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, 8 th 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);
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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,
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
Helen Dimaras, 12/08/15,
Fetuses? Since ‘infant’ suggests already born.
Helen Dimaras, 12/08/15,
Is the convention not to refer to pregnancies as first, second or third trimester?
Helen Dimaras, 12/08/15,
“Fewer” is for things you can count; “less” is for things you can’t count.
Helen Dimaras, 12/08/15,
Which results (data points) are you saying are similar? Since the paper also had a case that metastasized, which we did not have.
Helen Dimaras, 12/08/15,
Reference the data table or Figure that shows this.
Early delivery of children at risk for retinoblastoma
14
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
15
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
16
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
Sameh Gaballah, 12/08/15,
Only one or two authors to be written as per the JAMA guidelines
Early delivery of children at risk for retinoblastoma
17
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Early delivery of children at risk for retinoblastoma 20
Table 1: Occurrence of tumors at birth. *, significant difference.
Elise Heon, 12/08/15,
What is the number of cases you are referring to. in subsections it would be useful to see n=...
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
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
Helen Dimaras, 12/08/15,
Is ‘percentage’ the right term for the y-axis?Also, the ‘time in months’ is counting from what ‘time 0’? birth? Start of treatment?
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
)
Elise Heon, 12/08/15,
Do you need to put that equation? You need a correlation and a p value. Visual acuity is measured at what age. could you have that on another axis? Is this VA of better eye. Here we do not use decimal we use snellen or logMAR. Be careful on gathering that data as it can be very c onfusing