass

occupied a half circle of the duodenum with ulcer formation and was

mainly located in the submucosal layer. The tumor invaded to the head

of the pancreas, and extended into Santorini’s duct. Microscopic

examination revealed the tumor was ACC. Immunohistochemical

staining was diffusely positive for �1-antitrypsin. In electron micro-

scopic examination, zymogen granules were ultrastructually detected.

There are two possibilities concerning the origin of this unusual

ACC. One is ectopic pancreas in the duodenal wall, and the other is

acinar cells close to minor papilla.

Poster 3-08 PC Molecular Targeting

P3-08-1

DPD mRNA Expression Level andChemosensitivity for S-1 in PancreaticCancerK. Hayashi1, K. Uchida1, T. Hatori1, T. Imaizumi2, K. Takasaki1

1Department of Surgery, Institute of Gastroenterology,Tokyo Women’s Medical University, 2Tokai University, Tokyo, Japan

Purpose: Although the prognosis in patients with pancreatic

adenocarcinoma (PAC) has been awfully poor, we recently reported

unusually high response rate and survival benefit of S-1 treatment in

patients with PAC. The aim of this study was to reveal genetic back-

grounds of this unique activity of S-1 against PAC. S-1 is a novel oral

fluoropyrimidine derivative consisting of Tegafur (FT) and DPD

inhibitor (5-chloro-2,4-dihydroxypyridine; CDHP), and accordingly

we focused on DPD whether its mRNA expression level reflected

chemosensitivity in PAC.

Patients and Methods: 28 advanced PAC patients and 30

advanced colorectal cancer (CRC) treated with S-1 based chemother-

apy were enrolled in this study. The mRNA was isolated from paraf-

fin-embedded pretreatment primary tumor specimens, and relative

expression levels of each DPD/�-actin were measured using a quan-

titative reverse transcription polymerase chain reaction (RT-PCR)

(Taqman®) system.

Results: DPD gene expression was significantly higher in PAC

compared with CRC (p � 0.0001: median expression; 1.38/0.56).

DPD gene expression in PAC patients who responded to S-1

chemotherapy was significantly lower in PAC patients who did not

respond to the chemotherapy (p � 0.012, Mann-Whitney U test).

Conclusions: These results suggest one of reasons why S-1

based chemotherapy was successful in patients with PAC. And intra-

tumoral DPD gene expression of PAC could be a predictive factor for

response to chemotherapy with S-1.

P3-08-2

Involvement of p38 Mitogen-ActivatedProtein Kinase in Chemotherapy-InducedApoptosis in Human Pancreatic Cancer CellsK. Koizumi1, S. Tanno2, A. Habiro1, Y. Nakano1, M. Osanai1,Y. Mizukami1, T. Okumura2, Y. Kohgo1

1Third Department of Internal Medicine, 2Department ofGeneral Medicine, Asahikawa Medical College,Asahikawa, Japan

The p38 mitogen-activated protein kinase (MAPK) signaling

pathway is a stress-activated protein kinase involved in cellular

responses to various environmental perturbations. In this study, we


investigated the molecular mechanism of chemotherapeutic agents-

induced cytotoxicity with special reference to p38 MAPK in human

pancreatic cancer cell lines. We found that apoptosis was induced by

chemotherapeutic agents, such as gemcitabine, cisplatin, taxol or

5-FU, in PK-1, -8 and PCI-43 cell lines. p38 MAPK activation was

induced by these agents in a dose-dependent manner. A selective p38

MAPK inhibitor, SB203580, significantly inhibited chemotherapeu-

tic agents-induced apoptosis in both cell lines, suggesting that phos-

phorylation of p38 MAPK may play a key role in chemotherapeutic

agents-induced apoptosis in pancreatic cancer cells. We also demon-

strated that MKK3/6, an upstream activator of p38 MAPK, was phos-

phorylated by chemotherapeutic agents. These results suggest that

chemotherapeutic agents-induced apoptosis in human pancreatic can-

cer cells seems to be mediated by the MKK3/6-p38 MAPK signaling

pathway. To confirm that p38 MAPK activation is involved in apop-

tosis induced by chemotherapeutic agents, cells were transfected with

the expression vectors encoding dominant-negative (DN) or constitu-

tively-active (CA) cDNA for p38 MAPK. Activation of p38 MAPK

signaling by CA-p38 enhanced apoptosis induced by chemotherapeu-

tic agents, whereas DN-p38 suppressed the induction of apoptosis.

These results suggest that p38 MAPK is involved in chemotherapeu-

tic agents-induced cytotoxicity in human pancreatic cancer cells and

that p38 MAPK should be listed as a novel molecular target for

human pancreatic cancer therapies.

P3-08-3

Activation of Peroxisome ProliferatorActivated Gamma/Retinoid X Alpha Pathway Inhibit Pancreatic Cancer CellGrowthS. Nakamori, M. Tsujie, S. Nakahira, Y. Takahashi, S. Marubashi, A. Miyamoto, H. Nagano, K. Dono, K. Umeshita, M. Sakon, M. Monden


Peroxisome proliferator-activated receptor gamma (PPAR�), a lig-

and activated transcription factor, forms a heterodimer with retinoid

X receptor alpha (RXR�), and its transcriptional activity is thought to

be maximal in the presence of both PPAR� and RXR� ligands.

Although previous studies suggested that thiazolidinediones (TZDs),

known as PPAR� ligands inhibit the growth of certain types of cancer

cells, little is known about the growth inhibitory effects in pancreatic

cancer cells We examined the effects of troglitazone (one type of

TZDs) and 9-cis retinoic acid, a RXR� ligand on activation of

PPAR�/RXR� and growth inhibition of human pancreatic cancer cell

lines (AsPC1, BxPC3, PSN1, PCI6, Panc1, KMP-4, and KMP-7).

Combined treatment of troglitazone and 9-cis retinoic acid showed

enhanced transcriptional activity and enhanced antiproliferative

effects. In PSN1 cells, G1 cell cycle arrest and apoptosis were

induced by troglitazone and these effects were enhanced with addi-

tional 9-cis RA. Our findings suggest that activation of

PPAR�/RXR� pathway might play an important role in growth inhi-

bition of pancreatic cancer cells via G1 cell cycle arrest and apopto-

sis. This nuclear receptor may have a potential for a novel molecular

target for treatment of pancreatic cancers.

P3-08-4

Strategy toward the Molecular TargetsInvolved in the Invasion and Metastasis of Pancreatic CancerR. Doi, M. Koizumi, E. Toyoda, K. Kami, T. Mori, D. Ito, T. Masui, Y. Kawaguchi, K. Fujimoto, M. Imamura


The results of surgical treatments of pancreatic cancer are poor

because the disease usually relapses as liver, peritoneal and local

recurrence. To overcome the disease relapse, it is important to clarify

the mechanisms involved in cancer invasion and metastasis which

could be novel molecular targets. We tested several molecules that

would be a novel target of pancreatic cancer. We tested the involve-

ment of RECK, PDX-1 and SDF-1/CXCR4 axis in pancreatic cancer

tissues or pancreatic cancer cells. We have developed and evaluated

the effects of novel suppressor or antagonists against some of those

molecules. The RECK protein was not expressed in normal pancreatic

duct. Fifty-two percent of pancreatic cancer tissues expressed RECK

protein. The RECK expression was correlated with low invasiveness

(p � 0.044). The survival of the patients with RECK-positive cancer

was better than that with RECK-negative. Activation of MMP-9 was

not correlated with RECK expression, but activation of MMP-2

was inversely correlated with RECK expression. PDX-1 express-

ion was correlated with lymph-node metastasis and the tumor grade.

The survival of patients with negative PDX-1 was better than positive

PDX-1. PDX-1 expression was negative in pancreatic cancer cell

lines. Enforced expression of PDX-1 stimulated migration activity.

CXCR4 expressed in pancreatic cancer cells and SDF-1 stimulated

the invasion and migration of pancreatic cancer cells. Novel CXCR4

receptor antagonist suppressed the invasion and migration of pancre-

atic cancer cells. We conclude that the molecules that are involved in

the invasion and migration of pancreatic cancer could be a novel mol-

ecular target for pancreatic cancer treatment.

P3-08-5

The Dominant-Negative Form of ETS-1Efficiently Suppresses Angiogenesis and Induces Specific Gene Profiles inPancreatic Cancer CellsL.P. Lefter1, M. Sunamura2, T. Furukawa3, V. Scripcariu1, K. Takeda2, S. Matsuno2, A. Horii3

1Third Department of Surgery, University Hospital,Romania, 2Department of Gastroenterological Surgery,3Department of Molecular Pathology, Tohoku UniversityHospital, Sendai, Japan

ETS transcription factors regulate many genes associated with

tumor invasion, angiogenesis and cell adhesion. This particularity led

us to speculate that an enhanced antitumor effect could be achieved

by elimination of the transactivation activity of ETS-1 and also of its

targets. However, to date little is known about the role of ETS-1 in

pancreatic cancer.


In this study, we utilised an adenovirus vector encoding trans-

dominant mutant ETS-1 acting in a dominant negative manner over

ETS-1, by competing the DNA-binding.

Adenoviral transfer of ETS-DN in pancreatic tumor cell lines did

not affected their proliferation rate in vitro, but significantly inhibited

their in vivo growth in immunodeficient mice, at least in part through

down-regulation of MMP1 and u-AP expression. Micro-vessel den-

sity assessed in SCID mice xenografts demonstrated significantly

lower neovascularization in tumors with down-regulated ETS-1.

The underlying mechanism as well as the targets involved in ETS-1

downstream were further analysed using a systematic approach, based

on DNA microarray technology to establish a first catalog of genes

whose expression is altered by ETS-1 and, as such, potentially

involved in the regulation of pancreatic cancer cells behavior.

Interestingly, most of the genes encoding secretory proteins, receptors

and cytosolic proteins were down-regulated upon ETS-1 suppression.

The ‘benign’ transformations induced by ETS-DN indicate that

the suppression of ETS-1 activity may be considered as a therapeutic

option for pancreatic cancer. Additionally, this study establishes a

first catalog of genes whose expression is altered upon transcription-

ally down-regulation of ETS-1. Yet, the information gathered should

be quite useful to future investigations on the molecular mechanisms

of oncogenic transformation.

P3-08-6

BMP4 Inhibits Cell Growth with Induction of p21 in Pancreatic Cancer Cell Line Panc-1S. Hamada, K. Satoh, K. Kimura, T. Shimosegawa

Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan

Background and Aim: Bone morphogenetic protein 4 (BMP4)

is known as a potent cytokine which correlates with cell fate and

differentiation. The effects of BMP4 on pancreatic cancer cell have

not been well studied, thus, we investigated the role of BMP4 in pan-

creatic cancer cell growth and signal transduction systems.

Methods: Human pancreatic cancer cell lines used in this study

were Panc-1 and BXPC-3. BrdU assay was performed to assess the

BMP4 effect on cell growth. Inhibitor of differentiation and

DNA binding-1, 2, 3 (ID1, ID2, ID3) genes expression was analyzed

by reverse transcription-PCR. Cyclin D1 and p21 expression or

caspase3 activation, and phosphorylated smad 1 were analyzed by

Western blot.

Results: Thirty % of growth inhibitory effect was found in

Panc-1 cells, after 48 hours incubation at 50 ng/ml concentration of

BMP4 in Panc-1 cells. In contrast, no significant effect was observed

in BXPC-3. This growth inhibitory effect was completely abrogated

by adding noggin, natural specific inhibitor of BMP4. Both cells

showed smad 1 phophorylation 1 h. after adding BMP4, indicating the

activation of its downstream. BMP4 induced p21 expression and

caspase3 activation in Panc-1 cells, but not in BXPC-3 cells.

Interestingly, BMP4 induced ID family genes in both cells.

Conclusion: These results suggested that BMP4 act as growth

suppressor in Panc-1 cells through different signaling pathway from

that of BXPC-3, which did not show the growth inhibition. BMP4

induced p21 expression and caspase3 activation in Panc-1 cells

seemed to be possible mechanisms of its growth inhibitory effect.

P3-08-7

NDRG-1/CAP43 as a Novel Molecular Target for Malignancy in Pancreatic CancerY. Maruyama1,2, A. Jimi3, A. Kawahara3, T. Yokoyama3, M. Kage3, S. Oie5, M. Ono4, M. Kuwano1, S. Aoyagi2, H. Kinoshita2

Department of Research Center for Innovate Cancer 1Therapy, 2Surgery, 3Pathology, Kurume University, 4Department of Medical Biochemistry,Graduate School of Medical Science, Kyushu University,Fukuoka, 5Hanno Research Center of TAIHOPharmaceutical Co., Ltd., Saitama, Japan

Purpose: NDRG-1/CAP43 (N-myc downstream regulated

gene/43 protein free intracellular calcium) plays a key role in growth

and differentiation in normal tissues, and also in metastasis suppres-

sion in some human malignancies. The purpose of this study is to

examine whether this gene expression is closely associated with

malignant characteristics in pancreatic cancers. In particular, we

focused on whether NDRG-1/CAP43 gene expression is correlated

with poor prognosis and TNM classification.

Experimental Design: (1) In the immunohistochemical analy-

sis with clinical samples, we examined specimens taken from

34 patients after operation and 5 patients who were held an autopsy

after death with ductal adenocarcinoma of the pancreas. Expression

of NDRG-1/CAP43 and N-myc was immunohistochemically

determined by using specific antibodies against NDRG-1/CAP43 and

N-myc.

(2) By using pancreatic cancer cell lines in culture, we also deter-

mined expression levels of NDRG-1/CAP43 by Western blot analysis.

Invasion and angiogenesis activities of pancreatic cancer cells trans-

fected with NDRG-1/CAP43 cDNA in vitro as well as in vivo were

also assayed.

Results: NDRG-1/CAP43 protein expression was found to be

inversely correlated with N-myc expression when many pancreatic

cancer cell lines were examined. By immunohistochemical analysis,

in 34 patients we classified into two groups of NDRG-1/CAP43 pos-

itive (19) and reduce (15). Reduced expression group was signifi-

cantly correlated with a short period of over all survival after radical

operation (p � 0.007), but not with TNM classification.

Conclusion: From our present study, we first present our result

that patients with an unfavorable clinical outcome is characterized by

reduced expression of NDRG-1/CAP43 protein. NDRG-1/CAP43

could be be a useful candidate to predict over all survival of patients

with pancreatic cancer.


Poster 3-09 PC Biotherapy

P3-09-1

Dendritic Cell Immunotherapy forMetastatic Pancreatic CancerS. Egawa, K. Tsuchihara, T. Okada, H. Abe, S. Fukuyama,M. Sunamura, K. Takeda, S. Matsuno

Department of Gastroenterological Surgery, TohokuUniversity, Sendai, Japan

Background and Aim: Since the prognosis of metastatic pan-

creatic cancer is extremely poor, we have developed a dendritic cell

based immunotherapy using intraoperative radiotherapy (IOR) fol-

lowed by intra-tumoral injection of autologous dendritic cells (DCs),

aiming the uptaking of apoptotic cancer cells as bulk tumor antigens.

Patients and Methods: Patients with metastatic disease,

PS � 2, age � 70, underwent leukapheresis 6 days before laparo-

tomy. The monocyte-enriched fraction was cultured with 1,000 IU/ml

of GM-CSF and IL-4 to induce immature autologous DCs. IOR of

25 Gy and bypass procedures were followed by DC intratumor injec-

tion. Out of 16 patients who entered this protocol, last six patients

received systemic chemotherapy from 10th postoperative day.

Results: Obtained CD1a�, CD14�, CD86�, MHC class II�,

CD83� DCs (1–5 � 107) were successfully injected and there was no

severe toxicity Grade III or more. Several patients had systemic fever

38 degree, which was treated conservatively. Median survival of

16 patients was 5 months with no significant difference with histori-

cal controls. However, two patients survived 34 and 18 months with a

remarkable regression of the liver metastasis, while there was no long

term survivor in control group.

Conclusion: DC based immunotherapy is feasible with promis-

ing treatment results. Improvements by the combination with

chemotherapy and gene modifications will further be investigated.

P3-09-2

Improved Function of Circulating DendriticCells in Patients with Pancreatic Cancerafter Surgical ProcedureK. Takahashi, S. Takai, H. Yanagimoto, S. Satoi, H. Toyokawa, N. Terakawa, A.-H. Kwon, Y. Kamiyama

Department of Surgery, Kansai Medical University,Moriguchi, Japan

Purpose and Experimental Design: A defective host anti-

tumor imune response is an important mechanism allowing tumors to

evade immune system controls. Dendritic cells (DCs) play a central

role in immune surveillance and also contribute to an essential part of

protection against cancer. DCs could be divided into two subsets:

CD11c� DCs (DC1: myeloid DC population) and CD11c� DCs

(DC2: lymphoid DC population). This study aimed to investigate the

number and function of circulating DCs in patients with pancreatic

cancer using flow cytometric assays and mixed leukocyte reaction

(MLR), and we evaluated the effects of these changes in patients

with pancreatic cancer (PC) before and after surgical resection.

Here, 35 patients with pancreatic cancer and 18 healthy controls were

investigated.

Results: The number and function of DC1s were significantly

impaired in cancer patients. There were no significant differences in

peripheral blood mononuclear cells and lymphocyte subsets between

PC and controls. No significant differences in proliferative response

of T lymphocytes and Natural Killer cell activity were also found. The

reduced function of circulating DC1s was closely associated with the

tumor staging. In patients who underwent surgery, the allostimulatory

activity of DC1s at post surgery was significantly increased more than

those at pre surgery. Immunosuppressive cytokine, TGF-�1 level at

post surgery was significantly decreased than pre surgery. There were

no changes in CD4/8, NK activity and proliferative response of

T lymphocytes at peri-operative period.

Conclusion: It is suggested that surgical resection of pancreatic

cancer might be related to improve host immune function.

P3-09-3

Antitumor Immunity Induced by HybridsFused Mature DC with Mouse IL-12Expressing Human Pancreatic Ductal CellCarcinoma Cell LineT. Hisano, Y. Arita, T. Ito, K. Kawabe, T. Oono, J. Gibo, N. Inoue, M. Kojima, H. Nawata

Department of Medicine and Bioregulatory Science,Graduate School of Medical Sciences, Kyushu University,Fukuoka, Japan

In order to enhance antitumor immunity, it is necessary to recruit

both CD4� and CD8� T cell responses for the eradication of cancer

cells in patients. CD8� T cell’s response is major histocompatibility

complex class I (MHC-I)-restricted and high presentation is needed to

induce CTL response efficiently. However, the efficiency of cross-

priming is very low. On the other hand the fusion of DC with tumor

cells which include the endogenous expression of multiple tumor anti-

gens is considered to induce their presentation in context with high

levels of MHC-I, -II and co-stimulatory molecules of the DC partner.

Therefore the hybrid cells can induce CTL response efficiently.

However previous reports did not pay any attention to maturation of

the DC partner. CD4� T cell’s response is MHC-II-restricted and the

mature DCs enhance expressions of MHC and co-stimulatory mole-

cules, whereas those of expressions in immature DCs is low. To

express MHC-II, DCs must take up exogenous protein Ags, process

and present because most tumors express MHC-I but MHC-II.

Furthermore, though mature DC produces IL-12 and enhances T cell

response, IL-12 production by DC increases during the first 24 h of

maturation and declined by 48 h. Therefore if DC could produce IL-12

constantly, the T cell response could be enhanced. In the present

report, we fused DC with human pancreatic ductal cell carcinoma cell

line which transduced with vector expressing IL-12 and determined

tumor-specific CTL. Consequently we could induce CTL response

efficiently. Furthermore, we could induce stronger response under the

condition medium which contained IL-12.


P3-09-4

Non-Myeloablative Allogeneic Stem Cell Transplantation for Patients withUnresectable Pancreatic CancerK. Tsuruta, T. Takahashi, Y. Omuro, G. Matsumoto, H. Sakamaki, Y. Maeda, K. Hiruma, T. Sasaki

Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

Purpose: To clarify whether non-myeloablative allogeneic stem

cell transplantation (NST) can produce the graft versus tumor effect

(GVT effect) in patients with pancreatic cancer.

Patients and Methods: A pilot trial of NST was conducted in

5 patients with unresectable pancreatic cancer. Preparative condition-

ing consisted of administration of 60 mg of cyclophophamide per

kilogram on days 6 and 7 before transplantation, followed by 25 mg

fludarabine per square meter of body surface on each of the last

5 days prior to transplantation. Cyclosporine was started 4 days

before transplantation. Peripheral-blood stem cells from the patients’

HLA identical sibling were transfused into the patients.

Results: Complete donor-T cell chimerism in peripheral blood

was obtained in 4 patients on day 15 after transplantation. NST

resulted in tumor reduction on CT in 2 patients, decreasing levels of

tumor markers in 2 patients, pain relief in 2 patients and a decrease in

pleural fluid in 1 patient. Two patients developed acute graft versus

host disease (GVHD) of grade II or grade III and two had chronic

GVHD involving skin and/or liver. Administration of immunosup-

pressive drugs for treatment of GVHD resulted in the elevation of

tumor marker levels.

Conclusion: These findings suggest that NST induces a GVT

effect on pancreatic cancer.

P3-09-5

ZD1839 (IRESSA), a Selective EpidermalGrowth Factor Receptor Tyrosine KinaseInhibitor, Inhibits Pancreatic Cancer CellGrowth, Invasion, and Colony FormationH. Friess1, J. Li1, M.W. Büchler1, M. Korc2, J. Kleeff1

1Department of General Surgery, University of Heidelberg, Heidelberg, Germany, 2Departments ofMedicine, and Pharmacology and Toxicology, Dartmouth Hitchcock Medical Center, Dartmouth Medical School, Lebanon, NH, USA

Background: Pancreatic cancer is a devastating malignancy,

characterized by low responsiveness to conventional chemotherapies.

ZD1839 is a tyrosine kinase inhibitor of the epidermal growth factor

receptor (EGFR) that has shown clinical activity against EGFR-

expressing tumors. Since pancreatic cancers frequently overexpress

EGFR and its ligands, our aim was to investigate the potential role of

ZD1839 in this disease.

Methods: The GI50 of ZD1839 as well as the effects of ZD1839

on growth factor actions in pancreatic cancer cell lines was analyzed

using MTT assays. FACS analysis using Annexin and PI staining was

performed to study cell cycle, apoptosis, and cell death. Western blot

analysis was carried out to investigate EGFR expression levels in

pancreatic cancer cell lines, as well as MAP kinase and EGFR

phosphorylation. Soft agar assays were used to measure colony for-

mations. Invasiveness of cancer cells was analyzed using Matrigel

coated filters.

Results: ZD1839 inhibited cell proliferation of pancreatic can-

cer cell lines with GI50 concentrations ranging from 2.5 to over

10 M. ZD1839 completely inhibited EGF induced cell proliferation,

but did not significantly influence IGF induced mitogenesis. ZD1839

also completely abolished EGF induced phosphorylation of EGFR

and MAP kinase. Furthermore, ZD1839 inhibited basal and EGF

induced anchorage-independent cell growth and invasion.

Conclusion: Our data demonstrate that ZD1839 inhibits pan-

creatic cancer cell growth through EGFR dependent pathways.

ZD1839 also inhibits anchorage-independent growth and invasive-

ness, suggesting that ZD1839 may offer a new approach for the treat-

ment of pancreatic cancer.

P3-09-6

NF-�B Inhibitor Enhances the Anti-TumorEffect of Tumor Necrosis Factor-� andIonizing Radiation in Pancreas Cancer CellsG. Matsumoto1, M. Muta1, H. Baba1, K. Tsuruta1, A. Okamoto1, K. Umezawa2, M. Toi1

1Department of Surgery, Tokyo Metropolitan KomagomeHospital, 2Department of Applied Chemistry, Faculty ofScience and Technology, Keio University, Tokyo, Japan

Pancreatic cancer is often resistant to chemotherapy and ionizing

radiation (IR). Constitutive activation of NF-B is regarded as one of

the mechanisms of therapeutic resistance in pancreatic cancer. We

recently examined the impact of NF-B inhibition on the sensitivity

to tumor necrosis factor (TNF)-� and/or IR in four human pancreas

cancer cell lines including A818-1, Colo357, PK-8 and Panc-1.

DHMEQ was used for inhibiting NF-B function. Apoptotic effects

were assessed by Annexin-V staining and FACS analysis. Inhibitory

effects of cell growth were determined by MTT assay and trypan

blue exclusion. In A818-1, that is basically radio-resistant, the com-

bination of TNF-� and DHMEQ treatment for six hours induced

apoptosis remarkably either in the presence or absence of IR (20 Gy).

In Colo357, that is radio-sensitive, the combination effect of TNF-�was not so remarkable but was enhanced by IR significantly. Other

two cell lines also showed different properties with respect to the

combination effects of DHMEQ, TNF-�, and IR. The expression of

anti-apoptotic protein, c-FLIP changed in association with the apop-

totic events. Combination of TNF-� and DHMEQ treatment for

twenty-four hours showed synergistic inhibitory effects of cell

growth in A818-1, Colo357, and PK-8. Importantly, DHMEQ treat-

ment for three hours combined with TNF-� and/or IR also suffi-

ciently inhibited cell survival at twenty-four hours. These data

suggest that NF-B inhibition may enhance the sensitivity to anti-

tumor treatments including TNF-� and IR in pancreatic cancer.

DHMEQ might be a useful tool to overcome the therapeutic resis-

tance in pancreas cancer.


P3-09-7

Modification of Radiosensitivity ofPancreatic Cancer Xenograft by FarnesylProtein Transferase Inhibitor and MEKInhibitorY. Matsui1, M. Iwakawa2, T. Asano3, T. Kenmochi3, T. Ochiai3

1Department of General Surgery, Shimizu Kousei Hospital, 2Frontier Research Center, National Institute of Radiological Sciences, 3Department of AcademicSurgery, Graduate School of Medicine, Chiba University,Chiba, Japan

We investigated the effects of the farnesyl transferase inhibitor

(FTI) manumycin and the MEK inhibitor PD98059 on growth of

human pancreatic cancer, with mutant (SUIT2) or wild type (BxPC-3)

K-ras, xenografted into nude mice.

Tumor growth was not reduced by either of the agents at a dose of

3 mg/kg without irradiation. Growth of SUIT2 irradiated at 15 Gy or

30 Gy was reduced by manumycin and PD98059: at 15 Gy, tumor

volume doubling time (TVDT) increased from 18.6 � 3.8 days to

36.3 � 14.2 days with PD98059 (p � 0.05); at 30 Gy, TVDT

increased from 32.8 � 6.8 days to 70.5 � 10.5 days and 70.7 � 1.5

days, respectively. Manumycin tended to reduce growth of BxPC-3,

but the difference in TVDT was not statistically significant. PD98059

significantly increased the TVDT of BxPC-3 at 30 Gy from

34.4 � 18 to 62.6 � 9.8 at 30 Gy. The present results suggest that Ras

signaling pathways are potential targets for manipulation of radiosen-

sitivity, and that induction of an alternative pathway may enhance

radiosensitivity of pancreatic cancer.

Poster 3-10 Image Diagnosis

P3-10-1

Multidetector-Row CT (MDCT) for ClinicalStaging of Pancreatic CancerS. Satoi1, A. Komemushi2, S. Takai1, N. Tanigawa2, T. Ozaki1, R. Yui1, Y. Matsui1, A.-H. Kwon1, S. Sawada2, Y. Kamiyama1

Departments of 1Surgery and 2Radiology, Kansai MedicalUniversity, Osaka, Japan

Background: The use of multiple detector rows in CT scan

allows faster scanning and thinner collimation, which may result in

true volume acquisitions and accurate diagnoses. This study was per-

formed to determine the diagnostic value of preoperative MDCT on

liver metastasis and tumor extension of the pancreatic cancer.

Patients and Methods: Thirty-seven patients with pancreatic

cancer were evaluated with MDCT between September 2002 and

December 2003. Fifteen patients who had locally advanced tumors,

underwent pancreatectomies and 22 patients had metastatic liver

tumors. In all patients, CE-CT, MRI, and tube angiography were

performed. Findings of liver metastasis and tumor extension were

compared with MDCT. Furthermore, MDCT findings were compared

with intraoperative findings.

Results: On the diagnosis of liver metastasis, MDCT had a sen-

sitivity of 95% (21/22), and CT/CT angiogram/MRI had a sensitivity

of 73% (16/22). Five patients who were diagnosed with liver metas-

tasis with MDCT only had small liver tumors (around 10 mm in diam-

eter) on the surface of the liver, which were confirmed during surgery.

On the compatibility of MDCT findings with the operative findings

(n � 15), MDCT made more accurate diagnoses of tumor extension

than tube angiogram, CECT, and MRI. Especially, MDCT clearly

detected the extent of vascular invasion into the portal vein and artery.

Conclusion: MDCT provides valuable preoperative information

on the therapeutic strategy of pancreatic cancer and can be used as a

noninvasive alternative to catheter angiography before oncologic pan-

creatic surgery.

P3-10-2

A New Strategy for the 3D-Diagnosis of the Pancreatic and Biliary Diseases UsingMulti-Detector Row CT (MD-CT)-VirtualCholangiography and 3-D Multi-CholangiographyN. Sata, K. Shimura, M. Koizumi, M. Tsukahara, K. Yoshizawa, K. Kurihara, H. Nagai

Department of Surgery, Jichi Medical School, Tochigi,Japan

Background: Recent advances in the technology of multi-

detector row CT (MD-CT) provide a new aspect in the diagnosis of

the pancreatic and biliary diseases. Virtual cholangioscopy and 3-D

imaging of the biliary tree united with vessels, the upper GI tract and

the pancreas (3-D multi-cholangiography) are evaluated for the diag-

nosis of the pancreatic and biliary malignancies.

Materials and Methods: 10 cases (7: bile duct carcinoma,

2: pancreatic carcinoma, 1: ampullary carcinoma) were included in

this study. After administrating biliary contrast medium intravenously

(iotroxatemeglumine) or via bile drainage tube (iomeprol) for the

image of the biliary tree, intravenous bolus infusion of 300 ml iodine

contrast medium (iomeprol) was performed for the image of the arter-

ies and the portal vein and assessed by 16-row MD-CT (SOMATON

Sensation 16®, Siemens). The DICOM images were processed in a

workstation (M900 Quadra®, Ziosoft) and virtual cholangiographies

and 3-D multi-cholangiographies were produced from the sources.

Results: Virtual cholangioscopies contributed to the preopera-

tive diagnosis for the bile duct cancer and the ampullary cancer. 3-D

multi-cholangiographies clearly described the location of the pancre-

atic cancer and provided the information for its resection.

Conclusions: These novel imaging techniques contributed to

3-D preoperative simulation and could replace many of the legacy

images, such as various cholangiographies, hypotonic duodenogra-

phy, and angiography. Especially 3-D multi-cholangiography solely

provided most of the necessary preoperative information.


P3-10-3

Efficacy of Computed Tomography in the Diagnosis of Metastatic Lesions from Pancreatic CancerA. Sawaki1, K. Okubo1, N. Mizuno1, Y. Shimizu2, T. Isaka1,H. Imaoka1, Y. Okamoto1, R. Ashida1, K. Yamao1

1Department of Gastroenterology, 2Department of Gastroenterological Surgery, Aichi Cancer CenterHospital, Nagoya, Japan

Background: Computed tomograghy (CT) is one of the most

important diagnostic modalities for pancreatic cancer staging, but

diagnostic value of CT in small liver metastases and peritoneal dis-

semination is not obvious.

Purpose: We evaluated the usefulness of CT in the diagnosis of

liver metastases, peritoneal dissemination and ascites in patients with

pancreatic cancer.

Materials and Methods: A total of thirty-three patients

(18 men, 15 women; mean age 57.4 years) were suffering from gas-

trointestinal tract obstruction due to cancer invasion to the duodenum.

These patients underwent enhanced CT preoperatively, followed by

gastro-jejunostomy in our institute from April 1998 to March 2003.

Liver metastases and peritoneal disseminations were evaluated

macro- and microscopically during the operation. Retrospective eval-

uation by medical records was carried out.

Results: The diagnostic accuracy for liver metastases, peritoneal

dissemination and ascites was 78.8%, 72.7%, 72.7%, and the

specificity 60.0%, 69.7%, 72.7% respectively. In one case, small per-

fusion defects on CT during arterial portography was detected

although no metastatic lesion was recognized in conventional CT and

ultrasonography.

Conclusion: The diagnostic accuracy and specificity with CT

for metastatic lesions from pancreatic cancer was not enough. CT

during arterial portography or contrast-enhanced ultrasonography

may improve the diagnostic accuracy and specificity rate in especial

liver metastases.

P3-10-4

Three-Dimensional Structure of PeripheralExocrine PancreasN. Ashizawa1, T. Yoneyama2, T. Sakai3

1Department of Internal Medicine, Tamatsukuri Kousei-nenkin Hospital, Yatsuka, 2Department ofBiosignaling and Radioisotope Experiment Center forIntegrated Research in Science, Shimane University,Izumo, 3Sakai Electron Microscope ApplicationLaboratory, Saitama, Japan

The normal three-dimensional structure of the peripheral exocrine

pancreas is unclear and remains controversial. The intercellular secre-

tory canaliculi, the central lumina, and the lumina of peripheral inter-

calated ducts are each less than 1.0 m in diameter, and can not be

visualized by conventional light microscopic examination.

Furthermore, it is necessary for the identification of these lumina to

observe microvilli (0.1 m in diameter) on their inner surfaces by

electron microscopy. To elucidate the three-dimensional structure of

these cells and lumina, we prepared about five hundred 0.1 m-thick

serial sections of rat normal pancreatic tissue, and examined only one

section in each group constituted of 10 serial sections by transmission

electron microscopic (TEM) examinations. Using TEM photographs

(final magnification � 1,600) of about 50 sections, the basement

membranes of acini and intercalated ducts, the outlines of centroaci-

nar cells, and the inner surfaces of these lumina were traced onto

transparent sheets, after which the traced materials on each sheet were

reconstructed and examined. Our results showed that (1) the cyto-

plasmic process of centroacinar cells extended along the central

lumen, and then connected with an intercalated duct cell or another

centroacinar cell, and (2) the central lumen and intercellular secretory

canaliculus had branches, however, no anastomosis.

P3-10-5

New Diagnostic Method to Detect EarlyPancreatic CancerH. Hasegawa1, S. Matsuno2, K. Majima4, S. Egawa2, A. Sato4, Y. Shioyama3, R. Amemiya3, F. Yoshimi3, Y. Asato3, S. Mishiro1

1Toshiba General Hospital, 2First Department of Surgery,Tohoku University, School of Medicine, 3Ibaraki Pref.Central Hospital, 4Department of Radiology, TohokuUniversity,Sendai, Japan

As we reported in 2002, the pancreatic surface image or the pan-

creatic 3 dimensional en-relief image became useful in diagnosis of

early pancreatic cancer. At that time, regardless of the latest image

generator, the peri-pancreatic scar tissue was disturbing our task to

get scar-free surface in chronic pancreatic cases.

Since beginning 2004, however, we began the use of the Hasegawa

Prism to solve the scar problems at the pancreatic surface. First, in

this paper, the merits of the Hasegawa Prism are introduced with its

theoretical and practical points. Some characteristic surface image or

pancreatic deformity will be shown.

a) Normal pancreatic surfaces, including the duodenal orifice.

b) A minor cancer emerged in the pancreatic body, associated with a

marked single kink. This patient is alive three years, with no recur-

rence after surgery.

c) Surface images in chronic alcoholic pancreatitis with marked

multi-kink along the pancreatic body, and some CT-images after

the treatment of acute pancreatitis.

Conclusion: Simple Computer Tomography (without radio-

opaque media) and the DICOM data obtained from the CT machine

will be enough to make diagnosis of pancreatic small cancer in the

general check examinees, as far as the data is checked in a correct

manner as shown here.


P3-10-6

Advanced Use of Virtual Reality ImagingGenerator Using Hasegawa Prism inPancreatic DiseasesH. Hasegawa1, S. Matsuno2, K. Majima2, S. Egawa2, A. Sato6, Y. Shioyama3, R. Amemiya3, S. Mishiro1, Y. Aoki4, A. Tomomitsu5

1Toshiba General Hospital, 2First Department of Surgery,Tohoku University, School of Medicine, 3Ibaraki Pref.Central Hospital, 4Hitachi Medico, 5NEUES Inc.,6Department of Radiology, Tohoku University, Sendai, Japan

Hasegawa and his co-workers conducted VR image-generating

research in a variety of pancreatic diseases. When the pancreatic sur-

face is flat and free from the adhesion with the surrounding tissues

such as the transverse colon or omentum, the whole pancreatic sur-

face image was very easy to obtain. Such normal cases were, how-

ever, rather rare according to our experiences.

Because of the high incidence of alcoholic pancreatitis and result-

ing adhesion exemplified by the high false positive results of PET

examination, the pancreatic image generation has been not so easy in

the past.

To our pleasure, our technique that use Hasegawa prism solved

this problem because the paired prism and paired 3D image could

give us an authentic stereo-image. In other words, the paired images

generated with an angle difference of 5 degrees helped us to see the

right image with only right eye, and the left image with only the left

eye. This optical mechanism enabled us to scrape some mass, if nec-

essary, according to the two optical information entering into our

brain to be synthesized in the stereo manner. The use of the prism is

therefore requisite in the 3D image generation and analysis of the

pancreas.

P3-10-7

Assessment of Retroperitoneal Invasion of Pancreatic Carcinoma Using Thin-SectionHelical CTK. Maemura1, S. Takao1, H. Shinchi1, H. Kurahara1,Y. Fukukura2, M. Nakajou2, T. Aikou1

1Department of Surgical Oncology Digestive Surgery,2Department of Radiology, Kagoshima University Schoolof Medicine, Kagoshima, Japan

Purpose: The purpose of this study was to evaluate CT criteria

for retroperitoneal invasion of pancreatic carcinoma, with surgical

histopathological correlation.

Methods: Between January 1998 and December 2002, twenty-

four patients of pancreatic carcinoma underwent preoperative thin-

section multiphase helical CT and surgical resection. Contrast

enhanced CT was performed 30 sec after injection of contrast mater-

ial as arterial dominant phase. Retroperitoneal invasion (RP) was

evaluated in 3 mm thickness of the image, and classified according

to following five types: Type 1A, tumor had more than 5 mm margin

of normal pancreas tissue; Type 1B, tumor had less than 5 mm margin

of normal pancreas tissue; Type 2A, an edge of tumor reached the sur-

face of the pancreas; and Type 2B; tumor reached peripancreatic tis-

sue; Type 3, tumor protrude from pancreas. We assessed this

classification compared with clinicopathological results.

Results: The distribution is: Type 1A, n � 2; Type 1B, n � 6;

Type 2A, n � 4; Type 2B, n � 8; Type 3, n � 4. (1) Fourteen (87.5%)

of Type 2 and 3 had histological retroperitoneal invasion. (2) This

classification correlated with tumor size, conclusive stage of progres-

sion and the local progression. (3) There was a good correlation

between this classification and grade of lymph node metastases and

lymphatic vessel invasion. (4) The degree of Type was correlated with

the grade of residual tumor and survival rate.

Conclusion: This classification has good accuracy to diagnose

retroperitoneal invasion, and is well correlated with conclusive stage

of progression and local progression. Our grading system is useful to

evaluate pathological findings and predict tumor progression.

Poster 3-11 PC CombinedChemotherapy

P3-11-1

Gemcitabine Combined with S-1 in Advanced Pancreatic Cancer: A Phase I StudyH. Ueno1, T. Okusaka1, M. Ikeda1, Y. Takezako1, C. Morizane1, J. Furuse2, H. Ishii2, M. Nagase2

1National Cancer Center Hospital, Tokyo, 2National Cancer Center Hospital East, Kashiwa, Japan

Background: S-1, an oral fluoropyrimidine derivative, was

recently reported to demonstrated a response rate of 21% in

19 patients with advanced pancreatic cancer (Okada et al. ASCO

2002). The aim of this phase I study was to determine the maximum

tolerated doses and dose-limiting toxicities (DLT) of GEM and S-1

combination therapy in patients with advanced pancreatic cancer.

Methods: Histologically or cytologically proven chemotherapy-

naïve patients with unresectable or metastatic pancreatic cancer were

enrolled. The patients received a combination of GEM intravenously

over 30 min on days 1 and day 8, and S-1 orally twice daily from

days 1 to 14. Cycles were repeated every 21 days. Patients at 4 dose

levels were scheduled to receive escalating doses of GEM and S-1:

800/60, 1,000/60, 1,000/70, and 1,000/80 [GEM (mg/m2/week)/S-1

(mg/m2/day)].

Results: To date, 9 patients have been registered. All of them had

metastatic disease and had a performance status of 0 to 1. No grade 3

or 4 toxicities were observed at dose level 1. At dose level 2, although

2 patients developed grade 3 neutropenia and 1 patient developed

grade 3 nausea and anorexia, all the toxicities were reversible and DLT

was not observed. Accordingly, an additional 3 patients are now

receiving treatment at dose level 3. Of 4 evaluable patients receiving

more than 2 cycles of treatment, 1 patient achieved a partial response.


Conclusions: This combination chemotherapy regimen was

well tolerated and showed promising antitumor activity in the treat-

ment of pancreatic cancer. The study is still ongoing, and updated

results will be presented at the meeting.

P3-11-2

Phase I Study of Gemcitabine, Oxaliplatin,5-FU and Daily Oral Thalidomide (GOFT) inPatients with Advanced or MetastaticPancreatic CarcinomaY.-S. Shan, S.-S. Chang, C.J. Yen, W.T. Huang, C.J. Tsao, P.-W. Lin

National Cheng Kung University Hospital, Tainan, Taiwan

Purpose: Combination of gemcitabine/oxaliplatin, oxaliplatin/

5-FU, and gemcitabine/5-FU has synergistic activity in pancreatic or

colorectal malignancies in vitro. Thalidomide has significant effect

on the chemotherapy induced diarrhea, which is the common mor-

bidity during treatment of oxaliplatin/5-FU.

Objectives: The phase I study was conducted to determine the

maximum tolerated dose (MTD) and dose-limiting toxicity (DLT) of

gemcitabine/oxaliplatin/5-FU/thalidomide (GOFT) in patients with

advanced/metastatic pancreatic cancer.

Methods: Gemcitabine was given in 1-hour infusion followed by

oxaliplatin in 2-hour infusion on day 1, and 5-FU in 24-hour infusion

on day 2, and oral thalidomide was given daily every 2 week. DLT was

defined as NCI-CTC grade 3/4 toxicity. MTD was determined

after the first two cycles in each patient. Dose levels of GOFT were:

level I: gemcitabine 1,000 mg/m2 � oxaliplatin 60 mg/m2 � 5-FU

1,000 mg/m2 � thalidomide 100 mg per day, level II: gemcitabine

1,000 mg/m2 � oxaliplatin 70 mg/m2 � 5-FU 1,000 mg/m2 � thalido-

mide 100 mg per day, level III: gemcitabine 1,250 mg/m2 � oxaliplatin

60 mg/m2 � 5-FU 1,000 mg/m2 � thalidomide 100 mg per day.

Results: 15 patients enrolled; 13 were evaluable: level I

(6 patients), level II (6 patients), level III (1 patient), 2 patients who did

not complete 2 cycles were excluded. Patient characteristics: M/F 6/7,

median age 67 years (range 50–80), 5 patients with recurrent pancre-

atic cancer: 2 local recurrent with peritoneal seeding, 3 local recurrent

with liver metastasis, 7 patients with locally advanced cancer proved

by laparotomy, 1 patient with pancreatic cancer and liver metastasis.

8 patients received GOFT as a first-line therapy. There were 1 CR,

3 PR (1 patient received pancreaticoduodenectomy), 1 SD at level I

and 4 PR (3 patients planned to receive relaparotomy), 1 SD at level II

(1 patient each at level I and II progressed). The liver metastasis dis-

appeared in 2 of 4 patients and size decreased in 1 of 4 patients. There

were 1 of 6 patients with DLT in level I (grade 3 infection and vomit-

ing), 2 of 6 patients with DLT in level II (grade 3 leukopenia) and

1 patient in level III with DLT (grade 3 leukopenia and stomatitis).

Other toxicity at level I/II were grade 1/2 leukopenia (7 episodes),

grade 1/2 anemia (5), grade 1/2 nausea (5), grade 1 diarrhea (2), grade

1 alopecia (2), grade 1 skin (2), grade 1 allergy (1), weight gain �5%

(3: 12%, 12%, 5.5%), and weight loss �5% (1: 6%).

Conclusion: The GOFT regimen at dose level II is safe and may

be recommended for further clinical investigation in patients with

advanced/metastatic pancreatic cancer.

P3-11-3

Combination of Gemcitabine and Low-DoseCisplatin for Treatment of Patients withAdvanced Pancreatic CancerT. Ogawa, H. Kawamoto, E. Ishida, Y. Okamoto, J. Kato, H. Okada, M. Mizuno, Y. Shiratori

Okayama University Graduate School of Medicine and Dentistry, Okayama, Japan

Background: There are several studies demonstrating that all

over response rate in patients receiving gemcitabine (GEM) and cis-

platin (CDDP) are better than gemcitabine monotherapy in spite of high

frequency of gastrointestinal toxicity. The aim of this pilot study was to

evaluate efficacy and toxicity of the combination therapy using GEM

and low dose cisplatin for patients with advanced pancreatic cancer.

Patients and Methods: Patients received GEM at a dose of

600–800 mg/m2 as a 30-min infusion, followed by CDDP at a dose of

10 or 20 mg/body as a 120-min infusion weekly. One treatment cycle

consists of 2 week-administration and 1 week off.

Results: Nine patients (M/F 5/4, median age 55 yrs, range

48–66) were enrolled, and they received a total of 42 cycles

chemotherapy (range 1–8) with a median follow-up of 150 days (range

23–204). Because allergy (grade 2), neutropenia (grade 3) and nau-

sea/vomiting (grade 3) was observed in the initial 2 patients (CDDP

20 mg/body group), CDDP dose was reduced to 10 mg/body for the

remaining 7 patients. Grade 4 toxicity was not observed in all the 9

patients. Grade 3 toxicities such as neutropenia, thrombopenia and

nausea/vomiting were observed respectively in 3, 1 and 1 patient.

Partial responses have been observed in 2 patients. Disease of pancre-

atic cancer was stable in 4 patients, but was progressed in 3. Using this

regimen, clinical benefit was obtained in 4 of 9 patients (44%).

Conclusions: From this pilot study, the combination of GEM

and low-dose CDDP for patients with advanced pancreatic cancer

appears to be an effective and well-tolerated approach.

P3-11-4

Phase I Study of Gemcitabine and UFT Combination Chemotherapy forUnresectable/Recurrent Pancreatic CancerS. Nakamori, S. Nakahira, Y. Takahashi, M. Tujie, S. Marubashi, A. Miyamoto, H. Nagano, K. Dono, K. Umeshita, M. Sakon, M. Monden


Gemcitabine (GEM) has potential activity in advanced pancreatic

cancer. 5-fluorouracil (5-FU) is known as a major mediators of gem-

citabine uptake. Although the combination of GEM and 5-FU is con-

sidered as a possible effective therapy, the safety and clinical effect of

the combination have not been well examined. A Phase I study of GEM

and UFT (prodrug of 5-FU and uracil) combination chemotherapy was

performed for unresectable and recurrent pancreatic cancer. The regi-

men included UFT orally from day 1 through day 6 and from day 8

through 13, GEM intravenously on day 7 and 14, and one week rest in


out-patient clinic. It was repeated every 3 weeks for a minimum 3 per

patients more than 2 cycles, including doasage levels of 3 scheduled

steps. Nine patients were enrolled in the study. Leukopenia and neu-

tropenia of grade 3 occurred in 2 of 6 patient at level 2 and MTD was

considered as 800 mg/m2 for GEM and 250 mg/m2 for UFT. Clinical

effects of the patients included: 2 PR, 4 NC, and 3 PD, for response rate

of 22% (2/9 patients). Reduced CA19-9 level less than a half of that at

starting time was observed 4 of 9 (44%) patients. The recommended

dose for the phase II study is GEM 800 mg/m2 and UFT 250 mg/m2

with consideration of application to outpatients and continuing courses.

P3-11-5

Radiation Therapy in Pancreatic CancerJ. Itakura, K. Matsuda, H. Fujii

First Department of Surgery, University of Yamanashi,Faculity of Medicine, Yamanashi, Japan

Aim: The primary objective of this trial was to evaluate the effi-

cacy of radiation therapy as the adjuvant therapy of surgery for pan-

creatic cancer. A secondary objective was to evaluate the efficacy of

combination therapy of IOR and EBRT in combination with concur-

rent gemcitabine (IEG).

Methods: IOR was directed at the pancreatic tumor bed and

regional lymphatics to a dose of 20–25 Gy. EBRT was directed at the

same area with IOR to a total dose of 30–45 Gy by 2 Gy in fraction

5 days per week after surgery. Patients received weekly Gem

(200 mg/m2) on the first days of the week with concurrent EBRT.

Results: Between Aug 1999 to Dec 2003, 35 patients were

entered into this trial. Patients characteristics: 22 male/13 female;

mean age 64.4 years (36–79); Stage II 1, III 6, IVa 8, IVb 20.

The median overall survival of these 35 patients was 10.5 months, and

1, 2 and 3 years survival rate were 44.8, 34.6 and 17.3%, respectively,

and the survival rate was significantly higher than that of non-

radiation control group (p � 0.018). The median overall survival of

the resectable cases was significantly longer than that of unresectable

cases (27.1 and 4.9 months, p � 0.023). The 18 IEG patients showed

the tendency toward longer survival duration.

Conclusion: This preliminary data would suggest that combina-

tion radiation therapy is efficient as adjuvant therapy for surgery in

pancreatic cancer.

P3-11-6

Intraoperative Radiotherapy for InvasiveAdenocarcinoma of the Pancreas – A PilotStudyW. Kimura, A. Fuse, M. Kamiga, A. Takeshita, I. Hirai, M. Mizutani, T. Moriya, J. Ma

First Department of Surgery, Yamagata University School of Medicine, Yamagata, Japan

Intraoperative radiotherapy (IOR) or ‘direct view’ irradiation per-

mits the delivery of a single exposure of high-energy electrons to a

surgically exposed tumor or tumor bed and permits physical retrac-

tion of normal uninvolved tissues away from the IOR beam as well as

the accurate assessment of the target volume. A pilot retrospective

analysis of the efficacy of IOR in invasive adenocarcinoma of the

pancreas is presented. From 1999 through 2003, 24 patients with

invasive adenocarcinoma of the pancreas underwent surgical resec-

tion in First Department of Surgery, Yamagata University School of

Medicine. Among these, 14 patients underwent IOR after pancreatec-

tomy. Doses of 25 to 30 Gy with electron beams were delivered to

tumor beds, high risk lymph nodes and/or remaining cancer nests

through radiation cones ranging from 6 to 10 cm in diameter. Severe

complications were not found in any of these patients and the postop-

erative course was uneventful. In the IOR group, eight cases were

died at the time of this investigation, and local recurrence occurred in

4 of these died cases. While in control group (n � 10), seven cases

were died at the time of this investigation, and local recurrence

occurred in all of the cases. Mean survival time of the IOR group was

507 � 82 days and that of the control group was 265 � 68 days. In

the IOR group, survival rates of 1-year, 2-years and 3-years were

77%, 48% and 48%, respectively. Compared with those of control

group, 34%, 22%, 0%, respectively, a significant difference of sur-

vival rate was observed (P � 0.046, Log-Rank Method). These results

demonstrated that IOR is effective in preventing local recurrence after

surgical treatment and can prolong the survival of patients with inva-

sive adenocarcinoma of the pancreas.

P3-11-7

Intraoperative Radiation Therapy (IORT) for Pancreatic CancerK. Karasawa1, G. Matsumoto2, A. Okamoto2, K. Tsuruta2, N. Hanyu1, K. Harada1, Y. Kiguchi1, T. Umezawa1, H. Kawamura1

1Department of Radiology, 2Department of Surgery, Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

IORT has been considered to play an important role in the treat-

ment of pancreatic cancer. We have been giving IORT for pancreatic

cancer since our hospital began radiation therapy. In this paper, we

will present our 27-year experience. Between 1976 and 2002, 182 M0

cases were treated. Age ranged from 35 to 86 years (average 63.6).

There were 108 males and 74 females. Concerning the locus of the

tumor, there were head in 141 cases, body in 40 cases and tail in

1 case. Ninety-four cases received bypass operation without resection

of tumor (NR), 88 cases underwent resection of the tumor, 39 cases

of which were curative (CR) and 49 were non-curative (NCR). IORT

was given using Betatron or Microtron. The dose of IORT ranged

from 15 Gy to 35 Gy (median 20 Gy). Among them 144 cases

received postoperative external beam radiotherapy (EBRT). The dose

of EBRT ranged from 8 Gy to 61 Gy (median 50 Gy). Median follow-up

period of alive patients was 35 months. There was only 1 postopera-

tive death. Median survival time (MST), 1-, 2-, 3- and 5-year survival

rate of overall cases were, 11.1 months, 46.0%, 20.7%, 17.0% and

4.7%, respectively. MST of CR cases, NCR cases, and NR cases with

EBRT were 16.5 months, 10.8 months, and 10.6 months, respectively.

The survival curves of NCR cases and NR cases were relatively sim-

ilar, which recommended conservative approach for this cohort of the


patients. Treatment approach to further improve the results will be

discussed.

Poster 3-12 PC NeoadjuvantTreatment

P3-12-1

Neoadjuvant Chemotherapy for Patientswith Locally Advanced Adenocarcinoma ofthe PancreasH. Taoka, Y. Nobuoka, M. Yamashita, K. Tanigawa, S. Yoshimine, T. Imai

Department of General Surgery, Suzuka General Hospital,Mie, Japan

Purpose: The purpose of this study is to make clear the use of

neoadjuvant chemotherapy for locally advanced pancreatic cancer

and its potential ability to downstage operation.

Patients and Method: From January 2001 to December 2003,

5 patients received 5-FU and heparin as a continuous infusion, cal-

cium leucovorin and gemcitabine weekly by intravenous injection,

mitomycin-C every 6 weeks and dipyridamole daily orally for locally

advanced pancreatic cancer (TNM Stage IVA). All of these patients

were evaluable for response according to the new guidelines of

RECIST under CA19-9 and CT-scan. Histological findings and CT

imaging for sufficient response cases were evaluated.

Results: All patients had partial responses and total response rate

was from 31% to 60% (average 45%) under CT and every patient had

the response of CA19-9 decrease and its decrease rate was from 18% to

79% (average 59%). Four of 5 responding patients had sufficient tumor

regression to meet clinical criteria for resectability, three of whom

underwent a curative resection. All of them who underwent downstage

operation were still alive for our follow-up time (4�24 months). Two of

4 patients showed the inflammatory pseudotumor like lesion from the

histological findings.

Conclusion: Our experience with a six-drug chemotherapeutic

regimen resulted in sufficient downstaging of tumor in some patients

to justify surgical resection.

P3-12-2

Preoperative Concurrent Chemoradiation for Locally Advanced Pancreatic Cancer: A Single Institution ExperienceS. Takai, S. Satoi, H. Yanagimoto, K. Takahashi, N. Terakawa, M. Ishizaki, J. Fukui, H. Araki, Y. Matsui, Y. Kamiyama

Department of Surgery, Kansai Medical University, Osaka, Japan

Beginning in December 2000, we introduced preoperative

chemoradiotherapy (CRT) as a more effective modality and utilized

this therapy for 22 patients with locally advanced pancreatic cancer.

Methods: Pancreatic tumors were defined as locally advanced

cancer (Stage II-III-TNM) based on radiographic findings before

CRT. All patients received external beam radiotherapy (40 Gy/4

weeks). Concurrently, chemotherapy was performed with continuous

intravenous infusion of 5-FU 300 mg/day and intermittent infusion of

CDDP 5–10 mg/day for 4 weeks (Arm A: n � 11) or weekly infusion

of Gemcitabine 400 mg/m2 for 3 weeks (Arm B: n � 11).

Results: On restaging after CRT, 16 patients (73%) had stable

disease and pancreatectomy (PD: 12, DP: 3 and TP: 1) was per-

formed. Also, tumor marker levels were reduced more than 50% in 10

patients (45%). Surgical margins and all lymph node metastases were

negative in 9 (56%) of resected patients. In 7 of the resected patients

(44%), degradation and necrosis of more than 1/3 of cancer tissue

were found. All but one patient had a stable in PS score during CRT.

Of adverse effects, 13 patients (59%) complained of nausea and vom-

iting (grade 1 or 2) and two experienced grade 3 hematologic toxicity

that required dose reduction and treatment interruption. In arm A,

1-year survival rates were 53% and in Arm B were 66.7%. At this

time, the longest survival period has been 23 months for 1 patient in

each arm.

Conclusion: This preoperative chemoradiotherapy regimen was

well tolerated and merits further study in locally advanced pancreatic

cancer.

P3-12-3

The Down-Staging of Locally AdvancedPancreatic CancerH. Oishi, S. Egawa, M. Ishida, H. Abe, S. Fukuyama, M. Sunamura, K. Takeda, S. Matsuno


Introduction: Surgical operation is frequently required to con-

firm the histology and staging of pancreatic cancer. This is a retro-

spective analysis of multidisciplinary therapies for locally advanced

disease.

Patients: From 1988 to 2003, there are 61 cases of locally

advanced disease. Intraoperative radiotherapy (IOR), postoperative

chemoradiation using 5FU and out-patient chemotherapy were per-

formed in a variety of combinations. Gemcitabine (GEM) and/or

pacritaxel (TXL) was administrated in later cases. Second look


operation was performed for the cases with PR or long NC. Radical

resection was performed if down-staging was obtained.

Results: Twelve cases did not develop any distant metastasis.

The median survival time of all cases was 10 months, with a better

survival in whom GEM was administered. There were nineteen 1-year

survivors, two 2-year survivors and one 3-year survivor. The last case

had well-differentiated adenocarcinoma and underwent IOR using

PR-350, a radiation sensitizer, followed by chemoradiation. He is still

alive without recurrence at 45 month after IOR. Two cases underwent

second-look operation. One case underwent radical resection and died

of hepatic failure 21 months after the first operation without any

recurrence. In the other case, positive cytology of peritoneal cavity

was found in the second operation 11 month after the first operation.

Conclusion: Some cases do not develop distant metastasis until

the last moment. In these cases, chemoradiation and chemotherapy

might bring long term survival. Additionally, down-staging followed

by radical resection gives us the new insight of treatment for locally

advanced pancreatic cancer.

P3-12-4

Combination of IORT � EBRT and the ArterialInfusion Chemotherapy with HemodynamicChange of the Peripancreatic Blood VesselH. Baba, G. Matsumoto, K. Tsuruta, A. Okamoto

Tokyo Metropolitan Komagome Hospital, Tokyo, Japan

Background: Intraoperative radiation therapy (IORT) in combi-

nation with postoperative external beam radiotherapy (EBRT) was

thought to be the effective treatment for locally advanced pancreatic

cancer. However, the outcomes were far from satisfactory. Recently,

Homma et al., have introduced a novel arterial infusion chemotherapy

for the treatment of patients with advanced pancreatic cancer, regard-

less of liver metastasis with respectable results. We assessed the com-

bination of IORT � EBRT and the arterial infusion chemotherapy

with hemodynamic change of the peripancreatic blood vessels.

Methods: Ten patients with locally advanced pancreatic cancer

were enrolled. Every patient underwent distal gastrectomy, biliary

tract bypass and IORT. Postoperatively, the blood flow to the tumor

was restricted to gastroduodenal artery by selective embolization of

peripancreatic arteries including splenic artery, modifying the

Homma’s method. Via implanted subcutaneous injection port, gemc-

itabine, cisplatin, and 5-FU were administered during EBRT.

Results: The levels of serum tumor markers decreased in all

patients. Eight patients are currently surviving without liver metasta-

sis. At present, the longest survival period is eighteen months,

whereas the shortest being three months with the median survival

time (MST) of 12.5 months. Adverse effects of the chemoradiother-

apy were minor and controllable.

Conclusions: The evaluation of survival benefit of this treat-

ment is still now ongoing. Although the present study is preliminary

in nature, encouraging results were achieved. This newly devised

treatment strategy could be promising for locally advanced pancreatic

cancer.

P3-12-5

Arterial Infusion Chemotherapy for thePatient with Unresectable PancreaticCarcinomaK. Inami, M. Suyama, Y. Kubokawa, J.K. Sai, H. Tadokoro,T. Kamiya, H. Koshikawa, H. Okubo, Y. Matsumura, K. Kato


A 59-year-old patient was admitted to our hospital with continu-

ous epigastralgia. Computed tomography (CT) showed an avascular

tumor at the pancreatic body and, dilatation of the distal pancreatic

duct. Ultrasonography (US) showed a low echoic tumor at the pan-

creas (approximately 22 mm in diameter). Angiography revealed

encasement of the celiac artery and compression of the portal vein.

The tumor was finally diagnosed as pancreatic carcinoma stage III

(UICC); stage IVa (JSP) and deemed unresectable. Embolization of

the anterior superior pancreaticoduodenal artery (ASPDA), the poste-

rior superior pancreaticoduodenal artery (PSPDA) and the inferior

pancreaticoduodenal artery (IPA) and insertion of catheter in the

splenic artery was carried out for arterial infusion chemotherapy.

Gemcitabine (GEM) was administered 500 mg/m2 (Day 1, 8, 15)/4W

and Fluorouracil (5-FU) was administered 250 mg/m2 (Day 1–7,

15–21)/4W via the subcutaneous port connected to the catheter for

the induction therapy. As the outpatient setting, GEM was administered

500 mg/body (Day 1, 8, 15)/4W and 5-FU was administered 1000 mg/

body (Day 1, 8, 15)/4W via the port for the maintenance therapy. The

tumor regression was detected on CT (partial response), at the time

three month passed after the initial treatment. The tumor is still pro-

gression free, A year passed. In conclusion prognosis of advanced

pancreatic carcinoma is poor. However, arterial infusion chemother-

apy may be beneficial for patients with unresectable pancreatic carci-

noma stage III (UICC); stage IVa (JSP).

P3-12-6

A Novel Chemoradiotherapy after SurgicalTreatment for Advanced Pancreatic CancerUsing Iridium-192 Remote AfterloadingBrachytherapy with External Radiotherapyand GemcitabineN. Kuroda, Y. Iimuro, J. Yamanaka, T. Okada, J. Fujimoto

The First Department of Surgery, Hyogo College ofMedicine, Nishinomiya, Japan

Background/Aim: Brachytherapy has been used as boost irra-

diation in a multimodal treatment together with external radiotherapy

and simultaneous chemotherapy. Gemcitabine has been used as a

chemotherapeutic agent and a potent radiosensitizer, so the combina-

tion with remote afterloading brachytherapy (RALS), external radio-

therapy, and gemcitabine is a potent strategy in a treatment of

pancreatic cancer. In the present study, we performed iridium-192

RALS using guide catheters which were placed during surgical

procedure, and combined external radiotherapy and gemcitabine for



Patients and Methods: Nine patients with locally advanced

carcinoma of the pancreas have been treated with iridium-192 RALS.

In all cases, the residue of carcinoma was highly suspected peri-supe-

rior mesenteric artery (SMA) and/or peri-superior mesenteric vein

(SMV). Catheters of 14Fr. in were placed along with SMA and/or

SMV as guide catheters for iridium-192 RALS. Brachytherapy

started 3 weeks after operation. A total dose of 12 Gy was delivered.

Brachytherapy was followed by external radiotherapy, delivering an

additional dose of 40 to 52 Gy. All patients received simultaneous

chemotherapy with gemcitabine.

Results: Eight patients received brachytherapy completely.

Brachytherapy treatment was well tolerated without serious compli-

cations. All the patients were discharged from the hospital. Median

follow up period is 350 days, 7 of 8 patients died but their QOL had

been kept by the terminal period.

Conclusion: Although some improvements about RALS are

needed, this multidisciplinary treatment, including Iridium-192

RALS with external radiotherapy and gemcitabine after surgical pro-

cedure, may be potentially useful for the treatment of patients with


P3-12-7

Two Cases of Pancreas Carcinoma Duodenal Stenosis that Showed GoodProgress after Irradiation and Intra-ArterialChemotherapyA. Hirayama1, T. Nagakawa1, T. Yabana1, K. Kashiwaya1, K. Okamura1, T. Abe1, H. Miyakawa1, T. Suga1, N. Nomura2

1Bilio-pancreatology, Sapporo Kousei General Hospital,2Kitahiroshima Hospital, Japan

Malignant duodenal stenosis (MDS) is one factor that deteriorates

the QOL of pancreas carcinoma patients in the most serious way.

Irradiation and intra-arterial chemotherapy were applied to the cases

of pancreas carcinoma MDS that could not undergo operation.

I would like to report on these treatments because they showed good

progress. Case 1 is a male patient of 51 years old, and case 2 is a

76-year-old female patient. Both came to the hospital with the symp-

toms of abdominal pain and vomiting. They were diagnosed with pan-

creas carcinoma and duodenal stenosis after undergoing CT and

gastro-duodenal endoscopy; they were hospitalized. Both patients

opted for irradiation and intra-arterial chemotherapy. Duodenal stent-

ing was applied in combination with the treatments to the Case 1

patient, and he is showing a good progress. With the Case 2 patient,

the duodenal stenosis is gradually opening after intra-arterial

chemotherapy. Both show good progress without stenting or gastro-

jejunostomy. Irradiation and intra-arterial chemotherapy are effective

for the treatment of duodenal stenosis. The opening of stenosis can be

expected by combining these treatments with duodenal stenting in the

case of wide-spread invasion into the membrane and by intra-arterial

chemotherapy if there is no invasion into the membrane.

Poster 3-13 Surgical Techniques

P3-13-1

A Study of Pylorus-PreservingPancreatoduodenectomy: In Comparisonwith PancreatoduodenectomyM. Iwamoto, K. Takaori, M. Asakuma, I. Tsunematsu, H. Inoue, Y. Miyamoto, M. Hayashi, N. Tanigawa

Department of General and Gastroenterological Surgery,Osaka Medical College, Takatsuki, Japan

Background: There remains controversy regarding long-term

outcomes after pylorus-preserving pancreatoduodenectomy (PPPD)

in comparison to those after conventional pancreatoduodenectomy

(PD).

Objectives: To compare long-term postoperative outcomes

after PD and PPPD.

Subjects and Methods: Between 1973 and 2001, 145 patients

underwent pancreatoduodenectomy at Osaka Medical College. Fifty-

five patients who have been followed up for 3 years or longer after

surgery were subjected to this study. The 55 patients underwent PPPD

(23 cases) or PD (32 cases) for carcinoma of the papilla of Vater in

23, bile duct carcinoma in 13, pancreatic carcinoma in 5, duodenal

carcinoma in 4, chronic pancreatitis in 3 and other conditions in 10.

The incidence of postoperative stomal ulcers and that of fatty liver

were compared. Morphological changes of the pancreatic duct were

evaluated by CT and MRCP. Residual pancreatic function, perfor-

mance status (PS) and postoperative weight recovery were compara-

tively assessed.

Results: Stomal ulcers developed in one patient after PPPD

(4.3%) and treated conservatively. No stomal ulcer occurred after PD.

Fatty liver was diagnosed in 2 of 20 patients (10.0%) after PPPD and

in 9 of 31 (28.7%) after PD. In 2 patients who underwent PD, pancre-

atic duct dilation was detected. In both cases, the invagination method

was used for the anastomosis at the time of surgery. In all of the

23 patients who underwent PPPD, pancreaticogastrostomy was car-

ried out by duct-to-mucosa sutures. Duct dilatation was not demon-

strated in patients who underwent PPPD. Diabetes mellitus was

developed or exacerbated in 3 patients after PPPD and in 5 after PD.

Exocrine pancreatic function was well maintained except in one

patient after PPPD and another after PD. PS was rated as 0 or 1 in 19

of 20 patients (95.0%) after PPPD group and in 22 of 32 (67.7%) after

PD. Body weights recovered to preoperative value in 10 of 20 patients

(50.0%) after PPPD and in 10 of 31 (32.3%) after PD.

Conclusion: The incidence of fatty liver was higher after PD

than after PPPD. Pancreatic duct dilatation was developed after PD

presumably by poor patency of pancreatic duct anastmosis due to the

invagination method. The results suggest PPPD is superior to PD in

terms of PS and postoperative weight recovery.


P3-13-2

Prevention of Postoperative Pancreatic Duct Dilatation in Duct-to-MucosalPancreaticojejunostomyM. Tani, K. Uchiyama, H. Kinoshita, M. Kawai, T. Hama, M. Ueno, H. Terasawa, T. Nakase, H. Yamaue


We retrospectively reviewed the results of a duct-to-mucosal anas-

tomosis after 6 months of pancreaticojejunostomy. Seventy-six

patients with pancreatic head resection were performed between 1994

and 2002 in Wakayama Medical University Hospital. It was per-

formed by two kinds of end-to-side pancreaticojejunostomy in pan-

creatic head resection. Thirty-one patients underwent the complete

external stented drainage without duct-to-mucosal anastomosis

between 1994 and 1998. Forty-five patients underwent the duct-to-

mucosal anastomosis with a drainage tube inserted into the pancreatic

duct, for incomplete partial drainage, between 1999 and 2002. The

remnant pancreas was followed postoperatively by CT. Postoperative

digestive status was followed using the body weight ratio to preoper-

ative body weight and diarrhea at 6 months postoperatively. Diarrhea

with pancreatic resection was estimated using the National Cancer

Institute-common toxicity criteria version 2 score. The body weight

ratio was 0.80 � 0.71 (mean � SD) at 6 months postoperatively, and

no patient had diarrhea ( Grade 2) in the total drainage. On the other

hand, in the duct-to-mucosal anastomosis, the body weight ratio was

0.88 � 0.09, and 2 patients had diarrhea ( Grade 2). There were no

significant differences between two surgical groups in body weight

ratio or diarrhea. Fourteen of 29 patients with total drainage appeared

the postoperative pancreatic duct dilatation (48.3%), and those dilata-

tions were detected within six months by CT. On the other hand, one

patient with duct-to-mucosal anastomosis showed postoperative pan-

creatic duct dilatation by CT (p � 0.01).

Conclusion: The duct-to-mucosal anastomosis was the more

effective than stented drainage in terms of prevention of remnant pan-

creatic duct dilatation after pancreatic head resection.

P3-13-3

A Clinically-Relevant Definition of Pancreatic Anastomotic Leak afterPancreaticoduodenectomyH. Shinchi1, K. Wada2, L.W. Traverso2

1First Department of Surgery, Kagoshima UniversitySchool of Medicine, Kagoshima, Japan, 2Department of General Surgery, Virginia Mason Medical Center,Seattle, WA, USA

Introduction: Studies of pancreatic leak (LEAK) after a

Whipple procedure are difficult to compare as there is no accepted

definition. Our goal was to analyze actual patient data to determine

the best definition of a ‘Clinically-Relevant’ LEAK (CR-LEAK).

Methods: Initially LEAK was defined as an amylase-rich fluid

from external drains (�5X serum upper limit of normal) with a

volume of �30 ml/day on or after postoperative day 5. A CR-LEAK

was defined as any LEAK with a length of stay (LOS) � 1 Std Dev

beyond mean LOS or if percutaneous drainage was required.

Results: Between 1996 and 2002 a LEAK occurred in 13.5%

(30/223) while 16/30 had a CR-LEAK. The daily median amylase

values did not differ between the CR-LEAK and NON-LEAK groups

but the median daily volume of drainage on postop day 5 through 10

was significantly (p � 0.05) greater for the CR-LEAK (104–270 ml)

vs NON-LEAK (5–18 ml) groups.

Conclusions: Measuring drain amylase alone is not sufficient

to predict a clinically-relevant leak unless there is a volume of

�100 ml/day after postop day 5. With this definition patients are more

likely to have prolonged LOS or require percutaneous drainage. This

definition may be useful to compare clinical studies.

P3-13-4

Pancreatic Tube Guided Inferior PancreaticHead Resection for Intraductal PapillaryMucinous TumorsA. Horiguchi, K. Mizuno, S. Ishihara, M. Ito, H. Nagata, K. Furusawa, T. Shimizu, T. Yamamoto, S. Miyakawa

Fujita Health University School of Medicine, Aichi, Japan

Patients with intraductal papillary mucinous tumor (IPMT) have a

good prognosis after surgical treatments. One of the recent advances

in pancreatic surgery is organ preserving operation. Although local

resection can preserved pancreatic function, morbidity still occurs

frequently, especialy pancreatic fistula for the main pancreatic duct

injury. We performed pancreatic tube guided inferior pancreatic head

resection for brunch typed IPMT. This technique can prevent main

pancreatic duct injury.

Methods: Pancreatic tube was inserted in the main pancreatic

duct in preoperative day one or operative day. After preperation of the

superior mesenteric vein at the lower margin of the pancreas, pancre-

atic uncus removed from the pancreatic posterior membrane. A

Kocher maneuver was not performed to protect the mesoduodenum

and vessels to the duodenal 3rd portion. The resection line near the

main pancreatic duct decided by touching the ENPD tube. Location

of tumor and pancreatic tube confirmed by intraoperative ultrasonog-

raphy. Care must be taken to preserve the main pancreatic duct. The

patient was good course without postoperative complication.

Conclusions: Pancreatic tube guided inferior pancreatic head

resection is a safe method for prevent the main pancreatic duct injury.

This procedure is considered to be appropriate for treating benign dis-

ease and noninvasive malignant disease involving the uncinate

process.


P3-13-5

Pancreas Sparing Segmental Resection of the Duodenum for Focal Cancer inAdenoma of the Papilla of VaterM. Ryu1, M. Konishi2, A. Cho1, M. Izumi1, W. Takayama1,M. Sugaya1, S. Kobayashi1, T. Okada1

1Division of Surgery, Chiba Prefectural Sawara Hospital,2National Cancer Center Hospital East, Chiba, Japan

Background: Adenoma of the papilla of Vater is a premalignant

lesion with a high association rate of focal cancer. This adenoma has

been treated by a variety of methods, and a consensus for its treatment

has not been reached. Pancreaticoduodenectomy, although the most

commonly employed treatment, is considered excessive for adenoma

without lymph node metastasis. Local excision has a lower mortality

rate but higher rate of local recurrence. A resection method which is

safe and reliable is desired.

Method: The distal duodenum is detached from the pancreas.

The common tract of pancreatic and bile ducts are exposed outside

the pancreas and duodenum, and excised. Pancreas sparing segmental

resection of the distal part of the duodenum including the papilla of

Vater is performed. The jejunum is elevated upward and anastomosed

with the common duct reconstructed from the duodenum, bile and

pancreatic ducts.

Results: The resection was safely performed on 10 patients with

focal cancer in adenoma. The mean operation time was 208 minutes

and mean blood loss was 378 ml, and mean length of hospital stay was

39 days. There were no major complications, but delayed gastric emp-

tying was observed in 3 out of 9 cases. The mean follow up was 1,846

days. All patients lead a normal life and weigh the same as before

surgery without recurrence.

Conclusion: Pancreas sparing segmental resection of the duo-

denum including the papilla of Vater is a useful modality in treating

adenoma of the papilla of Vater, a premalignant neoplasm which is

frequently associated with cancer.

P3-13-6

Development of the Tele-Mentoring System for the Laparoscopic SurgeryUtilizing the High-Speed Cable Networkwith Lower Expense in JapanS. Fukuyama, M. Sunamura, K. Shibuya, K. Sugiyama, D. Sato, H. Abe, S. Egawa, K. Takeda, S. Matsuno

Department of Gastroenterological Surgery, TohokuUniversity, Graduate School of Medicine, Sendai, Japan

Background: Information Technology (IT) has the ability to

enhance, compress, and transmit video signals to other information

over long distances. Here in Japan, due to recent progress in IT and

tele-communication, we are being able to utilize the high-speed

network also in the surgical field with lower expense. We have

been developing the tele-mentoring system between 2 institutes with

the fiber optic cable network, and have been applying it for the

laparoscopic surgery. We report the actual cases and assess the feasi-

bility and the safety of this system.

Method: We developed the audiovisual signal information

transmitting system, so called Tele-mentoring system with video cam-

eras, monitors, microphones, processing computers and fiber optic

cable networks. The distance between two institutes was about

20 kilometers long. The operator and assistant were young surgeons

and the mentor was the expert of the laparoscopic surgery. We per-

formed laparoscopic splenectomy and cholecystectomy under the

instructions by the mentor utilizing this system. We recorded the

operative images and instructions from the mentor, time course of the

operative procedures, incidents, and measured the quality of the trans-

mitted signals over the fiber optic cable.

Result: All operations were performed successfully. There was

no incident during the operation. There was no signal loss over the

cable, and the quality of the video image from the operation room to

the mentor’s room was enough to perform the operation.

Conclusion: This study demonstrates that this tele-mentoring

system is feasible and safe in lower expense. This system will be an

effective method for the medical treatment and education of the sur-

geon in remote regions in the near future.

Topic: Robotics, Telesurgery and Virtual Reality.

P3-13-7

Intra-Pancreatic Complete Avulsion ofCommon Bile Duct and Intra-Hepatic BileDuct Due to Deceleration Injury after Blunt Abdominal Trauma Detected by theDrip Infusion Cholangiography – ThreeDimensional Computed Tomography and Treated by Choledochojejunostomy: A Case ReportK. Kumakura1, S. Sakurai1, K. Sakurai1, M. Aoki2, S. Ishimatsu2

1Surgery Department, 2Emergency Medicine Department,St. Luke’s International Hospital, Tokyo, Japan

A case of intra-pancreatic complete avulsion of the common bile

duct due to deceleration injury after blunt abdominal trauma in a traf-

fic accident is presented. This case was diagnosed with the drip infu-

sion cholangiography – three dimensional computed tomography

(DIC-3DCT) preoperatively and successfully treated by choledocho-

jejunostomy. The mechanism of this type trauma is thought that sud-

den deceleration force the biliary tree pulled out from liver,

duodenum and pancreas which are fixed to the retroperitoneum. Since

this type injury needs emergent exprolation occationaly, the early

diagnosis is desirable. This time, we excluded gastrointestinal and

arterial major injury by CT and angiography. So DIC-3DCT is

selected as the diagnostic modality for biliary tree injury. During

operation, we confirmed that the papilla Vater was intact. So that pan-

creas head was preserved. Abdominal CT scan was followed up post-

operatively, there was no findings of pancreatic duct occlusion of

pancreatitis. Although intra-pancreatic common bile duct injury is

rare, it’s important to rule out it during working up blunt abdominal

trauma patients. And to select safer procedure is also essential to treat

trauma patients.


Poster 3-14 Radical Surgery

P3-14-1

Resection of Ductal Adenocarcinoma of the Body and Tail of the PancreasA. Urakami, K. Iki, T. Kubozoe, H. Matsumoto, K. Yamashita, T. Hirai, T. Tsunoda

Department of Gastroenterological Surgery, KawasakiMedical School, Kurashiki, Japan

Carcinoma in the body and tail of the pancreas is less frequent

than pancreatic head carcinoma and its prognosis is worse. Because

curative resection is difficult and long-term survival is extremely rare.

We retrospectively reviewed our 18 years experience on ductal ade-

nocarcinoma in the distal pancreas and analysed survival and long-

term results after resection. Among 54 patients diagnosed, 28

underwent surgical resection. Twenty-seven patients underwent distal

pancreatectomy and 1 underwent total pancreatectomy. Resectability

rate was 52%. In 26 non-resected cases, palliative bypass was 5,

exploratory laparotomy was 10, and non-operated was 11 cases. In 28

resected cases, macroscopic radical resection was achieved in only

7 cases. Overall median survival was 7 months and 5-year survival

rate was 4.6%. In resected cases, median survival was 14 months and

5-year survival rate was 9.3%. In non-resected cases, median survival

was 5 months and patients did not survive more than 22 months. One

patient survived for 11 years after resection, and another patient is

still alive 7 years after resection. Both of them were T2N0M0, Stage-I,

according to TNM staging. The prognosis for patients with ductal

adenocarcinoma of the distal pancreas who were treated with poten-

tially curative resection is poor. However, surgical resection can offer

long-term survival for patients with localized cancer.

P3-14-2

Evaluation of Modified Appleby Operationfor Pancreatic CancerH. Shimamura, S.-I. Ishiyama, Y. Narushima, T. Yamaki, H. Kodama, S. Kikuchi

Sendai National Hospital, Sendai, Japan

Purpose: Evaluation of extended distal pancreatectomy accom-

panied with celiac axis resection (modified Appleby operation, here-

after abbreviated to Appleby-DP).

Methods: Pancreatic cancer patients who underwent Appleby-

DP operation between June 2002 and June 2003 in Sendai National

Hospital were retrospectively reviewed.

Results: Five patients (1 male and 4 females) were eligible.

Average age was 67.0. Average operation time was 247.8 min.

Average blood loss was 1,012.2 g, and 2 patients were required for

transfusion of concentrated red blood cells. Arterial invasion (splenic

artery and/or common hepatic artery) was observed in all cases, and

plexus invasion was observed in 4 of 5 cases. Two patients com-

plained of diarrhea, which, however, was controllable by medication.

Post-operative complications other than pancreatic fistula were gas-

tric ulcer, atrophic gastritis and leakage in the site of partial gastrec-

tomy. Three patients preoperatively required oral administration of

morphine due to severe epigastralgia and/or back pain. After the oper-

ation, however, cancer pain was absolutely disappeared in all these

cases. Four of 5 patients underwent adjuvant chemotherapy with gem-

citabine. Though, recurrent disease was detected in 2 patients.

Conclusion: Although Appleby-DP did not benefit patient

prognosis, this procedure could be admirable in terms of improving

patients’ quality of life by removal of severe cancer pain.

P3-14-3

Use of the Right Gastroepiploic Artery for Arterial Graft. Reconstruction afterResection of Hepatic Artery withPancreatoduodenectomyR. Hosotani1, M. Wada1, M. Nasu2, T. Kajiwara1

1Department Surgery and 2Cardiac Surgery, Kobe City General Hospital, Kobe, Japan

Invasion of pancreatic cancer into major arteries, such as celiac

axis and superior mesenteric artery (SMA), is now recognized as con-

traindication for pancreatoduodenectomy (PD). Replacing common

hepatic artery (HA) and right HA from SMA are the two major forms

of variations that surgeons may encounter during PD. We report here

the usefulness of the right gastroepiploic artery (RGEA) for arterial

graft after resection of HA with PD.

Case: A 60-year-old male patient presented with obstructive

jaundice. CT and angiography demonstrated a replacing common HA

that was involved by the pancreatic cancer. The cancer was about 2 cm

in diameter without obvious lymph node metastasis or portal vein

involvement.

Surgery: During PD procedure, 10 cm of RGEA was harvested

for a graft and stocked in heparinized blood. Replacing HA was suc-

cessfully resected from SMA take-off. RGEA graft was trimmed and

placed between splenic artery and proper HA, and side-to-end anast-

moses were performed on both sides. Patency of the graft was

checked by Laser Doppler flowmetry.

Historical Data: R0 surgery for pancreatic cancer (no residual

tumor) was performed on 92 patients, and 50% survival and 5-year

survival of these patients were 17.9 months and 28.2%. Nine patients

received arterial reconstruction with PD (HA; 5 patients, SMA;

3 patients, HA � SMA; 1 patient), and 50% survival was 11.7 months.

Conclusions: RGEA is easy to take enough length and has suit-

able diameter for arterial graft after resection of HA; therefore, might

be better than saphenous vein graft. Sophisticated vascular anasto-

mosis by the hands of cardiac surgeons could improve the surgical

outcome.


P3-14-4

Portal Vein Resection for Pancreatic CancerM. Ishida, S. Egawa, H. Abe, S. Fukuyama, M. Sunamura,K. Takeda, S. Matsuno


Background and Aims: Portal vein (PV) invasion frequently

lead the surgeons to hesitate to resect the cancer in the pancreas. This

study investigates the clinical significance of PV resection (PVR)

with pancreatectomy in a single institution.

Patients and Methods: Out of 540 operated patients from

1971 to 2003, 145 cases underwent pancreatectomy. There were 35

patients who underwent pancreatectomy with PVR. The survival was

analyzed using Kaplan-Meier’s method and approved by log-rank test.

Results: Out of 35 PVR cases there were 8 patients with arterial

invasion, 27 with lymph node metastasis including 3 patients with

paraaortic node metastases. Twenty-six patients were radiated intrao-

pratively. There was no prophylactic PVR without PV invasion. There

were two operative mortalities. In patients with PV invasion, median

survival time (MST) was 11 months in the patients with PVR, 12

months in patients who underwent pancreatectomy without PVR and

5 months without pancreatectomy. There was no statistically signifi-

cant difference between the pancreatectomized patients with or with-

out PVR.

Discussion: Because of the improvement of perioperative man-

agement, PVR is now a safer procedure in pancreatectomy. However,

PVR did not have an additive effect on the survival after pancreatec-

tomy. There seems no rational for the prophylactic PVR. If PVR is nec-

essary for the resection of the tumor, PVR is recommended. Additional

survival benefit should be pursued in multidisciplinary therapeutics.

P3-14-5

Para-Aortic Lymph Node Metastasis inCarcinoma of the Head of the PancreasM. Sakai, T. Kaneko, S. Takeda, S. Inoue, Y. Kodera, S. Nomoto, N. Kanazumi, H. Sugimoto, A. Nakao

Department of Surgery II, Nagoya University, School of Medicine, Nagoya, Japan

Background: Metastasis to para-aortic lymph nodes often

occurs in pancreatic head cancer, but factors that predict it are little

known.

Methods: Based on histopathological data of 178 patients who

underwent extended lymph node dissection for pancreatic head can-

cer, we analyzed the distribution of metastases to lymph node groups

classified in detail, and attempted to identify the lymph node groups

that have a strong relation with metastasis to para-aortic lymph nodes.

Results: One hundred eighteen of 178 patients (66.3%) with

carcinoma of the head of the pancreas had lymph node involvement.

A high incidence of lymph node metastasis was found in para-aortic

lymph nodes (No. 16, 19.1%) as well as regional lymph nodes such as

those on the posterior aspect of the pancreas head (No. 13, 46.6%), on

the anterior surface of the pancreas head (No. 17, 28.7%), along the

superior mesenteric artery (No. 14, 28.1%), and along the hepato-

duodenal ligament (No. 12, 18.5%). Statistical analysis showed that

metastases to para-aortic lymph nodes had a strong correlation with

metastases to No. 12, No. 17, No. 13, and No. 14 lymph nodes. Para-

aortic lymph node metastases were seldom observed among the

patients who had no metastases to No. 13, No. 14 and No.17 lymph

nodes.

Conclusion: Examination of No. 13, 14 and 17 lymph nodes

may be useful to predict the involvement of para-aortic lymph nodes.

P3-14-6

Increasing Hospital Volume Correlates with Better Surgical Outcome in PancreaticHead ResectionH. Yamaue, M. Tani, M. Kawai, H. Terasawa, H. Onishi, H. Kinoshita, T. Hama, K. Uchiyama


Pancreatic head resection is an aggressive surgery, and accompanies

with several postoperative complications, including pancreatic fistula,

intraabdominal hemorrhage and delayed gastric emptying. Between

1994 and 2003, 126 patients were undergone pancreatic head resection

in our hospital. The annual number of patients with pancreatic head

resection has been increasing steadily. It was divided recent 10-year

period into 3 terms. The average annual numbers of pancreatic head

resection were 6.3 � 1.9, 13.7 � 6.0, and 16.7 � 8.5 in 1994–1997,

1998–2000, and 2001–2003, respectively. Pylorus-preserving pancre-

aticoduodenectomy was 9 patients (36%) in the first term, 32 patients

(78%) in the second term, and 45 patients (75%) in the third term

(p � 0.01). The incidence of pancreatic fistula was 12%, 14.6% and

3.3%, intraabdominal hemorrhage was 8%, 4.9% and 1.7%, delayed

gastric emptying was 8%, 22% and 21.7%, for the first term, for the

second term and for the third term, respectively. Pancreatic fistula in the

third term was decreased compared with the first and the second term

(p � 0.05). The mortality was 1.7% in the third term, whereas the mor-

tality was 8% and 4.9% in the first and the second term, respectively

(p � 0.05). Pancreatic head resection is safe and effective if indication

is protected and much experience of central hospital is gained.

P3-14-7

Management of Proximal Pancreatic Stump after Left PancreatectomyG. Balzano, A. Zerbi, F. Scaltrini, P. Veronesi, F. Gavazzi, V. Di Carlo

Pancreas Unit, Department of Surgery, San RaffaeleHospital, Milan, Italy

Background: Pancreatic fistula is a frequent complication of

left pancreatectomy

Methods: Retrospective review of prospectively collected data

about 122 patients who underwent left pancreatectomy since 1996.


Pancreatic closure was accomplished by a hand-sewn technique

(32 patients) or two kinds of mechanical staplers: until 2001 the lin-

ear stapler Proximate TL™ (50 patients); then the Endo GIA II™ sta-

pler (40 patients). The choice of technique was not randomised.

Factors considered in the uni- and multivariate analysis: separate

suture ligation of the pancreatic duct, hand-sewn suture in addition to

stapling closure, spleen preservation, use of PTFE pledgets for rein-

forcing the suture, sex, age, indication for pancreatectomy, associated

diseases.

Results: Overall mortality was 0%, morbidity was 47%, pancre-

atic fistula rate was 33%, mean postoperative stay was 12 days. All

fistulas healed spontaneously (mean duration 54 days). Fistula rate

was 34% after hand-sewn closure, 26% after linear stapler and 42%

after Endo GIA II (p � NS). None of the factors considered in the

analysis reduced significantly the onset of fistula. The best result was

obtained in 13 patients with pledget suture (fistula rate 15% vs 36%,

p � 0.07). Also spleen preservation (28 patients) seemed a protective

factor (fistula rate 21% vs 37%, p � 0.12). Main duct ligation

(46 patients) had no significant effect (30% vs 35%, p � 0.5). At the

multivariate analysis no factor significantly influenced fistula onset.

Conclusion: Pancreatic fistula after left pancreatectomy

remains an unsolved problem. Mechanical closure of the pancreas did

not reduce fistula rate. The use of pledgets to reinforce the suture is

advisable.

Poster 3-15 Rare Tumors

P3-15-1

Mesenchymal Tumor of the Pancreas –Report of a CaseM. Hashimoto1, A. Tanimoto2, K. Seki2, T. Yoshiya1, S. Matoba1, T. Hayakawa1, M. Matsuda1, T. Sawada1, H. Matsushita2, G. Watanabe1

Departments of 1Digestive Surgery, 2Pathology,Toranomon Hospital, Tokyo, Japan

Mesenchymal tumors of the pancreas are rare and difficult to be

classified. We reported a solitary mesenchymal tumor in the body of

the pancreas. 77-year-old man had admitted to our hospital for the

treatment of the rectal cancer. Preoperative abdominal CT scan for the

screening of the distant metastasis from the rectal cancer disclosed

the tumor in the conjunction between the head and body of the pan-

creas. Abdominal ultrasonography showed a hypoechoic tumor with

clear margin and low echoic part in it. Magnetic resonance imaging

revealed a pancreatic tumor, 50 mm in diameter, which was observed

as an area of low intensity on the T1-weighted images and as an area

of high intensity on the T2-weighted images and slight dilatation of

the main pancreatic duct in the distal part of the tumor. The serum

tumor markers were elevated: CA19-9 155 U/ml (�37), Span-1

76 U/ml (�45). Other tumor markers were all within normal limits.

Enucleation of the pancreatic tumor was performed after the resection

of the rectal cancer in December 2002. The tumor had capsule and the

cut surface was solid and whitish. Microscopically spindle to oval

shape cells having indented vesicular nuclei and rather ample

cytoplasm arranged in a sheet-like fashion or a storiform pattern,

associated with irregular tumor necrosis. The tumor showed immuno-

cytochemical reactivity for Vimentin, a-SMA, CD34, whereas cytok-

eratins, desmin, S-100, chromogranin, c-Kit, CD99 and bcl-2 were

negative. Although mitosis and high cellularity were microscopically

observed, we considered this tumor to be low-grade malignancy. The

patient had no sign of recurrence of the tumor one year after the

operation. We cannot further classify this lesion because of unusual

clinicopathologic feature.

P3-15-2

A Case Report of Cystic LymphangiomaContiguous to the PancreasJ. Kumagai1, T. Igari2, T. Takizawa2, U. Tamahashi1, S. Takamatsu3, S. Arii3, Y. Eishi1, M. Koike1

1Department of Human Pathology, 2Department ofSurgical Pathology and 3Department of Hepato-Biliary-Pancreatic Surgery, Tokyo Medical and Dental UniversityGraduate School, Tokyo, Japan

A rare case of cystic lymphangioma occurred contiguous to the

pancreas is reported.

The patient is a 31-year-old female, who complained of fever and

left hypochondriac pain. Abdominal CT scan revealed a large cystic

mass in the retroperitoneum, just beside the pancreas. Cystectomy has

been performed under the diagnosis of solid and cystic tumor of pan-

creas.

Gross appearance of the cyst was unilocular, thick-walled, and

there were multiple microcysts within the wall. There was no solid

part in the wall and the inner surface was smooth. The cyst content

was yellowish and serous. There was no connection between the cyst

lumen and the pancreas tissue.

By histopathological examination, the cyst lumen was covered

with thin, flat cells without apparent atypia. The microcysts in the cyst

wall were also covered with same type of cells. Immunohisto-

chemistry demonstrated lymphatic endothelial antigen and CD34 in

these cells. Although the thick cyst wall was mostly composed of

fibrous tissue, there was thin muscular layer with abundant elastic

fibers all around the wall, separating the cyst lumen and pancreatic

tissue. Based upon these findings, this lesion was diagnosed as cystic

lymphangioma contiguous to the pancreas.

Although the lymphangioma is relatively common tumor, the

retroperitoneal lesion is quite rare. We present this case together with

a review of reported cases.


P3-15-3

A Case of Epidermoid Cyst ofIntrapancreatic Accessory SpleenA. Maeda, K. Iki, A. Urakami, T. Kubozoe, M. Yamamura, Y. Hirabayashi, H. Matsumoto, M. Ikeda, T. Hirai, T. Tsunoda

Department of Gastroenterological Surgery, KawasakiMedical School, Okayama, Japan

About 10% of the population is reported to have an accessory

spleen, which is usually located at or near the splenic hilum. However,

16% of these accessory spleens are found in the pancreatic tail. An

epidermoid cyst originating from an intrapancreatic accessory spleen

is very rare. To our knowledge, there have only been 13 previously

reported cases in the English literature since the first case reported

by Davidson et al. in 1980. Herein we report a rare case of epider-

moid cyst originating from an intrapancreatic accessory spleen in a

72-year-old Japanese female. Two hypoechoic masses were detected

incidentally by abdominal ultrasonography. One of them appeared to

be a splenic artery aneurysm and the other appeared to be a pseudo-

cyst of the pancreatic tail. On T2-weighted magnetic resonance imag-

ing, the cystic mass showed a super-high-intensity shadow and

appeared to be a unilocular cystic lesion in the pancreatic tail. A distal

pancreatectomy with splenectomy was performed. Microscopically,

the cyst was surrounded by fibrous tissue and a thin layer of splenic

tissue and adjoined normal pancreatic parenchyma. The inner surface

of the cyst was lined with non-keratinizing squamous epithelium. The

diagnosis of an epidermoid cyst occurring in an intrapancreatic acces-

sory spleen was confirmed. It could be misdiagnosed as a cystic neo-

plasm or pseudocyst of the pancreatic tail, thus requiring differential

diagnosis.

P3-15-4

Two Cases of Lymphoepithelial Cyst of the PancreasY. Nakano1, S. Tanno2, M. Osanai1, K. Koizumi1, T. Okumura2, Y. Kohgo1

1Third Department of Internal Medicine and 2Departmentof General Medicine, Asahikawa Medical College,Asahikawa, Japan

Lymphoepithelial cyst (LEC) is an extremely rare type of true

pancreatic cysts. We report two cases of LEC of the pancreas. Case 1:

A 49-year-old man with no subjective symptoms was incidentally

found to have a cystic lesion in the pancreatic head by an abdominal

US. The serum CA19-9, CEA, and Span-1 were elevated to 568 U/ml,

11.1 U/ml, and 120 U/ml, respectively. Endoscopic US (EUS) showed

a mixed echoic pattern in the mass. Both CT and MRI revealed the

mass to be a multilocular cyst measuring approximately 5.0 cm in

diameter with a relatively distinct boundary and intraluminal septa.

The cyst was well demarcated from the surrounding tissue, and then

enucleated by operation. The cut surface of the cyst revealed

multilocular and contained keratin material. Histopathologically,

the internal surface of the cyst was lined by squamous epithelium

and surrounded by lymphoid tissue with germinal centers. Case 2:

A 50-year-old man complaining of abdominal pain was admitted. The

serum CA19-9 was 156 U/ml. US/EUS showed a pancreatic mass

with dense internal echoes. CT/MRI confirmed the mass to be a mul-

tilocular cyst measuring approximately 5.0 cm in diameter in the

upper border of the pancreatic head. Enucleation was performed. The

cyst was lined by stratified squamous epithelium and surrounded by

lymphoid tissue. The superficial layer of squamous epithelium and

the cystic contents were immunohistologically positive for CA19-9.

Our cases suggest that LEC should be considered in the differential

diagnosis of pancreatic cyst with internal echoes and an elevation of

serum CA19-9.

P3-15-5

Unusual Location of a Large PancreaticCystic TeratomaS.-S. Chang, Y.-S. Shan, K.-H. Hsu, P.-W. Lin

Division of General Surgery, Department of Surgery,National Cheng Kung University Hospital, Tainan, Taiwan

Cystic teratomas involving the pancreas are extremely rare and

less than twenty cases have been reported since 1918. Preoperative

diagnosis remains challenge. Fatty component with a rim of calcifi-

cation along the wall in computed tomography is the diagnostic hall-

mark. However, fatty-containing lesions with typical signal can be

showed in magnetic resonance image. Here, we reported a large pan-

creatic cystic teratoma in an unusual location, which displaced and

separated the superior mesenteric vessels. Computed tomography

showed a 6 � 7 cm cystic tumor containing fatty component and faint

calcification along the wall in the uncinate process of the pancreas.

Fat-suppressed T2-weighted fast spin-echo showed loss of signal

intensity in magnetic resonance image. The relationship between cys-

tic tumor and surrounding mesenteric vascular structures was also

demonstrated. The pancreatic cystic teratoma was highly suspected

preoperatively. Though, complete surgical removal was difficult, the

postoperative course was uneventful.

P3-15-6

Successful Resection of a Benign Tumor ofPancreas and a Duodenal Gist withoutPancreatico-DuodenectomyM. Shimoda, J. Kita, K. Kubota

Second Department of Surgery, Dokkyo University Schoolof Medicine, Mibu, Japan

Aim: P-D is still a high-risk procedure among the gastrointesti-

nal surgeries. We succeed in resecting a benign tumor of uncas and a

duodenal GIST without P-D.

Case 1: A 65-year-old female was admitted to our medical cen-

ter with a pancreas tumor. CT and US demonstrated a multicystic

lesion in the head of pancreas, 4 cm in diameter. ERP showed no

dilatation of the pancreatic duct but hypervascular lesion was revealed

in the pancreas head by angiogram. We diagnosed the lesion as a cyst

adenoma or malignant pancreatic tumor. At laparotomy, the mass was


located in the uncinate process of the pancreas and was considered as

a benign multicystic lesion. We performed resection of the uncinate

process instead of P-D. Since the main pancreatic duct was exposed

with a few openings of the branches, we inserted a tube into the pan-

creatic duct following duodenotomy, we also performed biliary

drainage from the cyctic duct. After surgery, although she suffered

from pancreatic juice leakage, it revolved spontaneously. Then she

was discharged from our hospital 56 POD. Histological diagnosis was

a serous cyst adenoma.

Case 2: A 45-year-old male was admitted to the previous hospi-

tal with tarry stool. GFS showed a type 3 tumor in the third portion of

the duodenum. Abdominal CT revealed a solid tumor, 6 cm in diame-

ter, in the right middle side of the abdomen and hypervascular lesion

was shown in the same position by angiogram. We diagnosed the

lesion as a mesointestinal tumor or GIST of the duodenum. At laparo-

tomy, this tumor was located in the third potion of the duodenum,

5 cm in diameter, with invasion into the ascending colon. There was

no invasion into the SMA and lymph nodes. The part of the 2nd por-

tion and the 3rd and the 4th portions of the duodenum were resected,

as confirming the location of the papilla of Vater. Then, duodenal and

intestinal anastomosis was performed. The postoperative course was

uneventful and the patient was discharged from our hospital 32 days

after surgery. Histological finding was GIST of the duodenum. Thus,

in two patients, P-D was avoided successfully.

P3-15-7

Metastasis Induced Acute Pancreatitis inRenal Cell Carcinoma with Extension intothe Main Pancreatic DuctM. Sugimoto, T. Takada, H. Yasuda, I. Nagashima, H. Amano, M. Yoshida, F. Miura, T. Isaka, N. Toyota, K. Takagi, K. Kato

First Department of Surgery, Teikyo University School ofMedicine, Tokyo, Japan

While metastasis to the pancreas is uncommon, it may occur from

renal cell carcinomas (RCC). Its extension into the main pancreatic

duct (MPD) may cause symptoms of acute pancreatitis. We here pre-

sent a case of metachronous pancreatic metastasis from RCC extend-

ing into the MPD in a 58-year-old Japanese man presenting as acute

pancreatitis. The patient had histories of RCC treated with a radical

left nephrectomy 8 years previously and a radical right nephrectomy

2 years previously, complaint upper abdominal and back pain, was

found to have a mass approximately 3 cm in diameter in the body of

the pancreas on radiological images. Arteriography revealed that the

tumor of the pancreas body was characteristically hypervascular. The

patient was suspected of having pancreatic metastasis from RCC and

underwent a distal pancreatectomy with splenectomy. Histologically,

the tumor was compatible with a metastatic RCC. The pancreatic

tumor extended into the MPD. This condition is similar to RCC exten-

sion into the renal vein and the inferior vena cava. According to the

literatures, intrapancreatic duct extension reported only 7 cases for 20

years. There have been few previous reports of clinical pancreatitis

associated with metastatic tumor to the pancreas. The mechanism

may be severe obstruction of pancreatic ducts with premature activa-

tion of pancreatic proteases disruption of ductal epitherium.

Extension into the MPD may cause pancreatitis associated with a

metastatic RCC. The ultimate prognosis depends on the treatment of

the underlying condition as soon as the patient recovers from the ini-

tial attack of pancreatitis.

Abd-El-Ghaffar, S. Kh 298

Abe, H. 278, 283, 355, 363,

387, 391, 398, 402, 404

Abe, N. 291, 320, 342, 361

Abe, S. 349

Abe, T. 266, 400

Adsay, N.V. 276

Ahmed, A. 293

Aida, S. 307

Aiko, T. 274

Aikou, T. 304, 395

Aimoto, T. 333, 341, 370

Aiura, K. 336, 340

Ajiki, T. 337

Akada, M. 282

Akaishi, S. 315

Akhmedov, V.A. 304, 314, 378

Akiyama, T. 270

Aladawi, A. 292

Alexandre, A.S. de 343

Allavena, P. 277

Almeida, J.L. 375

Alsfasser, G. 284

Amano, A. 285

Amano, H. 407

Amaya, K. 329

Ambiru, S. 369

Ambrosi, A. 345

Amemiya, R. 394, 395

Amikura, K. 371

Ammerpohl, O. 281, 327

Amono, H. 370

Ando, G. 340

Andoh, A. 351

Ang, A.D. 288

Ansite, J.D. 291

Antoniu, B. 281, 284, 289,

324

Aoki, H. 351

Aoki, M. 402

Aoki, S. 297

Aoki, Y. 395

Aoyagi, S. 386, 390

Arai, H. 331

Arai, T. 302, 315, 336

Araki, H. 398

Araki, M. 340

Aridome, G. 349

Arii, S. 405

Arisaka, Y. 373

Arita, Y. 295, 305, 307, 311,

313, 391

Aruga, A. 319

Asakuma, M. 400

Asano, K. 369

Asano, T. 274, 363, 380, 393

Asato, Y. 394

Asaumi, H. 287

Asawa, S. 356

Ashida, R. 385, 394

Ashizawa, N. 394

Atomi, Y. 291, 320, 342, 361

Augusta, P. 378

Avila, J.G. 290

Awai, T. 316, 350

Baba, H. 392, 399

Baba, T. 369

Bacchella, T. 328, 330, 331,

343, 360

Bachellier, P. 280

Badea, V. 376

Balamurugan, A.N. 271

Balcom, J.H. 324

Balzano, G. 338, 404

Bamba, S. 351

Ban, S. 324

Bang, S. 381

Bartsch, D.K. 326

Bassi, C. 273, 275

Beech, I. 292

Beger, H. 273, 383

Beger, H.G. 257

Belyayev, V.V. 314

Belyayeva, N.V. 341

Beneduce, A. 338

Benz, S. 283, 288, 289, 306,

372

Benz, S.R. 352

Bernardes, A.L. 343

Bertuccelli, J. 344

Bessell, J.R. 377

Bhakta, V. 360

Bhatia, M. 288, 318, 373

Bigourdan, J.-M. 280

Bihalskyy, I. 341

Bochnig, S. 304, 315

Bottino, R. 271

Brooke-Smith, M.E. 307, 316,

317

Büchler, M.W. 273, 278, 299,

357, 392

Büchler, P. 299

Cao, Y. 288

Carati, C.J. 307, 317

Carrière, F. 382

Carter, R. 267

Chang, M.-C. 325

Chang, S.-S. 396, 406

Chang, Y.-T. 325

Chari, S.T. 270

Charnsangavej, C. 265

Chaube, J. 378

Chaube, S. 376, 378

Chelomanova, O.A. 314

Chen, H.-M. 267, 308, 377, 379

Chen, J.-T. 338

Chen, J.W.C. 377

Chen, M.-F. 301, 308, 377, 379,

382

Chiba, N. 336, 340

Chikaishi, T. 347, 349

Cho, A. 402

Chooklin, S. 309, 341, 342

Chung, J.B. 322, 352, 381

Chung, J.P. 322

Coelho, A.M.M. 284, 342, 343,

374, 375

Coffey, R.J. Jr 290

Corless, D.J. 333

Costea, R. 376, 378

Costello, E. 360

Coy, D.H. 307

Crnogorac-Jurcevic, T. 277,

282, 360

Csernay, L. 285

Cui, Y. 313

Cunha, J.E.M. 279, 284, 371,

375

Czakó, L. 285

Dadan, J. 332, 337

Dawiskiba, S. 317

Deakin, M. 333

Dervenis, C. 273

Di Carlo, V. 277, 338, 404

Dinca, V. 378

Dobschuetz, E.F. von 352

Dobschuetz, E.V. 288

Doi, R. 259, 274, 280, 289,

324, 325, 327, 329, 339,

354, 357, 358, 362, 389

Dolgich, T.I. 304, 314

Donadelli, M. 282

Dono, K. 294, 334, 389, 396

Dor, Y. 272, 280

Drognitz, O. 352

Duda, D.G. 299

Dumitrescu, C. 376

Duncan, H. 292

Dunn, J.A. 273

Ebata, T. 302, 315, 336, 384,

388

Egawa, N. 269, 309, 332

Egawa, S. 278, 283, 290, 299,

355, 363, 374, 391, 394, 395

398, 402, 404

Eguchi, H. 300, 321, 333

Eishi, Y. 405

El-Fitory, J. 299

El-Metwally, T.H. 298

Endo, T. 319

Endo, Y. 318

Endou, H. 361

Enosawa, T. 355

Evers, B.M. 289, 356

Falconi, M. 273, 275

Fang, X. 338

Feng, Y. 338

Fernandez-Cruz, L. 273

Fernandez-del Castillo, C. 276,

280, 281, 284, 289, 324

Fersini, A. 345

Fesce, E. 344

Filho, D.P. 330

Foitzik, T. 267

Friebe, V. 289

Friess, H. 273, 299, 357, 392

Frulloni, L. 270

Fujii, H. 397

Fujii, T. 308, 383

Fujiki, K. 317

Fujimori, N. 311

Fujimoto, J. 399

Fujimoto, K. 259, 280, 289,

325, 327, 329, 339, 354,

357, 358, 362, 389

Fujimoto, N. 368

Fujimoto, S. 376

Fujimura, T. 329

Fujino, Y. 337, 353

Fujita, N. 315, 385

Fujita, S. 385

Fujita, T. 335

Fujiyama, Y. 351

Fukata, S. 366

Fukiya, E. 376

Fukuda, A. 302, 303, 323,

383

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Accessible online at:

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Author Index for Abstracts


Fukuhara, T. 365, 385

Fukui, J. 340, 398

Fukukura, Y. 395

Fukumura, Y. 269, 296, 301,

311, 386

Fukuta, N. 365

Fukuyama, N. 355

Fukuyama, S. 283, 363, 374,

391, 398, 402, 404

Fukuyasu, A. 340

Funahashi, H. 358, 359, 361

Funakoshi, A. 274, 295, 312,

323, 333, 360, 368

Funata, N. 269

Funato, O. 335

Furukawa, H. 367

Furukawa, K. 302, 303, 323,

383

Furukawa, T. 264, 299, 355,

389

Furusawa, K. 401

Furuse, J. 368, 395

Furuta, K. 303, 355

Furuya, S. 317

Furuya, T. 343

Furuyama, K. 358

Fuse, A. 301, 384, 397

Fushida, S. 329

Gagner, M. 261

Gangeswaran, R. 360

Gavazzi, F. 404

Gibo, J. 295, 305, 311, 313,

391

Giese, N. 357

Go, V.L.W. 257

Godoy, R.S. de 284, 328, 330,

331, 342, 343, 360, 375

Goto, H. 317

Goto, T. 353

Gotoh, M. 356

Gradinaru, S. 376

Grandval, P. 305, 382

Gregory, P. 382

Grützmann, R. 281, 326, 327

Gu, Y. 290, 354

Guarise, A. 275

Gubergrits, N.B. 308, 313, 314,

341, 378

Gunji, T. 356

Gunn, S.R. 293

Guweidhi, A. 357

Habiro, A. 388

Hadori, T. 274

Hady, H.R. 332, 337

Hahn, J.-U. 304, 315

Hakamada, K. 386

Hama, K. 287, 351

Hama, T. 321, 371, 401, 404

Hamada, H. 363

Hamada, K. 362

Hamada, S. 326, 358, 390

Hamano, H. 269, 297

Hamano, K. 345, 346

Hanari, N. 384

Hanawa, K. 350

Hanyu, F. 366

Hanyu, N. 397

Harada, K. 397

Harada, N. 303, 366

Hareyama, M. 364

Haruki, M. 372

Hasegawa, H. 385, 394, 395

Hashimoto, M. 405

Hashimoto, N. 380

Hashimoto, T. 386

Hata, K. 376

Hatano, M. 365, 385

Hatori, T. 302, 303, 322, 323,

383, 388

Hattori, M. 321, 349, 350

Hayakawa, N. 366

Hayakawa, T. 358, 359, 405

Hayashi, K. 315, 388

Hayashi, M. 400

Hayashida, T. 336, 340

Hellmich, M.R. 356

Helmy, A. 344

Henne-Bruns, D. 298

Henne-Bruus, D. 383

Hennigues, F. 382

Hering, B.J. 291

Hickey, H. 273

Higuchi, S. 312

Hines, O.J. 299

Hirabayashi, Y. 406

Hirai, I. 301, 318, 362, 384,

387, 397

Hirai, T. 403, 406

Hirasawa, H. 293

Hirayama, A. 266, 400

Hirokawa, N. 364

Hiromatsu, T. 315

Hirota, M. 268

Hiruma, K. 392

Hisada, S. 305

Hisanaga, Y. 310, 371

Hisano, T. 307, 311, 391

Hishinuma, S. 274

Hiura, A. 290, 354

Honda, H. 315

Honda, K. 365, 385

Hongo, Y. 373

Honma, T. 292, 350

Hopt, U.T. 283, 288, 289, 306,

352, 372

Horiguchi, A. 401

Horii, A. 299, 389

Horiike, N. 310

Horinouchi, M. 265

Hoshino, H. 303, 355

Hoshino, Y. 305

Hosotani, R. 367, 403

Hruban, R.H. 259

Hsu, J.-T. 308, 377, 379

Hsu, K.-H. 406

Huang, S.-F. 301

Huang, W.T. 396

Hujioka, Y. 320

Huruse, J. 334

Hwang, T.-L. 301, 308, 328,

377, 379, 382

Hyodo, H. 364

Iana, G. 376

Ibuki, E. 345, 346

Ichimura, T. 364

Igarashi, H. 307

Igari, T. 405

Iguchi, H. 333, 368

Iijima, H. 366

Iimuro, Y. 399

Iishi, H. 294, 321, 367

Iizuka, Y. 305

Ikeda, H. 368, 369

Ikeda, M. 319, 334, 335, 368,

369, 395, 406

Ikeda, T. 270

Ikegami, A. 292, 350

Ikezawa, S. 376

Iki, K. 339, 403, 406

Imada, K. 347

Imai, A. 368

Imai, H. 297

Imai, K. 319

Imai, T. 398

Imaizumi, H. 340

Imaizumi, T. 303, 323, 329,

388

Imamura, M. 259, 274, 280,

289, 324, 325, 327, 329,

339, 354, 357, 358, 362,

389

Imamura, T. 292, 350

Imaoka, H. 385, 394

Imaoka, S. 300

Imawari, M. 292, 316, 350

Imoto, M. 347

Inagaki, H. 386

Inagaki, T. 318, 355

Inami, K. 341, 372, 399

Inatomi, O. 351

Ino, Y. 295

Inoue, H. 299, 400

Inoue, K. 256, 290, 318, 354

Inoue, M. 311

Inoue, N. 295, 305, 313, 391

Inoue, S. 286, 337, 370, 383,

404

Inoue, T. 373

Inui, K. 321, 347, 349, 350

Ioka, T. 294, 333, 367

Iovanna, J.L. 306

Isaji, S. 295, 296

Isaka, T. 370, 385, 394, 407

Ishibashi, T. 266

Ishida, E. 346, 396

Ishida, M. 398, 404

Ishiguro, H. 317

Ishihara, M. 356

Ishihara, S. 401

Ishihara, T. 286, 294, 300, 309,

322, 335, 347, 348, 369

Ishii, H. 334, 368, 395

Ishikawa, O. 300, 321, 333

Ishikawa, T. 383

Ishikawa, Y. 380

Ishimatsu, S. 402

Ishiwata, T. 308

Ishiwatari, H. 350

Ishiyama, S. 274

Ishiyama, S.-I. 403

Ishizaki, M. 398

Itakura, J. 397

Ito, D. 280, 324, 325, 327,

329, 339, 354, 357, 358,

362, 389

Ito, H. 319, 336

Ito, K. 385

Ito, M. 401

Ito, N. 386

Ito, R. 316, 339, 345

Ito, T. 295, 305, 307, 311, 313,

363, 391

Ito, Y. 340, 368, 369

Itoh, H. 369

Itoh, M. 297

Itoh, S. 343

Itoh, Y. 336

Itoi, T. 285, 366

Itokawa, F. 285, 350

Iwakawa, M. 393

Iwamoto, M. 400

Iwamoto, S. 372

Izai, J. 336, 384, 388

Izumi, J. 345, 346

Izumi, M. 311, 384, 402

Izumi, N. 320

Jaeck, D. 280

Jain, R.C. 378

Jain, S.K. 376

Jan, Y.-Y. 301, 308, 377, 379,

382

Jargon, D. 283, 306

Jaworek, J. 282

Jennische, E. 317

Jensen, R.T. 307

Jiang, P.-H. 306


Jimi, A. 360, 390

Johnson, C.D. 293

Jukemura, J. 284, 328, 330,

331, 342, 343, 360, 371,

375

Jureidini, R. 371

Kagami, Y. 368, 369

Kage, M. 390

Kajiwara, T. 367, 403

Kakinoki, K. 353

Kaku, T. 305, 311, 313

Kakuta, Y. 320

Kalthoff, H. 281, 327

Kamada, M. 296

Kami, K. 280, 324, 325, 327,

329, 339, 354, 357, 358,

362, 389

Kamiga, M. 301, 318, 397

Kamisawa, T. 269, 309, 332

Kamiya, J. 366

Kamiya, T. 341, 372, 399

Kamiyama, Y. 299, 325, 340,

391, 393, 398

Kanai, Y. 361

Kanazumi, N. 404

Kaneko, T. 286, 337, 370, 383,

404

Kanemitsu, D. 316, 339, 345

Kanemoto, H. 384, 388

Kang, J.K. 322, 381

Kaniwa, N. 334

Kanno, A. 373

Karasawa, K. 261, 397

Kashiwaya, K. 400

Kasugai, T. 310, 321

Katanuma, A. 350

Kataoka, K. 316, 339, 345

Kataoka, Y. 313

Katayama, M. 360

Kato, A. 336

Kato, H. 274, 295

Kato, J. 346, 396

Kato, K. 341, 370, 399, 407

Kato, Y. 319

Katoh, A. 369

Katoh, M. 305

Katono, Y. 366

Katori, M. 303, 355

Katsu, K.-I. 373

Katsuno, A. 333, 341, 370

Katsurahara, M. 385

Kawa, S. 269, 297

Kawabe, K. 295, 305, 307, 311,

313, 391

Kawachi, S. 340

Kawaguchi, M. 329

Kawaguchi, Y. 280, 289, 325,

327, 339, 354, 357, 358,

362, 389

Kawahara, A. 390

Kawahara, K. 308

Kawai, H. 300

Kawai, M. 321, 371, 401,

404

Kawai, Y. 364

Kawakami, H. 369

Kawamoto, H. 346, 396

Kawamoto, Y. 308

Kawamura, H. 335, 397

Kawanami, T. 323

Kawarada, Y. 274

Kawasaki, T. 365

Kawashima, M. 368

Kayahara, M. 303, 329

Keck, T. 283, 289, 306

Kenmochi, T. 380, 393

Kerner, W. 304, 315

Kerr, D.J. 273

Kersting, S. 281

Ketterer, K. 357

Khatri, A. 378

Kida, M. 340

Kida, Y. 340

Kiguchi, Y. 397

Kihara, Y. 287, 349

Kijima, H. 329

Kikuchi, H. 340

Kikuchi, S. 403

Kikuta, K. 287, 311, 312

Kikuyama, M. 372

Kim, D. 354

Kim, H. 352

Kim, M. 316

Kim, Y.-K. 363

Kimura, F. 336, 369

Kimura, H. 376

Kimura, K. 326, 358, 390

Kimura, W. 279, 301, 318, 362,

384, 387, 397

Kin, T. 290

Kinoshita, H. 371, 386, 387,

390, 401, 404

Kinoshita, T. 274, 286

Kinosita, H. 321

Kiriyama, S. 310, 371

Kishi, S. 379

Kita, J. 406

Kita, K.-I. 331, 360

Kitagawa, H. 303, 329

Kitagawa, M. 317

Kitagawa, T. 363

Kitagawa, Y. 366

Kitajima, M. 336, 340

Kitamura, K. 292, 350

Kitano, M. 293, 365

Kiyosawa, K. 269, 297

Kleeff, J. 299, 357, 392

Klimstra, D.S. 264

Klöppel, G. 265, 281, 327

Ko, S. 317

Kobari, M. 315, 385

Kobayashi, A. 286

Kobayashi, N. 365, 385

Kobayashi, S. 297, 384,

402

Kobayashi, T. 385

Kobayashi, Y. 372

Koch, R. 281, 326

Kodama, H. 403

Kodama, T. 386

Kodera, Y. 404

Koenig, H. 304, 315

Kohgo, Y. 388, 406

Kohsaki, T. 296, 335

Koide, N. 351

Koide, S. 372

Koike, M. 405

Koito, K. 364

Koizumi, K. 388, 406

Koizumi, M. 280, 324, 325,

327, 329, 339, 354, 357,

358, 362, 389, 393

Kojima, M. 295, 305, 307, 313,

355, 391

Kojiro, M. 387

Kokoszko, M. 332, 337

Kolkina, V.Y. 378

Komatsu, K. 269, 297

Komemushi, A. 393

Komoto, I. 259

Kondo, T. 381

Konishi, M. 286, 402

Kono, T. 266

Konturek, S.J. 282

Korc, M. 298, 357, 392

Kornmann, M. 298

Koshikawa, H. 341, 372, 399

Koshikawa, K. 383

Kow, L. 377

Kremer, B. 327

Kuboakawa, Y. 341

Kubokawa, Y. 372, 399

Kubota, K. 320, 406

Kubota, Y. 313

Kubozoe, T. 339, 403, 406

Kubrusly, M.S. 360

Kudo, D. 315, 385

Kudo, M. 293, 308, 365

Kuhara, T. 280, 325, 357

Kumada, T. 310, 371

Kumagai, J. 405

Kumakura, K. 402

Kume, K. 301, 312, 349,

386

Kunimura, T. 318, 355

Kuno, A. 297

Kurahara, H. 395

Kure, S. 337

Kurihara, K. 393

Kurihara, T. 285, 352

Kuroda, N. 399

Kuroda, Y. 283, 290, 291,

310, 337, 346, 353, 377,

379

Kurosaki, R. 319

Kusama, K. 316

Kutsumi, H. 376

Kuwano, M. 390

Kuzuya, T. 310

Kwon, A.-H. 299, 325, 340,

391, 393

Lacaine, F. 273

Ladny, J.R. 332, 337

Laheru, D.A. 277

Lakey, J.R.T. 290

Lange, S. 317

Lankisch, P.G. 260, 304, 315,

344

Laposata, M. 284

Lau, H.Y. 373

Laugier, R. 292, 305, 382

Leach, S.D. 290

Lebkowski, J. 258

Lee, C.M. 363

Lee, D.K. 322

Lee, J.H. 381

Lee, M.G. 317, 352

Lee, S.-J. 322

Leelawat, K. 364

Left, L.P. 299

Lefter, L.P. 389

Leja-Szpak, A. 282

Lemoine, N. 282

Lemoine, N.R. 282, 360

Leone, B.E. 277

Lerch, M.M. 344

Lewandrowski, K. 284

Li, J. 392

Li, L. 280, 281, 324

Li, S. 353

Liang, Y. 328

Lima, M.S. de. 371

Lin, J.-T. 325

Lin, P.-W. 396, 406

Liu, B. 291

Liu, K.-H. 377

Liu, T.-J. 338

Liu, X. 352

Lo, C.-H. 328

Longnecker, D.S. 264

Lonovics, J. 285

Lowenfels, A.B. 272, 304,

315

Lukashevich, G.M. 341

Lüttges, J. 281, 327

Ma, J. 301, 318, 362, 384, 387,

397


Machado, M.A.C. 331

Machado, M.C.C. 328, 330,

331, 342, 343, 360, 374, 375

Machadon, M.C.C. 284

Maeda, A. 339, 352, 384, 388,

406

Maeda, Y. 392

Maekawa, K. 365

Maemura, K. 304, 395

Maesawa, Y. 340

Maguchi, H. 319, 350

Mahidol, H.R.H.P.C. 364

Mahon, P.C. 282

Maisonneuve, P. 304, 315

Majima, K. 394, 395

Manabe, T. 334, 358, 359, 361

Marotta, F. 344

Marubashi, S. 294, 334, 389,

396

Maruyama, K. 312

Maruyama, Y. 390

Masaki, T. 285, 291, 320, 361

Masamune, A. 263, 287, 311,

312

Masui, T. 324, 389

Matheus, A.S. 284, 328, 330,

331, 342, 343, 360, 374, 375

Matoba, S. 405

Matsuda, H. 363

Matsuda, K. 283, 293, 374, 397

Matsuda, M. 405

Matsuhashi, Y. 379, 382

Matsui, H. 310

Matsui, Y. 340, 393, 398

Matsumoto, A. 379, 382

Matsumoto, G. 309, 392, 397,

399

Matsumoto, H. 339, 403, 406

Matsumoto, I. 291

Matsumoto, M. 296

Matsumoto, N. 361

Matsumoto, T. 319

Matsumura, H. 372

Matsumura, N. 283, 310, 346,

377, 379

Matsumura, Y. 341, 399

Matsunaga, K. 384, 388

Matsunaga, T. 350, 366

Matsuno, S. 270, 278, 282, 283,

290, 299, 363, 374, 389,

391, 394, 395, 398, 402, 404

Matsuo, Y. 358, 359, 361

Matsushita, H. 405

Matsushita, K. 351

Matsuura, B. 310

Matsuzaki, H. 381

Matuda, K. 355

Matuno, S. 355

McFaul, C. 326

Means, A.L. 290

Melton, D. 280

Melton, D.A. 272

Meszoely, I.M. 290

Mikami, Y. 283, 374, 385

Minami, H. 310

Minato, K. 381

Misaka, R. 352

Mishiro, S. 394, 395

Missiaglia, E. 282

Mitsufuji, S. 316, 339, 345

Mitsuhashi, T. 324

Mitsuya, T. 318

Miura, F. 370, 407

Miwa, K. 329

Miyagawa, S. 274

Miyaji, E. 296

Miyakawa, H. 266, 400

Miyakawa, K. 285

Miyakawa, S. 401

Miyake, H. 302

Miyamoto, A. 294, 334, 389,

396

Miyamoto, T. 295

Miyamoto, Y. 290, 400

Miyasaka, K. 312, 323

Miyatake, S.-I. 327, 362

Miyauchi, H. 380

Miyazaki, K. 274

Miyazaki, M. 336, 369

Miyoshi, H. 321, 347, 349, 350

Mizukami, Y. 388

Mizumoto, K. 334, 364

Mizuno, K. 401

Mizuno, M. 396

Mizuno, N. 275, 300, 332, 385,

394

Mizuno, O. 346

Mizuno, S. 295, 296

Mizushima, T. 351

Mizutamari, H. 312

Mizutani, M. 301, 318, 362,

387, 397

Molan, N.A.T. 342, 343, 374

Monden, M. 294, 334, 389, 396

Monti, P. 277

Mori, T. 280, 291, 320, 324,

325, 327, 329, 339, 354,

357, 358, 361, 362, 389

Moriki, H. 340

Morimoto, K. 296, 335

Morimoto, M. 365, 385

Morioka, C.Y. 284, 328, 330,

331, 342, 343, 360, 375

Morishita, S. 335

Morita, R. 355

Moriya, T. 301, 318, 362, 384,

387, 397

Moriyama, N. 367

Moriyasu, F. 285, 366

Morizane, C. 335, 369, 395

Morohoshi, T. 318, 355

Morvay, Z. 285

Motoi, F. 278, 299, 363

Motoo, Y. 306, 349, 353, 381

Motoyoshi, T. 316, 339, 345

Mouri, H. 353, 381

Murakami, H. 372

Murakami, K. 286

Muraki, T. 269, 297

Muta, M. 392

Nagahama, M. 318

Nagai, E. 334, 364

Nagai, H. 393

Nagai, S. 335

Nagakawa, T. 266, 303, 400

Nagano, H. 294, 334, 389, 396

Nagao, K. 296

Nagase, M. 368, 395

Nagashima, I. 370, 407

Nagashio, Y. 287

Nagata, H. 401

Nagata, K. 265

Nagata, M. 349, 350, 363

Nagino, M. 274, 302, 315, 336

Naito, H. 373

Naito, T. 315

Naito, Y. 387

Naito, Z. 308

Naitoh, Y. 324

Naitou, Z. 333, 341

Najima, M. 335

Nakada, Y. 330

Nakae, Y. 347

Nakagawa, A. 300

Nakagawa, K. 270

Nakagohri, T. 286

Nakahira, S. 294, 334, 389,

396

Nakaizumi, A. 294, 300, 321,

333, 367

Nakajou, M. 395

Nakamori, S. 294, 334, 389,

396

Nakamura, H. 287, 349, 376

Nakamura, K. 285, 286, 294,

366, 369

Nakamura, M. 293

Nakamura, S. 297

Nakamura, T. 300, 379, 382,

385

Nakamura, Y. 321, 333, 341,

347, 349, 350, 370

Nakanishi, T. 346

Nakano, H. 280

Nakano, I. 295

Nakano, M. 291

Nakano, Y. 388, 406

Nakao, A. 286, 337, 370, 383,

404

Nakaoka, R. 365

Nakase, T. 321, 371, 401

Nakata, K. 364

Nakayama, D. 366

Nakazawa, T. 297

Narumi, S. 386

Naruse, S. 317

Narushima, Y. 403

Nasu, M. 403

Nata, K. 270

Nawata, H. 295, 305, 307, 311,

313, 391

Nawrot-Porbka, K. 282

Neagu, S. 376, 378

Neeff, H.P. 352

Neesse, A. 360

Neoptolemos, J.P. 273, 360

Neri, V. 345

Niebergall-Roth, E. 258

Niikawa, J. 292, 350

Niimi, A. 352

Nimura, Y. 274, 302, 315, 336,

366

Ninomiya, E. 319

Ninomiya, I. 329

Nishida, K. 376

Nishida, M. 364

Nishikata, M. 335

Nishimori, I. 296, 335

Nishimura, G.-I. 329

Nishino, T. 323, 348

Nishio, H. 336

Nishiyama, K. 367

Nisio, H. 302

Nitta, H. 335

Niwa, T. 285

Nobukawa, B. 301, 386, 387

Nobuoka, Y. 398

Noda, A. 345, 346

Noguchi, N. 270

Nomiyama, Y. 287

Nomoto, S. 383, 404

Nomura, N. 400

Nonami, T. 386

Nonogaki, K. 310

Nozawa, F. 326, 364

Nozu, F. 316

Obermaier, R. 288, 372

Ochi, K. 351

Ochi, Y. 269, 297

Ochiai, T. 380, 393

Oda, K. 302, 315, 336, 366

Oda, S. 293

Oehmanns, C. 288

Ogata, S. 307

Ogawa, F. 324

Ogawa, M. 366

Ogawa, T. 295, 296, 346, 396

Ogawa, Y. 347, 382


Ogura, Y. 334

Ohara, H. 297

Ohhigashi, S. 380

Ohigashi, H. 300, 321, 333

Ohike, N. 318, 355

Ohkawa, S. 285

Ohnishi, H. 287, 351

Ohno, I. 295

Ohta, M. 345, 346

Ohta, S. 323

Ohta, T. 303, 329

Ohtake, K. 356

Ohtsubo, K. 353, 381

Ohtsuka, M. 336, 369

Ohzawa, K. 328, 331

Oi, I. 322, 348

Oie, S. 390

Oishi, H. 398

Oishi, K. 340

Okabe, S. 367

Okada, G. 381

Okada, H. 346, 396

Okada, T. 384, 391, 399, 402

Okada, Y. 358, 359, 361

Okamoto, A. 269, 309, 392,

397, 399

Okamoto, H. 270

Okamoto, N. 296, 335

Okamoto, T. 297

Okamoto, Y. 332, 346, 385,

394, 396

Okamura, K. 266, 400

Okanami, Y. 296

Okanoue, T. 316, 339, 345

Okazaki, K. 270, 313

Okubo, H. 341, 399

Okubo, K. 300, 332, 385, 394

Okumura, T. 388, 406

Okusaka, T. 334, 335, 368, 369,

395

Okushima, K. 321, 347, 349,

350

Okuyama, Y. 376

Omura, N. 278, 355, 363

Omuro, Y. 392

Onishi, H. 321, 371, 404

Onishi, S. 296, 335

Onizawa, S. 302, 303, 322, 323,

383

Onji, M. 310

Ono, M. 390

Ono, Y. 365, 385

Onogawa, T. 270

Oono, T. 295, 305, 307, 311,

313, 391

Oonuma, M. 278

Osanai, M. 388, 406

Oshima, T. 384

Otake, M. 345, 346

Otani, M. 263

Otomo, S. 282

Otonkoski, T. 271

Otsuki, M. 263, 287, 349

Ottomo, S. 278, 363

Oussoultzoglou, E. 280

Owa, Y. 386

Oyama, H. 348

Ozaki, T. 393

Ozawa, S. 334

P’eng, F.-K. 338

Padbury, R.T.A. 377

Palmieri, M. 282

Palonek, M. 282

Pap, Á. 262, 273

Park, B.K. 352, 381

Park, M.-S. 322

Park, S.W. 381

Patzina, R.A. 371, 375

Pawlik, W.W. 282

Pearce, C.B. 292, 293

Pederzoli, P. 273, 275

Pelmus, M. 376

Penteado, S. 342, 371

Perejaslov, A. 309, 341, 342

Petito, L. 345

Piemonti, L. 277

Piganelli, J.D. 271

Pilarsky, C. 281, 326, 327

Pleskovic, A. 359

Pontieri, V. 374

Pour, P.M. 298, 326, 364

Puchalski, Z. 332, 337

Qi, M. 290, 354

Rahman-Shield, Y. 344

Rau, B. 257

Reber, H.A. 260, 299

Reni, M. 338

Renou, C. 382

Richter, S. 283, 306

Ries, P. 292

Roslyakov, E.A. 378

Rosow, D.E. 280, 281, 324

Roy, S.D. 333

Ruiz, A.G. 292

Rustgi, A.K. 290

Ryu, M. 384, 402

Saccone, G.T.P. 307, 316, 317

Saeger, H.D. 281, 326, 327

Safran, P. 344

Sai, J.K. 341, 372, 399

Saigenji, K. 340

Saijo, N. 334

Saisho, H. 294, 295, 300, 309,

322, 347, 348, 369

Saisyo, H. 286

Saito, H. 289

Saito, K. 335, 355

Saito, S. 320, 328, 330, 331, 360

Saito, T. 350, 356

Saito, Y. 363

Saitoh, Y. 278

Sajin, M. 378

Sakagami, J. 316, 339, 345

Sakai, M. 404

Sakai, T. 291, 337, 353, 394

Sakamaki, H. 392

Sakamoto, H. 293, 365, 371

Sakamoto, M. 358, 361

Sakamoto, T. 331

Sakata, N. 290, 354

Sakoda, K. 274

Sakon, M. 294, 334, 389, 396

Sakurai, F. 301, 362, 387

Sakurai, K. 402

Sakurai, S. 402

Sakurai, Y. 295, 296

Salvia, R. 275

Sampietre, S.N. 284, 342, 374,

375

Sano, H. 297

Santacroce, C. 345

Saotome, T. 351

Sarles, J. 305

Sasada, Y. 372

Sasaki, K. 319

Sasaki, M. 386

Sasaki, R. 335

Sasaki, T. 392

Sata, N. 393

Sato, A. 394, 395

Sato, D. 402

Sato, K. 303, 355

Sato, M. 319

Sato, N. 372

Satoh, K. 326, 358, 390

Satoh, M. 287, 311, 312

Satoi, S. 299, 325, 340, 391,

393, 398

Satomura, Y. 349

Satou, T. 364

Sawa, H. 283, 310, 346, 377,

379

Sawabu, N. 306, 349, 353, 381

Sawada, S. 393

Sawada, T. 291, 405

Sawai, H. 358, 359, 361

Sawaki, A. 275, 300, 332, 385,

394

Scaltrini, F. 338, 404

Scanlon, K.J. 329

Scarpa, A. 282

Schackert, H.K. 281, 327

Schneider, M. 299

Scripcariu, V. 389

Seki, K. 405

Seki, M. 319

Serwatka, W. 332, 337

Seza, K. 347

Shan, Y.-S. 396, 406

Shapiro, A.M.J. 290

Sheng, S.-J. 382

Shibuya, K. 402

Shida, H. 345, 346

Shiga, H. 293

Shigemoto, M. 352

Shimada, H. 274

Shimada, K. 303, 355

Shimada, M. 351

Shimada, Y. 259

Shimamoto, T. 371

Shimamura, H. 403

Shimazu, M. 340

Shimizu, H. 336, 369

Shimizu, K. 263, 322, 329

Shimizu, M. 276, 324

Shimizu, T. 401

Shimizu, Y. 300, 324, 332, 385,

394

Shimizu, Z. 310

Shimoda, M. 406

Shimokata, H. 323

Shimosegawa, T. 287, 311, 312,

326, 358, 390

Shimura, K. 393

Shinchi, H. 304, 395, 401

Shinji, T. 351

Shino, Y. 363

Shinohara, T. 319

Shiomi, H. 376

Shiono, S. 296, 301, 386

Shioyama, Y. 394, 395

Shiozaki, M. 373

Shirahige, A. 351

Shirai, M. 365, 385

Shirai, O. 347

Shirai, Y. 319, 322

Shiraishi, T. 296

Shirasawa, H. 363

Shiratori, K. 263, 305, 322,

323, 348

Shiratori, Y. 346, 396

Shirinskaya, N.V. 304, 314, 378

Shirouzu, Y. 354

Shiroya, Y. 381

Shizuno, E. 379, 382

Shounai, T. 364

Siech, M. 383

Sina-Frey, M. 326

Singer, M.V. 258

Siqueira, S.A.C. 371

Slavin, J.P. 333

Soda, H. 363

Soeno, T. 343

Sofuni, A. 285, 366

Sogame, Y. 316, 345

Someya, M. 364


Sone, Y. 310, 371

Song, S.Y. 352, 381

Sonoda, Y. 307

Sonoue, H. 301, 386

Sonoyama, T. 339

Soriano, F.G. 374

Souza, L.J. de 328

Spooner, D. 273

Sporleder, B. 304, 315

Stachura, J. 282

Stamatoiu, A. 376, 378

Stanisavljevic, D. 359

Sternby, B. 317

Stirling, J.W. 316

Stocken, D.D. 273

Stoffers, D.A. 290

Strobel, O. 280, 281, 324

Suda, K. 269, 296, 301, 311,

386, 387

Suda, T. 379, 382

Sudo, K. 369

Suetomi, Y. 293, 365

Suga, T. 266, 400

Sugano, K. 287, 351

Sugaya, M. 384, 402

Sugimoto, H. 286, 383, 404

Sugimoto, M. 356, 370, 407

Sugiyama, K. 402

Sugiyama, M. 291, 320, 342,

361

Suh, J.H. 352, 381

Sumi, M. 368

Sumi, S. 290, 354

Sumii, T. 333, 360, 368

Sun, C.-T. 325

Sun, L. 338

Sunamura, M. 262, 274, 278,

282, 283, 290, 299, 355,

363, 374, 389, 391, 398,

402, 404

Sunouchi, K. 363

Sutherland, D.E.R. 291

Suyama, M. 341, 372, 399

Suzuki, A. 384

Suzuki, F. 301

Suzuki, K. 290, 363

Suzuki, M. 366

Suzuki, N. 287, 311, 312

Suzuki, S. 366

Suzuki, T. 347

Suzuki, Y. 290, 291, 320, 337,

353, 361

Suzumura, K. 386

Tabata, M. 295, 296

Tadenuma, H. 348

Tadokoro, H. 341, 372, 399

Tagawa, M. 362

Taguchi, M. 287, 349

Tajika, M. 300

Tajiri, T. 318, 333, 341, 355,

370

Takács, T. 285

Takada, H. 297

Takada, R. 316, 339, 345

Takada, T. 274, 356, 370, 407

Takagi, K. 370, 407

Takagi, N. 315

Takahashi, H. 358, 359, 361

Takahashi, I. 270

Takahashi, K. 275, 299, 325,

332, 343, 350, 386, 391, 398

Takahashi, M. 335, 373

Takahashi, S. 286

Takahashi, T. 303, 355, 392

Takahashi, W. 373

Takahashi, Y. 294, 334, 389,

396

Takai, S. 299, 325, 340, 391,

393, 398

Takakura, R. 294, 321, 333,

367

Takamatsu, S. 405

Takamido, S. 313

Takamura, H. 329

Takano, K. 319

Takao, S. 274, 304, 395

Takaori, K. 400

Takasaki, K. 274, 302, 303,

322, 323, 383, 388

Takasawa, S. 270

Takase, M. 269, 296, 311,

386

Takayama, M. 269, 297

Takayama, W. 384, 402

Takayama, Y. 263, 322

Takeda, K. 268, 282, 283, 355,

363, 374, 389, 391, 398,

402, 404

Takeda, S. 286, 337, 370, 383,

404

Takeda, Y. 274, 335

Takehara, Y. 266

Takemura, T. 317

Takenaka, A. 321

Takesako, Y. 369

Takeshita, A. 397

Takeyama, H. 358, 359

Takeyama, Y. 283, 310, 346,

377, 379

Takezako, Y. 335, 395

Takezawa, M. 340

Takiguchi, N. 363

Takizawa, T. 405

Talamini, G. 262

Tamahashi, U. 405

Tamai, S. 307

Tamm, E.P. 265

Tanabe, M. 340

Tanaka, H. 379, 382

Tanaka, M. 274, 275, 334, 358,

359, 361, 364

Tanaka, S. 292, 294, 300, 316,

333, 350, 367

Tanaka, T. 353

Tanaka, Y. 371

Tanano, A. 313

Tanase, H. 386, 387

Tando, Y. 379, 382

Tani, M. 321, 371, 401, 404

Tanigawa, K. 398

Tanigawa, N. 393, 400

Tanikawa, M. 310, 371

Tanimoto, A. 405

Tanioka, H. 351

Tanioka, Y. 337, 353

Tanizawa, Y. 286

Tanno, S. 388, 406

Taoka, H. 398

Tarao, K. 285

Tartaglia, N. 345

Tashiro, M. 287, 349

Tate, G. 318

Tatsuta, M. 294, 321, 367

Teng, M.J. 307

Terakawa, N. 299, 325, 391,

398

Terasawa, H. 321, 371, 401,

404

Tezel, E. 286

Thayer, S.P. 280, 281, 284, 324

Thikaishi, T. 321

Thompson, J.C. 257

Thumerer, S. 383

Tien, Y.-W. 325

Tobita, K. 329

Togawa, A. 336, 369

Toi, M. 392

Toki, F. 322, 323, 348

Tomaszewska, R. 282

Tomazic, A. 359

Tominaga, M. 337

Tomomitsu, A. 395

Toouli, J. 307, 316, 317, 377

Toyoda, E. 280, 324, 325, 327,

329, 339, 354, 357, 358,

362, 389

Toyoda, H. 371

Toyokawa, H. 299, 391

Toyoki, Y. 386

Toyota, H. 310

Toyota, N. 370, 407

Trainor, A. 280, 281

Trainor, A.G. 324

Traverso, L.W. 279, 401

Trucco, M. 271

Tsao, C.J. 396

Tsuchihara, K. 391

Tsuchiya, K. 352

Tsuchiya, M. 352

Tsuchiya, T. 285, 385

Tsuji, N. 297

Tsuji, T. 305

Tsujie, M. 294, 334, 389

Tsujii, H. 295

Tsujimura, T. 290

Tsukahara, M. 393

Tsukuma, H. 300

Tsunematsu, I. 400

Tsunoda, T. 339, 403, 406

Tsunoda, Y. 316

Tsuruta, K. 269, 309, 392, 397,

399

Tsuwano, S. 307

Tu, Y. 332

Tuchihara, K. 355

Tuchiya, T. 315

Tujie, M. 396

Tulachan, S.S. 354

Tuo, H. 342

Tyler, D. 273

Uchida, E. 333, 341, 370

Uchida, K. 388

Uchiyama, K. 321, 371, 401,

404

Ueda, M. 336, 340

Ueda, T. 283, 310, 337, 346,

377, 379

Uehara, H. 300, 321, 333

Uemoto, S. 295, 296

Ueno, H. 293, 334, 335, 368,

369, 395

Ueno, M. 285, 371, 401

Ueno, T. 373

Uesaka, K. 384, 388

Ueyama, Y. 329

Ulrich, A.B. 298

Umeshita, K. 294, 334, 389,

396

Umezawa, K. 392

Umezawa, T. 397

Unno, M. 270

Uno, T. 369

Urabe, T. 349

Urakami, A. 339, 403, 406

Urrutia, R. 276

Usui, M. 295, 296

Valentino, T.P. 345

Velasco, I.T. 374

Veronesi, P. 338, 404

Vinik, A. 271

Vladescu, R. 376

Wada, K. 401

Wada, M. 327, 362, 367, 403

Wakabayashi, G. 340

Wakabayashi, T. 347, 349, 350

Wakasugi, T. 359


Wallig, M. 288

Wang, J.C. 298

Warshaw, A.L. 280, 281, 284,

289, 324

Watanabe, A. 328, 330, 331,

360

Watanabe, F. 380

Watanabe, G. 405

Watanabe, H. 289, 319, 349,

353, 356, 381

Watanabe, K. 363

Watanabe, M. 303, 340, 355

Watanabe, N. 297

Watanabe, S. 287

Watanabe, T. 382

Watson, D.I. 377

Weber, J.-C. 280

Weber-Dany, B. 344

Whitcomb, D.C. 256

Wilson, T.G. 377

Wolff, R.A. 260, 272

Wolf-Vorbeck, G. 283

Wong, F.L. 318, 373

Woods, C.M. 307

Wright, C.V.E. 289

Wu, C.-C. 338

Wu, C.C. 344

Yabana, T. 400

Yagi, N. 376

Yagihashi, S. 386

Yajima, N. 386

Yalniz, M. 326, 364

Yama, N. 364

Yamada, H. 313

Yamada, K. 319

Yamada, S. 295

Yamada, Y. 373

Yamafuji, K. 305

Yamagishi, N. 305

Yamagiwa, K. 295, 296

Yamago, G.I. 330

Yamaguchi, A. 274

Yamaguchi, K. 275, 295

Yamaguchi, T. 263, 286, 287,

294, 295, 300, 309, 319,

322, 347, 348, 369

Yamaguchi, Y. 353, 381

Yamaki, T. 403

Yamamoto, A. 317

Yamamoto, C. 290, 354

Yamamoto, H. 363, 366

Yamamoto, J. 319

Yamamoto, M. 263, 287, 345,

346, 349, 358, 359, 361

Yamamoto, T. 401

Yamamura, M. 406

Yamanaka, J. 399

Yamano, M. 319

Yamao, J. 340

Yamao, K. 275, 300, 332, 385,

394

Yamasaki, S. 301, 386, 387

Yamashita, K. 352, 403

Yamashita, M. 398

Yamauchi, A. 270

Yamaue, H. 321, 371, 401, 404

Yanagi, K. 386

Yanagida, O. 291, 361

Yanagimachi, M. 379, 382

Yanagimoto, H. 299, 325, 391,

398

Yanagisawa, A. 319

Yasuda, C. 377

Yasuda, H. 316, 339, 345, 370,

407

Yasuda, M. 333, 368

Yasuda, S. 295

Yasui, H. 351

Yasui, K. 274

Yatsu, T. 299

Yatsuji, S. 305

Yatsuoka, T. 309

Yeh, D.-C. 338

Yeh, T.-S. 301

Yen, C.J. 396

Yokoi, H. 295, 296

Yokota, T. 310

Yokoyama, T. 299, 390

Yokoyama, Y. 315

Yonemori, K. 334

Yoneyama, T. 394

Yonezawa, S. 265

Yoshiba, M. 318

Yoshida, H. 292, 350, 373

Yoshida, M. 303, 355, 407

Yoshida, T. 285

Yoshida, Y. 312

Yoshidome, H. 336, 369

Yoshihara, S. 386

Yoshiike, M. 309, 332

Yoshikawa, T. 353

Yoshimi, F. 394

Yoshimine, S. 398

Yoshino, J. 321, 347, 349, 350

Yoshino, M. 368

Yoshiya, T. 405

Yoshizawa, K. 393

Yosida, M. 370

Yu, C.-C. 308

Yuasa, N. 302, 315, 336

Yui, R. 393

Zagorenko, Y.A. 313

Zamboni, G. 275

Zarnescu, N.O. 376, 378

Zbucki, R. 332, 337

Zerbi, A. 277, 338, 404

Zhang, D. 338

Zhang, H.J. 291

Zhao, H. 305, 313

Zheng, Z. 338

Zinkevich, V. 292

Zoumaras, J. 377

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