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 brenda@gallie.ca

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 (348/350)

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 anaesthesia.. 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

neurological and cognitive development and later school performance measured in children with a wide

Early delivery of children at risk for retinoblastoma

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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 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) 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

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

Early delivery of children at risk for retinoblastoma

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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 preterm 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 ……..

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) 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 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 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

Early delivery of children at risk for retinoblastoma

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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).

The age at first tumor per child (per eye??) was significantly 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 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) (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

Early delivery of children at risk for retinoblastoma

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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

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=0.009, 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 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)

Early delivery of children at risk for retinoblastoma

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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

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 (Figure 2). One child (#6) (11%) in Cohort

1 showed high 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 3).

Early delivery of children at risk for retinoblastoma

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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 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 children 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

Early delivery of children at risk for retinoblastoma

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and planned early delivery (Table/Figure #). Macular and paramacular tumors are difficult to manage by

laser therapy or application of a 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. 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 results are similar to our Cohort 1, who were also diagnosed postnatally but with

additional molecular 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.7,35 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%).36,37 We show that for infants confirmed to carry their family’s RB1 mutation, planned late

Early delivery of children at risk for retinoblastoma

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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 preterm delivery resulted in lower tumor burden at birth (Cohort 2)

that was significantly easier to treat than in Cohort 1 (Figure 2, 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, 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 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 delivery of prenatally diagnosed infants with familial

retinoblastoma results in improved outcomes. It is our experience that retinoblastoma survivors and their

Early delivery of children at risk for retinoblastoma

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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, have an improved

chance of good visual outcome with decreased treatment associated morbidity with prenatal molecular

diagnosis and safe, late-preterm delivery.

Acknowledgements

Early delivery of children at risk for retinoblastoma

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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

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33. Yague E, Arance A, Kubitza L, et al. Ability to acquire drug resistance arises early during the tumorigenesis process. Cancer research. 2007;67(3):1130-1137.

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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.

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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

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Early delivery of children at risk for retinoblastoma 20

Table 1: Occurrence of tumors at birth. *, significant difference.

Early delivery of children at risk for retinoblastoma 21

Table 2: Outcome parameters and their level of significa

Early delivery of children at risk for retinoblastoma

22

Early delivery of children at risk for retinoblastoma

23

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.

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

Gestational Age

20/20; 20/25

28 29 30 31 32 33 34 35 36 37 38 39 40 1 2 3 4 5 6 7 8 9 10

20/20; 20/200

3 20/20; E

1 20/20; 20/20

8

20/20; 20/25

20/30; 20/60

20/600; 20/60

9

10

E; 20/30

4 E(OS) 20/20, E

11

20/15; 20/10

20/50; 20/20

13

20/20; 20/25

15

Coho

rt 1

Coho

rt 2

5.6

18

7.1

18

14.8 5.2

12.8

9.5

8.8

4.3

6.4

FU (y)

Spontaneous birth Induced birth Birth to first tumor

monthsweeks

E(OS)

20/25; 20/25

17

3.2

6 NPL; 20/25 2.7

VA (OD, OS)

2 20/200* 3.7

5

IIRC (OD, OS)A, AC, B

A, BA, BA, B

B, A7 A, B 20/30; 20/30 2.8

(OS)

D, A

B, B

E; 20/20E(OD) 2.4

(OU) E(OD) E; 20/400 15.5

12

14

16

1819

20

21

A, A 15.5

B, AB, B

(OU) E(OD) 4.9B, B

A, A

A, A

A, A

B, B

A, A

20/25; 20/100

B, B 20/125; 20/25

A, A 2.3

EUAs25

41

24

22

21 33

36

30

30

24

31

20

30

43

18

81

41

28

21

23

22 20/20; 20/25 3.8 A, A

E(OD)

E

Focal Therapy Chemotherapy

Radiotherapy Enucleation

Early delivery of children at risk for retinoblastoma

24

Early delivery of children at risk for retinoblastoma

25

Figure 2: Kaplan Meyer curves of eye salvage without radiation showing a significant treatment success

in Cohort 2 versus Cohort 1.

.

Good point from Helen, explain “0” and percentage of what? Children without irradiation?

Perc

enta

ge

Time in months

Early delivery of children at risk for retinoblastoma

26

Figure 3: Correlation between visual acuity 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

)