· Web viewEarly Delivery of Children at Risk for Retinoblastoma. 22. Impact of early delivery

Impact of early delivery of children with familial retinoblastoma after

prenatal RB1 mutation identification

Sameh E. Soliman, MD; Helen Dimaras, PhD; Vikas Khetan, MD, BS; Jane A. Gardiner, MD,

FRCSC; Helen S. L. Chan, MB, BS, FRCSC; Elise Héon, MD, FRCSC; Brenda L. Gallie, MD,

FRCSC

Corresponding Author: Dr. Brenda Gallie at the Department of Ophthalmology and Vision

Sciences, the Hospital for Sick Children, 555 University Avenue, Toronto, ON M5G 1X8,

Canada, or at [email protected]

Authors’ Affiliations:

Departments of Ophthalmology & Vision Sciences, (Soliman, Dimaras, Khetan, Gardiner, Héon,

Gallie) and Division of Hematology/Oncology, Pediatrics (Chan), The 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), Faculty of Medicine, and the Division of Clinical

Public Health, Dalla Lana School of Public Health (Dimaras), University of Toronto, Toronto,

Ontario, Canada Department of Ophthalmology and Vision Science, University of British

Columbia, Vancouver, British Columbia, Canada (Gardiner).

Financial Support: None

Conflict of Interest: No conflicting relationship exists for any author

Running head: Early delivery of familial retinoblastoma

Word count: 3000 /3000 words

Numbers of figures and tables: 3 figures and 2 tables

mailto:[email protected]

Early Delivery of Children at Risk for Retinoblastoma

Key Words: prenatal retinoblastoma, retinoblastoma gene mutation, RB1, molecular testing,

late pre-term delivery, near-term delivery, amniocentesis

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At A Glance:

All the children of a parent who had retinoblastoma 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% versus 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.

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Abstract (336/350 words)

IMPORTANCE Familial retinoblastoma can be predicted by prenatal RB1 mutation

detection. Subsequent, early delivery and treatment of small tumors may achieve better

outcomes with minimal therapy.

OBJECTIVE To compare overall outcomes and intensity of treatment for children with

familial retinoblastoma diagnosed postnatal or by obstetrical ultrasound, to 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),

Toronto, Canada.

PARTICIPANTS Children born between 1 June 1996 and 1 June 2014 with familial

retinoblastoma, cared for at SickKids.

EXPOSURE(S) Cohort 1 consisted of spontaneously delivered infants who had

postnatal RB1 testing. Cohort 2 consisted of infants identified by amniocentesis to carry

the relative’s known RB1 mutant allele who had planned early delivery (36-38 weeks

gestation). All children received treatment for eye tumors.

MAIN OUTCOME MEASURES Main outcome measures were gestational age, age at

first tumor, eye classification, treatments given, visual outcome, number of anesthetics,

pregnancy or delivery complications and estimated treatment burden.

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RESULTS Vision-threatening tumors were present at birth in 67% (6/9) of Cohort 1

infants, and 25% (3/12) of Cohort 2 infants. Infants in both Cohorts eventually

developed tumors in both eyes. Useful vision (better than 0.21, legal blindness) was

achieved for 78% (7/9) of Cohort 1 compared to 100% (12/12) of Cohort 2 (p<0.02). At

first eye tumor diagnosis, 11% (1/9) of Cohort 1 had both eyes Group A (smallest and

least vision-threatening tumors) compared to 67% (8/12) of Cohort 2 (p<0.01).

Treatment success (defined as avoidance of enucleation and external beam irradiation)

was achieved in 33% (3/9) patients of Cohort 1 compared to 92% (11/12) patients of

Cohort 2 (p<0.002). There were no complications related to preterm delivery.

CONCLUSIONS AND RELEVANCE For expectant parents with a history of

retinoblastoma, prenatal molecular diagnosis with late preterm/near-term delivery

increases the likelihood of infants 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.

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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 (non-heritable retinoblastoma), or a germline mutation (50% of children)

predisposes to 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 an RB1 germline mutation may 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 anesthesia.11 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 delivery is the potential effect on

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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

hypothesized that retinoblastoma tumors would be smaller and easier to treat, the earlier they are

diagnosed.

We present the first report of outcomes of late preterm/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 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 tumor(s) in each eye; treatments used; International Intraocular

Retinoblastoma Classification18 of each eye (IIRC); Tumor Node Metastasis (TNM) staging for eyes and

child;11 active 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

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

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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 0.21 decimal (20/1200). Legal blindness is

defined as overall visual acuity worse than 0.1 in the best eye of the child.

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 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 (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: 3 were spontaneously

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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 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).

At first tumor per child and per eye, children with null mutations tended to be younger (mean 59,

median 20 days) than those with low penetrance mutations (mean 107, median 119 days) (Figure 2a).

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). Of Cohort

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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 with tumors threatening

optic nerve and fovea, and 6 with at least 1 tumor >3 mm size) was 9 days, tending younger than the 92

days for 24 IIRC18 A eyes (tumors are < 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=0.01, 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 17/24 (71%)

Cohort 2 eyes (Table 2b). One eye was an IIRC18 D eye (Cohort 1 patient) 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 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

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chemotherapy or external beam irradiation, 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, 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

33% (4/9) of Cohort 1 and 92% (11/12) of Cohort 2 patients (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 2b). One child (#6) (11%) in Cohort 1 showed high-risk histopathologic features24-26 in

the enucleated eye and received adjuvant treatment. All children are presently alive.

Children were legally blind in 22% (2/9) 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% (9/18) of eyes in Cohort 1 and 92%

(22/24) 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.

Combined treatment success 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

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was found between gestational age and final visual outcome (r=-0.03) with better visual outcome

observed for earlier deliveries (Figure 3).

Discussion

This is the first report on outcomes of elective early term or late preterm delivery of infants with

prenatal molecular confirmation of familial retinoblastoma. This approach allowed treatment of tumors as

they emerged, resulting in better ocular and visual 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 after 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.3,10,27 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 (not shown) require no surveillance.

Without molecular information, repeated retinal examination is recommended for all first degree

relatives until age 7 years, often with general anesthesia when under 3 years under.11 Such repeated

clinical screening may impose psychological and financial burden on the children and families. Early

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molecular RB1 identification of the children, who are not at risk and require no clinical intervention, costs

significantly less than clinical screening for tumors.19,28

The earliest tumors commonly involve the macular or perimacular region, threatening loss of central

vision, while tumors that develop later are usually peripheral, where they have less visual impact.5,29-32 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). Macular and perimacular tumors are difficult to manage by laser

therapy or radioactive 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. 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,33 or administer a single agent carboplatin chemotherapy.29

However, reduced doses carry risk of selecting for multidrug resistance in the tumor cells, making later

recurrences difficult to treat.34-36 Periocular topotecan for treatment of small-volume retinoblastoma37 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;and of eyes, 74% (27/34) had good visual acuity (defined by

vision >20/100). Our Cohort 1 children were also diagnosed postnatal but with additional molecular

13


confirmation of disease risk. In comparison, Cohort 2 showed fewer 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.7,38 In our series, amniocentesis (to collect sample

for genetic testing) was performed in the second half of pregnancy, where risks of miscarriage are low

(0.1-1.4%).39,40 We show that for those confirmed to carry their family’s RB1 mutation, planned late

preterm/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.41 We show that safe late preterm/early term delivery resulted in lower tumor burden at

birth (Cohort 2) that was significantly easier to treat than in Cohort 1 (Figure 3, 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).

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Counseling on reproductive risks is important for families affected by retinoblastoma including

unilateral probands. In developed countries, where current therapies result in extremely low 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 may wish to terminate an

affected pregnancy.42 There have been two prior reports indicating prenatal molecular testing for

retinoblastoma; in one, the fetus sibling of a proband was found not to carry the sibling’s mutation,43 and

in the other, 2 of 5 tested fetuses of a mosaic proband were born without the parental mutation.44

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 who are likely to

develop vision-threatening macular 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 acknowledge Ivana Ristevski for construction of some of the figures.

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,

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Acquisition, analysis, or interpretation of data: Soliman, Dimaras, Khetan, Gardiner, 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

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Table 1: Occurrence of tumors at birth. (*, Significant difference.)Table 1a Table 1b

Eyes 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 % YES

Null RB1 mutation 14 17 31 45% 9 7 16 56%

Low penetrance

RB1 mutation0 10 10 0% 0 5 5 0%

Total 41 21

Fisher'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 21

Fisher's exact test p=0.05* p=0.09

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Table 2: Outcome parameters and their level of significanceTable 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*TreatmentFocal 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 (> 0.1) 7 78% 12 100%0.017*

Legal Blind 2 22% 0 0%

Table 2b: Outcome parameters per eyeCohort 1(n=18)

Cohort 2(n=24)

No % No % P valueTumor(s) at birth 10 56% 5 21% 0.027*Good visual prognosis (A) at

first tumor8 44% 17 71% 0.1

Ocular salvage 13 72% 23 96% 0.07Treatment Success§ 11 61% 22 92% 0.025*Visual Outcome

Acceptable vision (> 0.1)

9 50% 21 88%0.014*

Poor Vision 9 50% 3 13%

Combined Treatment Success & Acceptable vision

9 50% 21 88% 0.014*

* significant result; § Avoided enucleation or external beam radiation

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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 (FU) duration.

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Figure 2: a, Comparison of birth age at diagnosis of first tumor in each eye, for

children with low penetrance versus null RB1 mutations. b, Kaplan Myer curves

showing significantly worse proportion avoiding failure (defined as enucleation or

external beam radiation) for Cohort 1 vs. Cohort 2 (P=0.02*, Log-rank (Mantel-Cox)

test (X2=5.7).

24


Figure 3: Negative correlation between visual acuity per eye at last follow up

(decimal) and gestational age at delivery in weeks.

26 28 30 32 34 36 38 400

0.5

1

1.5

2

f(x) = − 0.0284788135593221 x + 1.66274293785311R² = 0.0313248065403924

Gestational age (weeks)

Visu

al A

cuity

(dec

imal

)

25

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