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131 Osteosarcoma OSTEOSARCOMA, one of the most unpleasant malignant tumours, is mercifully rare-only about 200 cases occur in the United Kingdom each year. Its peak incidence is in the second decade, and boys are more commonly affected than girls. The metaphysis of a long bone, particularly of the femur or upper tibia, is the most common site, but no part of the skeleton is immune. Since the main symptom is local pain, which in active youngsters is such a common complaint in relation to the knee, it is hardly surprising that the diagnosis may be delayed. Occasionally, local swelling or pathological fracture may be the presenting feature. By the time the diagnosis is made, therefore, the tumour is usually large and in many cases has extended from bone into the surrounding soft tissues. Although radiographic appearances may strongly suggest the diagnosis, other less serious disorders such as osteomyelitis, stress fracture, or benign tumours may mimic osteosarcoma both clinically and radiologically. Thus the diagnosis must be confirmed by biopsy before treatment is undertaken. Open biopsy is preferred to needle biopsy in accessible sites; and the biopsy incision should be carefully placed so that the wound can be excised during the course of subsequent surgery. The - very rarity of osteosarcoma gives rise to difficulties in management: the average orthopaedic surgeon is likely to see one case every four years, and radiologists and pathologists may be similarly limited in their experience. It is important, therefore, that treatment of such patients should be limited to a few centres with expert knowledge and where the effect of different therapies can be evaluated. Historically, the treatment of osteosarcoma has consisted of either amputation through the joint or bone above the bone affected by the tumour, or radiotherapy. In the widely advocated Cade method,’ I local radiotherapy was followed by amputation after an interval of six to ten months, the object being to avoid amputation in the 50% of patients who would show metastases within six months of initial diagnosis.2 2 Whether primary amputation or radiotherapy was used, five-year survival before 1972 was limited to 1 Cade S Osteogenic sarcoma A study based on 133 patients J Roy Coll Surg Edinb 1955, 1: 79-111 2. Jeffree GM, Price CHG, Sissons HA The metastatic patterns of osteosarcoma Br J Cancer 1975, 32: 87-107 3 Marcove RC, Mike V, Hajek JV, Levin AG, Hutter RVP Osteogenic sarcoma under the age of twenty-one—a review of 145 operative cases J Bone Joint Surg 1970; 52A: 411-23 4. Friedman MA, Carter SK The therapy of osteogenic sarcoma. Current status and thoughts for the future J Surg Oncol 1972; 4: 482-510. 5 Carter SK The dilemma of adjuvant chemotherapy for osteogenic sarcoma. Cancer Clin Trials 1980 3: 29-36 about 20%.3-’; Clearly, occult metastases were present in most patients at the time of diagnosis and local . tumour ablation was inadequate treatment. The development of chemotherapeutic regimens, which had proved so successful in the treatment of some other malignancies, offered hope for improving the prognosis of osteosarcoma. In 1972, Cortes et al6 reported regression of metastases following treatment with adriamycin, and in the same year Jaffe’ showed that high-dose methotrexate was effective in advanced disease. Subsequent reports from several centres in the USA seemed to show that chemotherapeutic agents given as an "adjuvant" to local treatment delayed the appearance of metastases and improved the five-year survival rate to between 4007o and 50070.8-’6 The value of chemotherapy seemed to be established and the only questions were which drugs, at what dosage, and for how long. Also, if chemotherapy could prevent or control metastases, was it not logical that surgical excision of the tumour could now be more conservative and amputation could be avoided in selected cases? There were several reports of local resection of osteosarcoma with replacement of the bone defect by a custom-made endoprosthesis or bone allograft, and the results seemed no worse than those of amputation."-2’ Nevertheless, comparison of local and radical surgery is difficult because most surgeons reserve local resection for smaller tumours with limited soft-tissue spread and for those with more favourable histological characteristics that would in any event carry a better prognosis. When enthusiasm for chemotherapy was at its height, a paper from Taylor and his colleagues at the 6 Cortes EP, Holland JF, Wang JJ, Sinks LF Doxorubicin in disseminated osteosarcoma JAMA 1972; 221: 1132-38 7. Jaffe N Recent advances in the chemotherapy of metastatic osteogenic sarcoma Cancer 1972; 30: 1627-31. 8 Jaffe N, Frei E, Watts H, Traggis D High dose methotrexate in osteogenic sarcoma A 5 year experience. Cancer Treat Rep 1978; 62: 259-64 9 Eilber FR, Grant T, Morton DL Adjuvant therapy for osteosarcoma Pre-operative and post-operative treatment. Cancer Treat Rep 1978, 62: 213-16 10. Ettinger LJ Douglas HO, Higby DJ, et al. Adjuvant adriamycin and cis- diamminedichloroplatinum (cis-platinum) in primary osteosarcoma. Cancer 1981, 47: 248-54 11 Rosen G, Nirenberg A, Caparros B, et al. Osteogenic sarcoma Eighty per cent, three- year disease-free survival with combination chemotherapy (T7) Natl Cancer Inst Monogr 1981; 56: 213-20. 12. Cortes EP, Holland JF, Glidewell O. Amputation and adriamycin in primary osteosarcoma A 5-year report Cancer Treat Rep 1978; 62: 271-98 13 Pratt CB, Rivera G, Shanks E, Kumar APM, Green AA, George S Combination chemotherapy for osteosarcoma Cancer Treat Rep 1978, 62: 251-57 14. Sutow WW, Gehan EA, Dyment PG, Vietti T, Miale T Multi drug adjuvant chemotherapy for osteosarcoma. Interim report of the South West Oncology Group Studies Cancer Treat Rep 1978; 62: 265-70. 15 Rosenberg S, Chabner BA, Young RC, et al. Treatment of osteogenic sarcoma. I Effect of adjuvant high-dose methotrexate after amputation Cancer Treat Rep 1979; 63: 739-51. 16 Campanacci M, Bacci G, Pagani P, Giunti A. Multiple drug chemotherapy for the primary treatment of osteosarcoma of the extremities J Bone Joint Surg 1980, 62B: 93-101. 17. Marcove RC. En bloc resection of osteogenic sarcoma. Cancer Treat Rep 1978, 62: 225-31. 18 Morton DL, Filber FR, Townsend CM, Grant TT, Mirra J, Weisenburger TH Limb salvage from a multidisciplinary approach for skeletal and soft tissue sarcoma of the extremity Ann Sury 1976, 184: 268-78. 19 Rosen G, Murphy ML, Huvos AG, Gutierrez M, Marcove RC. Chemotherapy, en bloc resection and prosthetic bone replacement in the treatment of osteogenic sarcoma Cancer 1976; 37: 1-11 20 Goorin A, Link M, Jaffe N Adjuvant chemotherapy (chemo) and limb salvage procedures for osteosarcoma-A seven year experience Proc Am Soc Clin Oncol 1980; 21: 472 21 Scales JT Bone and joint replacement for the preservation of limbs Br J Hosp Med 1983, 304: 220-32.
Transcript
Page 1: Osteosarcoma

131

Osteosarcoma

OSTEOSARCOMA, one of the most unpleasantmalignant tumours, is mercifully rare-only about 200cases occur in the United Kingdom each year. Its peakincidence is in the second decade, and boys are morecommonly affected than girls. The metaphysis of a longbone, particularly of the femur or upper tibia, is themost common site, but no part of the skeleton isimmune. Since the main symptom is local pain, whichin active youngsters is such a common complaint inrelation to the knee, it is hardly surprising that thediagnosis may be delayed. Occasionally, local swellingor pathological fracture may be the presenting feature.By the time the diagnosis is made, therefore, thetumour is usually large and in many cases has extendedfrom bone into the surrounding soft tissues. Althoughradiographic appearances may strongly suggest thediagnosis, other less serious disorders such as

osteomyelitis, stress fracture, or benign tumours maymimic osteosarcoma both clinically and radiologically.Thus the diagnosis must be confirmed by biopsy beforetreatment is undertaken. Open biopsy is preferred toneedle biopsy in accessible sites; and the biopsyincision should be carefully placed so that the woundcan be excised during the course of subsequent surgery.The - very rarity of osteosarcoma gives rise to

difficulties in management: the average orthopaedicsurgeon is likely to see one case every four years, andradiologists and pathologists may be similarly limitedin their experience. It is important, therefore, thattreatment of such patients should be limited to a fewcentres with expert knowledge and where the effect ofdifferent therapies can be evaluated.Historically, the treatment of osteosarcoma has

consisted of either amputation through the joint orbone above the bone affected by the tumour, or

radiotherapy. In the widely advocated Cade method,’ Ilocal radiotherapy was followed by amputation after aninterval of six to ten months, the object being to avoidamputation in the 50% of patients who would showmetastases within six months of initial diagnosis.2 2Whether primary amputation or radiotherapy wasused, five-year survival before 1972 was limited to

1 Cade S Osteogenic sarcoma A study based on 133 patients J Roy Coll Surg Edinb1955, 1: 79-111

2. Jeffree GM, Price CHG, Sissons HA The metastatic patterns of osteosarcoma Br JCancer 1975, 32: 87-107

3 Marcove RC, Mike V, Hajek JV, Levin AG, Hutter RVP Osteogenic sarcoma underthe age of twenty-one—a review of 145 operative cases J Bone Joint Surg 1970; 52A:411-23

4. Friedman MA, Carter SK The therapy of osteogenic sarcoma. Current status andthoughts for the future J Surg Oncol 1972; 4: 482-510.

5 Carter SK The dilemma of adjuvant chemotherapy for osteogenic sarcoma. CancerClin Trials 1980 3: 29-36

about 20%.3-’; Clearly, occult metastases were presentin most patients at the time of diagnosis and local .

tumour ablation was inadequate treatment.The development of chemotherapeutic regimens,

which had proved so successful in the treatment ofsome other malignancies, offered hope for improvingthe prognosis of osteosarcoma. In 1972, Cortes et al6reported regression of metastases following treatmentwith adriamycin, and in the same year Jaffe’ showedthat high-dose methotrexate was effective in advanceddisease. Subsequent reports from several centres in theUSA seemed to show that chemotherapeutic agentsgiven as an "adjuvant" to local treatment delayed theappearance of metastases and improved the five-yearsurvival rate to between 4007o and 50070.8-’6 The value of

chemotherapy seemed to be established and the onlyquestions were which drugs, at what dosage, and forhow long. Also, if chemotherapy could prevent orcontrol metastases, was it not logical that surgicalexcision of the tumour could now be more conservativeand amputation could be avoided in selected cases?There were several reports of local resection ofosteosarcoma with replacement of the bone defect by acustom-made endoprosthesis or bone allograft, and theresults seemed no worse than those of amputation."-2’Nevertheless, comparison of local and radical surgeryis difficult because most surgeons reserve localresection for smaller tumours with limited soft-tissue

spread and for those with more favourable histologicalcharacteristics that would in any event carry a better

prognosis.When enthusiasm for chemotherapy was at its

height, a paper from Taylor and his colleagues at the

6 Cortes EP, Holland JF, Wang JJ, Sinks LF Doxorubicin in disseminatedosteosarcoma JAMA 1972; 221: 1132-38

7. Jaffe N Recent advances in the chemotherapy of metastatic osteogenic sarcoma Cancer1972; 30: 1627-31.

8 Jaffe N, Frei E, Watts H, Traggis D High dose methotrexate in osteogenic sarcoma A5 year experience. Cancer Treat Rep 1978; 62: 259-64

9 Eilber FR, Grant T, Morton DL Adjuvant therapy for osteosarcoma Pre-operativeand post-operative treatment. Cancer Treat Rep 1978, 62: 213-16

10. Ettinger LJ Douglas HO, Higby DJ, et al. Adjuvant adriamycin and cis-

diamminedichloroplatinum (cis-platinum) in primary osteosarcoma. Cancer 1981,47: 248-54

11 Rosen G, Nirenberg A, Caparros B, et al. Osteogenic sarcoma Eighty per cent, three-year disease-free survival with combination chemotherapy (T7) Natl Cancer InstMonogr 1981; 56: 213-20.

12. Cortes EP, Holland JF, Glidewell O. Amputation and adriamycin in primaryosteosarcoma A 5-year report Cancer Treat Rep 1978; 62: 271-98

13 Pratt CB, Rivera G, Shanks E, Kumar APM, Green AA, George S Combination

chemotherapy for osteosarcoma Cancer Treat Rep 1978, 62: 251-5714. Sutow WW, Gehan EA, Dyment PG, Vietti T, Miale T Multi drug adjuvant

chemotherapy for osteosarcoma. Interim report of the South West Oncology GroupStudies Cancer Treat Rep 1978; 62: 265-70.

15 Rosenberg S, Chabner BA, Young RC, et al. Treatment of osteogenic sarcoma. I Effectof adjuvant high-dose methotrexate after amputation Cancer Treat Rep 1979; 63:739-51.

16 Campanacci M, Bacci G, Pagani P, Giunti A. Multiple drug chemotherapy for theprimary treatment of osteosarcoma of the extremities J Bone Joint Surg 1980, 62B:93-101.

17. Marcove RC. En bloc resection of osteogenic sarcoma. Cancer Treat Rep 1978, 62:225-31.

18 Morton DL, Filber FR, Townsend CM, Grant TT, Mirra J, Weisenburger TH Limbsalvage from a multidisciplinary approach for skeletal and soft tissue sarcoma of theextremity Ann Sury 1976, 184: 268-78.

19 Rosen G, Murphy ML, Huvos AG, Gutierrez M, Marcove RC. Chemotherapy, enbloc resection and prosthetic bone replacement in the treatment of osteogenicsarcoma Cancer 1976; 37: 1-11

20 Goorin A, Link M, Jaffe N Adjuvant chemotherapy (chemo) and limb salvageprocedures for osteosarcoma-A seven year experience Proc Am Soc Clin Oncol

1980; 21: 47221 Scales JT Bone and joint replacement for the preservation of limbs Br J Hosp Med

1983, 304: 220-32.

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132

Mayo Clinic22 brought its protagonists sharply down toearth. They gave the Mayo results for osteosarcomatreated between 1963 and 1974 and showed that duringthe 1970s patients treated by conventional surgery didsignificantly better than those treated similarly in the1960s. Moreover, the results were at least as good asthe contemporary series which attributed the

improvement to chemotherapy. A further report fromthe Mayo Clinic23 brings their experience up to dateand confirms the earlier findings in a large series of 336patients. The five-year survival levelled off in the1970s at between 50% and 60%, compared with 25%during the ’60s; a similar improvement was also notedin frequency of metastases. Chemotherapy was used infew of their patients and did not improve the outcome.These results are hard to explain. It seems

improbable that the natural history of the disease hasaltered during this period. The Mayo group alsoexamined the possibility that new diagnostictechniques, such as scanning with radioisotopes orcomputed tomography, might have altered the stagingby identifying localised disease more accurately, butfound that the effect was marginal. Increasedawareness of the condition and hence earlier diagnosiswas also suggested as a possible factor, as was a moreaggressive attitude to the resection of pulmonarymetastases, a procedure of established value in selectedcases.24,25-Undoubtedly, investigation and treatment ofpatients at the Mayo Clinic is both prompt and efficientand their uniquely great experience must play a part insuch excellent results. Whatever the full explanation,the Mayo findings mean that the historic survival ratesso commonly used as "controls" against which trials ofnew therapies are compared can no longer be regardedas valid.The Mayo study has also identified six variables that

adversely affect the prognosis-age younger than tenyears, male sex, tumour diameter more than fifteen

centimetres, cell type osteoblastic or chondroblastic,duration of symptoms two months or less, andinvolvement of femur or humerus. The more of thesecharacteristics a patient possesses, the worse the

prognosis. It therefore follows that when the results ofdifferent series are compared these variables must betaken into account.

Despite the doubts generated by the Mayo reportsand by others,26-29 chemotherapy still has powerfuladvocates. Rosen and his colleagues at the Sloan-

22. Taylor WF, Ivins JC, Dahlin DC, Edmonson JH, Pritchard DJ. Trends and variabilityin survival from osteosarcoma. Mayo Clin Proc 1978; 53: 695-700.

23 Taylor WF, Ivins JC, Pritchard DJ, Dahlin DC, Gilchrist MD, Edmonson JH. Trendsand variability in survival among patients with osteosarcoma: A 7-year update. MayoClin Proc 1985; 60: 91-104

24. Sweetnam DR, Ross K. Surgical treatment of pulmonary metastases from primarytumours of bone. J Bone Joint Surg 1967; 49B: 74-79.

25 Spanos PK, Payne WS, Ivins JC, Pritchard DJ. Pulmonary resection for metastaticosteogenic sarcoma. J Bone Joint Surg 1976, 58A: 624-28.

26. Lange B, Levine AS. Is it ethical not to conduct a prospectively controlled trial ofadjuvant chemotherapy in osteosarcoma? Cancer Treat Rep 1982; 66: 1699-704.

27 Sugarbaker PH, Barofsky I, Rosenberg SA, Gianola FJ Quality of life assessment ofpatients in extremity sarcoma clinical trials Surgery 1982; 91: 17-23.

28. Kolata GB Dilemma in cancer treatment Science 1980; 209: 792-94.29. Carter SK. Adjuvant chemotherapy in osteogenic sarcoma: The triumph that isn’t?

J Clin Oncol 1984; 2: 147-48.

Kettering have obtained results unmatched by anyother group. I 30-32 Throughout the 1970s and early1980s they have consistently improved disease-freesurvival by developing powerful (and toxic)chemotherapeutic protocols. The first major advancewas use of high-dose methotrexate with citrovorumfactor rescue and doxorubicin (T5 protocol), which wasgiven for three months preoperatively and continued,with the addition of cyclophosphamide, for about fivemonths postoperatively. In 1979 they reported thattwenty-three of thirty-one patients (75%) had survived,twenty-one of whom were free of disease at a follow-upperiod of thirty to fifty-two months. Their patients,however, possessed a high proportion of the favourablecharacteristics identified by the Mayo group. A furthermodification was reported in 1979, when it was

emphasised that a certain minimum dose is necessaryto achieve response in patients with metastatic disease.Embracing this concept of a "dose-response effect",and recognising the value of cis-platinum as a second-line drug, they produced a regimen that was reported in1982 as the T10 protocol; first results were

spectacularly successful, with fifty-three of fifty-sevenpatients (93%) disease-free between six and thirty-fivemonths (median twenty months) from the start oftreatment. The novel feature of this regimen wastailoring of chemotherapy according to the tumourresponse (resected specimen) to the preoperativecourse of chemotherapy. Patients who had a very gooddegree of tumour destruction, as judged by carefulhistological grading, continued on the preoperativechemotherapeutic regimen after surgery, whereasthose who responded less well (approximately 60% ofpatients) were allocated to different chemotherapyregimens that included cis-platinum. Such

chemotherapy is highly toxic but manageable in

specialised centres.Faced with these results, even the most sceptical

must accept that appropriate drugs given in

appropriate doses and administered at specialisedcentres must improve the outlook for patients with thisaggressive tumour. Further studies are required toconfirm Rosen’s work, and many centres in the UK arecooperating with a European study under the auspicesof the Medical Research Council and the EuropeanOrganisation for Research on Treatment of Cancer.The drugs selected for this study are those that seem tobe the most active against osteosarcoma-

namely, cis-platinum, doxorubicin, and high-dosemethotrexate. Chemotherapy is given both pre-operatively and postoperatively, and when possibleconservative surgery is done to avoid amputation. So

30. Rosen G, Huvos AG, Modende C, et al. Chemotherapy and thoracotomy for metastaticosteogenic sarcoma: A model for adjuvant chemotherapy and the rational for thetiming of thoracic surgery Cancer 1978; 41: 841-49.

31. Rosen G, Marcove RC, Caparros B, Niremberg A, Kosloff C, Huvos AG. Primaryosteogenic sarcoma. The rational for pre-operative chemotherapy and delayedsurgery. Cancer 1979; 43: 2163-77

32. Rosen G, Caparros B, Huvos AG et al. Pre-operative chemotherapy for osteogenicsarcoma. Selection of a post-operative adjuvant chemotherapy based upon theresponse of the primary tumour to pre-operative chemotherapy. Cancer 1982, 49:1221-30.

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far the results of chemotherapy on the primary tumourhave been variable, occasional specimens showingstriking tumour necrosis. Whether these results willtranslate into long disease-free survival remains to beseen, but large multi-centre studies such as this musteventually give us much firmer data on the best

strategies for treatment.

Emotion and ImmunityACCORDING to folk wisdom, prolonged stress can

result in a state of debilitation ("being run down") inwhich the subject is unusually liable to colds and othermaladies. This notion has been explored in animals,and we learn that "a variety of manipulations regardedas stressful can modify the immunologic mechanismsof the host and alter the course of infection anddisease".’ In man the science of "psychoimmunology"had one of its first outings in 1977, when Bartrop andco-workers2 reported depression of the mitotic

response of lymphocytes in 29 subjects whose spouseshad died 6 weeks earlier; the comparison was with non-bereaved controls. For long this work stood alone, butin 19833 similar results were reported in a prospectivestudy of the spouses of 15 women dying of breastcancer; and the same phenomenon (ie, subnormallymphocytic response to extraneous mitogens) wassubsequently demonstrated45 in depressed patientsadmitted to hospital. In their latest contribution,6Schleifer et al report normal responses in three groups-outpatient depressives, inpatient schizophrenics,and subjects in hospital for elective

herniorrhaphy-and conclude that subnormal

responses are a feature of severe depression rather thanbeing related to hospital factors.The work of Bartrop and of Schleifer and their co-

workers has been in connection with cell-mediated

immunity (T lymphocyte responses). Jemmott et aFchose to look at an antibody measure-the salivarysecretory immunoglobin A. They measured it in first-year dental students by a radial immunodiffusionmethod and found lower secretion rates during themore stressful parts of the academic year than at othertimes; they were also able to correlate rates of secretionwith personality as assessed by the thematic

apperception test. The production of monoclonalantibodies to T lymphocyte subsets will allow furtherexploration of the effects of stress. Normally thenumber of lymphocytes (including helper cells) in

1 Ader R, ed. Psychoneuroimmunology New York Academic Press, 1981.2 Bartrop RW, Luckhurst E, Lazarus L, Kiloh LG, Penny R. Depressed lymphocyte

function after bereavement. Lancet 1977; i; 834-363 Schleifer SJ, Keller SE, Camerino M, Thornton JC, Stein M. Suppression of

lymphocyte stimulation following bereavement JAMA 1983; 250: 374-77.4 Kronfol Z, Silva J Jr, Greden J, Dembinski S, Gardner R, Carroll B. Impaired

lymphocyte function in depressive illness. Life Sci 1983, 33: 241-47.5. Schleifer SJ, Keller SE, Meyerson AT, Raskin MJ, Davis KL, Stein M. Lymphocyte

function in major depressive disorder. Arch Gen Psychiatry 1984; 41: 484-866 Schleifer SJ, Keller SE, Siris SG, Davis KL, Stein M. Lymphocyte function in

ambulatory depressed patients, hospitalised schizophrenic patients, and patientshospitalised for herniorrthaphy Arch Gen Psychiatry 1985; 42: 129-33

7. Jemmott JB III, Borysenko JZ, Borysenko M, McClelland DC, Chapman R, Meyer D,Benson H Academic stress, power motivation and decrease in secretion rate of

salivary secretory immunoglobulin A Lancet 1983, ii: 1400-02.

peripheral blood is highest in the evening and lowest inthe morning (the opposite of the diurnal fluctuation ofcortisol).8 Baker et al9 have lately reported that newstudents at medical school were more anxious, hadhigher serum cortisol levels, and had a higherpercentage of helper cells than second-year students (orfirst-year students some months later).

In cancer, the work of Greer and others" in the FaithCourtauld Unit at King’s College Hospital MedicalSchool has demonstrated’° clear psychologicaldifferences between women with benign and

malignant breast tumours and later showed" that thewomen’s psychological reaction to the diagnosis ofbreast cancer was strongly predictive of the 5 yearoutcome. Shekelle et al’2 in a prospectiveepidemiological study carried out a psychological test(the Minnesota Multiphasic Personality Inventory) ona randomly selected sample of 2020 middle-aged men,followed them up for 17 years, and found that thosewho scored depressed at the outset had a twice normalprobability of death from cancer, after allowance fortobacco and alcohol consumption, family history, andoccupation. These three results-personalitydifferences in breast cancer, effect of attitude on breastcancer prognosis, and correlation between depressionand subsequent cancer-indicate an effect of

psychological factors on cancer and are compatiblewith an effect via immunological mechanisms.’3What of other diseases? In 1962 Meyer and

Haggertyl-l showed in sixteen families that chronicstress was related to increases in streptococcalinfection, and Kasl et ap5 later showed that in militarycadets those experiencing great academic pressurewere more likely than others to contract infectiousmononucleosis. The "autoimmune" diseases,especially rheumatoid arthritis, are another interestinggroup in this context. Baker and Brewertonl6 have

reported a raised incidence of stressful lifecircumstances in the months before the onset of acuterheumatoid arthritis in women, and other

investigations have pointed the same way (though noneis wholly satisfactory in methodological terms). It is

possible that, in some cases of the disease, stress

contributes to a breakdown in the balance between the

patient’s immune system and other environmental

8. Ritchie AWS, Oswald I, Micklem HS, Boyd JE, Elton RA, Jazwinska E, James K.Circadian variation of lymphocyte subpopulations. A study with monoclonalantibodies Br Med J 1983; 286: 1773-75.

9. Baker GHB, Irani MS, Byrom NA, Nagvekar NM, Wood RJ, Hobbs JR, BrewertonDA. Stress, cortisol concentrations and lymphocyle subpopulations. Br Med J 1985;290: 1393.

10. Greer HS, Morris T. Psychological attributes of women who develop breast cancer JPsychosom Res 1975; 19: 147-53.

11 Greer S, Morris T, Pettingale KW Psychological response to breast cancer Effect onoutcome. Lancet 1979, ii. 785-87.

12. Shekelle RB, Raynor WJ Jr, Ostfeld AM, Garron DC, Bieliauskas LA, Liu SC, MalizaC, Paul O Psychological depression and 17-year risk of death from cancer.

Psychosom Med 1981, 43: 117-2513. Fox BH, Newberry BH, eds Impact of psychoendocrine systems in cancer and

immunity. Lewiston, NY: CJ Hogrefe, 198414 Meyer RJ, Haggertv R. Streptococcal infections in families factors altering individual

susceptibility Pediatrics 1962; 29: 539-4915 Kasl SV, Evans AS, Niederman JC Psychosocial risk factors in the development of

infectious mononucleosis Psychosom Med 1979; 41: 445-46.16. Baker GHB, Brewerton DA Rheumatoid arthritis A psychiatric assessment Br Med J

1981, 282: 2014


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