Impact of early delivery of children with familial
retinoblastoma after prenatal RB1 mutation
identification
Sameh E. Soliman, MD; Helen Dimaras, PhD; Vikas Khetan, MB, BS; Elise Héon, MD, FRCSC;
Helen S. L. Chan, MB, BS, FRCSC; Brenda L. Gallie, MD, FRCSC
Corresponding Author: Dr. Brenda Gallie at the Department of Ophthalmology and Vision
Sciences, the Hospital for Sick Children, 525 University Avenue, 8th floor, Toronto, ON M5G 2L3,
Canada, or at [email protected]
Authors’ Affiliations:
Departments of Ophthalmology & Vision Sciences, (Soliman, Dimaras, Héon , Gallie) and
Division of Hematology/Oncology, Pediatrics (Chan), Hospital for Sick Children, Toronto,
Canada; Division of Visual Sciences, Toronto Western Research Institute, Toronto, Canada
(Héon , Gallie); Ophthalmology Department, Faculty of Medicine, Alexandria University, Egypt
(Soliman); Sankara Nethralya Hospital, Chennai, India (Khetan); Departments of Pediatrics
(Chan), Molecular Genetics (Gallie), Medical Biophysics (Gallie) and Ophthalmology & Vision
Sciences (Dimaras, Héon, Gallie), and the Division of Clinical Public Health (Dimaras) University
of Toronto, Toronto, Ontario, Canada.
Financial Support: None
Conflict of Interest: No conflicting relationship exists for any author
Early delivery of children at risk for retinoblastoma
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Running head: Early delivery of familial retinoblastoma
Word count: 3262 /3000 words
Numbers of figures and tables: 3 figures and 2 tables
Key Words: prenatal retinoblastoma, retinoblastoma gene mutation, RB1, molecular testing,
late pre-term delivery, near-term delivery, amniocentesis
Early delivery of children at risk for retinoblastoma
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At A Glance:
All the children of a parent who had retinoblastoma as a child are at risk to also develop
retinoblastoma. However, if the unique RB1 mutation of that parent is molecularly
defined, their children can be determined prenatal to be at near 100% vs 0% risk to
develop retinoblastoma.
We compared children with familial retinoblastoma delivered spontaneously without
prenatal RB1 testing, to those with prenatal RB1 mutation identification and planned early
delivery. All children eventually developed tumors in both eyes.
Planned early term delivery resulted in more infants born with no tumors, whose tumors
could be detected early and treated when very small with less invasive therapies. This
resulted in better visual outcomes for the children identified prenatal to be at risk.
Early term delivery resulted in no perinatal complications.
Prenatal RB1 mutation detection is a good anticipatory planning tool for the family and
child.
Early delivery of children at risk for retinoblastoma
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Abstract (342/350)
IMPORTANCE: Familial retinoblastoma can be predicted by prenatal RB1 mutation detection. Early
delivery following prenatal detection for treatment of smaller tumors may achieve better outcomes with
minimal therapy.
OBJECTIVE: To compare overall outcomes and intensity of treatment for children with familial
retinoblastoma diagnosed postnatally or by obstetrical ultrasound, and those diagnosed by prenatal RB1
mutation identification and delivered preterm.
DESIGN: A retrospective, observational study.
SETTING: This study was conducted at The Hospital for Sick Children (SickKids), a retinoblastoma referral
center in Toronto, Canada.
PARTICIPANTS: All children born between 1 June 1996 and 1 June 2014 with familial retinoblastoma
who were cared for at SickKids.
EXPOSURE(S): Cohort 1 consisted of infants where were spontaneously delivered and had postnatal
RB1 testing. Cohort 2 consisted of infants who were identified by amniocentesis to carry the affected
relative’s known RB1 mutant allele and had planned early term or late preterm delivery (36-37 weeks
gestation). All children received treatment for eye tumors.
MAIN OUTCOME MEASURES: Primary study outcome measurements were gestational age, age at first
tumor, eye classification, treatments given, visual outcome, number of anesthetics, pregnancy or
delivery complications and estimated treatment burden.
RESULTS: Of Cohort 1 (n=9) infants, 67% (6/9) already had vision-threatening tumors at birth. Of Cohort
2 (n=12) infants, 25% (3/12) had vision-threatening tumors at birth. Both Cohorts eventually developed
Early delivery of children at risk for retinoblastoma
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tumors in both eyes. Useful vision (better than 0.1, legal blindness) was achieved for 78% of Cohort 1
compared to 100% of Cohort 2 (p<0.02). At first eye tumor diagnosis, 11% of Cohort 1 had both eyes
Group A (smallest and least vision-threatening tumors) compared to 67% of Cohort 2 (p<0.01). Eye
salvage (defined as avoidance of enucleation and external beam irradiation) was achieved in 33% of
Cohort 1 compared to 97% of Cohort 2 (p<0.002). There were no complications related to preterm
delivery.
CONCLUSIONS AND RELEVANCE: Prenatal molecular diagnosis with late preterm/near-term delivery
resulted in more eyes with no detectable retinoblastoma tumors at birth, and better vision outcomes
with less invasive therapy. Prenatal molecular diagnosis facilitates anticipatory planning for both child
and family.
Early delivery of children at risk for retinoblastoma
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INTRODUCTION
Retinoblastoma, the most common primary ocular malignancy in children, is commonly initiated
when both alleles of the RB1 tumor suppressor gene are inactivated in a precursor retinal cell,
followed by progressive mutations in other specific genes.1,2 Both alleles may be lost only in the
retinal cell from which one tumor arises, or a germline mutation (about 50% of children)
predisposes to the development of multiple retinal tumors during childhood and other cancers
later in life. Ten percent of patients inherit a family-specific mutation from a parent.1,3
Children with RB1 germline mutation may already have retinoblastoma tumor(s) at birth,
often in the posterior pole of the eye where they threaten vision.4-8 Because focal laser treatment
near the optic nerve and macula may compromise vision, treatment of these small tumors can be
difficult. Most of these children are bilaterally affected, with either simultaneous or sequential
detection of tumors.4,7 Later developing tumors tend to be located peripherally.7,9 Low penetrance
(10% of families)3 and mosaic10 mutations result in fewer tumors and more frequent unilateral
phenotype.10 The timing of first tumors after birth has not yet been studied.
It is recommended that infants with a family history of retinoblastoma be examined for
tumor detection and management as soon as possible after birth and repeatedly for the first few
years of life, including under anaesthesiaanesthesia.. Early diagnosis when tumors are small and
treatable with less invasive therapies is thought to optimize salvage of the eye and vision.6,7,11
Full term birth is defined as live birth after 37 weeks gestation.12 Preterm birth is defined as
live birth occurring before completion of 37 weeks. The American College of Obstetrics and
Gynecology has suggested the description of ‘early term’ be ascribed to infants born after
completion of 37 but before 39 weeks gestation.12,13 The main concern with preterm or early term
Early delivery of children at risk for retinoblastoma
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delivery is the potential effect on neurological and cognitive development and later school
performance measured in children with a wide range of indications for early delivery.14-16 For
otherwise normal children with high risk of cancer and visual dysfunction from large macular
tumors, blindness17 may exceed such risks of early delivery.
We present the first report of outcomes of late preterm/early term late preterm or early term
delivery for children demonstrated prenatal to carry the RB1 mutant allele of a parent. We show
that such children had earlier detection and treatment of small tumors, lower treatment
morbidity, and better tumor control and visual outcome, than children born spontaneously
without precise genetic diagnosis.
Methods
Study Design
Research ethics board approval (REB approval number 1000028725) was obtained from The
Hospital for Sick Children (SickKids). Data collected for children born between 1 June 1996 and
1 June 2014 included: relation to proband; laterality of retinoblastoma in proband; sex;
gestational age at birth; pregnancy, prenatal abdominal ultrasound if done; delivery or perinatal
complications; type of genetic sample tested and result; penetrance of RB1 mutation; age and
location of first and all subsequent tumor(s)(s) in each eye; treatments used; number of
anaesthetics; International Intraocular Retinoblastoma Classification18 of each eye (IIRC); Tumor
Node Metastasis (TNM)11 staging for eyes and child;11 treatment duration; date of last follow-up;
and visual outcome at last follow-up. RB1 mutation testing was performed by Impact Genetics
(formerly Retinoblastoma Solutions), as previously described.19
Early delivery of children at risk for retinoblastoma
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The gestational age at birth for each child was calculated (39 weeks was considered full
term). Vision threatening tumors were defined as IIRC18 Group B or worse, which includes
tumor size and proximity to optic nerve or macula. Treatments were summarized as focal
therapies (laser therapy, cryotherapy and periocular subtenon’s injection of chemotherapy) or
systemic therapies (systemic chemotherapy or stereotactic external beam irradiation). Active
treatment duration (time from diagnosis to last treatment) and number of examinations under
anesthesia (EUAs) were counted. Treatment success was defined as avoidance of enucleation or
external beam irradiation or extraocular disease. Acceptable visual outcome was defined as
visual acuity better than 0.1 decimal (20/200). Legal blindness is defined as visual acuity worse
than 0.1.
Data analysis
Basic descriptive statistics were used for comparisons between patients diagnosed postnatal
(Cohort 1) and those provided prenatal testing and planned late preterm or preterm early term
delivery (Cohort 2). These included Student T-Test, Chi Square Test, Fisher Exact Test, Mann
Whitney Test and Mood’s Median Test. Correlations and Kaplan-Meyer Survival Graphs were
plotted using Microsoft Excel 2007 and Prism 6 for Mac.
Results
Patient Demographics
Twenty-one children with familial retinoblastoma were reviewed (11 males, 10 females) and
eligible for this study (Supplementary Table 1, Figure 1). Diagnosis for Cohort 1 (9 children,
43%) was by observation of tumor or postnatal testing for the parental RB1 mutation. Six were
born full term and 3 were delivered late preterm because of pregnancy-induced hypertension
Early delivery of children at risk for retinoblastoma
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(child #7), fetal ultrasound evidence of retinoblastoma20 (child #9) or spontaneous delivery (child
#8). The 12 children (57%) in Cohort 2 were prenatally diagnosed to carry their family’s RB1
mutation and planned for late preterm or early term delivery: 3 were spontaneously premature
(children #10, 13, 15; 28-37 weeks gestation) and 9 were referred to a high-risk pregnancy unit
for elective late preterm/early term late preterm or early term delivery (36-38 weeks gestation).
Molecular diagnosis
All study subjects were offspring of retinoblastoma probands. Nineteen probands were bilaterally
and 2 were unilaterally (mother #8, father #19) affected. The familial RB1 mutations were
previously detected except for the unilaterally affected parent of #8. This unilaterally affected
parent had not been tested, because she believed that since she had unilateral retinoblastoma, her
children were not at risk for retinoblastoma. Cohort 1 children were (#1-9) tested postnatal for
their family’s RB1 mutation by blood; Cohort 2 children (#10-21) were tested prenatal by
amniocentesis at 16-33 weeks gestation.
Null RB1 mutations were present in 16 families. Five had low penetrance RB1 mutations (whole
gene deletion, #19; weak splice site mutations, #15, 18, 21; and a missense mutation,19,21 #5)
(Supplementary Table 1). No proband in this study was mosaic for the RB1 mutation. All study
subjects were eventually bilaterally affected. At birth, 9/16 (56%) infants with null RB1
mutations had tumors, affecting 14/31 (45%) eyes, but 0/5 infants with low penetrance mutations
had tumors at birth (Table 1a, b, P=0.02 for eyes, P=0.04 for children; Fisher’s exact test). (The
Group A eye of Child #8 was excluded from per eye calculations as the child was first examined
at 3 months of age with Group A/D tumors, so first detectable tumor in the Group A eye is
unknown. We presume the Group D eye had tumor at birth, Table 1).
Early delivery of children at risk for retinoblastoma
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The age at first tumor per child (per eye??) was insignificantly younger for those with null
mutations (mean 59, median 20 days), than those with low penetrance mutations (mean 107,
median 119 days) (P=0.03*, Phi=0.38, Mood’s median test). Figure x shows the data (Ivana’s
plot)…..The gestational age at first tumor tended to be insignificantly younger was also
significantly younger for those with null mutations (mean 48, median 25 days) tended to be
younger but was not significantly different, than for those with low penetrance mutations (mean
83, median 81 days). (Figure 2) (P=0.03, Phi=0.32, Mood’s median test).
Classification of Eyes at Birth
Of Cohort 1 eyes, 53% (9/17) had tumor at birth, compared to 21% (5/24) of Cohort 2 eyes
(P=0.05*, Chi Square test), excluding the IIRC18 Group A eye of child #8, as above (Table 1a).
We assumed that child #8 had tumor at birth since he had Group D IIRC18 in the right eye at 3
months of age. Of Cohort 1 children, 66% (6/9) and 25% (3/12) of Cohort 2 had tumor in at least
one eye at birth (Table 1b, Figure 1). At birth, 39% of eyes (7/18) in Cohort 1 had a visually
threatening tumor (IIRC18 Group B or worse) compared to 17% of eyes (4/22) in Cohort 2.
Tumors emerged at a younger age in the macular and peri-macular region (IIRC18 Group B), as
previously described.22 The median age of diagnosis of 15 IIRC18 B eyes (all threatening optic
nerve and fovea, 6 also >3 mm size) was 9 days, tending younger than the 92 days for 24 IIRC18
A eyes (< 3mm and away from optic nerve and fovea).18 The gestational age showed the same
tendency (7 and 60 days respectively).
Bilateral IIRC18 Group A eyes were present at initial diagnosis in 2/9 (22%) children in Cohort 1
compared to 8/12 (67%) in Cohort 2 (P=0.0109, Fisher exact test) (Table 2a). At first diagnosis,
tumors were not threatening vision (IIRC18 Group A) in 8/17 (47%) Cohort 1 eyes, compared to
Early delivery of children at risk for retinoblastoma
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17/24 (71%) Cohort 2 eyes (Table 2b). One eye was an IIRC18 D eye and presented at age of 3
months (child #8).
Treatment Course
All infants were frequently examined from birth onwards (except child #8 who presented at age
3 months) as per the National Retinoblastoma Strategy Guidelines for Care.11 If there were no
tumors at birth, each child was examined awake every week for 1 month, every 2 weeks for 2
months. After 3 months of age, the children had an examination under general anesthesia (EUA)
every 2-4 weeks. If there was tumor at birth, the children had EUAs every 2-4 weeks until
control of tumors was achieved. Cohort 1 patients were treated with focal therapy (all),
chemotherapy using vincristine, carboplatin, etoposide and cyclosporine (Toronto
protocol)23{Chan, 2005 #21688} (4), stereotactic radiation (2), and enucleation of one eye (5)
(Supplementary Table 1, Figure 1). Cohort 2 patients were treated with focal therapy (all);
chemotherapy (5), enucleation of one eye and stereotactic radiation (1) (Figure 1). Treatment by
focal therapy alone (avoidance of systemic chemotherapy or EBRT) was possible in 4/9 (44%) of
Cohort 1 and 7/12 (58%) of Cohort 2. (Table 2b).
The median active treatment duration was 458 days (0-2101 days) in Cohort 1, compared to 447
days (0-971 days) in Cohort 2. The median number of EUAs in Cohort 1 was 25 (range 18-81)
and for Cohort 2 was 29 (range 20-41). .
Outcomes
There were no adverse events associated with spontaneous preterm or induced late preterm or
early term birth. There were no pregnancy, delivery or perinatal complications reported for any
of the infants. Follow up (mean, median) was 8, 5.6 years; Cohort 1, 8.4, 5.6 years; and Cohort 2,
Early delivery of children at risk for retinoblastoma
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7.6, 5.8 years (Supplementary Table 1). At the last follow up, the mean age of Cohort 1 was 10
years (median 10, range 3-19) and the mean age of Cohort 2 was 9 years (median 9, range 3-16).
Neither enucleation nor external beam irradiation were required (defined as treatment success) in
44% of Cohort 1 and 92% of Cohort 2 (P=0.05*, Fisher exact test) (Table 2). Kaplan Meier
ocular survival for Cohort 1 was 62% compared to 92% for Cohort 2 (P=0.02, Log-rank (Mantel-
Cox) test) (Figure 23). One child (#6) (11%) in Cohort 1 showed high riskhigh-risk histo-
pathologic features in the enucleated eye and still under active treatment. All children are still
alive.
Children were legally blind (visual acuity less than 0.1 (20/200) using both eyes) in 22% of
Cohort 1 and 0% of Cohort 2 (P=0.02, Fisher exact test) (Table 2a). Visual outcomes were better
than 0.1 for 50% of eyes in Cohort 1 and 92% of eyes in Cohort 2 (P=0.02, Fisher exact test)
(Table 2b). Seventy one percent of eyes (17/24) of Cohort 2 had final visual acuity better than
0.5 (20/40) compared to 50% (9/18) of eyes in Cohort 1.
Treatment success (avoidance of enucleation and/or stereotactic radiation) and good vision per
eye was documented 50% (9/18) of Cohort 1 and 88% (21/24) of Cohort 2 (P=0.014*, Fisher
exact test) (Table 2b, Figure 1). A negative correlation trend was found between gestational age
and final visual outcome (r=-0.03) with better visual outcome observed for earlier deliveries
(Figure 34).
Discussion
This is the first report on the outcome of early delivery of children for retinoblastoma (true?). We
show that prenatal molecular diagnosis of familial retinoblastoma and elective late preterm/early
term delivery allowed treatment of tumors as they emerged, resulting in better ocular and visual
Early delivery of children at risk for retinoblastoma
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outcomes and less intensive medical interventions in very young children. This data illustrates
that for infants with high risk of developing retinoblastoma (RB1+/- or family history) the risk of
vision and eye loss despite intensive therapies with spontaneous delivery, outweighs the risks
associated with induced late preterm delivery (Figure 1). Consistent with previous reports,5 67%
of children with a germline gene mutation already had tumors at full term birth, compared to
25% when the germline mutation was detected prenatally with planned late preterm or early term
delivery (Table 2a).
It is practical to identify 96% of the germline mutations in bilaterally affected probands and to
identify the >15% of unilateral probands who carry a germline gene mutation.3,10,24 When the
proband's unique mutation is identified, molecular testing of family members can determine who
else carries the mutation and is at risk to develop retinoblastoma. We report 12 infants identified
in utero by molecular testing to carry the mutant RB1 allele of a parent. The 50% of tested
infants who do not inherit their family’s mutation require no surveillance.
Without molecular information, repeated retinal examination is recommended for all first degree
relatives until age 7 years, the first 3 years under general anesthesia.11 Such repeated clinical
screening may impose psychological and financial burden on the children and families. Early
molecular RB1 identification of the childrenchildren, who are not at risk and require no clinical
intervention, costs significantly less than clinical screening for tumors.19,25
The earliest tumors commonly involve the macular or paramacular region, threatening loss of
central vision, while tumors that develop later are usually peripheral, where they have less visual
impact.5,26-29 In our study, the risk of a vision-threatening tumor dropped from 39% to 17% by
prenatal mutation detection and planned early delivery (Table 2/Figure #). Macular and
paramacular tumors are difficult to manage by laser therapy or application of a radioactive
Early delivery of children at risk for retinoblastoma
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plaque, since these threaten the optic nerve and central vision. Systemic chemotherapy
effectively shrinks tumors such that focal therapy can be applied with minimal visual damage. In
our study, child #9 (Cohort 1) had a tumor at 36 weeks gestation large enough for detection by
obstetrical ultrasound, which showed drug-resistant tumor following reduced-dose chemotherapy
as a newborn,20 ultimately requiring enucleation. Systemic chemotherapy in neonates is difficult
due to the unknowns of immature liver and kidney function to metabolize the drugs, increasing
the potential of severe adverse effects. The conventional recommendation is to either reduce
chemotherapy dosages by 50%, particularly for infants in the first three months of life,30 or
administer a single agent carboplatin chemotherapy.26 However, reduced doses carry risk of
selecting for multidrug resistance in the tumor cells, making later recurrences difficult to treat.31-
33 Periocular topotecan for treatment of small-volume retinoblastoma34 may increase the
effectiveness of focal therapy without facilitating resistance.
Imhof et al7 screened 135 children at risk of familial retinoblastoma starting 1-2 weeks after birth
without molecular diagnosis and identified 17 retinoblastoma cases (13% of screened children at
risk). Of these, 70% had retinoblastoma in at least one eye at first examination and 41% of eyes
had vision threatening macular tumors; 41% of patients (7/17) had eye salvage failure (defined
by radiation or enucleation) and one case metastasized. Of eyes, 74% (27/34) had good visual
acuity (defined by vision >20/100). These Some of these results are similar to our Cohort 1, who
werewas also diagnosed postnatally but with additional molecular confirmation of disease risk.
In comparison, Cohort 2 showed fewer less vision threatening tumors (17%), fewer treatment
failures (8%) and better visual outcome (88%).
Early screening of at-risk infants with positive family history as soon as possible after birth is the
internationally accepted convention for retinoblastoma.7,35 In our series, amniocentesis (to collect
Early delivery of children at risk for retinoblastoma
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sample for genetic testing) was performed in the second half of pregnancy, where risks of
miscarriage are low (0.1-1.4%).36,37 We show that for infants those confirmed to carry their
family’s RB1 mutation, planned late preterm/ or early term delivery (36-38 weeks gestation)
resulted in smaller tumors with less macular involvement and better visual outcome. We did not
observe a difference in treatment burden between our two Cohorts, likely because treatment
course did not differ; however, early delivery and thus earlier treatment appeared to change
patient outcomes.
A concern with late preterm or early term delivery is its reported effect on neurological and
cognitive development and later school performance.14-16 One could argue that the visual
dysfunction from a large macular tumor common in retinoblastoma patients is equally
concerning, as it can cause similar neurocognitive defects due to blindness,17 though this has not
studied in a comparative manner. Moreover, the results from studies reporting on preterm and
early term babies may also be difficult to generalize, as they tend to include many children with
complex reasons for early delivery. In contrast, retinoblastoma children are otherwise healthy
normal babies, save for the tumor growing in their eye. Early term delivery requires an
interactive team of neonatologist, ophthalmologist and oncologist to reach the best timing for
better outcome.38 We show that safe late preterm/early term preterm delivery resulted in lower
tumor burden at birth (Cohort 2) that was significantly easier to treat than in Cohort 1 (Figure 23,
Table 2). Safe late preterm and early term delivery resulted in more infants born tumor-free,
facilitating frequent surveillance to detect tumors as they emerged, enabling focal therapy of
small tumors with minimal damage to vision (Figures 1, 3 2).
Counseling on reproductive risks is important for families affected by retinoblastoma including
unilateral probands. In developed countries, where current therapies result in extremely low
Early delivery of children at risk for retinoblastoma
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mortality, most retinoblastoma patients will survive to have children. Prenatal diagnosis also
enables pre-implantation genetics (to ensure an unaffected child) and informs parents who wish
to terminate an affected pregnancy.39 There have been two prior reports indicating pre-natal
molecular testing for retinoblastoma; in one, the fetus sibling of a proband was found not to carry
the sibling’s mutation,40 and in the other, 2 of 5 tested fetuses of a mosaic proband were born
without the parental mutation.41
This is the first report that elective safe late preterm/early term late-preterm delivery of
prenatally diagnosed infants with familial retinoblastoma results in improved outcomes. It is our
experience that retinoblastoma survivors and their relatives with full understanding of the
underlying risks, are often interested in early diagnosis to optimize options for therapy in
affected babies rather than termination of pregnancy. We also surmise that since germline
mutations predispose to future, second cancers in affected individuals, perhaps it is worth
investigating the role of cord blood banking infants that are prenatally molecularly diagnosed
with retinoblastoma, as a potential stem cell source in later anti-cancer therapy. We conclude that
the infants with familial retinoblastoma likely to develop vision-threatening macular
tumors,tumors, have an improved chance of good visual outcome with decreased treatment
associated morbidity with prenatal molecular diagnosis and safe, late-preterm delivery.
Acknowledgements
We would like to acknowledge Ivana….?? Who constructed some graphs in the statistical analysis.
Author contributions:
Early delivery of children at risk for retinoblastoma
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SS and BG had full access to all the data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis.
Study concept and design: Soliman, Gallie,
Acquisition, analysis, or interpretation of data: Soliman, Dimaras, Khetan, Gallie
Drafting of the manuscript: Soliman, Dimaras, Khetan, Gallie
Critical revision of the manuscript for important intellectual content: Dimaras, Gallie, Chan,
Héon
Statistical analysis: Soliman, Dimaras, Gallie
Study supervision: Chan, Héon, Gallie
Early delivery of children at risk for retinoblastoma
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27. Abramson DH, Niksarli K, Ellsworth RM, Servodidio CA. Changing trends in the management of retinoblastoma: 1951-1965 vs 1966-1980. J Pediatr Ophthalmol Strabismus. 1994;31(1):32-37.
28. Abramson DH, Greenfield DS, Ellsworth RM. Bilateral retinoblastoma. Correlations between age at diagnosis and time course for new intraocular tumors. Ophthalmic Paediatrics And Genetics. 1992;13(1):1-7.
29. Abramson DA, Gallie BL. Retinoblastoma. Current Opinion in Ophthalmology. 1992;3:302-311.30. Chan HS, Grogan TM, DeBoer G, Haddad G, Gallie BL, Ling V. Diagnosis and reversal of multidrug
resistance in paediatric cancers. European Journal Of Cancer. 1996;32A(6):1051-1061.31. Sreenivasan S, Ravichandran S, Vetrivel U, Krishnakumar S. Modulation of multidrug resistance 1
expression and function in retinoblastoma cells by curcumin. Journal of pharmacology & pharmacotherapeutics. 2013;4(2):103-109.
32. Barot M, Gokulgandhi MR, Pal D, Mitra AK. In vitro moxifloxacin drug interaction with chemotherapeutics: implications for retinoblastoma management. Exp Eye Res. 2014;118:61-71.
33. Yague E, Arance A, Kubitza L, et al. Ability to acquire drug resistance arises early during the tumorigenesis process. Cancer Res. 2007;67(3):1130-1137.
34. Mallipatna AC, Dimaras H, Chan HS, Heon E, Gallie BL. Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol. 2011;129(6):738-745.
35. Rothschild PR, Levy D, Savignoni A, et al. Familial retinoblastoma: fundus screening schedule impact and guideline proposal. A retrospective study. Eye (Lond). 2011;25(12):1555-1561.
36. Akolekar R, Beta J, Picciarelli G, Ogilvie C, D'Antonio F. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2015;45(1):16-26.
37. Tabor A, Vestergaard CH, Lidegaard O. Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2009;34(1):19-24.
38. Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet. 2012;379(9824):1436-1446.39. Dommering CJ, Garvelink MM, Moll AC, et al. Reproductive behavior of individuals with
increased risk of having a child with retinoblastoma. Clin Genet. 2012;81(3):216-223.
Early delivery of children at risk for retinoblastoma
20
40. Lau CS, Choy KW, Fan DS, et al. Prenatal screening for retinoblastoma in Hong Kong. Hong Kong Med J. 2008;14(5):391-394.
41. Castera L, Gauthier-Villars M, Dehainault C, et al. Mosaicism in clinical practice exemplified by prenatal diagnosis in retinoblastoma. Prenatal Diagnosis. 2011;31(11):1106-1108.
Early delivery of children at risk for retinoblastoma
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Early delivery of children at risk for retinoblastoma
22
Author contributions:
SS and BG had full access to all the data in the study and take responsibility for the integrity of
the data and the accuracy of the data analysis.
Study concept and design: Soliman, Gallie,
Acquisition, analysis, or interpretation of data: Soliman, Dimaras, Khetan, Gallie
Drafting of the manuscript: Soliman, Dimaras, Khetan, Gallie
Critical revision of the manuscript for important intellectual content: Dimaras, Gallie, Chan,
Héon
Statistical analysis: Soliman, Dimaras, Gallie
Study supervision: Chan, Héon, Gallie
Early delivery of children at risk for retinoblastoma
23
1. Corson TW, Gallie BL. One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes Chromosomes Cancer. 2007;46(7):617-634.
2. Dimaras H, Gallie BL. Retinoblastoma: The Prototypic Hereditary Tumor. In: Heike Allgayer, Helga Rehder, Fulda S, eds. Hereditary Tumors - From Genes to Clinical Consequences. Weinheim, Germany: WILEY-VCH Verlag GmbH & Co.KGaA; 2008:147-162.
3. Lohmann DR, Gallie BL. Retinoblastoma. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)2000.
4. Butros LJ, Abramson DH, Dunkel IJ. Delayed diagnosis of retinoblastoma: analysis of degree, cause, and potential consequences. Pediatrics. 2002;109(3):E45.
5. Abramson DH, Mendelsohn ME, Servodidio CA, Tretter T, Gombos DS. Familial retinoblastoma: where and when? Acta Ophthalmol Scand. 1998;76(3):334-338.
6. Noorani HZ, Khan HN, Gallie BL, Detsky AS. Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma. Am J Hum Genet. 1996;59(2):301-307.
7. Imhof SM, Moll AC, Schouten-van Meeteren AY. Stage of presentation and visual outcome of patients screened for familial retinoblastoma: nationwide registration in the Netherlands. Br J Ophthalmol. 2006;90(7):875-878.
8. Abouzeid H, Schorderet DF, Balmer A, Munier FL. Germline mutations in retinoma patients: relevance to low-penetrance and low-expressivity molecular basis. Mol Vis. 2009;15:771-777.
9. Abramson DH, Du TT, Beaverson KL. (Neonatal) retinoblastoma in the first month of life. Arch Ophthalmol. 2002;120(6):738-742.
10. Rushlow D, Piovesan B, Zhang K, et al. Detection of mosaic RB1 mutations in families with retinoblastoma. Hum Mutat. 2009;30(5):842-851.
11. National Retinoblastoma Strategy Canadian Guidelines for Care / Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44(Supp 2):S1-88.
12. Born Too Soon: The Global Action Report on Preterm Birth. Geneva: World Health Organization;2012.
13. ACOG Committee Opinion No 579: Definition of term pregnancy. Obstet Gynecol. 2013;122(5):1139-1140.
14. Cheong JL, Doyle LW. Increasing rates of prematurity and epidemiology of late preterm birth. Journal of paediatrics and child health. 2012;48(9):784-788.
15. Woythaler MA, McCormick MC, Smith VC. Late preterm infants have worse 24-month neurodevelopmental outcomes than term infants. Pediatrics. 2011;127(3):e622-629.
16. Poulsen G, Wolke D, Kurinczuk JJ, et al. Gestational age and cognitive ability in early childhood: a population-based cohort study. Paediatr Perinat Epidemiol. 2013;27(4):371-379.
17. Bedny M, Saxe R. Insights into the origins of knowledge from the cognitive neuroscience of blindness. Cogn Neuropsychol. 2012;29(1-2):56-84.
18. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmology clinics of North America. 2005;18:41-53.
19. Richter S, Vandezande K, Chen N, et al. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet. 2003;72(2):253-269.
20. Sahgal A, Millar BA, Michaels H, et al. Focal stereotactic external beam radiotherapy as a vision-sparing method for the treatment of peripapillary and perimacular retinoblastoma: preliminary results. Clinical Oncology (Royal College Of Radiologists). 2006;18(8):628-634.
21. Cowell JK, Bia B. A novel missense mutation in patients from a retinoblastoma pedigree showing only mild expression of the tumor phenotype. Oncogene. 1998;16(24):3211-3213.
22. Balmer A, Munier F, Gailloud C, Uffer S, van Melle G. [New retinal tumors in hereditary retinoblastoma]. Klinische Monatsblatter fur Augenheilkunde. 1995;206(5):328-331.
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24
23. Chan HSL. Combination Chemotherapy and Cyclosporine Followed by Focal Therapy for Bilateral Retinoblastoma NCT00110110. 2005; https://clinicaltrials.gov/ct2/show/NCT00110110?term=retinoblastoma&intr=cyclosporin&rank=1.
24. Lohmann D, Gallie BL. Retinoblastoma. In: Pagon RA AM, Bird TD, Dolan CR, Fong C-T, and Stephens K. , ed. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013. Available at http://www.ncbi.nlm.nih.gov/books/NBK1116/2013.
25. Houdayer C, Gauthier-Villars M, Lauge A, et al. Comprehensive screening for constitutional RB1 mutations by DHPLC and QMPSF. Hum Mutat. 2004;23(2):193-202.
26. Gombos DS. Retinoblastoma in the perinatal and neonatal child. Semin Fetal Neonatal Med. 2012;17(4):239-242.
27. Abramson DH, Niksarli K, Ellsworth RM, Servodidio CA. Changing trends in the management of retinoblastoma: 1951-1965 vs 1966-1980. J Pediatr Ophthalmol Strabismus. 1994;31(1):32-37.
28. Abramson DH, Greenfield DS, Ellsworth RM. Bilateral retinoblastoma. Correlations between age at diagnosis and time course for new intraocular tumors. Ophthalmic Paediatrics And Genetics. 1992;13(1):1-7.
29. Abramson DA, Gallie BL. Retinoblastoma. Current Opinion in Ophthalmology. 1992;3:302-311.30. Chan HS, Grogan TM, DeBoer G, Haddad G, Gallie BL, Ling V. Diagnosis and reversal of multidrug
resistance in paediatric cancers. European Journal Of Cancer. 1996;32A(6):1051-1061.31. Sreenivasan S, Ravichandran S, Vetrivel U, Krishnakumar S. Modulation of multidrug resistance 1
expression and function in retinoblastoma cells by curcumin. Journal of pharmacology & pharmacotherapeutics. 2013;4(2):103-109.
32. Barot M, Gokulgandhi MR, Pal D, Mitra AK. In vitro moxifloxacin drug interaction with chemotherapeutics: implications for retinoblastoma management. Exp Eye Res. 2014;118:61-71.
33. Yague E, Arance A, Kubitza L, et al. Ability to acquire drug resistance arises early during the tumorigenesis process. Cancer Res. 2007;67(3):1130-1137.
34. Mallipatna AC, Dimaras H, Chan HS, Heon E, Gallie BL. Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol. 2011;129(6):738-745.
35. Rothschild PR, Levy D, Savignoni A, et al. Familial retinoblastoma: fundus screening schedule impact and guideline proposal. A retrospective study. Eye (Lond). 2011;25(12):1555-1561.
36. Akolekar R, Beta J, Picciarelli G, Ogilvie C, D'Antonio F. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2015;45(1):16-26.
37. Tabor A, Vestergaard CH, Lidegaard O. Fetal loss rate after chorionic villus sampling and amniocentesis: an 11-year national registry study. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2009;34(1):19-24.
38. Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet. 2012;379(9824):1436-1446.39. Dommering CJ, Garvelink MM, Moll AC, et al. Reproductive behavior of individuals with
increased risk of having a child with retinoblastoma. Clin Genet. 2012;81(3):216-223.40. Lau CS, Choy KW, Fan DS, et al. Prenatal screening for retinoblastoma in Hong Kong. Hong Kong
Med J. 2008;14(5):391-394.41. Castera L, Gauthier-Villars M, Dehainault C, et al. Mosaicism in clinical practice exemplified by
prenatal diagnosis in retinoblastoma. Prenatal Diagnosis. 2011;31(11):1106-1108.
Early delivery of children at risk for retinoblastoma 25
Table 1: Occurrence of tumors at birth. (*, significantSignificant difference.)
Table 1a Table 1bEyes with tumors at birth Children with tumors at birth
(excluding IIRC A eye of child #8 first examined at age 3 months)
(child #8 included)
YES NO Total % YES YES NO Total % YESNull RB1 mutation 14 17 31 45% 9 7 16 56%Low penetrance RB1 mutation 0 10 10 0% 0 5 5 0%
Total 41 21Fisher's exact test p=0.02* p=0.04*
Cohort 1 9 8 17 53% 6 3 9 67%Cohort 2 5 19 24 21% 3 9 12 25%Total 41 21Fisher's exact test p=0.05* p=0.09
Early delivery of children at risk for retinoblastoma 26
Table 2: Outcome parameters and their level of significance
Table 2a: Outcome parameters per child
Cohort 1(n=9) Cohort 2 (n=12)
No % No % P value
Tumor(s) at birth 6 67% 3 25% 0.087IIRC AA at first tumor 2 22% 8 67% 0.009*Treatment
Focal therapy only 3 33% 7 58%0.39Systemic chemotherapy 6 67% 5 42%
Treatment success 3 33% 11 92% 0.002*Ocular salvage 4 44% 11 92% 0.046*Visual Outcome
Acceptable vision (better than 0.1) 7 78% 12 100% 0.017*Legal Blind 2 22% 0 0% Table 2b: Outcome parameters per eye
Cohort 1(n=18) Cohort 2(n=24)
No % No % P value
Tumor(s) at birth 10 56% 5 21% 0.027*Good visual prognosis (A) at first tumor 8 44% 17 71% 0.1Treatment success 11 61% 22 92% 0.025*Ocular salvage 13 72% 23 96% 0.07Visual Outcome
Acceptable vision (better than 0.1) 9 50% 21 88% 0.014*Poor Vision 9 50% 3 13%able 2: Outcome parameters and their level of significa
Early delivery of children at risk for retinoblastoma 27
Early delivery of children at risk for retinoblastoma
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Early delivery of children at risk for retinoblastoma
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Figure 1: Schematic representation of each child in Cohort 1 (postnatal RB1 detection) and Cohort 2
(prenatal RB1 detection) from delivery until time of first tumor, IIRC at first tumor per eye, treatment
burden (focal, systemic chemotherapy, or radiation treatment). Number of EUAs, visual acuity at last
follow up and follow up duration.
Early delivery of children at risk for retinoblastoma
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Early delivery of children at risk for retinoblastoma
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I suggest you put all VA in black , if there are no reason for bolding, do not bold some only or bold all, I
would ljustify the VA to the left
Early delivery of children at risk for retinoblastoma
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Figure 2: IVANA PLOT of Age versus type of RB1 mutation.
Early delivery of children at risk for retinoblastoma
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Figure 23: Kaplan Meiyer curves of eye salvage without radiationtreatment success percentage showing a
significant treatment success in Cohort 2 versus Cohort 1.
.
Perc
enta
ge
Time in months
Early delivery of children at risk for retinoblastoma
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Good point from Helen, explain “0” and percentage of what? Children without irradiation?
Early delivery of children at risk for retinoblastoma
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Figure 34: Correlation between visual acuity per eye at last follow up (decimal) and gestational age at
delivery in weeks showing a negative correlation.
26 28 30 32 34 36 38 400
0.5
1
1.5
2
f(x) = − 0.0284788135593221 x + 1.66274293785311R² = 0.0313248065403926
Gestational age (weeks)
Visu
al A
cuity
(dec
imal
)
Early delivery of children at risk for retinoblastoma
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