Retinoblastoma
Helen Dimaras1, Tim W. Corson2, David Cobrinik3, Abby White4, Junyang Zhao5, Francis L. Munier6, David H.
Abramson7, Carol L. Shields8, Guillermo L. Chantada9, Festus Njuguna10 and Brenda L. Gallie11
1| Department of Ophthalmology & Vision Sciences, The Hospital for Sick Children& University of Toronto, Toronto, Canada2| Eugene and Marilyn Glick Eye Institute, Departments of Ophthalmology, Biochemistry and Molecular Biology, and Pharmacology and Toxicology, and Simon Cancer Center,Indiana University, Indianapolis, USA3| The Vision Center and The Saban Research Institute Children's Hospital Los Angeles, Los Angeles, CA USA; and Department of Ophthalmology, Department of Biochemistry and Molecular Biology, The USC Eye Institute, and Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA4| Daisy's Eye Cancer Fund, Oxford, UK5| Department of Ophthalmology, Beijing Children’s Hospital, Capital Medial University, Beijing, China6| Department of Ophthalmology, Jules-Gonin Eye Hospital, Lausanne, Switzerland7| Department of Ophthalmlogy, Memorial Sloan Kettering Cancer Center, New York, USA8| Ocular Oncology Service, Wills Eye Hospital, Philadelphia, USA9| Hospital JP Garrahan, Buenos Aires, Argentina10| Department of Pediatric Oncology, Moi Teaching & Referral Hospital, Eldoret, Kenya11| Department of Ophthalmology & Vision Sciences, The Hospital for Sick Children& University of Toronto, 555 University Ave, Toronto, Ontario M5G1X8, Canada
Abstract 174/200
The genetic basis of human malignancy was determined through the study of retinoblastoma, a rare cancer of
infant retina. Tumours form when both RB1 alleles mutate in a susceptible retinal cell, likely a cone
photoreceptor precursor. The tumour suppressor functions of the retinoblastoma protein, pRB, relate to cell
division and genomic stability, but the key biochemical and molecular basis of tissue specificity remain
unknown. Retinoblastoma is diagnosed in 8,000 children each year worldwide, yet patient survival is >95% in
high-income countries, but <30% globally, depending on the socio-economical context. Stakeholder
collaboration is improving outcomes by increasing awareness for earlier diagnosis, sharing expertise, and
developing guidelines. Intra-arterial and intra-vitreal chemotherapy have emerged as a promising way to salvage
eyes. Ongoing international collaboration will replace the multiple different classifications of eye involvement
with standardized definitions that will facilitate assessment of eligibility, efficacy and safety of treatments.
Heritable retinoblastoma survivors are at risk for second cancers; defining the molecular basis of RB1 retinal
specificity may explain tissue specificity of second cancers, opening the path to cancer prevention.
Keywords
retinoblastoma, pediatric oncology, pediatric ophthalmology, tumour suppressor gene, RB1 gene, MYCN
oncogene, Systemic chemotherapy, Intra-arterial chemotherapy, Intra-vitreal chemotherapy, Cone
photoreceptor, Cancer therapy, Global health
Competing interests
There is NO competing interest.
[H1] Introduction(BLG) 291/300
Retinoblastoma is a rare cancer initiated by biallelic mutation of the retinoblastoma gene (RB1) in a single
susceptible developing retinal cell. Inheritance of one mutant RB1 allele strongly predisposes to retinoblastoma
tumours that form when the second RB1 allele is mutated.1 Although RB1 loss initiates cancer in specific
susceptible tissues, it is lost with progression in almost all human cancers.2 The principals discovered by study
of retinoblastoma led to the recognition that altered genes broadly underlie cancer initiation and progression.
Retinoblastoma starts when the second RB1 allele is damaged in susceptible retinal cell (RB1-/-) that undergoes
limited proliferation to form a non-malignant retinoma (Figure 1).3 An intra-retinal tumour develops after
genomic changes lead to uncontrolled proliferation — most commonly, the white tumour is visible through the
pupil (leukocoria) (Figures 3, 9) or blocks vision.4 When noticed early, prompt treatment usually cures. Delayed
diagnosis can lead to incurable invasion of the optic nerve and brain, or metastasis, sometimes cured by
extensive intervention.
Rigorous clinical trials in retinoblastoma are difficult for multiple reasons: too few patients in high-income
countries; often complex presentation (two eyes with differing severity); too few patients to interest the
pharmaceutical industry; multidisciplinary collaboration required; and high societal value on eyes and vision
imposes considerations beyond curing the cancer. New technologies showing dramatic primary treatment
response have been quickly embraced, without rigorous clinical trials.
The Internet has opened many avenues: parents diagnose retinoblastoma themselves; colleagues share patients
around the globe; centres of excellence are mapped (Figure 2); and a common database for all children no
matter where they live is within reach. These developments are set to empower a learning health system that
build and evidence base for care. This retinoblastoma Primer introduces unprecedented new science, ideas,
therapies and global collaboration.
[H1] Epidemiology (HD,GC, JZ, FN) 769/500
[H2] Global patients, resources and outcomes
The expected number of patients with retinoblastoma annually per country can be calculated by multiplying the
global retinoblastoma incidence (1 in 16,000-18,000 live births) by forecast births (Table 2).5-7 This predicts
approximately 8,000 new cases each year.
Of all affected children, 11% reside in high-income, 69% in middle-income and 20% in low-income countries.
Although the prevalence is higher in middle- to low-income countries, most retinoblastoma treatment centres are
in middle- and high-income countries, creating a gap in healthcare access (Figure 2). Consistent with income
being a surrogate for non-economic measures of standard of living, retinoblastoma in low-income countries is
associated with low patient survival (~30%8, 9) compared with high-income countries (>95%10), but
comprehensive nation-wide data is lacking.
Poor outcome correlates with late presentation, difficulty accessing retinoblastoma-specific health care, and
socio-economic issues leading to poor compliance, including family refusal to remove the affected eye and
abandonment of therapy.11-13 Without timely diagnosis and appropriate treatment, difficult-to-cure metastatic
disease may occur. Fortunately, with early diagnosis, many eyes can be safely treated to support a lifetime of
good vision, pointing to key elements for global focus: awareness, collaboration, and affordable expert care.
[H2] Solutions for global retinoblastoma
A number of initiatives address the inequality in retinoblastoma treatment between developing and developed
worlds. In 2009, the Canadian National Retinoblastoma Strategy (NRbS) published the first-ever retinoblastoma
clinical practice guidelines,10 adapted by the Kenyan National Retinoblastoma Strategy (KNRbS) and published
in 2014 in partnership with the Kenyan Department of Health.14 The KNRbS achieved standardization of
pathology processing and reporting to support treatment decisions and discussion of prognosis with families.
Adoption of upfront (first-line) enucleation with implants and immediate prosthetic eyes (sourced from India),
parent to parent interactions to allay uninformed fears, and standardization of information provided to parents
has reduced the rate of non-compliance with treatment.14, 15 In 2013, the Paediatric Oncology in Developing
Countries Committee of the SIOP (International Society of Paediatric Oncology) published a consensus
guideline for the management of retinoblastoma in countries with limited resources16 with clear ideas that can
shape resource development. The Mexican National Strategy17 and the Brazilian SOBOPE (Brazilian Society of
Pediatric Oncology)18 guidelines are also applicable at a national level with governmental support for treatment.
Peer-to-peer collaborations and twinning programmes have built a framework for knowledge and expertise
exchange, filling gaps in specialized training, and source donations of equipment and resources with the ultimate
aim of sustainable local capacity.19 Retinoblastoma-specific twinning programmes include partnerships between
St. Jude’s Children’s Research Hospital (USA) and the Middle-East,20 Central America21 and Mexico,17and
between the Institut Curie and a centre in Bamako, Mali.22 The Central American Association of Pediatric
Hematology Oncology (AHOPCA) created a cooperative group and implemented multicentre protocols for
retinoblastoma treatment,21, 23, 24 a major achievement, not yet paralleled in developed countries. The AHOPCA
funding is now 90% local. Twinning programmes benefit from strong participation of both non-governmental
and governmental organizations. However, where government may prove volatile and unpredictable, sustainable
local capacity is a challenge. Less formal cooperation between developed and less developed countries can also
result in highly efficient programmes.25, 26
A successful national strategy has been developed in China. About 1,100 newly diagnosed cases are forecast
annually, scattered over 32 provinces, imposing high travel costs. Before 2005, enucleation was the only
available treatment for most children. For better treatment options and follow-up, centres classified by expertise
and resources were established in 28 hospitals covering 25 provinces (over 90% of the population)27. The
improved efficiency and collaboration from 2006 to 2014 has led to standardized classification and treatment of
2,097 newly diagnosed patients with retinoblastoma on common protocols with gains in survival (unpublished
data, JZ). In Argentina, a single centre with high expertise coordinates affiliated retinoblastoma clinics. This
collaboration between governmental hospitals, local and international NGO’s with prospective protocols has
significantly improved survival in two decades.28 In addition, translational research and population-based
incidence and survival studies are reported.29, 30
In a rapidly changing world, Internet based strategies are opening up global collaboration. The One
Retinoblastoma World map (Figure 2) leads families to the nearest centre with known expertise. The
retinoblastoma-specific point-of-care database (eCancerCareRB, eCCRB) summarizes the medical record for
retinoblastoma for each child (Figures 3, 4 and 9). eCCRB on the Internet is freely accessible to every
retinoblastoma centre with local ethics and privacy approvals. The Disease-specific, electronic Patient
Illustrated Clinical Timeline (DePICT) is language-independent, well understood by parents, and supports fully
informed care choices.31 With guardian consent, fully identified data is accessible to those in the circle of care of
each child. Ultimately, the de-identified data will be fuel for a learning health system.
[H1] Mechanisms/pathophysiology (TWC, DC, BLG) 1069/1500
The search for the genetic basis of retinoblastoma provided the two-hit model of tumor suppressor gene
inactivation. In 1971, Knudson discovered that the age of diagnosis of retinoblastoma is consistent with one
rate-limiting event in bilaterally affected patients (who have heritable disease), and two events in unilaterally
affected patients with no family history (usually non-heritable).32 Others proposed that heritable retinoblastomas
result from a germline mutation (‘first hit’) and an acquired somatic mutation (‘second hit’), and non-heritable
retinoblastomas arise when two somatic mutations in the same transformation suppressor gene in a susceptible
cell (Figure 4).33 Chromosomal deletions in some patients pointed to a chromosome 13q14 locus. Loss of
heterozygosity of 13q14 polymorphic markers in 70% of retinoblastoma tumours34 implied that the second hit
involved the same locus. The breakthrough came when one retinoblastoma was missing the sequence of a 13q
DNA clone,35 that turned out to be a conserved, exonic sequence of RB1.35-38
RB1 is a large (190 kb) gene with 27 exons, encoding a 4.7 kb mRNA that translates into a 928 amino acid
protein, pRB. Many modifications impair pRB function, including point mutations, promoter methylation, and
small and large deletions.39 The A/B “pocket” region40 harbours most missense mutations.
The pRB functions that normally suppress retinoblastoma within the retina remain unknown. pRB is best known
as a cell cycle regulator that binds to E2F transcription factors to repress cell proliferation-related genes.
Hyperphosphorylation of pRB by cyclin-dependent kinases in response to mitogenic signals normally relieves
repression and promotes the G1 to S phase transition. pRB loss relieves this suppression in the absence of
mitogenic signals to enable tumourigenesis. It is tempting to speculate that pRB is primarily needed to suppress
E2F.40, 41 Several “low penetrance” RB1 mutations encode proteins with minimal ability to bind E2F, that that
result in fewer tumours than RB1 null alleles.42, 43 Such defective E2F-binding alleles may function to block
retinoblastoma development through an E2F-independent mechanism. pRB also up-regulates p27, implicated in
cell differentiation, apoptosis, and genomic integrity.40 Increased pRB expression is associated with decreasing
p27 during cone precursor maturation.41 pRB N-terminus functions may also be important.44, 45
Biallelic RB1 inactivation is necessary to initiate most retinoblastomas, but is not sufficient; the benign retinal
lesion, retinoma, has lost both RB1-/- alleles (Figure 4).3 Further genetic or epigenetic changes are likely needed
for malignant transformation.46 Comparative genomic hybridization studies identified several candidate
retinoblastoma oncogenes (mitotic kinesin KIF14 and p53 regulator MDM4 (1q32), transcription factors E2F3
and DEK (6p22), and the onco-miR clusters miR-106b~25 (7q22.1) and miR-17~92 (13q31)) and the cadherin-
11 (CDH11) tumour suppressor gene (16q22 loss). Whole-genome sequencing identified inactivating mutations
in the transcriptional corepressor BCOR.47 Epigenetic alterations might drive retinoblastoma formation by
inducing H3K4me3 and H3K9/14ac marks and expression of the SYK oncogene.47 Other genes and microRNAs
also show altered expression in retinoblastoma compared to normal retina.46 Gene expression profiles may
segregate RB1-/-retinoblastomas either into two subtypes or into a spectrum of phenotypes correlating with
histologic and cytogenetic aberrations.48, 49
Nearly all retinoblastomas have mutation of both RB1 alleles, but 1.4% of unilateral tumours show evidence of
RB1 mutation, but have high-level amplification of the oncogene MYCN (MYCNA).50 These RB1+/+MYCNA
tumours are diagnosed in much younger children than unilateral RB1-/- tumours with distinct histology,
reflecting a unique subtype. Another 1.5% of unilateral non-familial unexplained retinoblastomas have
apparently normal both RB1and MYCN genes.50
[H2] The retinoblastoma cell of origin
Since pRB is expressed in most if not all cells, the retina’s unique sensitivity to pRB loss is perplexing. Diverse
retinal cell type markers and RNAs suggest a pleuripotent cell of origin, aberrant expression of oncogenic
transformation or normal intra-tumour RB1+/+ cells.48, 51 Mouse models have not clarified the cell-of-origin, since
they require loss of Rb1 plus p107, p130, or p27,52 express different retinal markers, and may not extrapolate to
humans.53
The topographic distribution of emerging retinoblastomas mimics the horizontal visual streak characteristic of
red and green cones, evidence for a cone precursor to be the cell of orgin.43 RB1-/- retinoblastomas show
consistently express cone photoreceptor but not other retinal cell type-specific proteins; and maturing cone
precursors have unusually high expression of oncoproteins (MDM2 and N-myc) that could collaborate with RB1
loss.51 Moreover, experimental depletion of RB1 induced cone precursor cell proliferation in vitro and in vivo
experimental tumours typical of differentiated retinoblastomas.54 Proliferation depended upon high levels of N-
Myc and MDM2, cone-specific transcription factors RXR and TR2, and down-regulation of p27 associated
with cone precursor maturation.41, 54 pRB may counter an oncogenic programme associated with cone precursor
maturation.
Notably, small tumours detected via optical coherence tomography (OCT) appear to be centred in the inner
nuclear layer of the retina, not the outer nuclear layer where mature cones reside.55 However, they also extend
into the outer nuclear layer (Figure 5c). Perhaps blood vessels and retinal astrocytes in inner retina promote
retinoblastoma cell growth in the inner nuclear layer55 and in vitro.56 However, gene expression studies suggest
several different classes of RB1-/- retinoblastomas, that that may arise in different cell types.49
[H2] Translating knowledge of pathogenesis
Understanding retinoblastoma molecular pathways could lead to treatment and prevention opportunities.
Oncoproteins such as N-myc could be targeted57 in both RB1+/+MYCNA tumours50 and RB1-/- tumours that have
progressed to N-myc-dependence.51 Furthermore, studies based on molecular discoveries showed that exposing
retinoblastoma-prone murine fetuses to small molecule inhibitors of E2f or Cdk inhibited subsequent
tumorigenesis without disrupting normal retinal development.52
These new translational opportunities require cell lines and animal models that accurately reflect retinoblastoma
cell responses. Most in vitro studies have used two old cell lines, but many others are available.58 Primary
xenografts in immunodeficient mice59 are useful47 but will not reflect the cell and immune environment of
natural retinoblastoma, potentially limiting translation to patients. Genetically engineered mouse models can
also be used to assess novel treatments.60 While Rb1+/- mice do not develop retinoblastoma, retinal deletion of
Rb1 (using Pax6a, Nestin, or Chx10 promoters) in p107, p130 or p27 mutant backgrounds achieves retinal
tumour formation.53 Such models have been used to examine genetic interactions in vivo, such as the role of
microRNA miR-17~92 overexpression in Pax6a-Cre;Rb1lox/lox; p107-/- mice.61 However, experimental murine
tumours have different collaborating mutations and cell type origin, reducing their ability to predict human
treatment responses. Viral oncoproteins, such as Simian Virus 40 T-antigen, promote murine retinoblastoma
specifically in developing Müller cells.62, 63 There is lots of room for models that more precisely simulate
retinoblastoma1 pathogenesis, to develop novel therapies that will target RB1-/- cancers.
[H1] Diagnosis, screening and prevention (HD, GC, BLG) 1506/1500
[H2] Clinical Diagnosis
Diagnosis of retinoblastoma is usually clear from presenting signs and clinical examination.4 The most common
sign is leukocoria (white pupil), when light reflecting directly off the tumour is noticed by parents, often in
photographs (Figures 6, 9). When parents report a strange reflection in the child’s eye, retinoblastoma should be
at the top of the differential diagnosis. The second most common sign is strabismus (misaligned eyes) when
central vision is lost. Advanced disease may present with iris colour change, enlarged cornea and eye from
pressure, or non-infective orbital inflammation. Very late, the eye may bulge from the orbit, a common
presentation where awareness and resources are inadequate.
Diagnosis of retinoblastoma does not rely on pathology, since biopsy incurs risk of metastasis.64 With the pupil
pharmacologically dilated and the indirect ophthalmoscope the diagnosis is usually clear to an eye specialist.
Calcification, characteristic of retinoblastoma, is detected by ultrasonography (b-scan). MRI is used to assess
invasion the optic nerve and trilateral retinoblastoma (pinealoblastoma and primitive neuroectodermal
intracranial tumours associated with RB1 mutations) (Figure 6). CT scans are now avoided because radiation
induces second primary cancers in people carrying RB1 mutations.65
Detailed retinal examination under general anaesthesia is required to distinguish the differential diagnoses
(Coats disease, persistent fetal vasculature, and vitreous haemorrhage) and classify the severity of intraocular
disease. The wide-angle, hand-held fundus camera is used to view and record all the retina, while as expert
depresses the sclera to bring the most anterior retina into view, while watching for optic nerve arterial pulsations
indicative of excessive pressure. Very useful are high frequency (50 MHz) ultrasound biomicroscopy,66 and
OCT67 to discover invisible tumours in infants with familial disease (Figure 1). Good imaging of the whole
retina supports eye classification and cancer staging, documents treatment responses, supports consultation with
colleagues, and helps parents understand treatment options.
[H2] Classification and Staging
The Reese-Ellsworth classification68 for intraocular retinoblastoma predicted outcomes of external beam
radiation. When intravenous chemotherapy (IVC), systemic chemotherapy and focal therapy became the
common primary treatment to salvage eyes, new schemes were developed (Figure 7). An international
collaboration led by Murphree developed the International Classification of Intraocular Retinoblastoma (IIRC)69
which better predicted responses to IVC than the Reese-Ellsworth classification.69 Eyes are classified by the
IIRC Groups A to E, with E being the most severe. However, subsequent modifications70 results in two similarly
named but significantly different classifications: 25% of the most severely involved (dangerous) eyes are
classified differently (Figure 7).71 Subsequently, the Children’s Oncology Group (COG) insert a further minor
variation.72 This confusion undermines research in retinoblastoma.
A number of staging systems also exist for extraocular retinoblastoma. In a coordinated action with the original
IIRC69, the International Retinoblastoma Staging System focused on overall staging.73 The American Joint
Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system (TNM, defined by
primary tumour (T), lymph node extension (N), and distant metastasis (M) for retinoblastoma74 is under
revision, has wide cancer acceptance in general, and offers the potential to achieve a single, collaborative,
consensus classification of eyes and cancer staging, critical to clinical research.
[H2] Pathology
Retinoblastomas consist of small, round cells that stain blue on haematoxylin staining. Well-differentiated
regions form rosette structures: Flexner-Wintersteiner rosettes, highly indicative of retinoblastoma; Homer
Wright rosettes common in diverse neural cancers (not shown); and differentiated clusters of photoreceptor-like
cells termed fleurettes, characteristic of retinoma (Figure 4).3 The RB1+/+MYCNA tumors are histologically very
distinct, without rosettes (Figure 4).
Histological study of the enucleated eye is the only way to evaluate high-risk features (tumour invasion into the
optic nerve beyond the confines of the eye or to the cut end of nerve; more than 3 mm of invasion of the
vascular layer (choroid) under the retina; invasion of sclera) to establish pathological staging.75-79 High-risk
features are observed in 17% of Group D and 24% of Group E eyes using Shields classification,77 and 15%
Group D and 50% Group E75 using the Murphree classification.69 Documentation of high-risk pathological
features is critical to recognize need for adjuvant systemic chemotherapy and reduce risk of metastatic relapse.80
The preparation and examination of the enucleated eye have been optimized to completely evaluate risk
features.79, 81 Pathology specimens are staged using the pathology TNM (pTNM) and the International
Retinoblastoma Staging System.74, 79 Still, too frequently retrospective examination finds a previously unnoticed
risk after metastatic disease is diagnosed. Highly retinoblastoma-specific stains such as staining for the cone-rod
homeobox transcription factor (CRX; not normally seen outside the eye)82 and N-glycosylated ganglioside
(NeuGc-GM3)83 may facilitate observation of a few tumour cells lurking in a high-risk location.
[H2] Genetic Diagnosis
The majority (94%) of patients with retinoblastoma are the first individuals to be diagnosed in a family, only
141 out of 2,141 patients (6%) indicated that one or more family members were previously diagnosed with
retinoblastoma when tested for RB1 mutations.84 Approximately 50% of people with retinoblastoma carry one
RB1 mutation in their constitutional cells (100% of bilateral and 15% of unilateral patients).85 The remaining
unilateral patients develop retinoblastoma by somatic biallelic RB1 loss or somatic amplification of the MYCN
oncogene have no additional cancer risks.
Knowledge of the patient’s RB1 mutation enables precise screening of relatives and subsequent generations.
Without genetic testing, all children at risk (already one eye affected, and/or positive family history) undergo
multiple exams under anaesthesia in the first 3 years to detect small, easily treated tumors. When the RB1
mutation of the family is discovered by genetic testing, children at risks can be tested for that mutation: 85% of
patients with unilateral retinoblastoma will test negative with <1% residual risk for undetectable low level
mosaicism, which informs the decision to reduce the intensity of surveillance and accurate determination of
cancer risks of family members.10 The mutation can be detected prenatally from DNA in amniotic fluid when
amniocentesis can be safely performed during pregnancy, and, if necessary, labour can be induced near term to
detect and treat retinoblastoma tumours early. Pre-implantation genetic diagnosis for the known mutation of a
parent offers the option for a family to have an unaffected child.86, 87
Characterization of unique RB1 mutations of the tumour DNA (if available) can provide a highly sensitive
marker to screen CSF, bone marrow and harvested stem cells for minimal residual disease. Markers that have
been used are the RB1 tumour mutation (when mutation is not present or different from the germline
alleles),88the signature of post-RB1 genomic gains and losses89 and CRX expression.82
Best outcomes in familial retinoblastoma depend on the effectiveness of the healthcare team to identify and
counsel families. Parents need appropriate genetic counselling and understanding of the risks and actions for
each at-risk pregnancy. Alarmingly, a study of retinoblastoma in several developing countries observed that
familial cases were diagnosed later than non-familial probands.90 The authors inferred that the probands did not
understood the risks to their children, but they also might be frightened that there would be no treatment
available. Alternatively, socioeconomic or geographic barriers may have reduced desired healthcare access.
Clearly, study of social determinants of health, such as health seeking behaviour, perceptions of medical care,
and sociocultural issues related to cancer inheritance would inform counselling approaches that meet the needs
of families.91
[H2] Screening
[H3] Screening through eye examination
To detect retinoblastoma as early as possible, vision screening and eye examination have been developed.
General recommendations for childhood vision screening with effective training to detect signs of
retinoblastoma do occasionally identify a child with retinoblastoma. However, one negative childhood screening
test does not mean this child will remain tumour-free since a tumour might appear later, or may have been in the
periphery and not visible (false negative).
Leukocoria is most often first noted by parents (Figure 6), rarely first by physicians. Too often health workers
fail to take the parent’s complaint seriously, due to lack of awareness. Photoleukocoria refers to the appearance
of leukocoria on flash photographs (Figure 6). Awareness campaigns bring children to attention, but lose
effectiveness with time. An innovative study called PhotoRed in India trained healthcare professionals to use
flash photography to identify childhood eye diseases, including retinoblastoma.92 Another pioneering project is
developing software to enable cameras to detect photoleukocoria.93 A camera’s Red Eye Reduction technology
constricts pupils with a pre-photograph flash, limiting photoleukocoria detection. Red-eye and pet-eye
correction tools also enable unsuspecting parents to remove photoleukocoria. The global imaging industry could
play a role in early diagnosis of retinoblastoma.
[H3] Second Cancer Surveillance
Individuals with germline RB1 mutation and/or have been treated with radiotherapy have an elevated risk of
developing specific second cancers, including leiomyosarcoma, osteosarcoma, melanoma, lung and bladder
cancer.65 Surveillance screening for second cancers is a pressing need in the opinion of retinoblastoma survivors.
The first study to evaluate annual whole body MRI surveillance for individuals with predisposing RB1 mutation
showed it was feasible to detect second cancers but with modest sensitivity (5 out of 25 patients screened).94
This is an important area for further research so that early intervention can reduce mortality from second
cancers, as has been demonstrated in Li-Fraumeni syndrome.95
[H2] Prevention
Lifestyle counselling educates survivors on ways to mitigate their second cancer risk. In addition to being
vigilant about reporting unexplained lesions, they are encouraged to avoid an unnecessary radiation and
carcinogens (e.g. cigarettes and excessive alcohol). The extent to which these ideas will prevent second cancers
is unknown.
[H1] Management(FLM, CS, DA, GC, FN, JZ, BLG) 2559/3000
Management of retinoblastoma depends on extent of disease at diagnosis (classification of intraocular disease,
stage of systemic disease), status of the opposite eye, overall health of the child, socioeconomic opportunities
for the family, and access to expert care.4, 16, 96
96, 97[H2] Intraocular retinoblastoma
[H3] Primary Treatment
Choice of primary treatment is based on likelihood of cure (patient survival), eye salvage and ultimate vision–
weighed against short term and long term complications of treatment.96 In order of approximate frequency of
global use, primary treatments for intraocular disease include enucleation, intravenous chemotherapy (IVC) with
focal therapy (laser, cryotherapy), intra-arterial chemotherapy (IAC) with focal therapy, and focal therapy when
tumours are small at diagnosis. External beam radiotherapy (EBRT) is no longer recommended for primary
intraocular retinoblastoma, since radiation, especially in the first year of life, imposes on persons carrying an
RB1 mutation a very high risk of second cancers.98, 99 The preferred primary treatment depends on the severity of
disease of each affected eye (Figure 8). Recent advances in eye salvage technologies are very significant, but
clinical studies with clear eligibility and outcomes are not reported. For the simplest situation of unilateral
salvageable eyes (Groups69 B, C, D) comparison of primary treatment with enucleation, IVC, and IAC is
provided in Table 4. Bilateral advanced retinoblastoma where there is lack of expertise, equipment and
resources, and difficulties with close monitoring is best treated with bilateral enucleation.4, 16 Many bilaterally
enucleated retinoblastoma survivors lead active, productive and satisfying lives because they were treated by
timely surgery as infants.
[H3] Second-Line (Salvage) Therapy
Second line salvage means initiating a new plan of therapies, in a second attempt to save an eye that has failed
the first plan. A range of modalities is appropriate for second line therapy. However, each subsequent plan has a
lower success rate100 and long drawn out attempts to salvage an eye incur high costs of many kinds for the child
and family, including metastasis and death.101-103
Second line treatments have included focal therapies,104 104repeated systemic chemotherapy,104, 105 repeated
IAC,100 brachytherapy,106, 107, EBRT108-110 and 107whole-eye 111radiation with proton beam.111 Criteria for
secondary enucleation are not well defined but are dominated by refractory subretinal and vitreous seeding,105, 112
suggestion of risk of uncontrolled cancer111 such as vitreous haemorrhage and secondary neovascular glaucoma,
and socio-economic and psychological fatigue to save an eye with poor vision.102 Following primary enucleation
of Group69 D eyes, high risk pathology is uncommon. However, secondarily enucleated eyes showing scleral
invasion may develop extra-ocular relapse;113 and Group69 E eyes treated with systemic chemotherapy delaying
enucleation, have significant risk for death from retinoblastoma.114
Of Group69 D eyes treated with systemic chemotherapy and focal therapy 53% failed (required salvage EBRT
and/or enucleation).110, 115 First-line IAC has reduced the recurrence rate in Group69 D eyes116 and a combination
of repeat IAC and intravitreal chemotherapy (IViC) may play an important part in saving eyes that have failed
IVC.116-118 However, extensive treatments to save an eye increase risk for metastases and death.100, 103, 119
However, the major cause of failure from all primary treatments has remained vitreous seeding.
Pharmacokinetic studies show poor vitreous levels of drugs administered by either systemic chemotherapy or
IAC.120 The highest drug bioavailability in the vitreous is achieved by IViC using a safety-enhanced injection
technique in carefully selected eligible eyes.121 Following control of the source of seeds, IViC achieved two-year
Kaplan-Meier estimates of 98.5% control of target seeds and 90.4% event-free ocular survival.121-123 The efficacy
of IViC has eliminated the need for EBRT and decreased patient exposure to salvage systemic or IAC. The
toxicity of IViC is limited to technique-dependent localized peripheral retinal toxicity.124
Combinations of technologies can target salvage therapies to the site of relapse. For relapse confined to the
retina and/or vitreous, salvage therapy can consist of focal therapy and/or IViC, as long as whole-eye therapy is
not required. Relapses touching the optic nerve head and/or vision-critical regions such as the maculo-papillary
bundle, and diffuse shallow retinal/subretinal recurrence, represent good indications for IAC, which might
achieve better visual outcome than focal treatments.
[H2] Ocular Therapies
[H3] Enucleation
Enucleation is a first-line therapy for the majority of eyes with retinoblastoma globally; it is the fastest and least
costly treatment125, 126. Since the majority of children without a family history with intraocular retinoblastoma
have Group69 D or E disease at diagnosis, and more than 50% have unilateral disease with other eye unaffected,
cure can be achieved with enucleation (Figures 3 and 6). All Group69 E eyes require enucleation because by
definition they carry risk of extraocular extension which can only be confirmed by the identification of high risk
pathological features in the enucleated eye. Best cosmetic outcome is achieved by replacement of the volume of
the eye with an implant deep in the orbit, and provision of a prosthetic eye, worn in the conjunctival sac behind
the eyelids. Many different reconstruction techniques are used worldwide.127 Comparative studies have shown
best artificial eye motility with a simple implant and muscles sutured to conjunctiva to form the pockets to hold
the artificial eye (myoconjunctival approach), which is affordable world-wide.128, 129 Porous implants that
become vascularized with muscles sutured to the implant are commonly used in developed countries but have
higher rates of infection and extrusion and are more costly. Provision of a temporary prosthetic eye at the time
of enucleation has a positive psychological impact on families,130 observed in Kenya to help the family accept
enucleation for their child.
[H3] Intravenous chemotherapy and focal therapy
Since 1996 first-line therapy to control Groups69 B, C and D disease has been IVC with different combinations,
doses, schedules, and durations of carboplatin, etoposide and vincristine (CEV) followed by focal therapy to
consolidate the chemotherapy responses(Table 3).112, 131, 132Sometimes high dose acute cyclosporine is added to
modulate multidrug resistance.133, 134Eyes in Groups69 B and C do well with CEV and focal therapy. With follow-
up of 54 months, 47% of Group69 D eyes110 and 47% of Reese-Ellsworth Group V112 avoided enucleation and
EBRT(Figure 9).70
Fundamental principles for systemic cancer therapy apply to retinoblastoma: optimized outcomes are achieved
by high dose intensity and combination of several agents with complementary mechanisms of action. This is
illustrated by the reduced effectiveness of single agent, low dose carboplatin for retinoblastoma.135 Acute
toxicities of IVC for retinoblastoma are as for other paediatric cancers, including short-term transient
pancytopenia (reduction in red blood cells, white blood cells and platelets), hair loss, vincristine-induced
neurotoxicity, and infections. Long term toxicities include carboplatin-induced ototoxicity (toxicity to the
ear),136 second non-ocular cancer risk with alkylating agents137, 138 and secondary acute myeloid leukaemia
following intense chemotherapy including topoisomerase inhibitors, doxorubricin and alkylating agents.139, 140
IVC alone rarely eradicates the retinoblastoma entirely, and focal therapy with repeated examinations under
[Au:general?]anaesthesia is very important (Figure 9).141-143Tumours in the macular region, which threaten
vision, are particularly at risk of recurrence without focal therapy.144
Following control of retinoblastoma with IVC, location of tumour is the most important predictor of final visual
acuity (near-normal visual acuity ≥0.5 in 22% of eyes with macular tumour, 67% of eyes with extrafoveal
tumour).145, 146 In children with two eyes, patching of the better eye to force use-dependent development of the
eye with macular involvement (occlusion therapy) achieved near-normal vision in 53% and useful vision in
73%.147 There is no documented local toxicity of IVC to the eye.
[H3] Intra-arterial chemotherapy
IAC [Au: OK?] is a recently optimized technique in which the patient is heparinized and a micro-catheter is
inserted into the femoral artery and passed up to the orifice of the ophthalmic artery (but not into the artery)
where drugs or combination of drugs (typically melphalan, carboplatin, and [Au:OK?]topotecan) are infused in
a pulsatile fashion over many minutes.148Alternatively, a catheter with an inflatable balloon near the tip can be
used to ensure selective treatment to the eye. During the procedure, the internal carotid artery is temporarily
occluded by inflating the tip and melphalan is injected over a few seconds below the balloon with the intention
of having the drug directedinto the ophthalmic artery(so-called selective ophthalmic treatment)119 Cannulation
via OAC has been successful in almost 99% of cases.OAC is usually performed via the internal carotid artery
but sometimes also through the external carotid artery and [Au:OK?]through the middle meningeal artery (15%
of cases); in 10% of the procedures a modification of the balloon technique is used149Also, tandem therapy in
which both eyes are treatedin the same, one hour session has successfully been performed.150OAC is currently
performed in more than 30 countries worldwide of which nearly half in developing nations.151
Of the more than 2,500 infusions and >800 patients in the literature using OAC with a mean follow-up of less
than 5 years, only two patients have died of metastatic retinoblastoma[Au: over all groups, A-E?].In the USA,
patient survival was 100% at 5 years[Au: over all groups, A-E?].117 However, death from metastatic disease
can occur more than five years after any treatment. The longest follow-up study described for selective
ophthalmic treatment in Japan (including death from metastatic retinoblastoma and second cancers) showed an
overall survival of 95% at 15 years.119However, the 8 deaths from metastases of 343 patients cannot be clearly
assigned to IAC alone since only a minority of the patients received IAC exclusively.On the other hand, similar
figures of deaths from metastasis have been reported with other conservative therapeutic modalities.143
Many patients treated with IAC have advanced-stage disease and would have been candidates for enucleation
but for cultural reasons, families (and often physicians) refused this option. Despite this, ocular survival exceeds
all other approaches for advanced-stage retinoblastoma (which represent the majority of eyes at diagnosis
worldwide). It should be stressed that a comprehensive analysis of the published literature on eye survival
following IAC is confounded by the concomitant use of different classifications69, 70;Group, 2011 #21798}
(Figure 7, Extended Data 2), which prevents a clear-cut comparison of the results between centres, especially
regarding Group69 D and E eyes. We need a universally endorsed single classification in order to avoid
confusion regarding eligibility and salvage rates for new treatments. Ocular survival with IAC was 65% for
Group69 C and 45% for Group69 D in one study;119 a more recent study showed 96% in both Groups69 B and C,
and 94% in Group69 D.117, 152 Eyes with neovascular glaucoma, pthisis bulbi (a shrunken, non-functional eye),
and anterior chamber involvement were universally enucleated up front. Ocular survival is highest in treatment-
naive eyes with extensive retinal detachment (Figure 10a). With eyes with >50% retinal detachments, ocular
survival (Kaplan-Meier) was demonstrated to be 87.9% at two years and 76% had complete retinal reattachment
after IAC alone.153 The most common reason for second-line enucleation of eyes with retinoblastoma in
developed countries has been vitreous seeding.154 Only 20% of such eyes can be salvaged with EBRT.155 With
OAC, 74% of eyes with seeding have been salvaged(Figure 10b).100, 117, 118 With the selective ophthalmic
treatment, 58% of children with foveal tumours retained a visual acuity of >0.01 and for those without foveal
tumours 51% retained visual acuity of >0.5 with 36% >1.0 (2). Electroretinographic[Au: OK?]monitoring of
OAC patients148, 156-159 demonstrated remarkable stability of.OAC decreases the appearance of subsequent, new
(usually peripheral) intra-ocular tumours that commonly develop after systemic chemotherapy or radiation in
genetic[Au: patients with heritable retinoblastoma? All cancers are genetic.] cases resulting in fewer overall
treatments for the children.160[Au: Paragraph in Green moved up.]
Complications following OAC are currently few and include both short-term and long-term effects. In an
analysis of 198 catheterizations of the ophthalmic[Au: OAC technique?] artery in 70 consecutive eyes with
retinoblastoma, minor transient complications included transient eyelid oedema (5%), blepharoptosis (5%), and
forehead hyperaemia (2%).117 Lasting complications included vitreous haemorrhage (2%), branch retinal artery
obstruction (1%), ophthalmic artery spasm with reperfusion (2%), ophthalmic artery obstruction (2%), partial
choroidal ischaemia (2%), and optic neuropathy (< 1%).117 These complications are minimized at experienced
centres.
Historically, consolidative focal therapy (focal treatment once response to cytoreductive chemotherapy has been
achieved)[Au: definition for nonexperts OK?] was necessary in the majority of the eyes initially treated with
systemic chemotherapy (even including EBRT) so it was initially used in almost all of the original patients
treated with OAC. Subsequently, experience has shown that consolidation was not needed in 23-33% of
cases.161, 162
Although this procedure has been performed in children as young as three weeks of age, most centres withhold
cannulation until the patient is at least 3 months of age and 6-7 kg in weight because of concerns about repeated
puncture of the femoral artery. As a result, these very young children are given single agent (carboplatin) IVC in
modest doses (18.7 mg/kg) as an outpatient until they attain the 6-7 kg/3 month goal when they are suitable for
OAC. This approach is called “bridge therapy” and 94.7% of such eyes (Kaplan-Meier) have been salvaged
without the need of radiotherapy.163
[H3] Focal therapy [Au: Please add references to this section.]
Focal therapy is the local application of anti-cancer therapy – thermo-, cryo-, radio-, or chemotherapy – to the
eye, under direct visualization through the pharmacologically dilated pupil. This approach is useful for primary
treatment of Group69 A cancers and consolidation therapy for residual or recurrent small-volume, active tumours
after IVC or IAC. In general, focal therapy is repeated monthly until the tumour is completely atrophic or
calcified.
Transpupillary thermotherapy involves laser treatment through the dilated pupil. Photocoagulation treatment
with 532 nm, 810 nm or continuous wave 1064 nm laser is directly applied by multiple short (0.7 s) burns to
small volume active or suspicious tumour, starting at a sub-coagulation power intensity and increasing to attain
white, opaque coagulation. Both laser treatments are repeated monthly until the tumour is flat, atrophic or
calcified. Cryotherapy is performed to freeze the tumour through the sclera with a nitrous oxide probe; the
tumour is directly visualized and duration of freeze judged to completely eliminate the tumour. Since tumour
cells die when thawing, one minute is allowed for each thaw between freezing cycles. Cryotherapy effectively
destroys small primary tumour(s) or recurrences in the periphery of the retina. Plaque radiotherapy involves the
position of a radioactive probe on the eye to deliver trans-scleral radiotherapy with an apex dose of 35 Gy over
4-7 days.[Au: edits OK?]Plaque focal radiation has not been associated with second primary tumours and is
effective for treatment of a single primary or recurrent tumour in a location that will not compromise vision.
Paraocular chemotherapy has been useful under conjunctiva or in tenon’s capsule for small volume recurrences
and vitreous seeds.164-166
[H3] Intravitreal Chemotherapy
Vitreous seeds are the major cause of failure (enucleation or external beam radiation) of primary treatments.
IViC is adjunctive to many other treatments, initiated after source of the seeds is controlled, with promising
results. IViC using a safety-enhanced injection technique in carefully selected eligible eyes has shown excellent
responses with the most difficult to control form of retinoblastoma.121, 122, 124, 167, 168[Au: Sentence in green
moved up]The procedure involves lowering the intraocular pressure with an anterior chamber paracentesis or
by digital massage after induction of anesthesia. Intravitreal melphalan is injected through the conjunctival,
sclera, and pars plana with a small-gauge needle. On needle withdrawal, the injection site is sealed and sterilized
with cryotherapy and the eye is shaken gently to distribute the drug though the vitreous. Three classes of
vitreous seeds have been identified with significantly different median times to regression, mean number of
injections and cumulative and mean melphalan dose.122Ultrasound biomicroscopy may be used to evaluate the
otherwise hidden ciliary region behind the iris,66 to confirm that the injection site is tumour-free prior to IViC
treatment.
[H2] Extraocular retinoblastoma
[H3] Extraocular at presentation
Retinoblastoma may present with evident extraocular disease, especially in low-income countries., Orbital
extension of an intraocular retinoblastoma may be detected clinically in children with proptosis or a fungating
mass or occasionally by imaging studies. , Treatment includes neo-adjuvant chemotherapy, including
carboplatin, etoposide and vincristine, as for intra-ocular retinoblastoma; other agents that are useful include
cisplatin, cyclophosphamide and anthracyclines.16This is followed by enucleation or limited exenteration, orbital
radiation, adjuvant chemotherapy. Intrathecal chemotherapy may also be used and high dose chemotherapy with
stem cell rescue may be added in metastatic disease.. Children with orbital disease and those with metastatic
spread without CNS invasion may be cured with intensive therapy.
[H3] Adjuvant therapy for high-risk pathology
Extraocular retinoblastoma can develop despite initial diagnosis of intraocular disease. Recognition of high-risk
pathological features of primarily enucleated eyes followed by adjuvant chemotherapy with tight surveillance
for metastatic disease has good outcomes.76, 78 Enthusiasm to salvage eyes increases metastatic risk by masking
primary extraocular disease, and potentially continuing attempted salvage too long so that extraocular disease
develops that was not there at primary diagnosis.103, 114
[H2] Palliation
Palliation includes pain management, symptom relief, nutritional support, and psychosocial support for the child
and families.16Untreated retinoblastoma is highly sensitive to most chemotherapy agents. Children presenting
with orbital retinoblastoma are usually in severe pain and discomfort that may be alleviated with judicious use
of anticancer therapy, including conventional chemotherapy, even when no curative intent is pursued. These
children often present with severe emaciation needing prompt medical treatment. Radiotherapy may also be
helpful, especially for a CNS relapse or for the treatment of massive orbital extension, but it isoften unavailable
in low-income countries.169[Au: references?]
[H1] Quality of life(AW, HD, BLG) 844/500
[Au: I think this section would benefit from a short introduction that outlines what the major
QOL issues in retinoblastoma survivors are. For example, radiotherapy on a young brain can
lead to developmental issues, cognitive decline, etc. This will set up the rest of the section nicely
and need only be a sentence or two.]
“Quality of life” describes the level of physical, emotional and psychological wellbeing experienced by an
individual. Cancer, its treatment and effects on the developing body, brain and mind can significantly decrease
Quality of Life, with implications for treatment decisions, supportive and long-term follow up care.
[H2] Measured life-long impact
Analysis of life-long treatment impact shows that 170, 171overall, survivors diagnosed under 1 year of age
performed significantly better in short and long-term verbal memory, verbal learning and verbal reasoning
abilities compared with those diagnosed at over 1 year of age.170, 171 In bilaterally affected children, whole brain
radiation exposure at any age was significantly associated with poorer verbal memory[Au:reference?].170, 171In
children followed up from diagnosis to age 5 years, trajectories of developmental functioning declined over
time.171 However, verbal IQ of age-matched persons with the early infancy form of retinoblastoma was
significantly above[Au: Explanation for the higher IQ?]normal sighted and non-retinoblastoma blind
persons.172No explanation has been identified for this finding, though hypotheses of a genetic cause have been
proposed. There is altered development of visual, auditory and multisensory brain morphology in adults who
lost one eye to retinoblastoma in early life, suggesting that the remaining eye acquired increased contralateral
visual cortical connections.173, 174There is clinical and animal evidence that repeated anaesthesia of young
children may impair neurocognitive development.125, 175, 176Repeat anaesthesia is necessary in eye salvage and in
very young children to discover and treat small tumours. Going forward, one outcome to record in
retinoblastoma clinical studies is number of examinations under anaesthesia and age.
[H2] Direct insight from survivors[Au: This section contains 22 references. Please try to delete some,
since the reference list needs to be cut to 200 references. ]
Most important are insights from the retinoblastoma survivors themselves. Social media brings retinoblastoma
parents and survivors into peer-support communities. Research processes that deepen understanding of quality
of life following retinoblastoma are needed to learn from these valuable evidence sources.
[H3] Coping during treatment and psychosocial outcomes
A mother describes her son’s response to radiotherapy aged 16 months: “In the beginning he was extremely
combative. At the end of the treatment course, he was a broken child, withdrawn and passively accepting what
was happening to him. The long term damage caused took years of therapy to start to heal"[Au: source
reference?].Children’s perception of pain and medical interventions changes over time.177-183Repeated
procedures cause anticipation anxiety and intolerance of even minimally invasive experiences and mild pain.
The child’s initial strong emotions may be suppressed as the child gives up, and re-emerge as depression, post-
traumatic stress or developmental trauma disorder.101, 184-190Child Life interventions at any age and with any
treatment help children thrive during treatment, reduce treatment costs, ease family stress and improve long-
term mental health(Figure 11).5, 65, 191-200
Retinoblastoma treatment is often the child’s only life experience, forming the centerpiece of their earliest
memories. While adult survivors may not remember being anaesthetized, many describe acute fear of their
mouth and nose being covered. One adult describes how the scent and taste of strawberries makes her nauseous
– her mask was always coated with strawberry scent.
Extended isolation during therapy may impact social functioning. While most adult survivors perform well
socially, many report low confidence and intense anxiety, especially in large groups and crowded environments.
Most survivors are high cognitive performers.170 However, reduced vision causes some children to become
frustrated by their inability to keep up with peers, damaging self-esteem and confidence.201-203
[H2] Radiotherapy late effects
While radiotherapy is now rarely used for retinoblastoma, thousands of adult survivors live with its long-term
effects. Many feel neglected and demoralized by lack of follow up and prospective management. Facial
deformity causes low self-confidence and social anxiety. Reconstructive surgery is a painful process that may
impact remaining vision, but its cosmetic effects can dramatically improve quality of lie. Dry eye is very
painful, and corneal vascularization reduces already limited vision. Use of ocular lubricants may prevent
complications, and should be started early before pain and vision loss occur. Chronic primary headaches,
hormone dysfunction and seizures also impact quality of life after radiotherapy.[Au: reference?]
[H2] Second cancer risk
Individuals at risk of second primary cancers require life-long oncology follow up.137, 204, 205 Lack of agreed
protocols causes confusion, frustration and fear as adults struggle to access informed follow up care,
compounded by primary doctors who are not aware of late effects and lifelong implications of RB1 mutation.
Full information about the patient’s cancer history, genetic status and life-long risks will empower survivors to
be advocates for their own and their children’s health.206-209
[H2] Family planning
Many adult survivors have little knowledge of retinoblastoma genetics, genetic counselling or testing, their
status, or of options for their baby. Cost and availability of genetic testing and pre-implantation genetic
diagnosis is often prohibitive. Lack of an agreed screening protocol for at-risk babies causes anxiety among
survivor-parents. Profound anger and guilt about somehow being responsible for the child’s cancer is amplified
when diagnosis is delayed by inadequate screening. Agreed screening protocols for at-risk children will reduce
survivor-parent anxiety and enhance early diagnosis to achieve minimally invasive therapy.
[H1] Outlook(All) 977/1000
Retinoblastoma is curable if diagnosed early. We propose that within 10 years retinoblastoma can be a zero-
death cancer. Our anti-retinoblastoma arsenal will consist not only of curative treatments, but also measures to
prevent development of disease in predisposed individuals. To achieve this vision, critical efforts are needed to
build upon the current state-of-the-art for retinoblastoma as presented in this Primer. Now, we dream big with
key action items [BOX], responding to the immediate obvious targets for improvements, and setting the stage
for innovative discoveries in retinoblastoma.
[H2] Patient-centered, global research
Retinoblastoma will benefit from clinical science at the level that has achieved dramatic change for pediatric
cancer. Because most centres have too few affected children, or many children and inadequate resources to
study them, we have lagged behind in systematic accumulation of evidence on which to base therapy. Today we
are faced with sweeping change in treatment of retinoblastoma using IAC and salvage of unresponsive vitreous
seeds by IViC. However, we do not have full data on which to judge eligibility, long-term effectiveness or
outcomes.
We have opportunities now to learn from initiatives and innovations everywhere, and to listen to the patient’s
voice to become an inclusive, participatory global network. Patients and families, empowered by social media,
will be heard in the research approaches, making them relevant, ethical, and appropriate. Stakeholders from low-
and-middle income countries will be active innovators, assuring that protocols are feasible and acceptable
Equality for retinoblastoma will come by education (Internet access), with shared collaborative care coordinated
online. Retinoblastoma expertise will be developed locally (proportional to the local burden of retinoblastoma)
but derived globally, with best practices drawing on rigorous molecular and clinical research. Retinoblastoma
clinical trials will be collaborative, high enrolment studies. Effective innovations will include all outcomes and
sustainability (cost, uptake by health ministries, social acceptability of therapy, etc.).
The global burden of retinoblastoma shows the inherent inequity in how patients are diagnosed and cared for
around the world. Documentation of human and material resources required for optimal care, drawn from
established clinical care guidelines, represent the first step towards health equity. National strategies in areas
currently underrepresented in the retinoblastoma literature are poised to fill the knowledge gap.
Progress in therapy is critically dependent on achieving consensus on a standard classification of intraocular
disease. The ongoing AJCC/UICC international survey of features of eyes at diagnosis, treatments given and
outcomes will be used to derive ONE evidence-based classification to replace the current clinical staging
schemes that confuse analysis or eligibility or outcomes.69-71, 74
We are poised to collect uniform data on all children with retinoblastoma. The 1RBW.org map documents
“staff, stuff, systems and spaces”210 and provides an alternative system of global collaboration, perhaps unique
to small neglected diseases, but perhaps the a for-runner for the most developed health care system. The eCCRB
point-of-care database summarizes the health record from diagnosis, including features of eyes and patient,
treatments, complications, and outcomes, and is available to all retinoblastoma centres. eCCRB also supports the
caregivers by graphic display of information otherwise out of reach, ensuring high motivation for good data
quality. The next phase of this Internet project (aiming at 2020) will combine the 1RBW map with eCCRB de-
identified data. “Real-time” analysis of outcomes is planned to feedback to treating doctors, a “learning health
system”,211 to assist in selection of evidence-based care for the next affected child.
We propose to determine the most likely cause of every death from retinoblastoma. Similar in concept to the
groundbreaking Million Death Study,212 each death will be an opportunity to avoid more deaths. The identified
key risk factors will lead to systematic guidelines to avert preventable deaths. BOX These will fall into
categories such as Public Awareness (public and health system understanding of the urgency of
leukocoria, utilization of Social Media), Health Services213 (Infant screening, financial support for every
child, regional retinoblastoma expertise, etc.), Clinical Research (Co-operative Groups for clinical trials,
outcomes analysis from learning health records, etc.) and Basic Research (define in available
retinoblastoma tumour cells targets for new therapy, define molecular targetable pathways for treatment
of RB1-/- tumours and prevention of RB1-/- cancers, starting with heritable retinoblastoma).
[H2] Targeted therapies
Our knowledge of the retinoblastoma cell of origin and its unique sensitivities is steadily increasing, and may
reveal strategies to prevent tumorigenesis. Moreover, ongoing work to define molecular lesions in
retinoblastoma will continue to yield novel therapeutic targets. Advances in therapeutic development and
prevention depend on these molecular studies, but we do not yet have preclinical models that accurately reflect
retinoblastoma pathogenesis and treatment.
One of the earliest targeted therapies developed for retinoblastoma, based on preclinical information generated
by transgenic mice was Nutlin-3.214 Nutlin-3 blocks MDM2/MDM4, releasing p53-mediated apoptotic cell death
and showed promising activity in combination with topotecan for retinoblastoma control in preclinical models.
Although the SYK antagonist R406 was considered a promising candidate based on preclinical studies,47 its
ocular pharmacokinetic profile following peri-ocular administration rendered it unfavorable for clinical use.215
Preclinical studies further suggest that retinoblastoma initiation and tumor growth might be suppressed by
inhibitors of MYCN, SKP2, E2F, or CDKs (Figure 12).
Preclinical studies have also sought to identify and evaluate pharmacokinetics of new agents alone or in
combination216 before clinical deployment. A few translational studies have resulted in changes in
retinoblastoma clinical practice.217 Innovative delivery systems to target small volume sub-retinal tumour and
vitreous seeding include devices for sustained-release, periocular and intravitreal administration, episcleral
implants218 and nanoparticles219. Approaches adjusting chemotherapy schedules and dose intensity (Metronomic
therapy)220 may particularly play an important role in palliative care for retinoblastoma. New biomarkers for
molecular dissemination of retinoblastoma outside the eye may lead to earlier diagnosis of metastasis and
targeted treatments.82, 83
[H2] QoL
Without thinking about the lifelong outlook for patients, however, all of the above endeavours become moot.
Quality of life begins in infancy, assisted by Child Life and respect for the child’s need to play. Patient-oriented
research will develop and validate life-long survivor follow-up care protocols, including centralized specialist
eye care, genetic testing, second cancer screening, ongoing psychological support and fertility care. will
educate primary physicians and survivor clinics, reduce survivor morbidity and aid research that can inform
patient management to improve quality of life during retinoblastoma treatment and throughout life.
[Au: QoL section deleted to remove overlap.]
Display Item Legends
Box 1: [Au: Please consider including a box with explanations for the specialist terms.]
Complex integrated implants
EBRT and tantalum ring localization
brachytherapy
myoconjunctival approach
oraserrata
orbital retinoblastoma
salt and pepper retinopathy
Scleral depression
Stem cell therapy?
proton beam radiotherapy
Box 2: Outstanding research questions [Au: Titles OK?]
Patient-centered, global research focus
Address the "reluctance of healthworkers to confer the true risks"(such as in Jordan where
doctors do not want to destroy families) and choice of families who know and understand the
risks not to followthrough because of the same stigma.
Define treatment success: cure (life), salvage of vision (one eye), salvage of eye (vision and
cosmetic), fewest examinations under anaesthesia (cumulative toxicitiyof anaesthesia)
Meta-analysis of all children treated primarily with IAC.
Develop a “retinoblastoma index” relating levels of awareness, access to centres with the
necessary resources and expertise, and application of evidence-based care, as predictors of
outcome.
Pathogenesis
What is the genomic progression post RB1 loss?
What molecular changes promote (early) metastasis?
Are there other RB1+/+ subtypes beyond MYCN-amplified retinoblastoma?
What dictates the tissue specificity of RB1 loss leading to cancer?
What are the unique molecular features of second cancers in RB1 mutation carriers?
Figure 1| Progression of retinoblastoma. a) Normal eye until genomic damage (yellow lightening bolt)
damages the second RB1 allele (M2) resulting in biallelic functional loss of RB1 in a developing retinal cell
(possibly a cone phototreceptor precursor cell that is dependent on pRB to stop proliferationRB1. may block
differentiation of a cone precursor cell, as itfailsthat that fails to localize normally. b) Genomic instability
might leads to an intraretinal benign retinoma. Inset: a small retinoblastoma visualized by optical coherence
tomography[Au: OK? Or do RB1-/- cells always form retinomas.] [Au: Which kind of scan is shown in the
insert? Please add information to the legend.] . c) This tumourIntra-retinal retinoblastoma arises if additional
genomic changes release uncontrolled cell proliferation; only 5% of patients show retinoma without
retinoblastoma. Inset shows a small tumour not visible except by optical coherence tomography,can progress to
form a retinoblastoma if additional mutations are acquired [Au:OK? Or do all the retinomas progress to
retinoblastomas], andThe tumour which will grow and seeds seed under thesubretinallyunder the retina retina
and into the vitreous.; d) Retinoblastoma can invades adjacent tissues: past the lamina cribrosa of into the optic
nerve, uvea, or sclera to constitute high- risk pathologic features. e) Finally,Eventually, the tumorretinoblastoma
mightextends extraocularly into orbit, brain (direct or subarachnoid to CSFcerebro-spinal fluid)) or metastasizes
to especially to bone marrow.
[Au: Can we add percentages of to the figure, showing how many % of patients will progress to the next
stage – if data are available? How many % of RB1 carriers, for example, will progress to develop
retinoblastoma?][Au: It would be great if we could have an extra panel, preferably panel A, showing the
normal eye anatomy, with labels for all the relevant anatomical terms mentioned in this legend, or the
manuscript. ]
Figure 2 | Global Retinoblastoma Prevalence. Heat Map of estimated distribution of the global retinoblastoma
patient population as assembled by the One Retinoblastoma World (1RBW) initiative. The majority of cases
reside in low and middle income countries. The 1RBW Map of Treatment Centers (www.1rbw.org) connects
affected families to expert care close to home, providing rich global data for anyone to use. Without prior
awareness of retinoblastoma, parents now commonly self-diagnose on the Internet, and the 1RBW map connects
them to experts without delays. Images from www.1rbw.org . .[Au: I think only panel A should be sufficient.
It is quite clear that most cases are in the middle/lower income countries.]
Figure 3 | Triplets with retinoblastoma tumours. These triplets developed retinoblastomas in all six eyes
illustrating the full expressivity and penetrance of the RB1-/- germline mutations that result in no protein, such as
the mutation carried by each triplet. The eCCRB timelines reveal that all eyes had individualized therapy, with
choices considering the overall impact on each child. Each child lost one eye, and each has a normal vision eye
with disease control in less than one year. The number of eye exams under anaesthesia was least for the child
who had primary enucleation. OD, right eye; OS, left eye. Eye involvement at diagnosis is indicated in the
International Intraocular classification;69 the eye labelled “Group 0” had no tumour at initial diagnosis but
develop a tumour 6 weeks later.
Figure 4 | Genetic origins of retinoblastoma. Three genetic subtypes of retinoblastoma are known. Heritable
retinoblastoma patients have a constitutive inactivating mutation (M1) in the RB1tumor suppressor gene in all
cells of their body. A second, somatic mutation (M2) in a susceptible retinal cell can lead to benign retinoma.
Further genetic and/or epigenetic events (M3…Mn) are required to transform to retinoblastoma. Non-heritable,
RB1-/- retinoblastomas progress similarly, except both M1 and M2 occur in one susceptible retinal cell.
RB1+/+MYCN-amplified (RB1+/+MYCNA) retinoblastoma is a rare, non-heritable retinoblastoma subtype driven
by amplification of MYCN with normal RB1; other changes in these tumours remain uncharacterized. Retinoma
histology shows distinct photoreceptor-like fleurettes, while RB1-/- retinoblastoma can show Flexner-
Wintersteiner (indicated) and Homer Wright rosettes. RB1+/+MYCNA retinoblastoma show distinct histology with
rounded nuclei and prominent nucleoli related to the high MYCN protein.
Figure 5 | Retinal origin of retinoblastoma tumors. a, The retina has a complex structure and contains
multiple cell types. Haematoxylin and eosin staining of post-fertilization week 19 retina shows three post-
mitotic nuclear layers in the central retina near the fovea (left) and two nuclear layers in the less mature
periphery of the same histologic section (right). Cell types in each layer are indicated. b, Cone precursors
normally have high expression of the RB protein (pRB). Immunofluorescence staining of post-fertilization week
19 retina shows especially strong pRB signal (red) in maturing cone precursors in the central retina (left,
counterstained for cone arrestin, green) and in retinal progenitor cells in the peripheral retina of the same
histologic section (right). pRB staining is less intense in DAPI-stained nuclei (blue) in other retinal cell types. c,
Optical coherence tomography of a tiny retinoblastoma tumor in a 2.5 month old infant appearing to extend
from the inner nuclear layer to the outer nuclear layer. The tumour has an uncertain epicentre making it difficult
to infer the retinal layer from which the tumor arose. This layer-of-origin may be defined in the future with more
images of higher resolution OCT of retina in very young children carrying an inherited germline RB1 mutation.
Abbreviations: ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer; NBL, neuroblastic
layer; RPE, retinal pigment epithelium.
Figure 6 | Photoleukocoria to Internet diagnosis. a, Leukocoria was noticed only on this digital image. The
parents search on “white pupil” and diagnosied retinoblastoma. The left eye was enucleated two days later. The
other eye was normal at diagnosis but later developed a small tumour treated with only laser. b, One month later
the child presented with signs of high intracranial pressure, before a scheduled screening CT (today MRI would
be done to reduce radiation exposure for persons with retinoblastoma) and a large intracranial midline tumour
(trilateral disease) was diagnosed. c, The eCCRB timeline of treatment: the child received systemic chemotherapy
and high dose chemotherapy with hematopoietic rescue by stem cell transplant. Subsequently he had more than
70 injections of intrathecal (given directly into the cerebro-spinal fluid) chemotherapy through an implanted
intraventricular catheter (not all shown in timeline). At age years, d, followup MRI at age 8 years shows no
residual disease and e, the child is well.
Figure 7 | Different classification schemes for intraocular retinoblastoma confound comparison of
outcomes. The features listed determine the overall classification, ranging from small tumours not threatening
vision (“Group A”) to tumours clinically noted to have features suggesting potential spread outside the eye
(“Group E”). Most importantly, size of tumour alone does not make an eye dangerous by Murphree,69 Children’s
Oncology Group (COG),72 or TNM classification;74 but any eye with tumour >50% of eye volume is E
(advanced-stage disease) by Shields classification.70 The consequence is widespread confusion in the literature
undermining clinical research, since studies using the different classifications cannot be compared.
Figure 8 | Primary treatment choices for each eye based on the International Intraocular Retinoblastoma
Classification.69 Treatment depends on the combined severity of each of the affected eyes (Eye 1 / Eye 2); the
preferred option for each eye is depicted in the blue boxes. Group69 A eyes can be treated with laser or
cryotherapy (focal therapy) alone. Group69 B and C eyes require several cycles of systemic or intra-arterial
chemotherapy followed by focal therapy (Group69 B) and, for unresponsive vitreous seeds, intravitreal
chemotherapy (IViC) with melphalan (Group69 C). Isolated single tumours in Group69 B or C eyes may
occasionally be appropriate for primary radioactive plaque therapy. For safety of the child, it is important that all
eyes with features suggesting imminent extraocular extension be removed to enable accurate pathological
examination to determine if risk of metastasis requires adjuvant chemotherapy.
Figure 9 | Good Response to Systemic Chemotherapy: a, b, White pupillary reflexes in both eyes brought this
child to attention at age 8 months. c, Right eye and d, left eye at diagnosis showed total retinal detachment and
underlying large tumours. e, eCCRB time line of shows treatment with systemic chemotherapy and focal therapy,
then only follow-up visits. After 20 years, both eyes remain stable: f, right eye (0.25 vision) and g, left eye (0.1
vision) (Vision decimal system, 1 = normal, 0.1=legal blindness).
Figure 10 | Response to Primary Intra-arterial Chemotherapy: a, Before (Left) IAC for a massive exophytic
retinoblastoma with total retinal detachment; and after (Right) showing complete response and eye salvage,
leaving a 6 mm calcified scar. b, Before (left image) IAC for an endophytic retinoblastoma eye with extensive
vitreous seeding; and after (right image) showing complete control with clinically intact fovea and visual acuity
20/25. c, Before (left image) IAC treatment for an eye with macular retinoblastoma demonstrating excellent
extramacular tumor regression; and after (right image) leaving intact fovea and hope for vision.
Figure 11 | Child Life promotes effective coping through play, preparation, education, positive-touch and
self-expression activities, based on natural child development. Child Life helps children and their families
cope with challenging healthcare issues, hospitalization and therapeutic interventions. Even in palliation, play is
the job of a child. These children play doctor and nurse, wearing gloves and stethoscopes while they examine
Puppet Kevin who had one eye removed for retinoblastoma. Play (medical play and just general play) promotes
a sense of mastery for children within their medical experience. Photo taken at the Sally Test Pediatric Centre,
Moi Teaching and Referral Hospital, Eldoret, Kenya.
Figure 12 | Proposed roles for human L/M-cone precursor circuitry in retinoblastoma tumorigenesis and
targeted therapy. Recent studies suggest that signaling circuitry specific to maturing L/M-cone precursors is
uniquely conducive to oncogenic transformation in response to Rb loss.41, 51, 54 Following cone cell specification
and cell cycle exit, nascent L/M cone precursors prominently express the cone lineage transcription factors
RXRg and TRb2, yet do not take on cone photoreceptor morphology or function. During maturation, L/M- cone
precursors express especially high levels of N-Myc, MDM2, and pRB, and appear to down regulate p27 via a
SKP2-related mechanism. pRB depletion in maturing cone precursors enabled proliferation and survival
dependent upon MYCN, SKP2, and MDM2. Mouse models suggest that E2Fs and CDKs may contribute to the
proliferative response to pRB loss52, although it is not known if they appear in human cone precursors or are
induced following pRB loss. N-Myc, MDM2, and SKP2 are also needed for proliferation and survival of
patient-derived retinoblastoma cells {Xu, 2009 #14691;Wang, 2010 #22470} suggesting that cone precursor
features needed for retinoblastoma initiation also contribute to tumor growth. In addition, SYK was highly
expressed in retinoblastoma but not normal retina{Zhang, 2012 #21116}.
The identification of circuitry mediating cone precursor proliferative response to RB loss provides opportunities
to prevent tumor initiation usingclinical grade agents based on preclinical inhibitors of MYCN expression (JQ1)
{Puissant, 2013 #22473} (Puissant,PMID 23430699), inhibitors of MDM2-mediated p53 degradation (Nutlin
3a){Laurie, 2006 #10712}, (Laurie 2006), inhibitors of SKP2-mediated p27 degradation (C25){Chan, 2013
#22472}Chan,2013 PMID: 23911321), and inhibitors of E2F and CDK activities (HLM006474 and R547,
respectively){Sangwan, 2012 #21115}., Sangwan et al, 2012). Additional targeted agents may be effective
against growing tumors, such as improved versions of the SYK inhibitor R406 (Zhang 2012, Pritchard 2014).
{Pritchard, 2014 #21452;Zhang, 2012 #21116}
Tables
Table 2: Estimated Global Distribution of Retinoblastoma
Forecast births were calculated using most recent data (2012) for population, birth rate and mortality rate
(World Bank (http://data.worldbank.org] accessed on 5 February 2015. Low (1:18,000 live births) and high
estimates (1:16,000 live births) calculated, following the example of Kivela.5[Au: it might also be useful to list
in the table footnote which countries are included in the different categories.]
Category
Population,
total[Au:
approximations
might be
better: 7.0
billion; 1.3
billion; 250
million]
Birth
rate,
crude
(per
1,000
people)
Mortality
rate, infant
(per 1,000
live births)
Forecast Live
Birthstotal[Au:
approximations
might be better
total[Au:
approximations
might be
better]
Retinoblastoma
Cases (High)
1:16,000
Retinoblastoma
Cases (Low)
1:18000
% of World
Retinoblastoma[Au:
is this based on the
high or low
approximations?]
World 7,043,105,591 19.4 34.6 131,629,862 8,227 7,313 100%
High income 1,299,489,520 11.6 5.5 14,941,320 934 830 11.4%
High income:
nonOECD 249,927,994 13.8 10.3 3,418,872 214 190
High income:
OECD 1,049,561,526 11.0 4.4 11,518,845 720 640
Low &
middle
income 5,743,616,071 21.1 38.1 116,699,203 7,294 6,483 88.7%
Middle
income 4,913,580,797 19.2 33.7 91,300,546 5,706 5,072 69.4%
Upper middle
income 2,390,210,774 14.8 16.3 34,737,317 2,171 1,930 26.4%
Lower middle
income 2,523,370,023 23.4 45.3 56,490,388 3,531 3,138 42.9%
Low income 830,035,274 32.3 54.5 25,373,890 1,586 1,410 19.3%
Table 1. Availability of treatment and imaging at retinoblastoma centres worldwide.
Retinoblastoma centres worldwide were surveyed (up to March 25, 2015) and featured on the One
Retinoblastoma World Map (1rbw.org). Information is available for 54 countries (22 High-Income
countries, 28 Middle-Income countries and 4 Low-Income countries, following World Bank
Classification).The estimate of availability of intra-arterial chemotherapy was drawn from
Grigorovskiet al's study.[Au: Only the percentages would be sufficient.]
CountriesTotal
centres
Enucleation
(#, %)
Laser
therapy
(#, %)
Cryo-
therapy (#,
%)
IVC (#, %)
Retcam
imaging (#,
%)
High Income 47 47 (100%) 43 (91%) 42 (89%) 40 (85%) 42 (89%)
Middle Income 75 75 (100%) 68 (91%) 68 (91%) 52 (69%) 47 (63%)
Low Income 10 10 (100%) 5 (50%) 2 (20%) 5 (50%) 3 (30%)
Total 132 132 (100%) 116 (88%) 112 (85%) 97 (73%) 92 (70%)
Supplementary information
Acknowledgements
TWC: NIH NCATS KL2TR001106, Research to Prevent Blindness, Inc. Can contain grant and
contribution numbers. Should be brief, and should not include thanks to anonymous referees and editors,
inessential words, or effusive comments.
Author contributions
Introduction (B.G.); Epidemiology (B.G., H.D.); Mechanisms/pathophysiology (B.G., T.C., D.C.); Diagnosis,
screening and prevention (B.G., H.D., J.Z.); Management (B.G., F.M., D.A., C.S., G.C.); Quality of life (B.G.,
A.W.); Outlook (B.G., H.D., T.C., D.C., F.M.); overview of Primer (B.G.).
[Au: I noticed some discrepancies between the information in the online submission system and the
manuscript – with regard to author contributions. I took the info of the submission system. Please check
very carefully and make changes (with tracked changes on) so that I can update the submission system.
Also, Festus Njuguna does not have any contributions in the submission system; please add information
here.]
Competing interests
In the interests of transparency, the Nature Clinical Reviews journals have a competing financial
interests policy. A detailed explanation of the policy can be found in the Nature website
(http://www.nature.com/nature/submit/policies/competing/index.html). Each author is required to
disclose any relationship, financial or otherwise, that that could be perceived as a conflict of interest.
[Au: We need to have competing interested information before we can send the manuscript for peer-
review. Please add to the system or declare that none of the authors have conflicts.]
References242/200[Au: Try to cut down to 200 reference; especially the QOL section has quite a lot of reference. ]
1. Knudson, A.G. Two genetic hits (more or less) to cancer. Nat Rev Cancer 1, 157-62 (2001).
2. Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57-70 (2000).
3. Dimaras, H. et al. Loss of RB1 induces non-proliferative retinoma: increasing genomic instability correlates with progression to retinoblastoma. Hum Mol Genet 17, 1363-72 (2008).
4. Dimaras, H. et al. Retinoblastoma. Lancet 379, 1436-46 (2012).
5. Kivela, T. The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death. Br J Ophthalmol 93, 1129-31 (2009).
6. Broaddus, E., Topham, A. & Singh, A.D. Incidence of retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93, 21-3 (2009).
7. Seregard, S., Lundell, G., Svedberg, H. & Kivela, T. Incidence of retinoblastoma from 1958 to 1998 in Northern Europe: advantages of birth cohort analysis. Ophthalmology 111, 1228-32 (2004).
8. Nyawira, G., Kahaki, K. & Kariuki-Wanyoike, M. Survival among retinoblastoma patients at the Kenyatta National Hospital, Kenya. Journal of Ophthalmology of Eastern Central and Southern Africa, 15-19 (2013).
9. Dean, M. et al. Increased incidence and disparity of diagnosis of retinoblastoma patients in Guatemala. Cancer Lett 351, 59-63 (2014).
10. National Retinoblastoma Strategy Canadian Guidelines for Care / Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol 44, S1-88 (2009).
11. Kumar, A., Moulik, N.R., Mishra, R.K. & Kumar, D. Causes, outcome and prevention of abandonment in retinoblastoma in India. Pediatr Blood Cancer 60, 771-5 (2013).
12. Gichigo, E.N., Kariuki-Wanyoike, M.M., Kimani, K. & Nentwich, M.M. [Retinoblastoma in Kenya : Survival and prognostic factors.]. Ophthalmologe (2014).
13. Moreno, F. et al. A population-based study of retinoblastoma incidence and survival in Argentine children. Pediatr Blood Cancer 61, 1610-5 (2014).
14. (2014).
15. Dimaras, H., White, A. & Gallie, B.L. in Ophthalmology Rounds (Toronto, 2008).
16. Chantada, G. et al. SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries. Pediatr Blood Cancer 60, 719-27 (2013).
17. Perez-Cuevas, R. et al. Scaling up cancer care for children without medical insurance in developing countries: The case of Mexico. Pediatr Blood Cancer 60, 196-203 (2013).
18. de Castro Junior, C.G. & Macedo, C.R. Brazilian Society of Pediatric Oncology - SOBOPE: 30 years of history, a lot in the present, full of the future. Rev Bras Hematol Hemoter 33, 326-7 (2011).
19. Naseripour, M. "Retinoblastoma survival disparity": The expanding horizon in developing countries. Saudi J Ophthalmol 26, 157-61 (2012).
20. Qaddoumi, I. et al. Team management, twinning, and telemedicine in retinoblastoma: a 3-tier approach implemented in the first eye salvage program in Jordan. Pediatr Blood Cancer 51, 241-4 (2008).
21. Wilimas, J.A. et al. Development of retinoblastoma programs in Central America. Pediatr Blood Cancer 53, 42-6 (2009).
22. Traore, F. et al. Retinoblastoma: inventory in Mali and program to develop early diagnosis, treatments and rehabilitation. Bull Cancer 100, 161-5 (2013).
23. Luna-Fineman, S. et al. Retinoblastoma in Central America: report from the Central American Association of Pediatric Hematology Oncology (AHOPCA). Pediatr Blood Cancer 58, 545-50 (2012).
24. Barr, R.D. et al. Asociacion de Hemato-Oncologia Pediatrica de Centro America (AHOPCA): a model for sustainable development in pediatric oncology. Pediatr Blood Cancer 61, 345-54 (2014).
25. Waddell, K.M. et al. Improving survival of retinoblastoma in Uganda. Br J Ophthalmol (2015).
26. Waddell, K.M. et al. Clinical features and survival among children with retinoblastoma in Uganda. Br J Ophthalmol 99, 387-90 (2015).
27. One Retinoblastoma World is a global network with the bold idea that all children with retinoblastoma can have equal opportunity to optimal care. We aim for global collaboration to deliver coordinated, evidence-based retinoblastoma care. (Toronto, 2015).
28. Schvartzman, E. et al. Results of a stage-based protocol for the treatment of retinoblastoma. J Clin Oncol 14, 1532-6 (1996).
29. Chantada, G.L. et al. Impact of chemoreduction for conservative therapy for retinoblastoma in Argentina. Pediatr Blood Cancer 61, 821-6 (2014).
30. Chantada, G.L. et al. Results of a prospective study for the treatment of unilateral retinoblastoma. Pediatr Blood Cancer 55, 60-6 (2010).
31. Chiu, H.H., Dimaras, H., Downie, R. & Gallie, B. Breaking down barriers to communicating complex retinoblastoma information: can graphics be the solution? Canadian Journal of Ophthalmology (In Press).
32. Knudson, A.G. Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Science, USA 68, 820-823 (1971).
33. Comings, D.E. A general theory of carcinogenesis. Proc Natl Acad Sci U S A 70, 3324-8 (1973).
34. Cavenee, W.K. et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305, 779-784 (1983).
35. Dryja, T.P., Rapaport, J.M., Joyce, J.M. & Petersen, R.A. Molecular detection of deletions involving band q14 of chromosome 13 in retinoblastomas. Proceedings of the National Academy of Science, USA 83, 7391-4 (1986).
36. Friend, S.H. et al. A human DNA segment with properties of the gene that predisposes to retinoblastoma and osteosarcoma. Nature 323, 643-6 (1986).
37. Lee, W.H. et al. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235, 1394-9 (1987).
38. Fung, Y.K. et al. Structural evidence for the authenticity of the human retinoblastoma gene. Science 236, 1657-61 (1987).
39. Lohmann, D.R. RB1 gene mutations in retinoblastoma. Hum Mutat 14, 283-288 (1999).
40. Dick, F.A. & Rubin, S.M. Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 14, 297-306 (2013).
41. Lee, T.C., Almeida, D., Claros, N., Abramson, D.H. & Cobrinik, D. Cell cycle-specific and cell type-specific expression of Rb in the developing human retina. Invest Ophthalmol Vis Sci 47, 5590-8 (2006).
42. Lohmann, D.R., Brandt, B., Hopping, W., Passarge, E. & Horsthemke, B. Distinct RB1 gene mutations with low penetrance in hereditary retinoblastoma. Human Genetics 94, 349-354 (1994).
43. Munier, F.L., Balmer, A., van Melle, G. & Gailloud, C. Radial asymmetry in the topography of retinoblastoma. Clues to the cell of origin. Ophthalmic Genet 15, 101-6 (1994).
44. Goodrich, D.W. How the other half lives, the amino-terminal domain of the retinoblastoma tumor suppressor protein. J Cell Physiol 197, 169-80 (2003).
45. Cook, R. et al. Direct Involvement of Retinoblastoma Family Proteins in DNA Repair by Non-homologous End-Joining. Cell Rep 10, 2006-18 (2015).
46. Theriault, B.L., Dimaras, H., Gallie, B.L. & Corson, T.W. The genomic landscape of retinoblastoma: a review. Clin Experiment Ophthalmol 42, 33-52 (2014).
47. Zhang, J. et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481, 329-34 (2012).
48. McEvoy, J. et al. Coexpression of normally incompatible developmental pathways in retinoblastoma genesis. Cancer Cell 20, 260-75 (2011).
49. Kapatai, G. et al. Gene expression profiling identifies different sub-types of retinoblastoma. Br J Cancer 109, 512-25 (2013).
50. Rushlow, D.E. et al. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 14, 327-34 (2013).
51. Xu, X.L. et al. Retinoblastoma has properties of a cone precursor tumor and depends upon cone-specific MDM2 signaling. Cell 137, 1018-31 (2009).
52. Sangwan, M. et al. Established and new mouse models reveal E2f1 and Cdk2 dependency of retinoblastoma, and expose effective strategies to block tumor initiation. Oncogene 31, 5019-28 (2012).
53. Cobrinik, D. in Animal Models of Brain Tumors (eds. Martinez-Murillo, R. & Martinez, A.) 141-152 (Springer, New York, 2013).
54. Xu, X.L. et al. Rb suppresses human cone-precursor-derived retinoblastoma tumours. Nature 514, 385-8 (2014).
55. Rootman, D.B. et al. Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol 97, 59-65 (2013).
56. Xu, X.L. et al. Tumor-associated retinal astrocytes promote retinoblastoma cell proliferation through production of IGFBP-5. Am J Pathol 177, 424-35 (2010).
57. Hook, K.E. et al. An integrated genomic approach to identify predictive biomarkers of response to the aurora kinase inhibitor PF-03814735. Mol Cancer Ther 11, 710-9 (2012).
58. Gallie, B.L., Trogadis, J. & Han, L.-P. in Human Cell Culture (ed. Masters, J.) 361-374 (1999).
59. Gallie, B.L., Albert, D.M., Wong, J.J., Buyukmihci, N. & Puliafito, C.A. Heterotransplantation of retinoblastoma into the athymic "nude" mouse. Invest Ophthalmol Vis Sci 16, 256-9 (1977).
60. Pacal, M. & Bremner, R. Insights from animal models on the origins and progression of retinoblastoma. Curr Mol Med 6, 759-81 (2006).
61. Conkrite, K. et al. miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma. Genes Dev 25, 1734-45 (2011).
62. Windle, J.J. et al. Retinoblastoma in transgenic mice. Nature 343, 665-9. (1990).
63. Pajovic, S. et al. The TAg-RB murine retinoblastoma cell of origin has immunohistochemical features of differentiated Muller glia with progenitor properties. Invest Ophthalmol Vis Sci 52, 7618-24 (2011).
64. Karcioglu, Z.A. Fine needle aspiration biopsy (FNAB) for retinoblastoma. Retina 22, 707-10 (2002).
65. McCarthy, M. et al. Comfort First: an evaluation of a procedural pain management programme for children with cancer. Psychooncology 22, 775-82 (2013).
66. Moulin, A.P., Gaillard, M.C., Balmer, A. & Munier, F.L. Ultrasound biomicroscopy evaluation of anterior extension in retinoblastoma: a clinicopathological study. Br J Ophthalmol 96, 337-40 (2012).
67. Rootman, D.B. et al. Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations. Br J Ophthalmol (2012).
68. Reese, A.B. & Ellsworth, R.M. The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol-Otolaryngol, 164-172 (1963).
69. Murphree, A.L. Intraocular retinoblastoma: the case for a new group classification. Ophthalmology Clinics of North America 18, 41-53 (2005).
70. Shields, C.L. et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113, 2276-80 (2006).
71. Novetsky, D.E., Abramson, D.H., Kim, J.W. & Dunkel, I.J. Published international classification of retinoblastoma (ICRB) definitions contain inconsistencies--an analysis of impact. Ophthalmic Genet 30, 40-4 (2009).
72. Group, C.s.O. (2011).
73. Chantada, G. et al. A proposal for an international retinoblastoma staging system. Pediatr Blood Cancer 47, 801-5 (2006).
74. Finger, P.T. et al. in AJCC Cancer Staging Manual. (eds. Edge, S.B., Byrd, D.R., Carducci, M.A. & Compton, C.C.) 561-568 (Springer, New York, NY, 2010).
75. Wilson, M.W., Qaddoumi, I., Billups, C., Haik, B.G. & Rodriguez-Galindo, C. A clinicopathological correlation of 67 eyes primarily enucleated for advanced intraocular retinoblastoma. The British journal of ophthalmology 95, 553-8 (2011).
76. Kaliki, S. et al. Postenucleation adjuvant chemotherapy with vincristine, etoposide, and carboplatin for the treatment of high-risk retinoblastoma. Arch Ophthalmol 129, 1422-7 (2011).
77. Kaliki, S. et al. High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120, 997-1003 (2013).
78. Sullivan, E.M. et al. Pathologic risk-based adjuvant chemotherapy for unilateral retinoblastoma following enucleation. J Pediatr Hematol Oncol 36, e335-40 (2014).
79. Sastre, X. et al. Proceedings of the consensus meetings from the International Retinoblastoma Staging Working Group on the pathology guidelines for the examination of enucleated eyes and evaluation of prognostic risk factors in retinoblastoma. Arch Pathol Lab Med 133, 1199-202 (2009).
80. Kim, J.W. Retinoblastoma: evidence for postenucleation adjuvant chemotherapy. Int Ophthalmol Clin 55, 77-96 (2015).
81. Grossniklaus, H.E., Kivëla, T., Harbour, J.W. & Finger, P.T. (College of American Pathologists, 2011).
82. Torbidoni, A.V. et al. The cone-rod homeobox transcription factor (CRX) mRNA as a molecular marker in metastatic retinoblastoma. JAMA Ophthalmology (In press).
83. Torbidoni, A.V. et al. Immunoreactivity of the 14F7 Mab raised against N-Glycolyl GM3 Ganglioside in retinoblastoma tumours. Acta Ophthalmol (2014).
84. Genetic, I. (2015).
85. Gallie, B., Erraguntla, V., Heon, E. & Chan, H. in Pediatric Ophthalmology and Strabismus (eds. Taylor, D. & Hoyt, C.) 486-504 (ELSEVIER, 2004).
86. Xu, K. et al. Preimplantation genetic diagnosis for retinoblastoma: the first reported liveborn. Am J Ophthalmol 137, 18-23 (2004).
87. Dommering, C.J., Moll, A.C., Imhof, S.M., de Die-Smulders, C.E. & Coonen, E. Another liveborn after preimplantation genetic diagnosis for retinoblastoma. Am J Ophthalmol 138, 1088-9 (2004).
88. Dimaras, H. et al. Retinoblastoma CSF metastasis cured by multimodality chemotherapy without radiation. Ophthalmic Genet 30, 121-6 (2009).
89. Bowles, E. et al. Profiling genomic copy number changes in retinoblastoma beyond loss of RB1. Genes Chromosomes Cancer 46, 118-29 (2007).
90. Chantada, G.L. et al. Familial retinoblastoma in developing countries. Pediatr Blood Cancer 53, 338-42 (2009).
91. He, L.Q. et al. Developing clinical cancer genetics services in resource-limited countries: the case of retinoblastoma in Kenya. Public Health Genomics 17, 221-7 (2014).
92. Patel, T. et al. Consumer Digital Cameras: A feasible strategy for the early detection of childhood blindness. Association for Research in Vision and Ophthalmology (ARVO) (2012).
93. Abdolvahabi, A. et al. Colorimetric and longitudinal analysis of leukocoria in recreational photographs of children with retinoblastoma. PLoS One 8, e76677 (2013).
94. Friedman, D.N. et al. Whole-body magnetic resonance imaging (WB-MRI) as surveillance for subsequent malignancies in survivors of hereditary retinoblastoma: a pilot study. Pediatr Blood Cancer 61, 1440-4 (2014).
95. Villani, A. et al. Biochemical and imaging surveillance in germline TP53 mutation carriers with Li-Fraumeni syndrome: a prospective observational study. Lancet Oncol 12, 559-67 (2011).
96. Shields, C.L. et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye (Lond) 27, 253-64 (2013).
97. Abramson, D.H. et al. Presenting signs of retinoblastoma. J Pediatr 132, 505-8 (1998).
98. Eng, C. et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 85, 1121-8 (1993).
99. MacCarthy, A. et al. Non-ocular tumours following retinoblastoma in Great Britain 1951 to 2004. Br J Ophthalmol 93, 1159-62 (2009).
100. Francis, J.H. et al. Efficacy and Toxicity of Second-Course Ophthalmic Artery Chemosurgery for Retinoblastoma. Ophthalmology (2015).
101. Hamama-Raz, Y., Rot, I. & Buchbinder, E. The coping experience of parents of a child with retinoblastoma-malignant eye cancer. J Psychosoc Oncol 30, 21-40 (2012).
102. Soliman, S.E., Dimaras, H., Souka, A.A., Ashry, M.H. & Gallie, B.L. Socioeconomic and Psychological Impact of Treatment for Unilateral Intraocular Retinoblastoma. French Journal of Ophthalmology (In Press).
103. Mathew, A.A., Sachdev, N., Staffieri, S.E., McKenzie, J.D. & Elder, J.E. Superselective intra-arterial chemotherapy for advanced retinoblastoma complicated by metastatic disease. J AAPOS 19, 72-4 (2015).
104. Manjandavida, F.P., Honavar, S.G., Reddy, V.A. & Khanna, R. Management and outcome of retinoblastoma with vitreous seeds. Ophthalmology 121, 517-24 (2014).
105. Gunduz, K. et al. Causes of chemoreduction failure in retinoblastoma and analysis of associated factors leading to eventual treatment with external beam radiotherapy and enucleation. Ophthalmology 111, 1917-24 (2004).
106. Shields, C.L. et al. Iodine 125 plaque radiotherapy as salvage treatment for retinoblastoma recurrence after chemoreduction in 84 tumors. Ophthalmology 113, 2087-92 (2006).
107. Munier, F.L. et al. New developments in external beam radiotherapy for retinoblastoma: from lens to normal tissue-sparing techniques. Clin Experiment Ophthalmol 36, 78-89 (2008).
108. Pica, A. et al. Preliminary experience in treatment of papillary and macular retinoblastoma: evaluation of local control and local complications after treatment with linear accelerator-based stereotactic radiotherapy with micromultileaf collimator as second-line or salvage treatment after chemotherapy. Int J Radiat Oncol Biol Phys 81, 1380-6 (2011).
109. Chan, M.P., Hungerford, J.L., Kingston, J.E. & Plowman, P.N. Salvage external beam radiotherapy after failed primary chemotherapy for bilateral retinoblastoma: rate of eye and vision preservation. Br J Ophthalmol 93, 891-4 (2009).
110. Berry, J.L. et al. Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage. Pediatr Blood Cancer 60, 688-93 (2013).
111. Mouw, K.W. et al. Proton radiation therapy for the treatment of retinoblastoma. Int J Radiat Oncol Biol Phys 90, 863-9 (2014).
112. Shields, C.L. et al. Chemoreduction plus focal therapy for retinoblastoma: factors predictive of need for treatment with external beam radiotherapy or enucleation. Am J Ophthalmol 133, 657-64 (2002).
113. Chantada, G.L. et al. Risk factors for extraocular relapse following enucleation after failure of chemoreduction in retinoblastoma. Pediatr Blood Cancer 49, 256-60 (2007).
114. Zhao, J. et al. Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis. Journal of clinical oncology : official journal of the American Society of Clinical Oncology 29, 845-51 (2011).
115. Abramson, D.H. & Schefler, A.C. Update on retinoblastoma. Retina 24, 828-48 (2004).
116. Schaiquevich, P. et al. Intra-arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma. Pediatr Blood Cancer 60, 766-70 (2013).
117. Shields, C.L. et al. Intra-arterial chemotherapy for retinoblastoma in 70 eyes: outcomes based on the international classification of retinoblastoma. Ophthalmology 121, 1453-60 (2014).
118. Abramson, D.H. et al. Intra-arterial chemotherapy for retinoblastoma in eyes with vitreous and/or subretinal seeding: 2-year results. Br J Ophthalmol 96, 499-502 (2012).
119. Suzuki, S., Yamane, T., Mohri, M. & Kaneko, A. Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis. Ophthalmology 118, 2081-7 (2011).
120. Schaiquevich, P. et al. Pharmacokinetic analysis of topotecan after superselective ophthalmic artery infusion and periocular administration in a porcine model. Retina 32, 387-95 (2012).
121. Munier, F.L. et al. Intravitreal chemotherapy for vitreous disease in retinoblastoma revisited: from prohibition to conditional indications. Br J Ophthalmol 96, 1078-83 (2012).
122. Francis, J.H. et al. The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan. Ophthalmology (2015).
123. Shields, C.L. et al. Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol 132, 319-25 (2014).
124. Munier, F.L. Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013. Ophthalmic Genet 35, 193-207 (2014).
125. Rappaport, B.A., Suresh, S., Hertz, S., Evers, A.S. & Orser, B.A. Anesthetic neurotoxicity--clinical implications of animal models. N Engl J Med 372, 796-7 (2015).
126. Mallipatna, A.C., Sutherland, J.E., Gallie, B.L., Chan, H. & Heon, E. Management and outcome of unilateral retinoblastoma. J AAPOS 13, 546-50 (2009).
127. Mourits, D.L., Hartong, D.T., Bosscha, M.I., Kloos, R.J. & Moll, A.C. Worldwide enucleation techniques and materials for treatment of retinoblastoma: an international survey. PLoS One 10, e0121292 (2015).
128. Shome, D., Honavar, S.G., Raizada, K. & Raizada, D. Implant and prosthesis movement after enucleation: a randomized controlled trial. Ophthalmology 117, 1638-44 (2010).
129. Yadava, U., Sachdeva, P. & Arora, V. Myoconjunctival enucleation for enhanced implant motility. result of a randomised prospective study. Indian J Ophthalmol 52, 221-6 (2004).
130. Vincent, A.L., Webb, M.C., Gallie, B.L. & Heon, E. Prosthetic conformers: a step towards improved rehabilitation of enucleated children. Clin Experiment Ophthalmol 30, 58-9 (2002).
131. Gallie, B.L. et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114, 1321-8 (1996).
132. Kingston, J.E., Hungerford, J.L., Madreperla, S.A. & Plowman, P.N. Results of combined chemotherapy and radiotherapy for advanced intraocular retinoblastoma. Archives of Ophthalmology 114, 1339-1343 (1996).
133. Chan, H.S. et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Clin Cancer Res 2, 1499-508 (1996).
134. Chan, H.S.L. (ClinicalTrials.gov, 2005).
135. Dunkel, I.J. et al. A phase II trial of carboplatin for intraocular retinoblastoma. Pediatr Blood Cancer (2007).
136. Jehanne, M. et al. Analysis of ototoxicity in young children receiving carboplatin in the context of conservative management of unilateral or bilateral retinoblastoma. Pediatr Blood Cancer 52, 637-43 (2009).
137. Wong, J.R. et al. Risk of subsequent malignant neoplasms in long-term hereditary retinoblastoma survivors after chemotherapy and radiotherapy. J Clin Oncol 32, 3284-90 (2014).
138. Draper, G.J., Sanders, B.M. & Kingston, J.E. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 53, 661-71 (1986).
139. Gombos, D.S. et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology 114, 1378-83 (2007).
140. Smith, M.A. et al. Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17, 569-77 (1999).
141. Shields, C.L. et al. Factors predictive of recurrence of retinal tumors, vitreous seeds, and subretinal seeds following chemoreduction for retinoblastoma. Arch Ophthalmol 120, 460-4 (2002).
142. Gombos, D.S., Kelly, A., Coen, P.G., Kingston, J.E. & Hungerford, J.L. Retinoblastoma treated with primary chemotherapy alone: the significance of tumour size, location, and age. Br J Ophthalmol 86, 80-3 (2002).
143. Lee, V. et al. Globe conserving treatment of the only eye in bilateral retinoblastoma. Br J Ophthalmol 87, 1374-80 (2003).
144. Shields, C.L. et al. Macular retinoblastoma managed with chemoreduction: analysis of tumor control with or without adjuvant thermotherapy in 68 tumors. Arch Ophthalmol 123, 765-73 (2005).
145. Demirci, H., Shields, C.L., Meadows, A.T. & Shields, J.A. Long-term visual outcome following chemoreduction for retinoblastoma. Arch Ophthalmol 123, 1525-30 (2005).
146. Narang, S., Mashayekhi, A., Rudich, D. & Shields, C.L. Predictors of long-term visual outcome after chemoreduction for management of intraocular retinoblastoma. Clin Experiment Ophthalmol 40, 736-42 (2012).
147. Watts, P. et al. Visual results in children treated for macular retinoblastoma. Eye 16, 75-80. (2002).
148. Abramson, D.H., Dunkel, I.J., Brodie, S.E., Kim, J.W. & Gobin, Y.P. A phase I/II study of direct intraarterial (ophthalmic artery) chemotherapy with melphalan for intraocular retinoblastoma initial results. Ophthalmology 115, 1398-404, 1404 e1 (2008).
149. Klufas, M.A. et al. Intra-arterial chemotherapy as a treatment for intraocular retinoblastoma: alternatives to direct ophthalmic artery catheterization. AJNR Am J Neuroradiol 33, 1608-14 (2012).
150. Abramson, D.H., Dunkel, I.J., Brodie, S.E., Marr, B. & Gobin, Y.P. Bilateral superselective ophthalmic artery chemotherapy for bilateral retinoblastoma: tandem therapy. Arch Ophthalmol 128, 370-2 (2010).
151. Grigorovski, N. et al. Use of intra-arterial chemotherapy for retinoblastoma: results of a survey. Int J Ophthalmol 7, 726-30 (2014).
152. Abramson, D.H. et al. Ophthalmic artery chemosurgery for less advanced intraocular retinoblastoma: five year review. PLoS ONE 7, e34120 (2012).
153. Palioura, S. et al. Ophthalmic artery chemosurgery for the management of retinoblastoma in eyes with extensive (>50%) retinal detachment. Pediatr Blood Cancer 59, 859-64 (2012).
154. Abramson, D.H. Retinoblastoma in the 20th century: past success and future challenges the Weisenfeld lecture. Invest Ophthalmol Vis Sci 46, 2683-91 (2005).
155. Abramson, D.H., Beaverson, K.L., Chang, S.T., Dunkel, I.J. & McCormick, B. Outcome following initial external beam radiotherapy in patients with Reese-Ellsworth group Vb retinoblastoma. Arch Ophthalmol 122, 1316-23 (2004).
156. Brodie, S.E. et al. ERG monitoring of retinal function during systemic chemotherapy for retinoblastoma. Br J Ophthalmol 96, 877-80 (2012).
157. Brodie, S.E., Pierre Gobin, Y., Dunkel, I.J., Kim, J.W. & Abramson, D.H. Persistence of retinal function after selective ophthalmic artery chemotherapy infusion for retinoblastoma. Doc Ophthalmol 119, 13-22 (2009).
158. Francis, J.H., Abramson, D.H., Marr, B.P. & Brodie, S.E. Ocular manipulation reduces both ipsilateral and contralateral electroretinograms. Doc Ophthalmol 127, 113-22 (2013).
159. Francis, J.H. et al. Electroretinogram monitoring of dose-dependent toxicity after ophthalmic artery chemosurgery in retinoblastoma eyes: six year review. PLoS One 9, e84247 (2014).
160. Abramson, D.H. et al. Ophthalmic artery chemosurgery for retinoblastoma prevents new intraocular tumors. Ophthalmology 120, 560-5 (2013).
161. Gobin, Y.P., Dunkel, I.J., Marr, B.P., Brodie, S.E. & Abramson, D.H. Intra-arterial Chemotherapy for the Management of Retinoblastoma: Four-Year Experience. Arch Ophthalmol (2011).
162. Abramson, D.H. Chemosurgery for retinoblastoma: what we know after 5 years. Arch Ophthalmol 129, 1492-4 (2011).
163. Gobin, Y.P. et al. Combined, sequential intravenous and intra-arterial chemotherapy (bridge chemotherapy) for young infants with retinoblastoma. PLoS ONE 7, e44322 (2012).
164. Abramson, D.H., Frank, C.M. & Dunkel, I.J. A phase I/II study of subconjunctival carboplatin for intraocular retinoblastoma. Ophthalmology 106, 1947-50 (1999).
165. Mulvihill, A. et al. Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma. Arch Ophthalmol 121, 1120-4 (2003).
166. Mallipatna, A.C., Dimaras, H., Chan, H.S., Heon, E. & Gallie, B.L. Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol 129, 738-45 (2011).
167. Ghassemi, F. & Amoli, F.A. Pathological findings in enucleated eyes after intravitreal melphalan injection. Int Ophthalmol 34, 533-40 (2014).
168. Ghassemi, F., Shields, C.L., Ghadimi, H., Khodabandeh, A. & Roohipoor, R. Combined intravitreal melphalan and topotecan for refractory or recurrent vitreous seeding from retinoblastoma. JAMA Ophthalmol 132, 936-41 (2014).
169. Bansal, M., Patel, F.D., Mohanti, B.K. & Sharma, S.C. Setting up a palliative care clinic within a radiotherapy department: a model for developing countries. Support Care Cancer 11, 343-7 (2003).
170. Brinkman, T.M. et al. Cognitive function and social attainment in adult survivors of retinoblastoma: a report from the St. Jude Lifetime Cohort Study. Cancer 121, 123-31 (2015).
171. Willard, V.W. et al. Developmental and adaptive functioning in children with retinoblastoma: a longitudinal investigation. J Clin Oncol 32, 2788-93 (2014).
172. Tobin, M., Hill, E. & Hill, J. Retinoblastoma and superior verbal IQ scores? British Journal of Visual Impairment 28, 7-18 (2010).
173. Kelly, K.R., McKetton, L., Schneider, K.A., Gallie, B.L. & Steeves, J.K. Altered anterior visual system development following early monocular enucleation. Neuroimage Clin 4, 72-81 (2014).
174. Kelly, K.R., DeSimone, K.D., Gallie, B.L. & Steeves, J.K. Increased cortical surface area and gyrification following long-term survival from early monocular enucleation. Neuroimage Clin 7, 297-305 (2015).
175. Ing, C. et al. Long-term differences in language and cognitive function after childhood exposure to anesthesia. Pediatrics 130, e476-85 (2012).
176. Rappaport, B., Mellon, R.D., Simone, A. & Woodcock, J. Defining safe use of anesthesia in children. N Engl J Med 364, 1387-90 (2011).
177. Khin Hla, T. et al. Perception of pediatric pain: a comparison of postoperative pain assessments between child, parent, nurse, and independent observer. Paediatr Anaesth 24, 1127-31 (2014).
178. Romsing, J., Dremstrup Skovgaard, C., Friis, S.M. & Henneberg, S.W. Procedure-related pain in children in a Danish University Hospital. A qualitative study. Paediatr Anaesth 24, 602-7 (2014).
179. Fox, J.K., Halpern, L.F., Dangman, B.C., Giramonti, K.M. & Kogan, B.A. Children's anxious reactions to an invasive medical procedure: The role of medical and non-medical fears. J Health Psychol (2014).
180. Chen, E., Zeltzer, L.K., Craske, M.G. & Katz, E.R. Children's memories for painful cancer treatment procedures: implications for distress. Child Dev 71, 933-47 (2000).
181. Silver, G.H., Kearney, J.A., Kutko, M.C. & Bartell, A.S. Infant delirium in pediatric critical care settings. Am J Psychiatry 167, 1172-7 (2010).
182. Caes, L. et al. The relationship between parental catastrophizing about child pain and distress in response to medical procedures in the context of childhood cancer treatment: a longitudinal analysis. J Pediatr Psychol 39, 677-86 (2014).
183. Dahlquist, L.M. & Pendley, J.S. When distraction fails: parental anxiety and children's responses to distraction during cancer procedures. J Pediatr Psychol 30, 623-8 (2005).
184. van Dijk, J. et al. Behavioural functioning of retinoblastoma survivors. Psychooncology 18, 87-95 (2009).
185. van Dijk, J. et al. Coping strategies of retinoblastoma survivors in relation to behavioural problems. Psychooncology 18, 1281-9 (2009).
186. Cloitre, M. et al. A developmental approach to complex PTSD: childhood and adult cumulative trauma as predictors of symptom complexity. J Trauma Stress 22, 399-408 (2009).
187. van der Kolk, B. Developmental Trauma Disorder. Psychiatric Annuals, 401-408 (2005).
188. Kaplan, L.M., Kaal, K.J., Bradley, L. & Alderfer, M.A. Cancer-related traumatic stress reactions in siblings of children with cancer. Fam Syst Health 31, 205-17 (2013).
189. Buchbinder, D. et al. Psychological outcomes of siblings of cancer survivors: a report from the Childhood Cancer Survivor Study. Psychooncology 20, 1259-68 (2011).
190. Gold, J.I. in RESEARCHLA Blog (Children's Hospital Los Angeles The Saban Research Institute, Los Angeles).
191. Committee on Hospital, C. & Child Life, C. Child life services. Pediatrics 133, e1471-8 (2014).
192. Care, C.o.H. & Council, C.L. Child life services. Pediatrics 133, e1471-8 (2014).
193. Landier, W. & Tse, A.M. Use of complementary and alternative medical interventions for the management of procedure-related pain, anxiety, and distress in pediatric oncology: an integrative review. J Pediatr Nurs 25, 566-79 (2010).
194. Shockey, D.P. et al. Preprocedural distress in children with cancer: an intervention using biofeedback and relaxation. J Pediatr Oncol Nurs 30, 129-38 (2013).
195. Wohlheiter, K.A. & Dahlquist, L.M. Interactive versus passive distraction for acute pain management in young children: the role of selective attention and development. J Pediatr Psychol 38, 202-12 (2013).
196. Willis, D. & Barry, P. Audiovisual interventions to reduce the use of general anaesthesia with paediatric patients during radiation therapy. J Med Imaging Radiat Oncol 54, 249-55 (2010).
197. O'Callaghan, C., Sexton, M. & Wheeler, G. Music therapy as a non-pharmacological anxiolytic for paediatric radiotherapy patients. Australas Radiol 51, 159-62 (2007).
198. Post-White, J. et al. Massage therapy for children with cancer. J Pediatr Oncol Nurs 26, 16-28 (2009).
199. Sposito, A.M. et al. Coping Strategies Used by Hospitalized Children With Cancer Undergoing Chemotherapy. J Nurs Scholarsh (2015).
200. Hildenbrand, A.K., Clawson, K.J., Alderfer, M.A. & Marsac, M.L. Coping with pediatric cancer: strategies employed by children and their parents to manage cancer-related stressors during treatment. J Pediatr Oncol Nurs 28, 344-54 (2011).
201. van Dijk, J. et al. Restrictions in daily life after retinoblastoma from the perspective of the survivors. Pediatr Blood Cancer 54, 110-5 (2010).
202. Friedman, D.N. et al. Long-term medical outcomes in survivors of extra-ocular retinoblastoma: the Memorial Sloan-Kettering Cancer Center (MSKCC) experience. Pediatr Blood Cancer 60, 694-9 (2013).
203. van Dijk, J. et al. Quality of life of adult retinoblastoma survivors in the Netherlands. Health Qual Life Outcomes 5, 30 (2007).
204. MacCarthy, A. et al. Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer 108, 2455-63 (2013).
205. Shinohara, E.T., DeWees, T. & Perkins, S.M. Subsequent malignancies and their effect on survival in patients with retinoblastoma. Pediatr Blood Cancer 61, 116-9 (2014).
206. Ford, J.S., Chou, J.F. & Sklar, C.A. Attendance at a survivorship clinic: impact on knowledge and psychosocial adjustment. J Cancer Surviv 7, 535-43 (2013).
207. Schulz, C.J., Riddle, M.P., Valdimirsdottir, H.B., Abramson, D.H. & Sklar, C.A. Impact on survivors of retinoblastoma when informed of study results on risk of second cancers. Med Pediatr Oncol 41, 36-43 (2003).
208. Rowland, E. & Metcalfe, A. Communicating inherited genetic risk between parent and child: a meta-thematic synthesis. Int J Nurs Stud 50, 870-80 (2013).
209. Clarke, S.A., Sheppard, L. & Eiser, C. Mothers' Explanations of Communicating Past Health and Future Risks to Survivors of Childhood Cancer. Clinical Child Psychology and Psychiatry 13, 157-170 (2008).
210. Farmer, P. & Mukherjee, J. (2014).
211. Grossmann, C., Sanders, J. & English, R.A. KNOWLEDGE GENERATION IN A LEARNING HEALTH SYSTEM: Workshop Summary (National Academies Press, Washington, DC 20001, 2013).
212. Jha, P. et al. Prospective study of one million deaths in India: rationale, design, and validation results. PLoS Med 3, e18 (2006).
213. Farmer, P. Who Lives and Who Dies? Medical Examiner (2015).
214. Laurie, N.A. et al. Inactivation of the p53 pathway in retinoblastoma. Nature 444, 61-6 (2006).
215. Pritchard, E.M. et al. Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor r406 after ocular delivery for retinoblastoma. Pharm Res 31, 3060-72 (2014).
216. Mahida, J.P. et al. A synergetic screening approach with companion effector for combination therapy: application to retinoblastoma. PLoS ONE 8, e59156 (2013).
217. Taich, P. et al. Clinical pharmacokinetics of intra-arterial melphalan and topotecan combination in patients with retinoblastoma. Ophthalmology 121, 889-97 (2014).
218. Carcaboso, A.M. et al. Episcleral implants for topotecan delivery to the posterior segment of the eye. Invest Ophthalmol Vis Sci 51, 2126-34 (2010).
219. Kang, S.J., Durairaj, C., Kompella, U.B., O'Brien, J.M. & Grossniklaus, H.E. Subconjunctival nanoparticle carboplatin in the treatment of murine retinoblastoma. Arch Ophthalmol 127, 1043-7 (2009).
220. Oronsky, B. et al. The war on cancer: a military perspective. Front Oncol 4, 387 (2014).
221. Wang, H. et al. Skp2 is required for survival of aberrantly proliferating Rb1-deficient cells and for tumorigenesis in Rb1+/- mice. Nat Genet 42, 83-8 (2010).