Improved visual outcome in familial retinoblastoma with late
preterm or early term delivery after prenatal RB1 mutation
identificationComment by Sameh Gaballah: Cover LetterInclude a
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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
This work was partly presented as an oral presentation in the
Research Day of the Department of Ophthalmology and Visual Sciences
of the University of Toronto in Toronto, 29 May 2015 Presented by
Sameh Soliman
Corresponding Author: Dr Brenda Gallie at the Department of
Ophthalmology and Vision Sciences, the Hospital for Sick Children,
525 University Avenue, Toronto, ON M5G 2L3, Canada, or at
[email protected]
Authors’ Affiliations:
Departments of Ophthalmology & Vision Sciences, (Sogyliman,
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 (Dimaras, Héon , Gallie); Ophthalmology Department,
Faculty of Medicine, Alexandria University, Egypt (Soliman);
Sankara Nethralya Hospital, Chennai, India (Khetan); Departments of
Pediatrics (Chan), Molecular Genetics and Medical Biophysics
(Gallie) and Ophthalmology (Dimaras, Héon, Gallie), University of
Toronto, Toronto, Ontario, Canada.
Author contributions:
Drs. Soliman and Gallie 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, Dimaras, Gallie, Khetan
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
Financial Support: None
Conflict of Interest: No conflicting relationship exists for any
author
Running head: Early delivery of familial retinoblastoma
Address for reprints: Dr. Brenda Gallie at the Department of
Ophthalmology and Vision Sciences, the Hospital for Sick Children,
525 University Avenue, Toronto, ON M5G 2L3, Canada
Word count: 3183 3359 /3000 words
Numbers of figures and tables: 1 3 figures and 2 tables
Key Words: prenatal retinoblastoma, retinoblastoma gene
mutation, RB1, molecular testing, late pre-term delivery, near-term
delivery, amniocentesis
Abstract ( /350)Comment by Sameh Gaballah: AbstractsInclude a
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manuscriptAbstracts for Reports of Original Data:Reports of
original data should include an abstract of no more than 350 words
using the headings listed below For brevity, parts of the abstract
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section should include the following content:Importance: The
abstract should begin with a sentence or 2 explaining the clinical
(or other) importance of the study questionObjective: State
the precise objective or study question addressed in the report
(eg, “To determine whether…”) If more than 1 objective is
addressed, the main objective should be indicated and only key
secondary objectives stated If an a priori hypothesis was tested,
it should be statedDesign: Describe the basic design of the
study State the years of the study and the duration of follow-up If
applicable, include the name of the study (eg, the Framingham Heart
Study) As relevant, indicate whether observers were masked to
patient groupings, particularly for subjective
measurementsSetting: Describe the study setting to assist
readers to determine the applicability of the report to other
circumstances, for example, general community, a primary care or
referral center, private or institutional practice, or ambulatory
or hospitalized careParticipants: State the clinical
disorders, important eligibility criteria, and key sociodemographic
features of patients The numbers of participants and how they were
selected should be provided (see below), including the number of
otherwise eligible individuals who were approached but refused If
matching is used for comparison groups, characteristics that are
matched should be specified In follow-up studies, the proportion of
participants who completed the study must be indicated In
intervention studies, the number of patients withdrawn because of
adverse effects should be given For selection procedures, these
terms should be used, if appropriate: random sample (where random
refers to a formal, randomized selection in which all eligible
individuals have a fixed and usually equal chance of selection);
population-based sample; referred sample; consecutive sample;
volunteer sample; convenience sampleNote: For accepted manuscripts,
the above 3 sections are usually combined during the editing
process (as "Design, Setting, and Participants"), but for
manuscript submission these sections should be kept
separateIntervention(s) for Clinical Trials or Exposure(s) for
observational studies: The essential features of any
interventions or exposures should be described, including their
method and duration of administration The intervention or exposure
should be named by its most common clinical name, and
nonproprietary drug names should be usedMain Outcome
Measure(s): Indicate the primary study outcome measurement(s)
as planned before data collection began If the manuscript does not
report the main planned outcomes of a study, this fact should be
stated and the reason indicated State clearly if the hypothesis
being tested was formulated during or after data collection Explain
outcomes or measurements unfamiliar to a general medical
readershipResults: The main outcomes of the study should be
reported and quantified, including baseline characteristics and
final included/analyzed sample Include absolute numbers and
measures of absolute risks (such as increase/decrease or absolute
differences between groups), along with confidence intervals (for
example, 95%) or Pvalues Approaches such as number needed to
treat to achieve a unit of benefit may be included when appropriate
Measures of relative risk also may be reported (eg, relative risk,
hazard ratios) and should include confidence intervals Studies of
screening and diagnostic tests should report sensitivity,
specificity, and likelihood ratio If predictive value or accuracy
is reported, prevalence or pretest likelihood should be given as
well All randomized clinical trials should include the results of
intention-to-treat analysis, and all surveys should include
response ratesConclusions and Relevance: Provide only
conclusions of the study that are directly supported by the
results, along with implications for clinical practice or health
policy, avoiding speculation and overgeneralization Indicate
whether additional study is required before the information should
be used in usual clinical settings Give equal emphasis to positive
and negative findings of equal scientific merit Also, provide a
statement of relevance indicating implications for clinical
practice or health policy, avoiding speculation and
overgeneralization The relevance statement may also indicate
whether additional study is required before the information should
be used in clinical settings
Importance: The abstract should begin with a sentence or 2
explaining the clinical (or other) importance of the study
questionComment by Sameh Soliman: Don’t forget
IMPORTANCE Prenatal Sameh???RB1 Mutation detection made
prediction of familial retinoblastoma more accurate and if combined
with earlier delivery would have an impact on tumor size and
overall treatment outcome.
OBJECTIVE: State the precise objective or study question
addressed in the report (eg, “To determine whether…”) If more than
1 objective is addressed, the main objective should be indicated
and only key secondary objectives stated If an a priori hypothesis
was tested, it should be stated
OBJECTIVE To determine overall outcomes of infants with familial
retinoblastoma diagnosed prenatally and delivered early term or
late preterm compared to infants diagnosed postnatally.
Design: Describe the basic design of the study. State the
years of the study and the duration of follow-up. If applicable,
include the name of the study (eg, the Framingham Heart Study) As
relevant, indicate whether observers were masked to patient
groupings, particularly for subjective measurements
DESIGN A retrospective, observational study of children born
between 1 June 1996 and 1 June 2014 with familial retinoblastoma
cared for at Hospital for Sick Children, followed till April
2015.
Setting: Describe the study setting to assist readers to
determine the applicability of the report to other circumstances,
for example, general community, a primary care or referral center,
private or institutional practice, or ambulatory or hospitalized
care
SETTING This study was conducted at the academic institutional
retinoblastoma referral center.
Participants: State the clinical disorders, important
eligibility criteria, and key sociodemographic features of patients
The numbers of participants and how they were selected should be
provided (see below), including the number of otherwise eligible
individuals who were approached but refused If matching is used for
comparison groups, characteristics that are matched should be
specified In follow-up studies, the proportion of participants who
completed the study must be indicated In intervention studies, the
number of patients withdrawn because of adverse effects should be
given For selection procedures, these terms should be used, if
appropriate: random sample (where random refers to a formal,
randomized selection in which all eligible individuals have a fixed
and usually equal chance of selection); population-based sample;
referred sample; consecutive sample; volunteer sample; convenience
sample
PARTICIPANTS: All children with familial retinoblastoma treated
at SickKids were included. All children remain under care at the
Hospital for Sick Children.
Intervention(s) for Clinical Trials or Exposure(s) for
observational studies: The essential features of any
interventions or exposures should be described, including their
method and duration of administration The intervention or exposure
should be named by its most common clinical name, and
nonproprietary drug names should be used
EXPOSURE(S) Infants shown on amniocentesis to carry the parent’s
RB1 mutant allele were planned for early pre-term or late preterm
delivery (36-37 weeks of gestation), compared to normal term
delivery (40 weeks of gestation) and postnatal RB1 testing. All
children received treatments for eye tumors.
Main Outcome Measure(s): Indicate the primary study outcome
measurement(s) as planned before data collection began If the
manuscript does not report the main planned outcomes of a study,
this fact should be stated and the reason indicated State clearly
if the hypothesis being tested was formulated during or after data
collection Explain outcomes or measurements unfamiliar to a general
medical readership
MAIN OUTCOME MEASURES The hypothesis prior to data collection
was that preterm delivery of infants at near 100% risk of bilateral
retinoblastoma safely optimizes visual outcome and minimizes use of
invasive treatments. Primary study outcome measurements were
gestational age, age at first tumor, eye classification and
staging, treatments given, visual outcome, number of anesthetics,
pregnancy or delivery complications, and estimated overall cost of
care.
RESULTS: The main outcomes of the study should be reported
and quantified, including baseline characteristics and final
included/analyzed sample Include absolute numbers and measures of
absolute risks (such as increase/decrease or absolute differences
between groups), along with confidence intervals (for example, 95%)
or Pvalues. Approaches such as number needed to treat to
achieve a unit of benefit may be included when appropriate.
Measures of relative risk also may be reported (eg, relative risk,
hazard ratios) and should include confidence intervals. Studies of
screening and diagnostic tests should report sensitivity,
specificity, and likelihood ratio. If predictive value or accuracy
is reported, prevalence or pretest likelihood should be given as
well… All randomized clinical trials should include the results of
intention-to-treat analysis, and all surveys should include
response rates.
RESULTS Of 21 infants shown to carry their parent’s RB1
mutation, 12 had been tested prenatally and 9 after birth. Of the
infants tested prenatally, 9 were induced at 36-38 weeks gestation
because of risk for retinoblastoma and 3 were born spontaneously
preterm. Immediate postnatal examination revealed
vision-threatening tumors in 25% (3/12) of infants diagnosed
prenatal to carry the family’s RB1 mutation, compared to 67% (6/9)
of those diagnosed postnatal. All patients eventually developed
tumors in both eyes. Good vision was maintained in all patients
diagnosed prenatal; treatments included focal therapy (all), later
systemic chemotherapy (5), enucleation and stereotactic radiation
(1). Full-term infants received focal therapy (all), systemic
chemotherapy (4), stereotactic radiation (2), and enucleation of
one eye (4), with worse visual outcome. One child in the postnatal
RB1 mutation detection developed extraocular disease and still
under active treatment.
Conclusions and Relevance: Provide only conclusions of the
study that are directly supported by the results, along with
implications for clinical practice or health policy, avoiding
speculation and overgeneralization. Indicate whether additional
study is required before the information should be used in usual
clinical settings. Give equal emphasis to positive and negative
findings of equal scientific merit. Also, provide a statement of
Relevance indicating implications for clinical practice or health
policy, avoiding speculation and overgeneralization. The relevance
statement may also indicate whether additional study is required
before the information should be used in clinical settingsComment
by Gallie Brenda: SAmeh, add this to below….
CONCLUSIONS AND RELEVANCE: Prenatal diagnosis of retinoblastoma
followed by late preterm and near-term delivery had shown a
decrease in eyes with tumor at birth and a better visual outcome
when compared to those with full term delivery with no
complications related to preterm delivery. facilitated expedient
intervention and optimized outcomes.
Introduction
Retinoblastoma, the most common primary ocular malignancy in
children, is initiated when both alleles of the RB1 tumor
suppressor gene are inactivated in a precursor retinal cell, and
progresses when mutations in other specific genes occur.1,2 Both
alleles may be lost only in the somatic cell from which the tumor
arises, however, in about 50% of children, a germline mutation
predisposes to the development of multiple retinal tumors during
childhood, and other cancers later in life. Ten percent of patients
display a family history of disease, inheriting a family-specific
mutation from a parent.1,3
Children with RB1 germline alleles may already have
retinoblastoma tumor(s) at birth, which are often in the posterior
pole of the eye where they threaten vision.4-8 Preservation of
vision with treatment of these small tumors is often difficult,
because focal treatment in proximity to the optic nerve and macula
may damage compromise vision. Most of these children are
bilaterally affected, with either simultaneous or sequential
detection of tumors.4,7 Later developing tumors tend to will
develop more tumors in the first year of life, which tend to be
located peripherally. The child is bilaterally affected in either
simultaneous or sequential involvement. 4,7 Low penetrance
mutations (10% of families)3 and mosiacism result in fewer tumors
and more unilaterally affected children9. The timing of first
tumors after birth has not been studied.
It is recommended that infants with a family history of
retinoblastoma be screened as soon as possible after birth and
repeatedly for the first few years of life, including under
anaesthesia, aiming at early diagnosis when tumors are small and
easy to treattreatable with less invasive therapies for salvage of
the with oculareye and visualion salvage.6,7,10
Preterm birth is defined as a live birth occurring before
completion of 37 weeks gestation. Full term birth is generally
defined as a live birth occurring at 40 weeks gestation. Infants
born after completion of 37 and before 39 weeks gestation are
technically considered early term. . (8-9). 11,12 The main concern
with late preterm or early term delivery is its reported effect on
neurological and cognitive development and later school performance
in children with a wide range of indications for early delivery,
,13-15 but visual dysfunction from a larger macular tumor can may
risk cause similar neurocognitive defects due to blindness16,
although this has not been studied. despite never studied in a
comparative manner.
We now present the first report of outcomes of prenatal genetic
screening and late preterm or early term delivery for treatment of
retinoblastoma for children demonstrated to carry the RB1 mutant
allele of a parent. We show that for children at 50% risk to
inherit a germline RB1 mutant allele, prenatal molecular diagnosis
and preterm delivery resulted in early allowed detection and
treatment of small , early tumors, resulting in lower treatment
morbidity, and better tumor control and visual outcome, compared to
children born full term at 39-40 weeks.
MethodsStudy Design
Research ethics board approval (REB approval number 1000028725)
was obtained from The Hospital for Sick Children (SickKids) for a
retrospective review of medical records of all children with
familial retinoblastoma seen at SickKids, and born between 1 June
1996 and 1 June 2014. Data collected 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 mutaion; age and location of first and
all subsequent tumor (s) in each eye; treatments used; number of
anaesthetics; International Intraocular Retinoblastoma
Classification17 of each eye (IIRC); Tumor Node Metastasis (TNM)
staging for eyes and child10; treatment duration; date of last
follow-up; and visual outcome at last follow-up in Snellen and
LogMAR values. RB1 mutation testing was performed by Retinoblastoma
Solutions before 2013, and Impact Genetics after 2013, as
previously described.18Comment by Gallie Brenda: I though we went
decimal???We went 1-LogMAR. We collected LOGMAR. And then used
1-LoGMAR.
The corrected age for gestation at birth for each child was
calculated (taking 39 weeks as full term). Vision threatening
tumors were defined as in close to optic nerve or macular area
(IIRC17 Group B or worse). Treatments will were be
devidedsummarized as into focal therapies (Laser therapy,
cryotherapy and periocular subtenon’s injection of chemotherapy)
and or systemic therapies (systemic chemotherapy or stereotactic
external beam irradiation). Treatment burden (defined by the impact
of treatmnet course on general health and development of the child
and potential impact on the his family) was evaluated based on i)
duration of active treatment (time from diagnosis to last
treatment), ii) use of systemic chemotherapy or radiation, and iii)
number of examinations under anesthesia (EUAs), and iv) occurrence
of extraocular disease. (Figure 1). Treatment success was defined
as avoidance of enucleation or external beam irradiation or
extraocular disease. Good Acceptable visual outcome was defined as
visual acuity > 20/200 (>0 in 1-LogMAR scale or <1 in
LogMAR) (cut edge of legal blindness). A legally blind child is
defined as best eye visual acuity < 20/200 (<0 in 1-LogMAR
scale). Comment by Gallie Brenda: Anything better than blind is
GOOD???Sameh: I tried stratifying them into good (>0.5),
Acceptable (0-0.5), Ambulatory (or legally blind) less than 0. Only
4 eyes and no patients are present in the Acceptable group. All are
either >0.5 or legally blind. I think we can change the word
Good into Acceptable and say that a subset has very good
vision.Comment by Gallie Brenda: I think ??? 1-LogMAR is
DECIMAL???? See methods.Sameh: No. 1-LogMar is not equivalent to
decimal. Please see table in excel titled LOGMAR. A detailed
comparison between different VA outcomes is present.
Statistics
Basic descriptive statistics (student t-test, chi square test
(when all cell frequencies are more than 5), Fisher exact test
(when any cell frequency is less than 5), Mann Whitney test and
Mood’s median test) were used for statistical comparisons between
patients who underwent prenatal testing and preterm delivery
(Cohort 1) and those who were diagnosed post-natal (Cohort 2).
Correlations and Kaplaen- Meyer survival graphs were plotted using
Microsoft Excel 2007.
ResultsPatient Demographics
The records ofTwenty-one 21 children with familial
retinoblastoma children were reviewed (11 males, 10 females) were
eligible for this study (Supplementary Table 1). Diagnosis for
Cohort 1 (9 children) was by observation of prenatal retinoblastoma
tumor (child #9) or postnatal tumor (child #8) or postnatal testing
for the parental RB1 mutation for Cohort 1: 6 were delivered full
term and 3 late preterm because of pregnancy-induced hypertension
(#7), fetal ultrasound evidence of retinoblastoma19 (#9) ADDIN
EN.CITE ADDIN EN.CITE.DATA 19 or spontaneous delivery (#8). The
Twelve 12 children (57%) (Cohort 2) were prenatally diagnosed to
carry an their family’s RB1 mutation and planned for late preterm
or early term delivery: 3 were spontaneously premature (#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
affected (mother #8, father #19). The familial RB1 mutations were
previously detected except for the unilaterally affected parent of
#8, who was neverhad not been tested and understood that her
children had no risk since she was unilaterally affected. Cohort 1
children (#1-9) were tested postnatal for their family’s RB1
mutation on by blood; Cohort 2 children (#10-21) were tested
prenatal on by amniocentesis at 16-33 weeks gestation.
Null RB1 mutations were present in 16 families; 5 had low
penetrance RB1 mutations (whole gene deletion #19; weak splice site
mutations #15, 18, 21; and C712R18). No proband in this study was
mosaic for the RB1 mutation. All study subjects were eventually
bilaterally affected. At birth, null RB1 mutations resulted in nNo
tumors were detected at birth (IIRC17 Group 0) in 7/15 (47%)
infants and 17/30 (57%) eyes with null RB1 mutations;, and low
penetrance mutations resulted in and inno tumors in 5/5 (100%)
infants and 10/10 (100%) eyes with low penetrance mutations
(p=0.04* for patients, p=0.02* for eyes; Fisher exact test) (Table
1).
The age at first tumor in either eye was significantly younger
for those with null mutations (mean 84, median 39 days), than those
with low penetrance mutations (mean 135, median 120 days) (P=0.03*,
Phi=0.38, Mood’s median test). However, the gestational age at
first tumor for those with null mutations (mean 71, median 33 days)
tended to be was younger but was not significantly different, than
for those with low penetrance mutations (mean 111, median 81 days)
(P=0.06, Phi=0.32, Mood’s median test). (Child #8 was excluded from
these calculations as the child was first examined at 3 months of
age with Group A/D tumors, so age at first detectable diagnosis
tumor is unknown.) (table 1c).
Stage Classification of Tumors Eyes at Birth
Thirty-three percent (3/9) of Cohort 1 and 75% (9/12) of Cohort
2 were free of visible tumor in either eye at birth (Table 1a,
Figure 1) (p=0.09). We assumed that child #8 had tumor at birth
since he had a group D IIRC17 eye at 3 months of age. Of eyes, 79%
(19/24) of Cohort 1 eyes were tumor-free at birth, compared to 33%
(6/18) of Cohort 2 eyes (p=0.026*, Chi Square test), excluding the
IIRC17 Group A eye of child #8, as above (Table 1b).
All patients eventually developed tumors in both eyes regardless
of whether their RB1 mutation was full or low penetrance. Tumors
emerged at a younger age first in the macular and peri-macular
region (IIRC17 Group B), as previously described20. The median
gestational age of diagnosis of 14 IIRC17 B eyes (all threatening
optic nerve and fovea, 6 also >3 mm) was 38 days, tended to be
younger than of the 103 days for 26 IIRC17 A eyes (< 3mm and
away from optic nerve and fovea) was 103 days, and of 14 IIRC17 B
eyes (all threatening optic nerve and fovea, 6 also >3 mm) was
38 days, which is younger reflecting the early development of
visually threatening tumors (P=0.32, Phi=-0.19, Mood’s median
test).
Bilateral IIRC17 Group A eyes were present at initial diagnosis
(optimal situation for achieving good vision with minimally
invasive therapy) in 2/9 (22%) children in Cohort 1 and compared to
8/12 (67%) in Cohort 2 (p=0.009*, Fisher exact test) (Table 2a).
IIRC17 Group A was the initial diagnosis of 9/18 (50%) eyes in
Cohort 1, and compared to 15/22 (77%) eyes in Cohort 2 (p=0.33,
Table 2a). One eye was an IIRC17 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.10 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 will havehad an examination under general anesthesia (EUA)
every two2-4 weeks. If there was any tumor at birth, the children
will havehad EUAs every two 2-4 weeks till until control of tumors.
Cohort 1 patients were treated with focal therapy (all),
chemotherapy (4), stereotactic radiation (2), and enucleation of
one eye (45) (Supplementary Table 1, Figures 1). Cohort 2 patients
were treated with focal therapy (all); later systemic chemotherapy
using vincristine, carboplatin, etoposide and cyclosporine (Toronto
protocol)(5), enucleation of one eye and stereotactic radiation (1)
(Figure 1). Comment by Gallie Brenda: Define the interval…? (mean,
median, range of intervals…… of EUAS???done
The Treatment burden showed no statistical significant
difference between Cohort 1 and 2 ina any of the four parameters
tested. The median active treatment duration was 458 days (0-2101
days) in Cohort 1, compared to 447 days (0-971 days) in Cohort 2
(p=1, Mood’s median test). 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 (P=0.67, Fisher exact
test) (Table 2b). The median number of EUAs in cohort 1 is 25
(range 18-81) and for cohort 2 is 29 (range 20-41) EUAs (p=1,
Mood’s median test). One child (11%) from Cohort one 1 had
developed extraocular orbital disease and still under active
treatment (P=0.4, Fisher exact test) (table 2b). Comment by Gallie
Brenda: DEFINITION??? How calculated? What are the numbers?
Definition of burden is now added in methods. It will not be in
numbers unless we want to develop a score but we will assess it
indirectly through the four mentioned parameters in the
methods.
OutcomesComment by Gallie Brenda: IS THIS NOT PART OF TREATMENT
(INTERVENTION) IMPACT SCORE?
There were no adverse effects associated with induced or natural
preterm or early term birth, and no pregnancy, delivery or
perinatal complications reported for any of the infants. Follow up
(years) was Overall mean Follow up (mean, median) of was overall 8,
5.6 years (median 5.6); years; Cohort 1, mean follow up was 8.4,
years (median 5.6), years; and Cohort 2, mean follow up was 7.6,
years (median 5.8 ), years (Supplementary Table 1).
Neither enucleation nor external beam irradiation were required
(defined as treatment success) in 44% of Cohort 1 and 92% of Cohort
2 (P=0.046*, Fisher exact test). Kaplan Meier ocular survival for
Cohort 1 was 6762% compared to 92% for Cohort 2 (Figure 2). All
children from both Cohorts are still alive; , only one child from
Cohort one 1 is still under active treatment.
Visual outcomes were good acceptable for 50% of eyes in Cohort 1
and 92% of eyes in Cohort 2 (P=0.014*, Fisher exact test). Children
were legally blind (visual acuity less than 20/200 using both eyes)
in 22% of Cohort 1 and 0% of Cohort 2 (p=0.017*, Fisher exact
test). Seventy one percent of eyes (17/24) of cohort 2 had final
visual acuity better than 20/40 compared to 50% (9/18) of eyes in
cohort one.Comment by Gallie Brenda: DEFINITION?? VA > 20/200
written in methods. But not clear with respect to LogMar or
1-LogMAR.Sameh: in methods it is written in both Snellen and
1-LogMAR
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 was found between
gestational age and final visual outcome (r=-0.24) with better
visual outcome in earlier deliveries. (Figure 3).
Discussion
In the first study of its kind, we report that prenatal
molecular diagnosis of familial retinoblastoma and elective
late-preterm or early term delivery allowed monitoring for, and
treatment of, tumors as they emerged, which resulted in better
ocular and visual outcomes and less severe medical interventions in
very young children. This data illustrates that for infants with
close to 100% risk of retinoblastoma in both eyes because they
carry an RB1 mutant allele, the risk of vision and eye loss despite
intensive therapies, 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. This reducedReduction to 25% when the
germline mutation is was prenatally detected and earlier delivery
(late preterm or early term) was plannedaccomplished.
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.3,9,21 When
the family's unique mutation is identified in the proband,
molecular testing of family members can determine who else carries
the mutation and is at risk to develop retinoblastoma. We report on
12 infants identified by in utero molecular testing to carry the
mutant RB1 allele of a parent. The 50% of tested infants who did
not inherit their family’s mutation require no surveillance, can be
born at full term and do not need examinations to detect tumors,
since they are at no greater risk of developing retinoblastoma than
the general population.
Without molecular information, repeated retinal examination is
recommended for all first degree relatives until age 7 years, the
first 3 years under general anesthesia.10 Multiple studies now
suggest deleterious effects of multiple general anesthetics in
early infancy on the neurocognitive development of the child.22-24
Such repeated clinical screening also imposes psychological and
financial burden on the children and families. Identification by
early molecular RB1 testing of the children who are not at risk and
require no clinical intervention cost significantly less than
direct costs than clinical screening for tumors.18,25
Optimal treatment for retinoblastoma includes combined
therapeutic modalities to optimize vision and minimize treatment
morbidity, while achieving tumor control. However, retinoblastoma
treatment in the first 3 months of life is a challenge since these
young children may not have sufficient renal function for full dose
systemic therapies. In our study child #9, who had a tumor at 36
weeks gestation large enough to detectfor detection by obstetrical
ultrasound, showed drug-resistant tumor following reduced-dose
chemotherapy, ultimately requiring enucleation of one eye.19 The
onlyGood treatment options at this age are limited to are focal
therapy (laser and cryotherapy) and periocular chemotherapy.26
The earliest tumors commonly involve the macular or paramacular
region, dangerously riskingthreatening loss of central vision,
while tumors that develop later on are usually peripheral, where
they have less visual impact.5,26-29 In our cohort, the risk of
having a vision threatening tumor dropped from 39% to 17% by
prenatal mutation detection and planned earlier delivery. Macular
and paramacular tumors are difficult to manage by laser therapy or
application of a radioactive plaque, since these will threaten
damage the optic nerve or and central vision. Systemic chemotherapy
effectively shrinks tumors such that focal therapy can be applied
with minimal visual damage. Systemic chemotherapy in neonates has
other associated morbiditiesis difficult due to the unknowns of
immature liver and kidney function to metabolize the drugs
increasing the potential of severe adverse effects. The . We
recognize 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; but the partial doses set up for development of
multidrug resistance proteins in the tumor cells that promote
chemotherapeutic drug efflux from tumor cells preventing drug
accumulation in tumor cells, making later recurrences difficult to
treat. 31-33 The development of Periocular topotecan for treatment
of small-volume retinoblastoma 34 also may increase the
effectiveness ofassisted in the number of patients that were able
to be treated by focal therapy. alone, avoiding systemic modalities
on the young infants, and a greater rate of eye salvage with good
visual outcome (Table 2).
Imhof et al{al 7 in the Netherlands screened 135 children at
risk of familial retinoblastoma 1-2 weeks after birth without
molecular diagnosis and discovered 17 cases of familial RB
retinoblastoma (13% of screened children at risk). and 70% of them
had RB in at least one eye at first examination and 41% of eyes had
vision threatening tumor to the macula. 41% (7/17) of patients had
failure of treatment (EBRT or enucleation) and one case of
metastasis. 73.5% of eyes (27/34) had good visual acuity (defined
by vision >20/100) that will reduce to 56% (19/27) if we
consider eyes with EBRT as failure. These results correspond to our
postnatal screening cohort showing similar results. On the
contrary, the prenatal diagnosis and planned earlier delivery
cohort showed less vision threatening tumors (17%), less treatment
failure (8%) and better visual outcome (88%).
Early screening of at risk infants with positive family history
as soon an possible after birth is the internationally accepted
model (whether intensive screening is utilized or not).7,35 Here we
propose the prenatal screening of the known mutation in the
probands by amniocentesis in the second half of pregnancy where the
risks of miscarriage are minimal (0.1-1.4%).36,37 For those who are
confirmed to have the mutation; planned late preterm or early term
delivery at 36-38 weeks of gestation and as a result a smaller
tumor with less macular involvement leading to better visual
outcome is anticipated. there was no difference between the two
Cohorts in the treatment burden and the systemic chemotherapy usage
as we didn't change the treatment course by early delivery but
changed the treatment outcome by catching the tumors at earlier
stage also multiple focal treatments in both Cohorts were for small
new tumors that occurred due to the nature of the germline tumor
and not related to early delivery or prenatal detection.
The main concern with late preterm or early term delivery is its
reported effect on neurological and cognitive development and later
school performance (30-32),13-15 but visual dysfunction from a
larger macular tumor can cause similar neurocognitive defects due
to blindness16 despite never studied in a comparative manner. So,
earlier delivery must be discussed thoroughly through the team of
neonatologist ophthalmologist and oncologist to reach the best
timing for better outcome{outcome 38 so rather than focusing on the
combination of treatments to tackle burdensome disease, we showed
safe preterm delivery resulted in a decreased tumor burden at birth
that was significantly easier to treat (Figure 2, Table 2). Safe
preterm delivery resulted in more infants born tumor-free,
facilitating frequent surveillance to detect tumors as they
emerged, and focal therapy of smaller, easier to control masses,
causing minimal damage to vision (Figure 1,2).
Counseling on reproductive risks is imperative for families
affected by retinoblastoma even in unilateral probands. In
developed countries; where current therapies result in extremely
low mortality, most retinoblastoma patients will survive to have
children. Prenatal diagnosis in the published literature has been
cited as useful in preimplantation genetics (to ensure an
unaffected child) or to inform parents who wish to terminate an
affected pregnancy{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{mutation 40, and in the other, 3 of 5 tested fetuses of a
proband were terminated once molecular testing confirmed the
mutation in the offspring.41 We are first to report that elective
safe late-preterm delivery of prenatally diagnosed infants with
retinoblastoma results in improved outcomes. It is our experience
that for retinoblastoma survivors and their relatives who
understand fully the underlying risks, they are more interested in
early diagnosis to optimize options for therapy in affected babies
rather than to consider 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. A long-term study could show the
impact of such an approach to patient outcomes in their adulthood.
We conclude that since infants with familial retinoblastoma are
likely to develop vision-threatening macular tumors, prenatal
molecular diagnosis and safe, late-preterm delivery will increase
the chance of good visual outcome with decreased treatment
associated morbidity.
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Table 1: Occurrence of tumors at birth according to the type of
RB1 mutation (Null vs Low penetrance mutation) in the whole child
(table 1a), eyes (table 1b) and prevalence of bilateral IIRC group
A tumors (table 1c).
Table 1a
Table 1b
Table 1c
Children with tumors at birth
Eyes with tumors at birth
Children with A/A eyes at first tumors
(child #8 included)
(excluding IIRC A eye of child #8 first examined at age 3
months)
(child #8 included)
YES
NO
total
% NO
YES
NO
total
% NO
YES
NO
total
% NO
Null RB1 mutation
9
7
16
44%
14
17
31
55%
6
9
15
60%
Cohort 1
5
2
7
9
6
15
1
6
7
Cohort 2
3
5
8
5
11
16
5
3
8
Low penetrance RB1 mutation
0
5
5
100%
0
10
10
100%
3
2
5
40%
Cohort 1
0
1
1
0
2
2
0
1
1
Cohort 2
0
4
4
0
8
8
3
1
4
Total
21
41
21
FET
p=0.04*
p=0.02*
p=0.61
Table 2: Outcome parameters for both groups per eye (table 2a)
and per child (table 2b) and their level of significance.
Table 2a: Outcome parameters per eye
Postnatal RB1 test (n=18)
Prenatal RB1 test (n=24)
P value
No
%
No
%
Tumor(s) at birth
10
0.56
5
21%
0.027*
Treatment success
11
0.61
22
92%
0.025*
Ocular salvage
13
0.72
23
96%
0.07
Visual Outcome
0.014*
Good vision
9
50%
21
88%
Poor Vision
9
50%
3
12%
Table 2b: Outcome parameters per child
Postnatal RB1 test (n=9)
Prenatal RB1 test (n=12)
P value
No
%
No
%
Tumor(s) at birth
6
67%
3
25%
0.087
IIRC AA at first tumor
1
11%
8
67%
0.009*
Treatment burden
0.67
Focal therapy only
4
44%
7
58%
Systemic chemotherapy
5
56%
5
42%
Treatment success
3
33%
11
92%
0.002*
Ocular salvage
4
44%
11
92%
0.046*
Extra-ocular disease
1
11%
0
0%
0.4
Visual Outcome
0.017*
Good vision
7
78%
12
100%
Blind
2
22%
0
0%
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.
Figure 2: Kaplan Meyer curves of treatment success showing a
significant treatment success in the prenatal RB1 detection group
versus the postnatal RB1 detection group.
Figure 3: A correlation between the Visual acuity at last follow
up (1-LogMAR) at Y axis and the gestational age at delivery in
weeks on X.axis showing a negative correlation.
Postnatal RB1
detection0.02.04.06.08.010.012.014.016.018.020.022.024.026.028.030.032.034.036.038.040.046.052.058.064.01.00.9444444444444450.9444444444444450.9444444444444450.9444444444444450.8888888888888890.7777777777777780.7777777777777780.7777777777777780.7777777777777780.7777777777777780.7777777777777780.7222222222222220.7222222222222220.7222222222222220.7222222222222220.7222222222222220.7222222222222220.7222222222222220.6666666666666670.6666666666666670.6666666666666670.6666666666666670.6111111111111110.611111111111111Prenatal
RB1
detection0.02.04.06.08.010.012.014.016.018.020.022.024.026.028.030.032.034.036.038.040.046.052.058.064.01.00.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.9166666666666660.916666666666666
37.037.036.037.037.037.040.040.040.040.040.028.032.037.037.037.037.038.040.028.032.034.034.036.036.037.037.036.037.038.036.040.036.039.039.037.036.036.040.040.040.037.01.31.11.01.01.01.01.01.01.01.01.01.01.00.90.90.90.90.90.90.90.90.80.80.80.80.80.6000000000000020.50.50.20.00.0-0.3-0.3-0.3-0.5-1.0-1.0-1.0-1.0-1.0-1.0
Gestational Age
20/20; 20/2528 29 30 31 32 33 34 35 36 37 38 39 401 2 3 4 5 6 7
8 9 10 20/20; 20/200320/20; E120/20; 20/20 820/20; 20/2520/30;
20/6020/600; 20/60910E;20/304
E(OS)
20/20,E 1120/15; 20/1020/50; 20/201320/20; 20/2515
Postnatal RB1testPrenatal RB1test
5.6 18 7.1 18 14.8 5.2 12.8 9.5 8.8 4.36.4
FU (y)
Spontaneous birth Induced birth Birth to first tumor
monthsweeks
E(OS)
20/25; 20/25173.26E;20/252.7
VA (OD, OS)
2 20/200*3.75
IIRC (OD, OS)
A, AC, BA, BA, BA, BB, A7A, B20/30; 20/302.8
(OS)
D, AB, BE; 20/20
E(OD)
2.4
(OU)
E(OD)
E; 20/40015.5 12141618192021A, A15.5 B, AB, B
(OU)
E(OD)
4.9B, BA, AA, AA, AB, BA, A20/25; 20/100B, B20/125; 20/25A,
A2.3
EUAs
25 41 24 22 21 3336 30302431 20304318 81 41 282123 22 20/20;
20/253.8 A, A
E(OD)
M
E
Focal Therapy Chemotherapy Radiotherapy Enucleation
MMetastasis
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
Postnatal RB1 test
Prenatal RB1 test
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
months
weeks
E(OS)
20/25; 20/25
17
3.2
6
E; 20/25
2.7
VA (OD, OS)
2
20/200*
3.7
5
IIRC (OD, OS)
A, A
C, B
A, B
A, B
A, B
B, A
7
A, B
20/30; 20/30
2.8
(OS)
D, A
B, B
E; 20/20
E(OD)
2.4
(OU)
E(OD)
E; 20/400
15.5
12
14
16
18
19
20
21
A, A
15.5
B, A
B, B
(OU)
E(OD)
4.9
B, 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
EUAs
25
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)
M
E
Focal Therapy
Chemotherapy
Radiotherapy
Enucleation
M
Metastasis
Figure 1. Tumor timing, therapy and outcomes. Patients in each
of the postnatal and prenatal retinoblasotma detection shown by
gestational age at birth, international intraocular retinoblastoma
classification (IIRC), treatment at time of first tumor occurrence
and subsequently, final visual outcome and total follow-up
time.
9