improved visual outcome in familial retinoblastoma with ... · web viewfull-term infants received...
TRANSCRIPT
Improved visual Outcome outcome in familial retinoblastoma with late
preterm or early term delivery after prenatal RB1 mutation identification.
Helen Dimaras, Ph.D., Sameh E. Soliman, M.D., ** Vikas Khetan, M.B. B.S.*, Elise Héon,
M.D., F.R.C.S.C., Helen S.L. Chan, M.B. B.S., F.R.C.S.C., Brenda L. Gallie, M.D., F.R.C.S.C.
From the Department of Ophthalmology & Vision Sciences (H.D., E.H., B.L.G.), Pediatrics
(H.S.L.C.), Molecular Genetics and Medical Biophysics (B.L.G.), University of Toronto,
Toronto, Ontario, Canada; the Division of Hematology/Oncology (H.D., H.S.L.C.) and
Departments of Ophthalmology & Vision Sciences (E.H., B.L.G., V.K.) and Pediatrics
(H.S.L.C.), The Hospital for Sick Children, Toronto, Canada; the Division of Visual Sciences,
Toronto Western Research Institute, Toronto, Canada (H.D., B.L.G.); and the Campbell Family
Institute for Cancer Research, Princess Margaret Hospital (B.L.G.), Toronto, Canada. *Current
Affiliation: Sankara Nethralya Hospital, Chennai, India.
**Ophthalmology Department, Faculty of Medicine, Alexandria University
Address reprint requests to Dr. Brenda Gallie at the Campbell Family Institute for Cancer
Research, Ontario Cancer Institute/Princess Margaret Hospital, Room 8-415, 610
University Avenue, Toronto, ON M5G 2M9, Canada, or at [email protected].
Running Head: early delivery of familial RB.
Key Words: prenatal retinoblastoma, Retinoblastoma gene mutation, RB1, molecular testing, late
pre-term delivery, near-term delivery, amniocentesis
Submitted as Original Article to JAMA ophthalmology.
Abstract
Purpose: To study the ocular and visual outcomes of infants with familial retinoblastoma when
they are prenatally molecularly diagnosed and safely delivered preterm to initiate treatment, and
compare to outcomes of those diagnosed postnatally.
Methods: A retrospective study of Sickkids medical records documented children born between
1 June 1996 and 1 June 2014, seen at Sickkids because of relation to a retinoblastoma proband.
Patients who inherited their family’s RB1 mutation were included in this study. Data collected
included: relation to proband; sex; gestational age at birth; pregnancy or delivery complications;
date of RB1 molecular testing, type of sample tested and result; timing and location of first and
all subsequent tumor appearance(s) in each eye; treatment history; International Intraocular
Retinoblastoma Classification of each eye; laterality; Tumour Node Metastasis staging; date of
last follow-up; and visual outcome.
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 and 3
were born spontaneously preterm. Immediate postnatal examination revealed vision-threatening
tumors present only in 25% (3/12) of infants prenatally diagnosed, compared to 67% (6/9) of
those diagnosed postnatally. All patients eventually developed tumors in both eyes. Good vision
was maintained in all prenatally diagnosed patients; 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 poorer visual outcome.
Conclusion: Expedient intervention and optimal outcomes were facilitated by prenatal molecular
detection coupled with safe late preterm and near term delivery.
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
Familial retinoblastoma tends to be discovered earlier during the first six months if properly
screened and children with germline null alleles might have retinoblastoma tumor(s) already at
birth, which are often in the posterior pole of the eye (where they threaten vision4-7 + munier
ref), ). Most of these children will develop more tumors in the first year of life, which tend to be
located in more peripheral to the macular area. The 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 vision. The child is bilaterally affected in either simultaneous or sequential
involvement. 4,7 Low penetrance mutations (10% of cases)3 can cause low burden of disease with
fewer tumors and higher unilaterally affected children8. The timing of first tumors after birth has
not been studied.
Infants in families with a history of retinoblastoma are recommended to be screened as soon
as possible after birth, and then repeatedly for the first few years of life, including under
anaesthesia, aiming at early diagnosis when tumors are small and easy to treat with ocular and
visual salvage. (6-7) 6,7
Preterm birth is defined as a live birth occurring before completion of 37 weeks gestation.
Subcategories of preterm birth include: extremely preterm (<28 weeks gestation), very preterm
(28 to <32 weeks) and moderate-to-late preterm (32 to <37 weeks). 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). 9,10 The main concern
with late preterm or early term delivery is its reported effect on neurological and cognitive
development and later school performance ,11-13 but visual dysfunction from a larger macular
tumor can cause similar neurocognitive defects due to blindness14 despite never studied in a
comparative manner.
We now present the first report 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 allowed detection and treatment of small,
early tumors, resulting in lower treatment morbidity, better tumor control and visual outcome,
compared to those born full term at 40 weeks.
Methods
Study Design
Research ethics board approval (REB approval number 1000028725) was obtained from
The Hospital for Sick Children (SickKids). A retrospective study of medical records of all
children with familial retinoblastoma seen at SickKids medical records documented children
diagnosed with retinoblastomaand born between 1 June 1996 and 1 June 2014, seen at SickKids
with relation to a retinoblastoma proband. Data collected included: relation to proband;
laterality of RB retinoblastoma in proband; sex; gestational age at birth; birth dateage;
pregnancy, prenatal abdominal ultrasound if done; delivery or perinatal complications; date of
molecular testing, type of sample tested and result; type of penetrance of mutaion detected;
timing and location of first and all subsequent tumor (s)appearance(s) in each eye; treatment
history; number of anaesthetics; International Intraocular Retinoblastoma Classification of each
eye (IIRC); (Murpheree paper)Tumor Node Metastasis (TNM) staging; date of last treatment;
date of last follow-up; and visual outcome at last follow-up in Snellen and LogMAR values. If
any of the above data was not explicitly noted in the medical record, it was deduced from the
available clinical information.
RB1 mutation testing was performed by Retinoblastoma Solutions before 2013, and Impact
Genetics after 2013, as previously described.15
The corrected age for gestation for each child was calculated (taking 39 weeks as full term).
Eyes with vision threatening tumor was defined any tumor involving the macular area i.e. IIRC
group B (in posterior pole) or higher. Treatment burden was evaluated by an impact score
ofbased on i) duration of active treatment (time from diagnosis till last treatment), and ii) adding
systemic chemotherapy to the focal therapies. And , and iii) number of examinations under
anesthesia (EUAs). Treatment success was defined as avoidance of enucleation or external beam
irradiation. Good visual outcome was defined as visual acuity > 20/200 (???? (>0 in 1-LogMAR
scale) (cut edge of legal blindness). A blind child is defined by as best eye visual acuity < 20/200
in both eyes (<0 in 1-LogMAR scale). or only eye if one is enucleated). For proper statistical
analysis, (1-LogMAR visual acuity) value will be used to describe best corrected visual acuity
for each eye.
Statistics
Basic descriptive statistics were used for all comparisons between patients who underwent
prenatal testing and preterm delivery and those who were diagnosed post-natally.
Results
Patient Demographics
During the period studied, we reviewed Tthe files records of 21 familial retinoblastoma
children were reviewed (11 males, 10 females). Twelve children (57%) were prenatally
diagnosed to carry an RB1 mutation and planned to be deliveredfor late preterm or early term
delivery. Three of these were spontaneously premature (Patients 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). The molecular diagnosis was confirmed performed
postnatal in 9 children (43%). In these children, 6 were delivered at full term and 3 were
delivered late preterm due to pregnancy-induced hypertension (1), fetal ultrasound evidence of
retinoblastoma (1) or spontaneous (1). (Table 1)
Molecular diagnosis
All study subjects were offspring of retinoblastoma probands. Nineteen probands were
bilaterally, and 2 were unilaterally affected (mother child 8, father child 19). The familial RB1
mutations were previously detected and known except for the unilaterally affected parent of child
8, whose mutation was discovered identified after finding her son’s mutation as she was tested
previously and considered to be a non germline mutation. Childrens 1-9 were tested post-natally
in blood; one child inherited a low penetrance mutation; while,. Childrens 10-21 were tested
prenatally on amniocentesis at 16-33 weeks gestation; four children had low penetrance
mutations (Table 1).
Tumors at Birth
The aim of elective preterm delivery is to diagnose tumors early in their development, as they
emerge and are easy to control. In the prenatally diagnosed cohort, 75% (9/12) were free of
visible tumor at birth (Figure 1); 33% (3/9) of patients postnatally detected were tumor free at
birth (p=0.09). After excluding the low penetrance mutation cases (which by definition results in
a lesser burden of disease), 58% (3/8) of prenatally detected full penetrance mutations and 25%
(2/8) of patients with were tumor-free at birth (p=0.31) (Table 2). Only one patient was not seen
at birth (Case 8) and was seen at 3 months with bilateral RB but as one eye had a group D IIRC
eye it was assumed that he had tumor at birth.
Looking at the numbers on a per eye basis, 79% (19/24) of eyes in prenatally diagnosed
babies were free of tumor at birth, compared to 33% (6/18) of postnatal diagnosed babies
(p=0.026*) (Table 2b).
All patients eventually developed tumors in both eyes regardless of the mutation whether full
or low penetrance. Tumors emerged first in the macular and peri-macular region. By the
International Intraocular Retinoblastoma Classification,16 58% (7/12) of prenatally diagnosed
infants had bilateral Group A eyes at the time of initial tumor development in each eye (the
classification that denotes the lowest level of tumor involvement, free foveal center and hence
least visual threat), compared with only 22% (2/9) of postnatally diagnosed infants (Table 2a). on
a per eye basis 39% (7/18) of postnatally diagnosed cohort eyes were visually threatening in
comparison with 17% (4/24) in the prenatal diagnosis cohort eyes (p=0.15)
The mean age at first tumor showed statistical significant difference between full penetrance
and low penetrance mutation eyes (90 days versus 134 days respectively, P=0.04*), after
correcting the age for the gestational age (as some of them were preterm), the mean age at first
tumor became 79 days versus 110 days respectively, p=0.24. (Case eight were excluded from
this calculations as the child presented at 3 months of age)
Treatment Course
All infants were frequently examined from birth onwards (except case 8 that presented at 3
months) as per the National Retinoblastoma Strategy Guidelines for Care.17 For patients who
were prenatally diagnosed and delivered late preterm or early term, treatments included focal
therapy (all); later systemic chemotherapy (5), enucleation of one eye and stereotactic radiation
(1) (Figure 1, 2). Postnatally diagnosed infants received focal therapy (all), chemotherapy (4),
stereotactic radiation (2), and enucleation of one eye (4) (Figure 1, 3). Successful treatment by
focal therapy alone (avoidance of systemic chemotherapy) was possible in 58% of prenatally
diagnosed babies (7/12) compared with only 22% (2/9) of postnatally diagnosed infants (Table
2a, Figure 2).
The treatment burden showed no statistical significant difference between those prenatally or
postnatally diagnosed (percentage of patients requiring systemic therapy and active treatment
duration). The mean active treatment duration was 579 days (0-2101 days) in the postnatal
detection group compared to 473 days (0-971 days) in the prenatal detection group.
Outcome
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. Overall
mean follow up was 8 years (median 5.6 years) (Table 1).
Treatment success
92% of prenatally diagnosed mutation patients didn’t require either enucleation or external
beam irradiation in comparison to 44% in the postnatally diagnosed mutation patients
(P=0.046*, Fisher exact test). Kaplan Meier ocular survival graph for prenatal versus postnatal
diagnosis is shown in figure it is estimated at 67% in postnatal cohort compared to 92% in the
prenatal cohort at 4 years. None of the cases developed extra ocular or metastatic disease and all
of them are alive at the end of the study.
Visual outcome
As per eye, 92% of eyes of the prenatal detection and planned earlier delivery were of good
visual outcome compared to 56% of eyes in the postnatal detection; a difference found to be
statistically significant (P=0.010*, Fisher exact test). As per child, 22% of children in the
postnatal detection group were considered blind (visual acuity less than 20/200 both eyes) in
comparison none of the patients in the prenatal detection group (p=0.174, Fisher exact test)
Treatment success (avoidance of enucleation and/or stereotactic radiation) accompanied with
resultant good vision was documented for 88% (21/24) eyes in the prenatal diagnosis cohort,
compared to 50% (9/18) of eyes from the postnatal diagnosis cohort with significant difference
(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 )
Discussion
In the first study of its kind, we report that prenatal molecular diagnosis of familial
retinoblastoma was possible, and that elective late-preterm or early term delivery allowed
monitoring and treatment of tumors as they emerged, resulting in better ocular and visual
outcomes. Our cases illustrate well that the risk of visual loss from delayed therapy for macular
retinoblastoma tumors outweighs the risks associated with induced late preterm delivery (Figure
1).
With the most current technologies, it is practical to identify 96% of the germline mutations
in bilaterally affected probands, and to identify the 10% of unilateral probands who carry a
germline gene mutation by studying the tumor .17 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 of developing the disease. We reported on in utero testing that
identified 12 mutation carriers, but did not include the number of infants tested who did not
inherit their family’s mutation. These infants can go to full term and do not need examination to
detect retinoblastoma tumors, since they are at no greater risk of developing the disease than the
general population. Without molecular information, repeated retinal examination is essential for
all first degree relatives until the age of 7 years, the first 3 years under general anesthesia.17 Such
repeated screening can be a great burden on patients and their families, finances, time and
resource utilization than the one-time-only molecular genetic testing that would conclusively
determine their risk.4 Also multiple studies18-20 showed the deleterious effects of multiple
anesthesias in early infancy on the neurocognitive development of the child.
Optimal treatment for retinoblastoma today includes combined therapeutic modalities to
optimize vision and minimize morbidity of treatment, while achieving tumor control; the relative
ease or difficulty of this task is affected by the age and the degree of tumor burden at diagnosis.21
Retinoblastoma treatment in the first 3 months of life represents a challenge as most of the
therapeutic modalities as systemic chemotherapy, chemosurgery or radiation therapy can’t be
used. The only treatment options at this age are focal therapy (laser and cryotherapy) and
periocular chemotherapy. 22 Consistent with previous reports,5 we showed that 62% of children
with a germline gene mutation already have tumors at birth. This percentage reduces to 31%
when the germline mutation is prenatally detected and earlier delivery (late preterm or early
term) was planned.
The earliest tumors commonly involve the macular or paramacular region, dangerously
risking loss of central vision, while tumors that develop later on are usually peripheral, where
they have less visual impact.5,22-25 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 damage the optic nerve or central vision. Systemic
chemotherapy effectively shrinks tumors such that focal therapy can be applied with minimal
visual damage. In our setting, the Toronto Protocol using high dose, short duration cyclosporine
to counteract multidrug resistance26,27 has allowed many retinoblastoma tumors to be treated with
combination chemotherapy and focal therapy without resorting to radiation. In our experience,
infants as young as 30 days tolerate the Toronto Protocol with cyclosporine A, 26,27 however
systemic chemotherapy in neonates has other associated morbidities. We recognize the
conventional recommendation to reduce chemotherapy dosages by 50%, particularly for infants
in the first three months of life, to offset the immaturity of their liver and kidneys,28-30 but note
that this also breeds the optimal conditions for cancer cells to develop multidrug resistance,
making later recurrence difficult to treat. The development of periocular topotecan for treatment
of small-volume retinoblastoma31 also assisted 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 al7 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 (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).7,32 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%).33,34 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 groups 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 groups 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),11-13 but visual
dysfunction from a larger macular tumor can cause similar neurocognitive defects due to
blindness14 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 outcome21 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 pregnancy35. 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 mutation36, and in the other, 3 of 5 tested fetuses
of a proband were terminated once molecular testing confirmed the mutation in the offspring.37
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.
References
1. Corson TW, Gallie BL. One hit, two hits, three hits, more? Genomic changes in the development of retinoblastoma. Genes Chromosomes Cancer. 2007;46(7):617-634.
2. Dimaras H, Khetan V, Halliday W, et al. Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet. 2008;17(10):1363-1372.
3. Lohmann DR, Gallie BL. Retinoblastoma. In: Pagon RA, Adam MP, Ardinger HH, et al., eds. GeneReviews(R). Seattle (WA)2000.
4. Abramson DH, Du TT, Beaverson KL. (Neonatal) retinoblastoma in the first month of life. Arch Ophthalmol. 2002;120(6):738-742.
5. Abramson DH, Mendelsohn ME, Servodidio CA, Tretter T, Gombos DS. Familial retinoblastoma: where and when? Acta Ophthalmol Scand. 1998;76(3):334-338.
6. Noorani HZ, Khan HN, Gallie BL, Detsky AS. Cost comparison of molecular versus conventional screening of relatives at risk for retinoblastoma. Am J Hum Genet. 1996;59(2):301-307.
7. Imhof SM, Moll AC, Schouten-van Meeteren AY. Stage of presentation and visual outcome of patients screened for familial retinoblastoma: nationwide registration in the Netherlands. Br J Ophthalmol. 2006;90(7):875-878.
8. Rushlow D, Piovesan B, Zhang K, et al. Detection of mosaic RB1 mutations in families with retinoblastoma. Hum Mutat. 2009;30(5):842-851.
9. ACOG Committee Opinion No 579: Definition of term pregnancy. Obstet Gynecol. 2013;122(5):1139-1140.
10. Born Too Soon: The Global Action Report on Preterm Birth. Geneva: World Health Organization;2012.
11. Cheong JL, Doyle LW. Increasing rates of prematurity and epidemiology of late preterm birth. Journal of paediatrics and child health. 2012;48(9):784-788.
12. Woythaler MA, McCormick MC, Smith VC. Late preterm infants have worse 24-month neurodevelopmental outcomes than term infants. Pediatrics. 2011;127(3):e622-629.
13. Poulsen G, Wolke D, Kurinczuk JJ, et al. Gestational age and cognitive ability in early childhood: a population-based cohort study. Paediatr Perinat Epidemiol. 2013;27(4):371-379.
14. Bedny M, Saxe R. Insights into the origins of knowledge from the cognitive neuroscience of blindness. Cogn Neuropsychol. 2012;29(1-2):56-84.
15. Richter S, Vandezande K, Chen N, et al. Sensitive and efficient detection of RB1 gene mutations enhances care for families with retinoblastoma. Am J Hum Genet. 2003;72(2):253-269.
16. Murphree AL. Intraocular retinoblastoma: the case for a new group classification. Ophthalmology clinics of North America. 2005;18:41-53.
17. National Retinoblastoma Strategy Canadian Guidelines for Care / Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol. 2009;44(Supp 2):S1-88.
18. DiMaggio C, Sun LS, Ing C, Li G. Pediatric anesthesia and neurodevelopmental impairments: a Bayesian meta-analysis. Journal of neurosurgical anesthesiology. 2012;24(4):376-381.
19. Ing C, DiMaggio C, Whitehouse A, et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics. 2012;130(3):e476-485.
20. Wilder RT, Flick RP, Sprung J, et al. Early exposure to anesthesia and learning disabilities in a population-based birth cohort. Anesthesiology. 2009;110(4):796-804.
21. Dimaras H, Kimani K, Dimba EA, et al. Retinoblastoma. Lancet. 2012;379(9824):1436-1446.22. Gombos DS. Retinoblastoma in the perinatal and neonatal child. Semin Fetal Neonatal Med.
2012;17(4):239-242.23. Abramson DH, Gamell LS, Ellsworth RM, et al. Unilateral retinoblastoma: New intraocular
tumours after treatment. Br.J.Ophthalmol. 1994;78(9):698-701.24. Abramson DH, Greenfield DS, Ellsworth RM. Bilateral retinoblastoma. Correlations between age
at diagnosis and time course for new intraocular tumors. Ophthalmic Paediatrics And Genetics. 1992;13(1):1-7.
25. Abramson DH, Servodidio CA. Retinoblastoma in the first year of life. Ophthalmic Paediatrics And Genetics. 1992;13(4):191-203.
26. Salmonsen PC, Ellsworth RM, Kitchen FD. The occurrence of new retinoblastoma after treatment. Ophthalmology. 1979;86:840-843.
27. Gallie BL, Budning A, DeBoer G, et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol. 1996;114(11):1321-1328.
28. Chan HS, DeBoer G, Thiessen JJ, et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Clin Cancer Res. 1996;2(9):1499-1508.
29. Campbell AN, Chan HS, O'Brien A, Smith CR, Becker LE. Malignant tumours in the neonate. Arch Dis Child. 1987;62(1):19-23.
30. Crom WR, Glynn-Barnhart AM, Rodman JH, et al. Pharmacokinetics of anticancer drugs in children. Clin Pharmacokinet. 1987;12(3):168-213.
31. Mallipatna AC, Dimaras H, Chan HS, Heon E, Gallie BL. Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol. 2011;129(6):738-745.
32. 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.
33. Akolekar R, Beta J, Picciarelli G, Ogilvie C, D'Antonio F. Procedure-related risk of miscarriage following amniocentesis and chorionic villus sampling: a systematic review and meta-analysis. Ultrasound in obstetrics & gynecology : the official journal of the International Society of Ultrasound in Obstetrics and Gynecology. 2015;45(1):16-26.
34. 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.
35. 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.
36. Lau CS, Choy KW, Fan DS, et al. Prenatal screening for retinoblastoma in Hong Kong. Hong Kong Med J. 2008;14(5):391-394.
37. Castera L, Gauthier-Villars M, Dehainault C, et al. Mosaicism in clinical practice exemplified by prenatal diagnosis in retinoblastoma. Prenatal Diagnosis. 2011;31(11):1106-1108.
Figures
Tables