· web viewretinoblastoma. helen dimaras, tim corson, david cobrinik, abby white, junyang zhao,...

RetinoblastomaHelen Dimaras, Tim Corson, David Cobrinik, Abby White, Junyang Zhao, Francis L Munier, David Abramson, Carol Shields, Guillermo Chantada, Festus Njuguna, Brenda Gallie

Brenda Gallie Overall Canada

Helen Dimaras Global Canada

Tim Corson Basic Molecular USA

Francis L. Munier Ophthalmology Switzerland

David Abramson Ophthalmology USA

Carol Shields Ophthalmology USA

Junyang Zhao Ophthalmology China

Guillermo Chantada Peds Oncology Argentina

Festus Njuguna Peds Oncology Kenya

Abby White Patient Advocate/Survivor UK

David Cobrinik Basic Science Cell of Origin USA

[No titles or qualifications are permitted, but these can be included in the author biographies at the end of the document]

[[Total: maximum 7,500–8,000 words]] might be 11,000 now….

Abstract

[The unstructured abstract should describe the disease/disorder, and summarize the key points from the Primer. 200 words maximum. ]

Write Last BG

Keywords

[Please include a list of up to 10 keywords. These will be placed in a box on the online (HTML) version of the article and link to the relevant subject page on nature.com. Please note that not all your key words might be dedicated subject terms on the website, but our editors will make alternative suggestions should this be the case.]

retinoblastoma

Introduction 333/300

Gallie

Retinoblastoma is a rare cancer initiated by mutation of the retinoblastoma gene (RB1) in a specific developing retinal cell, resulting in cell division rather than differentiation. Biological processes first revealed in retinoblastoma led to recognition that all cancer is initiated and progresses, by altered genes. Cost-effective translation of this knowledge has improved outcomes for affected families.

The number of children affected depends on the birth rate and infant death rate, available for each country. The disease progresses from the first RB1-/- susceptible retinal cell, to tiny intraretinal tumors, which grow until they spread within the eye to form a white mass that is visible through the pupil of the eye (the most common first sign) or block vision causing the eye to lose central visual fixation (the second most common sign). If knowledge and health resources are available when these signs are first noticed, prompt treatment likely cures. If not, the cancer grows beyond the confines of the eye, (into the optic nerve, then the brain; usually incurable) or spreads through the blood to metastasize (particularly to bone marrow; may be curable with modern medicine).

Clinical trials in retinoblastoma are difficult for multiple reasons: too few patients in high income countries; complex disease presentation (two eyes of different severity); too rare to interest the pharmaceutical industry; multidisciplinary collaboration is necessary; and eyes and vision have high value in society and blindness is poorly understood. New technologies showing a dramatic primary response in the intraocular tumor have been quickly embraced for eye salvage. Despite the lack of rigorous randomized trials retinoblastoma survival in high income countries has gone from <5% to >95%.

The Internet has opened many avenues for retinoblastoma: parents make the diagnosis themselves; colleagues discuss and share patients around the globe; centers of retinoblastoma excellence are mapped; and a common database for all children no matter where they live is within sight, that could empower a learning health system to achieve an evidence base for retinoblastoma care. We review retinoblastoma now, at a time when new science, new ideas, new therapies and global collaboration are unprecedented. The concept of One Retinoblastoma World (1RBW) is a reality.

Epidemiology 1148/500

Dimaras, Festus, Zhao

Retinoblastoma is the same disease everywhere. Every newborn child has the same risk for developing this cancer, unless the child has a germline RB1 mutation. Yet, the outcomes of retinoblastoma are vastly different worldwide. We explore these issues here through the lens of epidemiology, “the branch of medicine that deals with the incidence, distribution and control of disease”.

Betty He, 03/11/15,

Bold main headings should be used to break up the text. They should be 38 characters maximum, including spaces. Secondary (bold) and tertiary (italic) subheadings may be used to further organize text. They should be 45 characters maximum, including spaces.

Gallie Brenda, 03/16/15,

Helen Dimaras; 500 words (at 768!)Maximum 500 words. Use this section to describe the global burden of disease, who is primarily affected in the different regions, incidence, prevalence, etc. Please note any areas in which there is no available data, or where the data is unreliable.


[Maximum 300 words. The introduction should define the disease and outline, briefly, its staging and classification.]

Distribution of Patients & Resources

The expected retinoblastoma patients annually per country can be calculated by multiplying the retinoblastoma incidence (1 in 16,000-18,000 live births) by forecast births (forecast births = population x birth rate x [1 - infant mortality rate]). (Table X; Supplementary Table).1-3

Of the global retinoblastoma patient population 11% reside in high-income countries, 69% in middle-income countries and 20% in low income countries. However the mismatch in resources:patients creates a gap in healthcare access: most centres are in middle- and high-income countries, but most children are in middle- to low-income countries (see www.1rbw.org).

The 1RBW Map of Treatment Centers (www.1rbw.org) aims to 1) connect affected families to expert care; 2) promote evidence-based retinoblastoma treatment; and 2) facilitate enhanced collaboration. Understanding where and how retinoblastoma children are managed worldwide provides an efficient and rapid path for parents to access urgent care. Paths of referral and multicenter co-management aim to keep affected children close to home while optimizing access to advanced therapies when needed. Understanding incidence vs location and capabilities for treatment reveals opportunities to increase regional capacity, collaboration and service.

Solutions for retinoblastoma globally

In epidemiology and global health, income is used as a classification variable because reliable figures for it exist (e.g. World Bank), that often correlate with non-economic measures of quality of life (e.g. life expectancy, child mortality, education). Retinoblastoma in low-income countries is associated with poor outcomes when compared with the high-income countries. Published national figures indicate retinoblastoma survival as high as 99%,4 and as low as 30%,5 but solid data is lacking.

The main factors that contribute to the poor outcome include late presentation, difficulty accessing or lack of health care expertise in retinoblastoma, and socio-cultural issues that lead to poor compliance to therapy, for example, family decline of enucleation and abandonment of therapy.6-8 The simplest and most reliable therapy is enucleation, a procedure with few required resources; cure, however is dependent on early diagnosis. Without timely diagnosis and appropriate means to treat, metastatic disease ensues and, is difficult to cure. This points to the key importance of awareness (e.g.public, medical community) and availability and access to expert care.

Guidelines

In 2009, the first ever retinoblastoma clinical practice guidelines were published in Canada4. Optimal resources and expertise for retinoblastoma management were outlined, which serves as a guide to inform health policy for retinoblastoma, at national, regional and institutional levels. These guidelines were adapted by the Kenyan National Retinoblastoma Strategy and published by the Kenyan Department of Health9. In both countries, a situational analysis of key treatment centres has informed systems of patient referral, educational capacity initiatives, and is predicted to result in enhanced patient care.


Table Xa shows the estimated retinoblastoma cases per country; Table Xb shows estimated retinoblastoma cases by World Bank income status.

http://www.1rbw.org/

http://www.1rbw.org/

Twinning programs

To address training and capacity needs, peer-to-peer collaborations and twinning programs have shown success.10 Retinoblastoma-specific twinning programs include North-South partnerships between St. Jude’s Children’s Research Hospital (USA) and King Hussein Cancer Hospital in Jordan,11 and several Central American institutions12. Twinning programs help to build a framework for knowledge exchange and sharing of expertise, provide specialized training to fill gaps in the health workforce, and source donations of much needed equipment and resources.

However, from a programmatic and implementation science perspective, twinning initiatives have been criticized for their unidirectional leadership (i.e. high-income country partner holds the ‘power’ in the partnership), promoting dependence on high-income country partners, and the need for funds that may not sustainable in the long-term. Focused efforts to build capacity in individual centers may also undermine national efforts by local Ministries of Health, so care must be taken to assure equitable partnerships fully integrating the local stakeholder

National retinoblastoma trategies

Development and implementation of national retinoblastoma strategies may avoid some of the challenges described above, as they focus on asset-based development locally. The Kenyan National Retinoblastoma Strategy (KNRbS) includes all concerned about retinoblastoma (ophthalmologists, oncologists, pediatricians, pathologists, Ministry of Health, nurses, child life specialists, parents, survivors and others), meets annually, and collaborates year-long. A major breakthrough came in 2014 with publication by the Kenyan Ministry of Health of the Guidelines.9 The KNRbS has facilitated collaboration among the institutions that treat retinoblastoma and the Ministry of Health, with stratification of care depending on available facilities. Standardization of processing and reporting of the pathology specimens now supports treatment decisions and discussion of prognosis with the families. There are fewer incidences of declined enucleation as a result of adoption of upfront enucleation with implants and immediate prosthetics eyes (sourced from India), parent to parent interactions to allay uninformed fears, and standardization of information provided to parents.9, 13

One national multicentre clinic

A unique model has developed in China, where more than 1100 newly diagnosed cases annually, scattered over 32 provinces. More than half the treatment cost is travel. Before 2005, the enucleation was the only treatment available for most children. At presentation 28.7% were IIRC14 Group D, 55.5% Group E; 70% of unilateral patients were Group E.

For the better treatment and follow-up, Dr. Junyang Zhao established multiple centres in 28 hospitals covering 25 provinces (over 90% of the population). These hospitals are on the 1RBW map, classified by level based on personnel and resources: basic, ophthalmologist and RetCam for normal EUA, (10 hospitals); medium, ophthalmologist, RetCam, laser or cryo (9 hospitals); advanced, ophthalmologist, oncologist, laser/cryo (3 hospital); and comprehensive, ophthalmologist, oncologist, pathologist, radiologist, all required ophthalmic equipment (6 hospitals). Each hospital appointed one local ophthalmologist coordinator to oversee the EUAs, communicate with Dr. Zhao and the local multidisciplinary team (such as oncologist, radiologist, pathologist). All patients are classified by IIRC14 (eyes) and TNM staging15 and are treated with common protocols. With network efficiency and collaboration, 2097 new diagnosed retinoblastoma patients were treated from 2006 to 2014. Survival rate

increased from 30%~50% to 80%~90%. This is an unprecedented opportunity for clinical research in retinoblastoma.

One Retinoblastoma World

1RBW (www.1rbw.org) is a global network with the bold idea that all children with retinoblastoma can have equal opportunity to optimal care. A global collaborative, constellation-modelled approach aims to harness the power of all the individual activities, institutions and national strategies and networks, and deliver coordinated, evidence-based retinoblastoma care. The Internet networking links retinoblastoma experts everywhere, proportional to numbers of patients and their geographical distribution. Without prior awareness of retinoblastoma, parents now commonly self-diagnose on the Internet, arrive at the 1RBW map and discover means to directly connect them to experts, without delay and obstacles. We look to a day when equality for retinoblastoma comes by education (Internet access), retinoblastoma expertise developed locally (proportional to local burden of retinoblastoma), with shared care coordinated online, can improve outcomes for patients and families.

Display items

Table/Figure:

Estimated Global Distribution of Retinoblastoma // Figure Combo with heat map from www.1RBW.org

Supplementary Table: Global Retinoblastoma Burden by Country (excel sheet)

Table shows estimated retinoblastoma casesfor each country.

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 (1:18000 live births) and high estimates (1:16000 live births)calculated, following the example ofKivela.1

Disease Mechanisms/pathophysiology 1573/1500

Corson, Cobrinik, Gallie

Knudson’s mathematical analysis of age at diagnosis showed that retinoblastoma formation in bilaterally affected, predisposed individuals (heritable disease) is consistent with one rate-limiting event, while two events are necessary for retinoblastoma to develop in most unilaterally affected children with no family history.16

Comings clarified that Knudson’s data suggested that hereditary cancers result from a heritable germline mutation (first hit) and an acquired somatic mutation (second hit) in the cell of origin.17 In 70% of retinoblastoma tumors the somatic mutation is loss of heterozygosity (LOH), two alleles carry the same mutation; 30% of tumors arise when a new


Maximum 1,500 words Currently 1650 excluding scrap notes. This section should focus on the molecular mechanisms of the disease/disorder and must include at least one figure that highlights the established (and/or speculative) pathways involved and one figure that shows the ‘healthy’ pathways for comparison. Specific guidance on figures can be found here. Key proteins and genes can be described here. You might like to include subsections that describe important disease models (be they cell lines, animal models or computational). INSERT SOME HEADINGS

http://data.worldbank.org/

somatic change disrupts the somatic allele.18 Search for genomic regions of LOH in tumors led to discovery of loci of many tumor suppressors accounting for heritable cancers.19

The retinoblastoma gene was the first tumor suppressor gene to be cloned.20-23 Chromosomal deletions in some patients led investigators to chromosome 13q14, where LOH for polymorphisms enabled fine mapping of the locus. Eventually, Southern blotting confirmed loss from a tumour of both copies of a 13q probe20 that was expressed in mRNA and turned out to be a conserved, exonic sequence, leading to cloning of the RB1 gene.19

RB1 is a large (190 kbp) gene with 27 exons. A huge number of different mutations knock out function, including point mutations, promoter methylation, and small and large deletions.24 Nearly all retinoblastoma tumours have mutation of both copies of RB1. However, 1.4% of unilateral patients have tumours with no detectable RB1 mutation, and instead primary high-level amplification of the oncogene MYCN (MYCNA) drives initiation of retinoblastoma. RB1+/+MYCNA retinoblastomas show very early onset and a distinct histology, reflecting a unique subtype.25

RB1 encodes a 4.7 kb mRNA, translated into the 928 aa protein, pRB. The A/B “pocket” region26 is best characterized, mediating numerous protein-protein interactions and harboring missense mutations. The A/B pocket is conserved in two other pRB family members or “pocket proteins”, p107 (RBL1) and p130 (RBL2). These proteins share some of the functions of pRB, but are rarely mutated in cancer, although a large region of chromosome 16q containing p130 is lost in some retinoblastoma and other cancers.

pRB is best known as a cell cycle regulator, with function mediated by binding to E2F transcription factors, repressing cell proliferation-related genes. Hyperphosphorylation of pRB by cyclin-dependent kinases in response to mitogenic signals relieves repression and promotes the G1 to S phase transition. However, additional functions in cell cycle, maintenance of genomic stability, and apoptosis are now also well documented and could also contribute to tumor suppression.26

Although biallelic loss of RB1 is necessary to initiate most retinoblastomas, this is not sufficient; RB1-/-retinal cells likely either undergo apoptosis, or proliferate in a limited fashion to form the benign retinal lesion, retinoma.27 Further genetic or epigenetic lesions are associated with malignant transformation.28 Comparative genomic hybridization (CGH) studies identified common regions of DNA gain or loss in retinoblastoma, which led to identification of candidate oncogenes: the mitotic kinesin KIF14 and p53 regulator MDM4 (1q32), transcription factors E2F3 and DEK (6p22), and the oncomiR clusters miR-106b~25 (7q22.1) and miR-17~92 (13q31). Loss at 16q22 led to identification of cadherin-11 (CDH11) as a tumor suppressor gene, while whole-genome sequencing identified inactivating mutations in the transcriptional corepressor BCOR in some samples.29 Epigenetic alterations may also drive retinoblastoma formation: the oncogenic kinase SYK has an activated histone signature in retinoblastoma.29 Numerous other genes show altered expression in retinoblastoma as compared to the normal retina,30 including those altered at the DNA level (above), several microRNAs, and the multidrug resistance gene (MDR1), which increases resistance to chemotherapy.

Retinoblastomas show distinct histology. Similar to other pediatric cancers, they are a “small, round, blue cell tumor”. Well-differentiated regions form rosette structures: Flexner-Wintersteiner rosettes are virtually pathognomonic of retinoblastoma while Homer-Wright rosettes are common in diverse neural cancers (Fig x).31 Retinomas feature more

David Cobrinik, 16/03/15,

seems normal retina is usually the reference but might not be as relevant a reference as the cell of origin

differentiated photoreceptor-like clusters of cells termed fleurettes.27 Poor prognosis histopathological features increasing the risk of metastasis, include invasion of tumor into the optic nerve, choroid, or sclera.

While retinoblastoma histology, genomic changes, and protein and gene expression are widely accepted, the origin of retinoblastoma has been hotly debated. Prior proposals for cell-of-origin were based on controversial features of retinoblastoma cells. For example, evidence of a neural-glial phenotype in the widely used Y79 cell line was proposed to support an origin from a primitive neuroectodermal cell with bidifferentiation potential,32 then challenged.33 Similarly, retinoblastoma cells expressing markers of different retinal cell types suggested a multipotent cell-of-origin, yet may also represent normal RB1-positive retinal cells within the tumor mass.34 Moreover, single retinoblastoma cells were found to co-express RNAs characteristic of diverse retinal cell types,35 suggesting a “hybrid” gene expression profile consistent with multipotent origin. However, these same features could also reflect an artifact of oncogenic transformation, rather than cell-of-origin properties. Mouse retinal tumor models have not clarified the cell-of-origin, since the Rb1 loss is combined with loss of p107, p130, or p27,36 and retinal marker expression differs, cautioning against extrapolation to humans.37

One of our groups has detected in RB1-/- tumors consistent expression of cone photoreceptor proteins compared to other retinal cell type proteins. Maturing cone precursors prominently express oncoproteins (MDM2 and N-Myc) that could collaborate with RB1 loss to enable retinoblastoma growth,34 supporting a cone precursor origin. Nevertheless, the cone precursors’ oncopotent features and the retinoblastoma cells’ cone-like phenotype and reliance upon cone circuitry were only circumstantial evidence leaving the possibility that the cone phenotype is acquired after tumors initiate elsewhere. More direct evidence is that experimental depletion of RB1 induced cone precursor proliferation, and orthotopic xenografts elicited tumors with histology, protein expression, and a lack of cytogenetic changes typical of differentiated retinoblastomas.38 Proliferation depended upon the cone precursors’ high level N-Myc and MDM2 expression, the cone-specific transcription factors RXR and TR2, and a down-regulation of p2738 that occurs during cone precursor maturation.39 These features suggest that RB1 counters a mitogenic program that is intrinsic to maturation of cone precursors.

The cone precursor origin of retinoblastoma is challenged by detection by optical coherence tomography (OCT) of very early tumors in infants carrying an inherited RB1 mutation. The smallest tumors are centered in the inner nuclear layer of the retina, not the outer nuclear layer where mature cones reside.40 This discrepancy could relate to inappropriate migration of RB1-deficient cone precursors either when they are born or after they begin to divide. The location of these early tumors could reflect a retinoblastoma cell requirement to interact with blood vessels and retinal astrocytes, which are present only in the inner retina and ubiquitous in tumors, and promote retinoblastoma cell growth in vitro.41

Despite progress, questions regarding the retinoblastoma cell of origin remain. For example, it is uncertain whether cone precursors originate all RB1-/- retinoblastomas, or only the highly differentiated variety that usually lack cytogenetic changes.42

RB1+/+MYCNA retinoblastomas are diagnosed much younger age than RB1-/- tumors, even those that arise in predisposed persons carrying RB1 mutations. The trend of increasing MYCN copy number with age at diagnosis, and the very young age of presentation of very large tumors, suggests that the cell of origin of RB1+/+MYCNA tumors is developmentally

earlier than that of RB1-/-tumors.25 RB1+/+MYCNA retinoblastomas have yet to be modeled in mice but there are several cell lines.

Moreover, the pRB functions that normally suppress retinoblastoma with such strong specificity for one embryonic cell type, remain unknown. In addition to its ability to suppress E2F, pRB can up-regulate p27 via stabilization of SKP2, and is implicated in cell differentiation, apoptosis, and genomic integrity.26 However, pRB seems unlikely to sustain p27 expression in maturing cone precursors, since increasing pRB expression is associated with decreasing p27 during cone precursor maturation.39 It is tempting to speculate that pRB is primarily needed to suppress E2F. Howerver, several “low expressivity/penetrance” RB1 mutations encode proteins that have minimal ability to bind E2F, yet typically predispose carriers to only one or no retinoblastomas43 in contrast to the mean of 5 tumors in carriers of RB1 null alleles.44 Such E2F-binding defective alleles may suppress the remaining, otherwise expected retinoblastoma through an E2F-independent mechanism. Clearly, there is opportunity to further define tumor suppressor functions in the clinical retinoblastoma scenario.

Human retinoblastoma cell line as well as mouse models have been used to test therapeutic approaches. Most cell culture studies of retinoblastoma have used just two cell lines, Y79 and WERI-Rb1, developed in the 1970s.45, 46 Many other lines exist, but are not widely distributed.47 Primary retinoblastoma cells form xenografts in immune deficient mice.48 and were recently used to evaluate SYK inhibitors as preclinical candidate therapies.29

Genetically engineered mouse models are also powerful for genetic studies and treatment testing.49 Rb1-/- mice are embryonic lethal and heterozygotes do not develop retinoblastoma. However, chimeric or deletion of Rb1 (using Pax6a, Nestin, or Chx10 promoters) targeted to retina, in mutant p107, p130 or p27 backgrounds, achieves retinal tumor formation. miR-17~92 was confirmed as an oncomiR by overexpression in Pax6a-Cre;Rb1lox/lox; p107-/- mice.50 However, given that these mouse tumors require different collaborating mutations and might not originate from the same retinal cell type, their ability to predict human retinoblastoma treatment responses is not certain.

Similarly, viral oncoproteins can also promote retinoblastoma, including sporadic tumors when adenovirus E1A is delivered to the retinas of p53-/- mice, and “TAg-RB,” in which Simian Virus 40 T-antigens are expressed in a developing Müller cell, promoting retinoblastoma.51 Subconjunctival topotecan was tested in this latter model and is now in the clinic, and Cdh11 was confirmed as a tumor suppressor by crossing a knockout into this model.52

Viral oncoproteins can also promote retinoblastoma, including sporadic tumors when adenovirus E1A is delivered to the retinas of p53-/- mice, and “TAg-RB,” in which Simian Virus 40 T-antigens are expressed in a developing Müller cell, promoting retinoblastoma.51 Subconjunctival topotecan was tested in this latter model and is now in the clinic, and Cdh11 was confirmed as a tumor suppressor by crossing a knockout into this model.52

References: Nature Reviews Style. Must annotate 2-3 references total as of key importance; please indicate 1-2 nominees for each subsection.

Figures: ideas (at least two desired by editor): Genomic events leading to retinoblastoma Retinal precursor cells of potential origin of retinoblastoma

Human retinoblastoma comparing retinal OCT and human in vitro retinal stem cells culture??

Diagnosis, screening and prevention 1751/1500

Dimaras, Gallie, White, Zhao

This section describes diagnosis (primary detection by a healthcare professional), screening (prospective procedures to diagnose as early as possible) and prevention (pre-empt the development) of retinoblastoma and second cancers.

Clinical Diagnosis

Retinoblastoma can affect one (unilateral) or both (bilateral) eyes; midline primitive neuroectodermal tumors or pinealoblastoma can rarely arise in a similar cell of origin (trilateral). The most common first sign noticed worldwide for retinoblastoma is leukocoria, a white reflection inn the pupil due to light reflecting off the surface of the tumor directly into the observer’s eye. Second most common sign is strabismus, or misaligned eyes, due to the tumor damaging central vision. This develops when tumor damages or blocks macular vision, or if a retinal detachment extends into the macula. Other signs of advanced disease include change in iris color, an enlarged eye due to glaucoma, and orbital cellulitis. Proptosis (protrusion of the eye from the socket) as a first sign of retinoblastoma, is common where awareness and access to healthcare are poor. Often the parents notice leukocoria, but are unaware of its significance, or self-diagnose (on the Internet) but can not convince their health advisors that there is a problem. Importantly, as awareness efforts are being implemented globally, advanced retinoblastoma at diagnosis is declining.

Unlike most cancers where pathology provides the definitive diagnosis, retinoblastoma diagnosis is clinical; biopsy incurs high risk of metastasis. The most dangerous cause of leukocoria is retinoblastoma, this observation necessitates rapid referral to an expert who can accurately diagnose retinoblastoma by simply looking with the indirect ophthalmoscope after pharmacologic dilation of the pupil of the eye. A dilated eye exam/fundoscopy and ultrasound effectively diagnose and estimate extent of tumour in the eye. MRI provides information on the pineal gland or other involved structures. Fundus cameras and OCT add further detail to the diagnosis. All of this information is used to describe severity of cancer in each eye and assign a stage (see next).

Clinical Staging

The first ocular classification scheme was the Reese-Ellsworth (RE) classification.53 It predicted outcomes of external beam radiation largely based on size, retinal location of tumor and vitreous seeding. When systemic chemotherapy (IVC)/focal therapy became the common primary treatment to salvage eyes, Murphree led international collaboration toward the International Classification of Intraocular Retinoblastoma (IIRC) which better predicted responses to IVC than the RE scheme.14 Shields subsequently published a different version54 that results in discrepant classification of 25% of the most severely involved eyes (Figure x: Inconsistent Classification of Intraocular Retinoblastoma).55, 56 . Further confusing clinical research, the Children’s Oncology Group (COG) put forward another classification with minor measurement differences from the Murphree IIRC, further compromising


HELEN keep this in see email to david and tim I want to get the forward thinking of true prevention. Ie the bremner prevention grant into it.


[Maximum 1,500 words Currently 2070. What are the risk factors (genetic or environmental) for the disease? How is the disease clinically diagnosed? Discuss point of care tests, bloods, imaging, histology, etc. What is the differential diagnostic procedure? What are the factors that hinder a diagnosis? Are screening methods available for this disease (for example, PSA screening for prostate cancer, or mammography for breast cancer)? How do these differ in different geographical areas/countries? What are the documented advantages and disadvantages? Biomarkers can be discussed in this section, as can imaging innovations and uses. Are preventive measures available to stop the disease or disorder? How do they work, how effective are they and what impact have they had on the burden of disease for the patient and from a global public health perspective? You might wish to separate these discussions using subheadings.]

prognostication and research (Figure x: Inconsistent Classification of Intraocular Retinoblastoma). For this Nature Reviews Disease Primer, we choose the Murphree IIRC.14

The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system, called TNM, is defined by the primary tumor (T), lymph node extension (N), and distant metastasis (M). It provides standard description of all cancers, empowering research that has had major impact on patient outcomes. The 7th edition of the AJCC Cancer Staging Manual provided the first widely accepted staging system for eye cancer57, that has been validated for uveal melanoma58. However, the 7th edition TNM for retinoblastoma15 is not widely used.

Pathology Staging

For Group E eyes, histopathological assessment of extent of tumor in the enucleated eye is used to assess risk for metastases and need for adjuvant therapy. Pathology specimens are staged using the pathology TNM (pTNM) (Table X), scoring the eye tumor, nodes and metastasis.15

Genetic Diagnosis

The majority (94%) of patients with retinoblastoma are the first individuals to be diagnosed in a family, based on 141/2141 probands who indicated family history when tested for RB1 mutations. The remaining 6% of retinoblastoma patients are familial, meaning one or more family members were previously diagnosed with retinoblastoma. Approximately 50% of people with retinoblastoma carry one RB1 mutation in their constitutional cells (all bilateral and 15% of unilateral isolated patients).59 The remaining unilateral retinoblastomas arise by somatic mutational events involving either biallelic RB1 loss or somatic amplification of the MYCN oncogene and carry no additional cancer risks.

Knowledge of the predisposing mutation in the proband enables precise screening of relatives and subsequent generations for that mutation. The mutation can be detected prenatally, and labour induced near term to screen the baby’s eyes and treat tumors at the earliest time. Without genetic testing, it is recommended that patients with possible predisposition (e.g. unilateral, positive family history) continue to undergo multiple exams under anaesthetic.

After genetic testing, 85% of unilateral retinoblastoma patients will test negative with <1% residual risk for undetectable mosaicism, but will still need surveillance.4 Knowing the disease causing mutation also allows accurate screening in family members, reducing risks for cancer for those found not to be predisposed.

Knowledge of tumor mutations can also be used to screen CSF and bone marrow for possible tumor dissemination, and to screen harvested stem cells for minimal residual disease. Conventional screening is by standard cytology, but recent evidence shows that molecular screening can be more sensitive. Markers that have been used are the RB1 tumor mutation (when different from germline mutation, or the child is not germline carrier)60 and the M3-Mn signature.61

Taking a detailed family history can help define risk of retinoblastoma for individual family members, and in some cases, uncover a previously unknown family history of retinoblastoma where a newly affected child is the presumed proband. Genetic testing of the proband can identify the causative RB1 mutation, and this knowledge applied to screen family members and further define their risk of developing retinoblastoma. Without genetic testing, it is

Helen Dimaras, 11/03/15,

I’m having trouble fitting this into the appropriate section. In some ways, family history is part of CLINICAL DIAGNOSIS. But GENETIC DIAGNOSIS is relevant too. Also, when either family history or genetic testing is known, this is relevant to the SCREENING for familial cases. I’m not sure where each piece best fits…

recommended that the patients continue to undergo multiple exams under anaesthetic.62 After genetic testing, 85% of unilateral retinoblastoma patients test negative and require only standard clinical exams without the requirement for anaesthetic.

Achieving best outcomes in familial retinoblastoma rest on alertness of the healthcare team to identify and counsel families, and communicate clearly to ensure appointments are made and met. Education of parents is vital, so that they not only receive appropriate genetic counselling but understand the risks and/or necessary actions to strive for best care for each at-risk pregnancy. Alarmingly, a study of retinoblastoma in several developing countries found that familial cases were diagnosed later than new probands.63 The authors inferred that the probands were not fully informed and did not understood the risks to their children, resulting in the delayed diagnosis. Alternatively, socioeconomic or geographic barriers (i.e. low income, living in remote areas) may have reduced access to healthcare for families that may have indeed known and understood their risks. Attitudes, influenced by culture and society, towards genetic screening for cancer may have also influenced the likelihood of seeking medical attention in such cases. Clearly, study of social determinants of health, such as health seeking behaviour, perceptions of medical care, and sociocultural issues related to cancer inheritance may are necessary to design counselling approaches that better need the needs of families.64

Vision Screening / Eye Examination

Screening refers to attempts taken to detect retinoblastoma with the aim of diagnosing as early as possible. We explore both vision screening / eye examinations, and screening for second cancers.

While a dilated fundus examination could potentially detect retinoblastoma, screening for retinoblastoma in the general population is difficult due to its relative rarity. General recommendations for childhood vision screening are appropriate, and with effective training to pick up retinoblastoma signs, it is possible the rare case could be identified. However, a clear childhood vision test doesn’t mean this child is in the clear for retinoblastoma; the timing of tumor initiation is yet to be determined (one could imagine a tumor appearing after a vision screening) or a tumor may have been in the periphery and not seen by the person conducting the screening. While broader vision screening programs could detect the odd case of retinoblastoma, they are not to be relied on.

Leukocoria is most often first noted by parents, and rarely found first by physicians. More troubling are frequent reports of the physician failing to take the parental complaint of leukocoria seriously, due to their own lack of awareness. Photoleukocoria refers to the appearance of leukocoria on flash photographs. Awareness campaigns educating parents to examine photographs for this sign attempt to educate parents and lead to earlier diagnosis. In an innovative study called PhotoRed, investigators in India are looking at training healthcare professionals to use flash photography to identify childhood eye diseases, including retinoblastoma.65 In a similar pioneering project, researchers are exploring how software development may enable cameras to detect photoleukocoria.66

A camera’s Red Eye Reduction technology contracts pupils when the photograph is taken, limiting photoleukocoria detection. Red-eye and pet-eye correction tools also enable unsuspecting parents to remove photoleukocoria (Figure: Lancet photos or example photo). Engaging the global imaging industry may dramatically improve early diagnosis.

Awareness is key to screening. Education of survivors, parents and primary health carers about actual risk (based on genetic knowledge), symptoms and action to take when concerned will improve early diagnosis.

Second Cancer Surveillance

Individuals with germline RB1 mutation and/or treated with radiotherapy have an elevated risk of developing second cancers. The most common second cancers for retinoblastoma are leiomyosarcoma, osteosarcoma, melanoma, lung and bladder cancers.67

Genetic and follow-up oncology counselling can alert individuals with RB1 mutations to these risks. Survivors are often urged to be extra vigilant about unexplained lumps, pains or skin changes. However, screening for second cancers is not yet standard of care. 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.68 This is an important area for further research so that second cancers can be identified for early intervention and reduction in mortality.

Prevention

Pre-implantation genetic diagnosis offers the family the option for unaffected children when the mutation of a parent is identified.69

Lifestyle counseling for retinoblastoma survivors educates individuals on ways to reduce their second cancer risk. In addition to being vigilant about detecting unexplained lesions, they are encouraged to eat an anti-oxidants rich diet, avoid an unnecessary radiation (including X-ray and CT) and carcinogens like cigarettes and excessive alcohol. The extent to which these ideas will reduce or prevent second cancers is unknown.

The future of retinoblastoma care is to move from prediction to prevention. While a bold assertion, there is promising evidence from other familial cancer syndromes such as Li-Fraumeni syndrome,70 von Hippel-Lindau disease71 and mismatch repair diseases72, suggesting this could soon be reality.

References

36 references max

Display item

(only 1, we have 3 potentials, but perhaps we could refer to another section for some of these, if overlap)

Table X: Staging Differences (from Brenda’s TNM database table) Table Y: Impact Genetics numbers on familial cases Figure: Leukocoria image?

Management /3000

Munier, Abramson, Shields, Chantada, Njuguna, Gallie, Zhao


[Maximum 3,000 words. Use this section to describe the current standard of care (around the world) and adverse effects of treatment. Are biomarkers available for drug response? What treatments are currently in the pipeline? Relate targets back to the pathophysiology section, and the main drivers of disease. Are there issues of treatment resistance?]


[Maximum 3,000 words. Currently around 3600 Use this section to describe the current standard of care (around the world) and adverse effects of treatment. Are biomarkers available for drug response? What treatments are currently in the pipeline? Relate targets back to the pathophysiology section, and the main drivers of disease. Are there issues of treatment resistance?] Current Standard of Care (refer back to staging, importance of time, leukocoria first sign high cure rate, impact of vitreous seeds) (refer back to staging, importance of time, leukocoria first sign high cure rate, impact of vitreous seeds) note for staging discussion (dimaras)

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 accessibility to expert care where the child lives.73, 74 Diagnosis is usually clear from presenting signs75 (See DimarasDx section) and clinical examination. Biopsies are not performed on presumed intraocular retinoblastoma due to risk of seeding tumor outside of the eye. The leading simulators of retinoblastoma include Coats disease, persistent fetal vasculature, and vitreous hemorrhage.76

INTRAOCULAR RETINOBLASTOMA PRIMARY TREATMENT

Choice of primary treatment reflects first, consideration of patient survival, and second, eye salvage and ultimate visual potential, both weighed against short term and long term complications of treatment.73 In order of approximate frequency of use globally, primary treatment options for presumed intraocular disease include enucleation, intravenous chemotherapy (IVC) with focal therapy (laser, cryotherapy), intra-arterial chemotherapy (IAC) with focal therapy, and focal therapy alone for patients/eyes with small tumors at diagnosis. External beam radiotherapy (EBR) is now reserved for refractory cancer in the last eye with a chance for useful vision, since radiation incurs a very high risk of second cancers on persons carrying an RB1mutation, especially in the first year of life.77, 78

Treatments considered for intraocular retinoblastoma are dependent on the classification of severity of disease (section diagnosis…). We use the Murphree IIRC14 for this Review (Figure x: Inconsistent Classification of Intraocular Retinoblastoma;Table x: Treatments for Retinoblastoma Based on Classification and Stage). The availability of treatments globally varies directly with expertise and resources. The safest treatment for cure, available everywhere, is enucleation. Eye salvage Eye salvage can be achieved using conservative methods. attempts incur risk of metastasis and death, high costs (economic, psychological impact of multiple procedures and anaesthetics, family stress, etc), to be weighed against the lifelong value of the eye (vision, cosmetic, etc). Choices of primary treatment for each child are best arrived at by fully informed discussion of all factors with the parents and guardians.

Where resources are limited, even bilateral disease may be treated with bilateral enucleation since lack of equipment and difficulties with close monitoring risk metastases and death .79, 80

Primary treatment options depend on the IIRC of each eye (Table x: Primary Treatment for Intraocular Retinoblastoma). Group A eyes can be treated with laser/cryo focal therapy only. If the other eye is Group B, C or D, laser to the Group A eye may be delayed to allow the systemic chemotherapy to reach the tumor before the blood supply is cut off by laser. Group B eyes require several chemotherapy cycles followed by focal laser/cryo to optimize vision by minimizing focal therapy near the macula and optic nerve. Group C eyes require several chemotherapy cycles because minimal extension beyond the retina is evident as vitreous or subretinal seeding; intravitreal melphalan (IViC) () for vitreous seeds may be included in the primary plan, after systemic chemotherapy. Isolated Group B, C eyes with one tumor may occasionally be appropriate for primary radioactive plaque therapy.

Group D eyes are can be managed by enucleation, IVC or IAC. when unilateral, Enucleation is the fastest and cheapest treatment for such eye incurring the least invasive procedures and anaesthetics.81, 82 but the eye is lost. Eye salvage with either, or both, intravenous IVC or intra-arterial chemotherapyIAC, or both, followed by repeated EUAs for focal therapy has been usedoffers hope to save the eye safely. The success to save the a Group D eye with intravenous chemotherapyICV is 47% with high dose vincristine, etoposide and carboplatin

(VEC) (Table x: Chemotherapy drugs and doses.) and optimal focal therapy.83 The success rate for IAC for Group D eyes (Shields IIRC)54, 84 was 94%.84 The major reason for failure of IVC and IAC was recurrence of subretinal or vitreous seeding within 3 years.,85, 86 Since vitreous seeds at diagnosis predicts recurrence, IViC may be included in the initial treatment plan, to be delivered after control of the source of seeds by IVC or IAC87. which may be similar after IAC.

IIRC14 Group E eyes by the Murphree IIRC14 have clinical features that suggest risk for imminent or actual extension of retinoblastoma beyond the confines of the eye, with 10% risk of metastatic death.88-90.89 Attempts to salvage Group E eyes haves a negative impact on survival,90 since pre-enucleation treatment may mask the high risk for metastasesextraocular extension is masked by pre-enucleation systemic chemotherapy.90 When high risk features are documented, adjuvant chemotherapy may abort incipient metastases.88, 91-94 This effect can logically be anticipated if intra-arterial chemotherapy is used as primary treatment for a Murphree Group E eye, since the chemotherapy targets the region of the eye, while systemic chemotherapy might treat extraocular tumor cells. No studies address this issue, but mMetastatic disease case is reported after IAC in a Group E eye.95;Starrs, 2015 #21557} Therefore, for safety, enucleation is uniformly recommended for Murphree IIRC14 Group E eyes. Evaluation of the present literature on IAC is very difficult, since the Shields IIRC96 Group E includes labels many Murphree IIRC14 Group D eyes as Group E..14.;Shields, 2006 #21122} (Table x: ……)

For those who undergo upfront enucleation, high risk pathology features point to the need for adjuvant treatment with several modalities, depending on the extent and risks for distant metastases, central nervous system or orbital extension/metastases.94

Bilateral retinoblastoma in much of the less developed world is best treated with bilateral enucleation, where there is lack of expertise, equipment and resources, and especially when there are difficulties with close monitoring.79, 80 There Many are Many bilaterally enucleated retinoblastoma survivors who lead active, productive and satisfying lives because they were cured by timely surgery as infants. (urls??)

Intraocular Retinoblastoma: Second Line (Salvage) Therapy

Second line salvage means initiating a new plan of therapies, to make a second attempt to save an eye that has failed the first plan. All retinoblastoma treatments involve multiple modalities, and a range of modalities is appropriate for second line therapy. However, each subsequent plan has a lower success rate86 and long drawn out attempts to salvage an eye incur high costs of many kinds for the child and family.97, 98 98 97

Second line treatments have included focal therapies including peri-ocular chemotherapy,99 repeated systemic chemotherapy,99, 100 repeated IAC,86 iodine or ruthenium brachytherapy,101,

102 EBRT83, 103, 104 and tantalum ring localization105 or whole-eye106 proton beam radiotherapy. Criteria for secondary enucleation after to salvage an eye are not well defined but are dominated by refractory subretinal and vitreous seeding,100, 107 complications such as vitreous hemorrhage and secondary neovascular glaucoma suggesting risk of extraocular extension,106 and socio-economic and psychological fatigue to save an eye with poor vision.98 Unlike pathologic risk factors following primary enucleation, scleral invasion in secondarily enucleated eyes was most associated with extra-ocular relapse.108

Prior to the advent of intra-arterial chemotherapy (IAC), over 60% of eyes with advanced retinoblastoma treated by chemoreduction and focal therapy failed (required salvage external beam radiotherapy and/or enucleation).109 First-line IAC reduced the recurrence rate in group D eyes.110 Combination of IAC and intravitreal chemotherapy (IViC) can play an important role to save eyes that have failed systemic chemotherapyIVC.84, 110, 111 However, there are a significant number of children with metastases now reported, after an extensive series of treatments to save an eye may increase risk for metastases, indicating that the whole child needs to be kept in mind at all times.86, 95, 112

Despite advances in the conservative management of advanced retinoblastoma, the major cause of failure remains the persistence or recurrence of vitreous seeding. Pharmacokinetic studies have shown poor vitreous levels of drugs administered by either systemic chemotherapy or IAC.113 The highest drug bioavailability in the vitreous, is achieved by IViC using a safety-enhanced injection technique in carefully selected eligible eyes.114 Following control of the source of seeds, IViC achieved two-year Kaplan-Meier estimates of 98.5% and 90.4% event-free survival for target seeds and ocular survival respectively.87, 114, 115 The number of IViC treatments to attain control of vitreous seeds is dependent on the type and extent of seeding.116 The efficacy of IViC has eliminated the need for EBR, and decreased patient exposure to salvage systemic or intra-arterial chemotherapy. The toxicity of IViC is limited to localized peripheral salt-and-pepper retinopathy, the extent of which is technique-dependent.117

Combinations of new routes for therapy can target salvage therapy to the site and extent 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. Conversely, eyes with relapse touching the optic nerve head and/or vision-critical regions such as the maculo-papillary bundle, and eyes with diffuse retinal/subretinal recurrence, represent good indications for IAC, which might achieve better visual outcome than focal treatments. However, it is clear that therapies that have already failed to control the intraocular tumor are unlikely to succeed as salvage therapy for the same eye.

Ophthalmic Imaging for retinoblastoma Care

Fundus Photography

The armamentarium of imaging devices used for retinoblastoma care are applied for diagnostic and documentation purposes. They are beneficial for second opinion consults or as follow-up status reports on referrals. Imaging is helpful when informing parents of the progression or regression of tumours.

The mainstay of retinoblastoma documentation is retinal imaging. Under general anaesthesia, fundus photography is performed at the bedside using a hand-held fundus camera, the RetCam®, which can provide a comprehensive pan-retinal view when images are taken of the posterior pole, superior, inferior, nasal and temporal fields. The device has several interchangeable lenses. As a standard, a wide field lens (130° or 120°) documents multifocal tumour locations. A wide field lens, combined with ample coupling gel and scleral depression, provides visualization of the ora serrate and any possible tumour activity there. The 80° lens, if available, reveals high contrast detail of posterior pole lesions. Imaging of peripheral lesions with this lens is also possible using scleral depression. Care must be taken during imaging to minimize the occurrence of pulsations within the optic nerve from compression of the eye.

Retinal photography in the clinic may be performed with standard table-top fundus cameras for patients who are compliant enough to sit at a chinrest. Most systems have a narrow to medium field of view. Images may be captured of specific tumour or scar locations, or a general sweep of the posterior pole and mid periphery may be done. The OPTOS, a non-mydriatic wide field camera of 200° may also be a useful for an overall general view of peripheral tumour locations.

Intravenous Fluorescein Angiogram (IVFA)

RetCam® Intravenous Fluorescein Angiogram (IVFA) may be performed at the bedside with the wide field or 80° lenses to evaluate vascular abnormalities including suspicious areas of residual tumours, new vessel activity over scars, and areas of non-perfusion. It may also be helpful in differentiating retinoblastoma from other pediatric retinal diseases.

Optical Coherence Tomography (OCT)

The OCT, in the clinic or for patients under anaesthesia, is used to assess cross-sectional retinal changes. A hand-held OCT in the operating room is used in patients less than 1 year of age, to sweep the posterior pole to detect sub-clinical new small posterior tumors which cannot be seen grossly via an indirect ophthalmoscope or RetCam®. The OCT is also used to monitor treatment response and tumour activity, to evaluate foveal architecture/disruption, scars, dragging or detachment and to identify causes of visual loss such as retinal atrophy, retinal edema, persistent retinal detachment, optic disk edema or atrophy.

B-scan Ultrasound

Demonstration of calcium is important in the diagnosis of RB. The 10MHz b-scan is one of the tools commonly used at diagnosis to detect the presence or absence of calcification. During disease management the b-scan is used to measure tumour height, to evaluate the posterior of the eye when there is a poor view, to monitor progression or regression of tumour masses, to assess retinal changes including retinal detachment and to evaluate the optic nerve, although infiltration or extra-ocular disease is not well resolved by b-scan ultrasound.

Echographically, retinoblastoma tumors may have a smooth, dome shape or an irregular configuration. Internal reflectivity varies with calcification. Non-calcified tumors present with low to medium reflectivity, whereas calcium produces extremely high internal reflectivity. Calcium produces shadowing of the underlying sclera and orbit.

Ultrasound Biomicroscopy (UBM)

High frequency ultrasound (50MHz) in UBM devices is employed to evaluate the anterior segment. It’s application in retinoblastoma care is to evaluate the anterior retina and ciliary body region for tumour that may not be easily seen with other imaging methods. It is important tool used prior to intravitreal melfalan treatment to confirm the injection site is tumour free.

External Photography

Imaging using a digital camera may be helpful in the documentation of any external features including the face, both eyes, the socket, implant extrusions, granulomas and features related to the ocular prosthesis. The photo slit lamp will also provide high magnification the socket

and adnexa. External photography by parents may be one of the first images of the disease if leucocoria is present.

Ocular Therapies

Enucleation

Enucleation is a first-line therapy for the majority of eyes with retinoblastoma globally. The procedure is readily available wherever there are ophthalmologists. Since the majority of children with intraocular retinoblastoma have Group D or E eyes at diagnosis, and more than 50% have unilateral disease with another normal eye, cure can be achieved with enucleation. All IIRC14 Group E eyes require enucleation since by definition, they carry risk of extraocular extension, determined only by pathology. Best cosmetic outcome is achieved by replacement of the volume of the eye with an implant buried in the orbit, and provision of a prosthetic eye, worn in the conjunctival sac. Many different reconstruction techniques are used worldwide;118 Comparative studies have shown enhanced prosthetic eye motility with the myoconjunctival approach (Fig. Triplets), which is also affordable world-wide.119, 120 Complex integrated implants are commonly used but have a higher rate 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,121 observed in Kenya to help the next family accept enucleation for their child.

Histological study of the enucleated eye the only way to evaluate high-risk features and establish pathological staging57 (tumor invasion into the optic nerve, post lamina cribosa, cut end of nerve; invasion of uvea ≥3 mm dimension; or both optic nerve and uveal invasion).57,

89, 93, 122 High-risk features are observed in 17% of IIRC14 Group D eyes and 24% of Group E eyes.89, 122 The role of adjuvant systemic chemotherapy to reduce risk of metastatic relapse in patients with high-risk pathological features is reviewed.93, 94

Intravenous chemotherapy (IVC) and focal therapy Since 1996 first-line therapy to control IIRC Groups B, C and D eyes has been IVC with different combinations, doses, schedules, and durations of carboplatin, etoposide and vincristine (CEV) (Table x. Chemotherapy for retinoblastoma) followed by focal therapy to consolidate the chemotherapy responses.107, 123, 124 One group used high dose acute cyclosporine (CSA) to modulate multidrug resistance.125, 126 126add REF trial The Groups B and C eyes do very well with CEV and focal therapy. With follow-up of 54 months, 47% of IIRC14 Murphree Group D eyes83 and 47% of RE Group V107 avoided enucleation or external beam radiation. 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.REF This is illustrated by the reduced effectiveness of single agent low dose carboplatin for retinoblastoma.127 Acute toxicities of IVC for retinoblastoma are as for other pediatric cancers, including short-term transient pancytopenia, hair loss, vincristine-induced neurotoxicity, and infections. Long term toxicities include carboplatin-induced ototoxicity,128 second non-ocular cancer risk with alkylating agents129, 130 and secondary acute myeloid leukemia following intense chemotherapy including topoisomerase inhibitors, doxorubricin and alkylating agents.131, 132

Even the best ChemotherapyIVC alone rarely protocol does not finally eradicates the last retinoblastoma cell in in the eye, and focal therapy consolidation is very important with repeated EUAs.85, 133 After chemotherapy is completed, focal ophthalmic tumor consolidation is applied to regions suspicious of cancer activity, on repeated EUAs. However, focal therapy

to Tumors in the macular region damages visual acuityare at risk of recurrence without focal therapy.134 and better treatments are required for these visually threatening tumors.

Following control of retinoblastoma with IVC, 50% of patients have visual acuity at 5-years of 20/20-20/40; 67% have 20/200 or better.135, 136 Foveal involvement with tumor or subretinal fluid at presentation contribute to poor vision. There is no documented local toxicity of IVC to the eye.

Intra-arterial chemotherapy (IAC) For this section we need a consensus with the other co-authors of the management section before submitting.

Historical combination of IAC with an alkylating agent and radiation incurred significant risk of second cancers, beyond radiation alone.129, 137 Technical success of delivery of melphalan chemotherapy to the ophthalmic artery was reported in 2004 without information on efficacy or safety.138 Long term follow-up has focused on eye salvage, with minimal information on outcomes such as death or vision.112 This sentence could be eraed (see David’s comments in his last email)

In 2008, direct cannulation of the ophthalmic artery achieved more localized delivery of drug to the eye.139 IAC requires a comprehensive team of specialists inaccessible to many treatment centers worldwide. IAC is used in some centresin centres with significant specific interventional expertise as primary treatment to avoid enucleation or for salvage therapy.84, 138-

142 Overall, 5 year ocular survival is about 72% for first-line IAC and 62% for second-line IAC.84, 140, 141 Successful treatment of IIRC Group B and, C and D eyes is excellent.,84, 140 similar to systemic chemotherapy with focal therapy.REFs However, the different definitions of IIRC Groups D and E for (severely involved eyes)14, 54 used by different authors (Table x), must be resolved to move forward to define eligibility for IACmakes overall outcomes of primary IAC difficult to assess.

Systemic complications of IAC include groin hematoma at catheter entry site, transient pancytopenia, potential for carotid vascular spasm and stroke, and neutropenia associated with dose.143 Local ocular toxicities of IAC relate to vascular compromise of the ophthalmic artery, retinal artery, or choroidal vessels.84, 144, 145 In a non-human primate model of IAC, melphalan caused retinal vascular whitening and choroidal blanching at injection.89, 146 Ocular vascular compromise may relate to pooraffect visual outcome, but visual acuity has not been reported; and electroretinography (ERG) has been used as a proxy for visual function.147

Retinoblastoma recurrence, metastases or death can occur more than five years after any treatment, and most IAC publications have short follow-up with the focus on ocular survival. The longest follow-up study indicates 8 deaths from metastases of 343 patients treated with IAC112; if we assume that those metastases were in the 18 patients with IIRC Group E eyes, there is a significant risk of trying to salvage such eyes.86, 90, 95, 112 On the other hand, it should be stressed that similar figures of deaths from metastasis have been reported with other conservative therapeutic modalities (Globe conserving treatment of the only eye in bilateral retinoblastoma. Lee V, Hungerford JL, Bunce C, Ahmed F, Kingston JE, Plowman PN. Br J Ophthalmol. 2003 Nov;87(11):1374-80. The published evidence on the efficacy or safety of IAC compared to other treatment modalities does not yet fully address its relative benefits and harmswill be best determined by rigorous comparative studies.

Focal Therapy

Focal therapy is local application of anti-cancer therapy to the eye, under direct visualization through the pharmacologically dilated pupil. This approach is useful for primary treatment of IIRC Group A eyes and “consolidation” therapy for residual or recurrent small volume active tumor after systemic or intra-arterial chemotherapy. Focal Therapy generally is repeated monthly until the tumor is completely atrophic or calcified.

Transpupillary thermotherapy is 810 nm diode laser delivered through the dilated pupil at sub-photocoagulation level for a period of 3-5 minutes per spot. 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 tumor, starting at a sub-coagulation power intensity and increasing to attain white, opaque coagulation. Both laser treatments are repeated monthly until the tumor is flat, atrophic or calcified.

Cryotherapy is freezing of tumor through the sclera with a nitrous oxide probe; since tumor cells die when thawing, triple freeze-thaw is applied with one minute for each thaw. Cryotherapy is effective to destroy primary tumor(s) or small recurrence in the periphery of the retina.

Plaque radiotherapy is trans-scleral radiotherapy to deliver an apex dose of 35 Gy to an isolated single intraocular tumor or recurrence, over 4-7 days. Plaque focal radiation has not been associated with second primary tumors. Plaque radiotherapy is effective for treatment of a single primary or recurrent tumor in a location that will not compromise vision.

Paraocular Chemotherapy ……148-150

IntravitrealMelphalan

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.87, 114, 117, 151, 152

After induction of anesthesia, the intraocular pressure was lowered with an anterior chamber paracentesis or by digital massage. Intravitreal melphalan (20-40 µg in 0.05 to 0.15 ml) is

injected through the conjunctival, sclera, and pars plana with a 32- or 33-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.87 There was a significant difference in the median time to regression for the 3 seed classifications (P < 0.0001): class 1 (dust) regressed in the shortest interval, and class 3 (clouds) took significantly longer. Each seed class received a different mean number of injections and amount of melphalan: compared with the other classes, class 3 (cloud) received a significantly increased number of injections (P < 0.01) and amount of cumulative (P < 0.01) and mean melphalan dose (P < 0.05).

Extraocular retinoblastoma

Extraocular at presentation

Retinoblastoma may present with evident extraocular disease, especially in low income countries. Children with orbital retinoblastoma, which may be massive and disfiguring, benefit from up-front adjuvant chemotherapy. The preferred chemotherapeutic agents are carboplatin, etoposide and vincristine, as for intra-ocular retinoblastoma; other agents that are useful include cisplatin, cyclophosphamide and adriamycin.79

Those who present with overt extraocular disease have a low chance of survival, especially in low income settings. Chemotherapy followed by enucleation, orbital radiation, adjuvant chemotherapy, intrathecal chemotherapy and high dose chemotherapy with stem cell rescue have potential for cure.

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 (repeated BM, LP and MRI, etc) has good outcomes.REF Enthusiasm to salvage eyes increases metastatic risk by both masking primary extraocular disease90 and continued hope eye salvage in the face of failure95. Bone marrow metastasis without central nervous system disease has potential for cure with extensive therapy including stem cell transplant. However, extension of retinoblastoma into the brain has a very low likelihood of cure.

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 (repeated BM, LP and MRI, etc) has good outcomes.REF Enthusiasm to salvage eyes increases metastatic risk by both masking primary extraocular disease90 and continuing eye salvage attempt despite failure of primary and subsequent treatment plans95. Bone marrow metastasis without central nervous system disease has potential for cure with extensive therapy including stem cell transplant. However, extension of retinoblastoma into the brain has a very low likelihood of cure.

Palliation

Important palliation modalities to alleviate symptoms and to prolong the life of the child. External beam radiotherapy and chemotherapy are useful for pain control in palliation but are often unavailable in low income countries. NEED MORE details: festus and chantada

Important palliation modalities to alleviate symptoms and to prolong the life of the child. External beam chemotherapy is useful for pain control in palliation but it is often unavailable in low income countries. NEED MORE detailsUntreated retinoblastoma is highly sensitive to most chemotherapy agents. Children presenting with orbital retinoblastoma are usually in severe pain and discomfort which may be alleviated with judicious use of anticancer therapy even when no curative intent is pursued. These children usually present with severe emaciation needing prompt medical treatment. Easily available, moderate intensity chemotherapy should be offered to these children since life prolongation will be likely achieved and their quality of life will significantly improve.

abby, 16/03/15,

Do you mean the initial attempt gets parents hooked on the idea of eye salvage so they can’t accept enucleation when it’s needed? If so, needs clarification.

Options include the combination of cyclophosphamide (which may also be administered orally) and vincristine, or carboplatin and etoposide which will seldom cause severe toxicity. Radiotherapy may also be helpful, especially for a CNS relapse or for the treatment of massive orbital extension. However, in these cases, it is more convenient to administer it after the tumor has shrunk with chemotherapy. Radiotherapy may not be easily available in many developing countries. Intrathecal chemotherapy may be considered when leptomeningeal dissemination is present (when it is not contraindicated by a CNS mass), but active agents like topotecan are not always available in these settings. Widely used combinations for intrathecal therapy for acute leukemias such as methotrexate or cytarabine are less active. There have been anecdotal responses to oral etoposide (Dunkel, 2004). Tumor response will likely occur within a few weeks after these agents and children may be managed on an outpatient basis.

Role of being at home; pain control; oral morphine; short cycle chemo? Benefit or not? Etc.

Long-term surveillance planning

Surveillance: 68, 153

Solimann: social

Global perspective

Conclusion

In summary, the diagnosis of retinoblastoma is unequivocally established prior to embarking on therapy. Globally…..

To save an eye……

Dependent on biology….same everywhere

Only resources are different.

Easy to target and work towards common achievable endpoints

First-line therapy for children with bilateral retinoblastoma may be systemic IVC with focal tumor consolidation. and for those with unilateral retinoblastoma is generally IAC. Enucleation remains a first-line alternative for advanced disease at risk to become extraocular. Periocular chemotherapy and intravitreal chemotherapy are reserved for eyes with recurrent localized or vitreous seeds, respectively.

Biomarkers for drug response

No retinoblastoma biomarkers for drugs

Treatments in the pipeline

The distress experienced by patients and their families facing cancer and the need for enucleation has prompted a search for eye-salvaging treatments by pioneers in the field. Each innovative idea will most rapidly achieve its long-term relevance by

Clinical trial standards include approval from research ethics boards, detailed informed consent processes, and the registration of patients to avoid selective reporting of outcomes with substandard follow-up timelines. Under the American College of Surgeons (ACS) published guidelines on “Issues to be Considered Before New Surgical Technology is Applied to the Care of Patients”,154 IAC treatment for unilateral retinoblastoma requires careful clinical trialsX, Y COG planned study??? to assess safety and efficacy compared with the current standard of care, enucleation.155

Informed consent can be complicated by the emotional challenges faced by families of retinoblastoma patients, with fear of death and blindness.97 Qualitative literature reports stories of parents negotiating with physicians to avoid removing their child’s eye. Further, given the excellent long-term survival in developed countries, ophthalmologists with less resources may falsely believe it is no longer a fight for life, but rather a fight for an eye.97

Preclinical studies are crucial to identify new molecular targets to block the drivers of tumorigenesis in retinoblastoma and for pharmacokinetic evaluation of new agents alone or in combination156 before their incorporation to the clinics and for assessing their toxicity profile. However, very few translational studies have actually resulted in significant changes in clinical practice for retinoblastoma. In most instances, preclinical studies have helped in optimizing treatments already available in the clinic, mostly by providing information on the ocular pharmacokinetics of drugs by comparing different routes157. In addition, preclinical studies have been carried out for the development of innovative delivery systems to the vitreous for the treatment of vitreous seeding such as devices for sustained released preparations or metronomic administration for periocular or intravitreal routes. Fibrin-sealant carboplatin and topotecan150, episcleral implants158 or nanoparticles159 and exoplants have been evaluated, but only the first one is currently used in clinical practice albeit for restricted indications. Other agents such as those targeting the tumor vasculature160 or hypoxia161 have been evaluated with some degree of detail in preclinical models but they have not yet progressed to clinical use. As new biomarkers for molecular dissemination of retinoblastoma outside the eye are identified, treatments may be targeted based on that information.162

One of the earliest targeted therapies developed for retinoblastoma that was based on preclinical information generated by transgenic mice was reported for Nutlins.163 Nutlin-3 showed promising activity in combination with topotecan for retinoblastoma control in preclinical models. Nutlin 3targets MDM2/MDMXpathway as a negative regulator of p53 resulting in apoptotic cell death mediated by p53.This drug combination is currently undergoing evaluation in a prospective study in combination with local chemotherapy. Based upon information obtained from sequencing the whole genome and the epigenome of retinoblastoma tumors, thespleen tyrosine kinase (SYK), an upregulated proto-oncogene required for retinoblastoma cell survival has been identified as a potential new target for the treatment of retinoblastoma.29 The SYK antagonist R406,wasconsidered a promising candidate from preclinical studies, but later it was found that its ocular pharmacokinetics was not favorable for clinical useby periocular administration.164 Drugs targeting MYCN, which has been recently identified as a candidate driver for retinoblastoma tumorigenesis in cases

Betty He, 11/03/15,

Brenda, plz re-insert these two references. They are not recognized by the library from this side.

with no RB1 gene mutation,25 may also be considered for targeted therapy but this is still under development.

Transgenic mice models of retinoblastoma do not entirely recapitulate the tumorigenic steps of human retinoblastoma, so drugs targeting specific molecular pathways may behave differently in these models. On the other hand, xenografts from patient-derived specimens show a different eye anatomy since injected human retinoblastoma cells in the vitreous or the subretinal space modify the natural anatomic barriers of the eye potentially affecting drug distribution and limiting translation to the patient.

In summary, novel targeted agents undergoing intensive investigation for retinoblastoma, may significantly change future treatment.

Quality of life

White, A

“Quality of life” (QoL) describes the level of physical, emotional and psychological wellbeing experienced by an individual. Cancer significantly decreases QoL, with implications for treatment decisions, supportive and long-term care.165-168

We present iInsights below are gathered primarily from observation of and participation in retinoblastoma social media parent and survivor peer-support communities. Research processes that deepen understanding of QoL following retinoblastoma are needed diagnosis, while respecting user privacy, need to be developed to learn from these valuable evidence sources. Quotes below are used with permission of the authors.

Coping During Treatment

Child Life

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". Children’s perception of pain and medical interventions changes over time.169-175 Repeated 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 and developmental trauma disorder.97, 176-182 Child life promotes effective coping through play, preparation, education, positive-touch and self-expression activities based on natural child development. Child 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.67, 183-191

Treatment Choices

When only one eye is involved, choice between eye salvage (with potential long term intensive therapies) and enucleation (loss of the eye) is complex. A comparative retrospective study of socioeconomic and psychosocial impacts of attempted ocular salvage in a middle-income country concluded that primary enucleation is a good treatment for unilateral retinoblastoma.98. Challenges following enucleation range from discomfort with appearance


[Maximum 500 words.( Currently 1036 excluding a table) For patients, what are the major QoL issues? How are these influenced by the treatments described in the previous section? Please discuss life expectancy, patient-reported outcomes, palliative care and comorbities.]

or handling their prosthesis, to fear, shame and non-compliance. Facilitated self-expression activities that build self-esteem and confidence help children overcome these negative feelings.

Shopping for therapy at multiple centres is a complex journey that can ravage family life and finances. Delay is therapy while seeking alternatives can result in curable children dying.192-194 Follow up is also compromised by limited funds, poor forward planning and inconsistent communication.195, 196 In the 1RBW model, prospective management protocols will build collaboration, communication and efficiency, to achieve optimized care as close to home as possible, with coordinated trips to meet special needs.

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. Most lethal is the risk of second cancers induced by radiation of cells already predisposed by an RB1 mutation.129, 197, 198

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 QoL. Dry eye is very painful, and corneal vascularization reduces already limited vision. Use of ocular lubricants may prevent complications, best started early before pain and vision loss occur. Chronic primary headaches, hormone dysfunction and seizures also impact QoL after radiotherapy.REF?

Second Cancer Risk

Individuals at risk of second primary cancers require life-long oncology follow up.129, 197, 198 However, most adults struggle to access informed follow up care, often turned away from survivorship clinics because they are ‘too complex’ or are a carrier of RB1 mutation who did not have retinoblastoma. Lack of agreed protocols for ongoing care causes confusion, frustration and fear. This is compounded by inaction of primary doctors unfamiliar with late effects and lifelong implications of an RB1 mutation.

One mother describes attending an oncology appointment with her 14 year old: “My son asked about long term issues as an RB1 mutation carrier. The doctor emphatically replied that he had 'nothing to worry about'”.

To be responsible advocates for their health and that of their children, survivors must be fully informed about their cancer history, genetic status and life-long risks.199-202 They seek honesty, compassion and support in learning about how their cancer may impact them throughout life.

Psychosocial Outcomes

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 as the child’s social development is delayed. While most adult survivors perform very well socially, many report low confidence and intense anxiety, especially in large groups and crowded environments. Most survivors are high cognitive performers.203 However, reduced vision causes some children to become frustrated by their inability to keep up with peers, damaging self-esteem and confidence.204-206

Family Planning

Many adult survivors have not received genetic counselling or testing, do not know their genetic status, understand retinoblastoma genetics, or know of options to prevent retinoblastoma in 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 for minimally invasive therapy.

One survivor observes “We're the center of the world when we go through treatment, but the moment we survive, we're last on the list, and no one wants to be anywhere near us, as if surviving cancer is the black plague, especially if you survive with vision loss – I can't imagine doing this for the rest of my life”.

Agreed 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.

Outlooks

Gallie, Dimaras, Corson, Munier, Zhao, and all.

[Maximum 1,000 words. What are the key outstanding research questions, and why? Where will the field focus its efforts on in the next 5–10 years? What are the advances to look out for, for bench researchers and clinicians? Will emerging technologies and advances in other fields influence the research trajectory in this disease?]

National strategies in areas currently under-represented in the retinoblastoma literature are poised to fill the knowledge gap with new approaches and evidence. For example, much of the evidence-base for care has been built in high-income countries, yet socio-cultural issues (e.g. treatment compliance) are a bigger factor in low-income countries, yet another form of resource-gap. New research approaches can be focused to address such gaps.

Perhaps we can 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.

Summary & Looking forward

Progress in treatment of retinoblastoma is critically dependent on standard classification of intraocular disease. A current international survey of outcomes will compare initial clinical staging by Murphree IIRC,14 Shields IIRC54 and the 7th edition TNM15. This evidence will be used to formulate the 8th edition TNM for retinoblastoma, to achieve one cancer staging and eye classification recognized by all cancer-related organizations and endorsed by eye journals.

Prevention of retinoblastoma is a goal of therapy for predictable cases (where genetic mutation is known). Transgenic murine retinoblastoma can be prevented, and newborn infants with an RB1 mutation present the opportunity for a clinical trial of therapy (perhaps ocular, one eye) and then count emerging tumors in each eye. Such a trial would only take a few years, since retinoblastoma quickly; this therapy we dream of could then be considered to reduce risk of second cancers.

Reference

Maximum 200 references. Please annotate 2-3 references from each section, describing why these papers are of particular importance.

Supplementary information

Acknowledgement

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

Where appropriate, we would like to attribute sections to individual authors, either with their initials at the end of each section or with a statement at the end of the article (referring authors by initials here, too). Please make clear author contributions in the main document.

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 could be perceived as a conflict of interest.

General instructions

Each major section must have at least one display item—be it Figure, Table or Box. Our art editors will offer support in developing and drawing these elements. The mechanisms section must have at least two figures: one showing the ‘healthy’ state, and the other depicting the pathogenesis/molecular biology aspects of the disease. The figures may be inserted within the text at the appropriate positions or grouped at the end, and each figure legend should be presented together with its figure. Also, please include line numbers within the text.

Betty He, 26/01/15,

Must contain only 1 column of text (300 words). Can have headings/bullets

Betty He, 27/01/15,

Provided as part of main article; must fit on one portrait-oriented A4 page; no smaller than 9 pt font. All abbre defined in footnotes, short bolded title.

Betty He, 27/01/15,

All symbols and abbre used must be defined in a key and figure legend. See artwork guidelines. For guidance, Nature’s standard figure sizes are 89 mm (single column) and 183 mm (double column) and the full depth of the page is 247 mm.

Betty He, 27/01/15,

With caption: title, explanation, alphabetically listed definitions of abbreviations . if not original, state in legend whether permission is needed.


We will have more….

Betty He, 27/01/15,

Any competing interests declared both within the text, and via web-based manuscript tracking system. The corresponding author is responsible for submitting a statement on behalf of all authors.Authors who have made a declaration as part of the online manuscript submission process do not need to complete and send a separate form. For some commissioned papers, the editorial office will send the form.


Betty can you look at what we need to do….i think I (ie you) collect the forms from all authors, and I sing off for everyone,….?

Betty He, 27/01/15,

All authors are required to declare their contributions to the article via manuscript submission and tracking system, and a short statement including this info is published with the articleThe level of detail varies, authors are left to structure it as they see fit. allow one set of up to six co-authors to be specified as having contributed equally to the work. No author should be left outFor example, see http://blogs.nature.com/nautilus/2007/11/post_12.html


This is what I want, since we all overlap so much. Betty get examples…


Betty can you get us examples how this works in other NR articles? – Other review articles don’t publish this annotated bibliography section, though examples can be found at http://www.lib.sfu.ca/help/writing/annotated-bibliography

Betty He, 01/27/15,

In numerical order; citation style can be downloaded for endnote

http://www.nature.com/nature/submit/policies/competing/index.html

Use Oxford UK English spelling

Supplementary materials: should be provided in a format suitable for converting to PDF for publication. Items should be cited in first

Author biographies: for each listed author, require a 100 word. Current/past roles, training and research,society memberships, only main affiliation will appear in print

Formatting: Nature will edit; http://www.nature.com/nature/authors/gta/index.html#a4; 12-point Times New Roman

Corresponding author: At submission, the corresponding author must include written permission from the authors of the work concerned for mention of any unpublished material included in the manuscript, for example others' data, in press manuscripts, personal communications or work in preparation, previously published materials, for example, figures

References

1. 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).

2. Broaddus, E., Topham, A. & Singh, A.D. Incidence of retinoblastoma in the USA: 1975-2004. Br J Ophthalmol 93, 21-3 (2009).

3. 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).

4. National Retinoblastoma Strategy Canadian Guidelines for Care / Stratégie thérapeutique du rétinoblastome guide clinique canadien. Can J Ophthalmol 44, S1-88 (2009).

5. 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).

6. 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).

7. Gichigo, E.N., Kariuki-Wanyoike, M.M., Kimani, K. & Nentwich, M.M. [Retinoblastoma in Kenya : Survival and prognostic factors.]. Ophthalmologe (2014).

8. Moreno, F. et al. A population-based study of retinoblastoma incidence and survival in Argentine children. Pediatr Blood Cancer 61, 1610-5 (2014).

9. (2014).

10. Naseripour, M. "Retinoblastoma survival disparity": The expanding horizon in developing countries. Saudi J Ophthalmol 26, 157-61 (2012).

http://www.nature.com/nature/authors/gta/index.html#a4

11. 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).

12. Wilimas, J.A. et al. Development of retinoblastoma programs in Central America. Pediatr Blood Cancer 53, 42-6 (2009).

13. Dimaras, H., White, A. & Gallie, B.L. in Ophthalmology Rounds (Toronto, 2008).

14. Murphree, A.L. Intraocular retinoblastoma: the case for a new group classification. Ophthalmology Clinics of North America 18, 41-53 (2005).

15. 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).

16. Knudson, A.G. Mutation and cancer: statistical study of retinoblastoma. Proceedings of the National Academy of Science, USA 68, 820-823 (1971).

17. Comings, D.E. A general theory of carcinogenesis. Proc Natl Acad Sci U S A 70, 3324-8 (1973).

18. Cavenee, W.K. et al. Expression of recessive alleles by chromosomal mechanisms in retinoblastoma. Nature 305, 779-784 (1983).

19. Presneau, N., Manderson, E.N. & Tonin, P.N. The quest for a tumor suppressor gene phenotype. Curr Mol Med 3, 605-29 (2003).

20. Dryja, T.P., Friend, S. & Weinberg, R.A. Genetic sequences that predispose to retinoblastoma and osteosarcoma. Symp Fundam Cancer Res 39, 115-9 (1986).

21. Lee, W.H. et al. Human retinoblastoma susceptibility gene: cloning, identification, and sequence. Science 235, 1394-9 (1987).

22. 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).

23. Fung, Y.K. et al. Structural evidence for the authenticity of the human retinoblastoma gene. Science 236, 1657-61 (1987).

24. Lohmann, D.R. RB1 gene mutations in retinoblastoma. Hum Mutat 14, 283-288 (1999).

25. Rushlow, D.E. et al. Characterisation of retinoblastomas without RB1 mutations: genomic, gene expression, and clinical studies. Lancet Oncol 14, 327-34 (2013).

26. Dick, F.A. & Rubin, S.M. Molecular mechanisms underlying RB protein function. Nat Rev Mol Cell Biol 14, 297-306 (2013).

27. 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).

28. 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).

29. Zhang, J. et al. A novel retinoblastoma therapy from genomic and epigenetic analyses. Nature 481, 329-34 (2012).

30. Theriault, B.L., Dimaras, H., Gallie, B.L. & Corson, T.W. in Clin Experiment Ophthalmol 33-52 (2014).

31. Eagle, R.C., Jr. The pathology of ocular cancer. Eye (Lond) 27, 128-36 (2013).

32. Kyritsis, A.P., Tsokos, M., Triche, T.J. & Chader, G.J. Retinoblastoma--origin from a primitive neuroectodermal cell? Nature 307, 471-3 (1984).

33. Virtanen, I. et al. Expression of intermediate filaments and synaptophysin show neuronal properties and lack of glial characteristics in Y79 retinoblastoma cells. Lab Invest 59, 649-56 (1988).

34. 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).

35. McEvoy, J. et al. Coexpression of normally incompatible developmental pathways in retinoblastoma genesis. Cancer Cell 20, 260-75 (2011).

36. 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 (2012).

37. Cobrinik, D. in Animal Models of Brain Tumors (eds. Martinez-Murillo, R. & Martinez, A.) 141-152 (Springer, New York, 2013).

38. Xu, X.L. et al. Rb suppresses human cone-precursor-derived retinoblastoma tumours. Nature 514, 385-8 (2014).

39. 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).

40. 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).

41. 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).

42. Kapatai, G. et al. Gene expression profiling identifies different sub-types of retinoblastoma. Br J Cancer 109, 512-25 (2013).

43. 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).

44. Abramson, D.H. & Gombos, D.S. The topography of bilateral retinoblastoma lesions. Retina 16, 232-9 (1996).

45. Reid, T.W. et al. Characteristics of an established cell line of retinoblastoma. J National Cancer Inst 53:1347-360 (1974).

46. McFall, R.C., Sery, T.W. & Makadon, M. Characterization of a new continuous cell line derived from a human retinoblastoma. Cancer Res 37, 1003-10 (1977).

47. Gallie, B.L., Trogadis, J. & Han, L.-P. in Human Cell Culture (ed. Masters, J.) 361-374 (1999).

48. 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).

49. Pacal, M. & Bremner, R. Insights from animal models on the origins and progression of retinoblastoma. Curr Mol Med 6, 759-81 (2006).

50. Conkrite, K. et al. miR-17~92 cooperates with RB pathway mutations to promote retinoblastoma. Genes Dev 25, 1734-45 (2011).

51. Windle, J.J. et al. Retinoblastoma in transgenic mice. Nature 343, 665-9. (1990).

52. Marchong, M.N. et al. Cdh11 acts as a tumor suppressor in a murine retinoblastoma model by facilitating tumor cell death. PLos Genetics 6, e1000923 (2010).

53. Reese, A.B. & Ellsworth, R.M. The evaluation and current concept of retinoblastoma therapy. Trans Am Acad Ophthalmol-Otolaryngol, 164-172 (1963).

54. Shields, C.L. & Shields, J.A. Basic understanding of current classification and management of retinoblastoma. Curr Opin Ophthalmol 17, 228-34 (2006).

55. 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).

56. Mallipatna, A., Dimaras, H., Héon, E. & Gallie, B. Published International Classification of Retinoblastoma (Icrb) Definitions Contain Inconsistencies: An Analysis of Impact. Evidence-Based Ophthalmology 10, 183-185 (2009).

57. The 7th edition AJCC staging system for eye cancer: an international language for ophthalmic oncology. Arch Pathol Lab Med 133, 1197-8 (2009).

58. Simpson, E.R. et al. International Validation of the American Joint Committee on Cancer's 7th Edition Classification of Uveal Melanoma. JAMA Ophthalmol (2015).

59. Gallie, B., Erraguntla, V., Heon, E. & Chan, H. in Pediatric Ophthalmology and Strabismus (eds. Taylor, D. & Hoyt, C.) 486-504 (ELSEVIER, 2004).

60. Dimaras, H. et al. Retinoblastoma CSF metastasis cured by multimodality chemotherapy without radiation. Ophthalmic Genet 30, 121-6 (2009).

61. Bowles, E., Corson, T.W. & Gallie, B.L. in International Congress of Ocular Oncology (eds. Gallie, B.L. & Paton, K.) (Whistler, British Columbia, 2005).

62. Genetics, I. (2012).

63. Chantada, G.L. et al. Familial retinoblastoma in developing countries. Pediatr Blood Cancer 53, 338-42 (2009).

64. 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).

65. 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).

66. Abdolvahabi, A. et al. Colorimetric and longitudinal analysis of leukocoria in recreational photographs of children with retinoblastoma. PLoS One 8, e76677 (2013).

67. McCarthy, M. et al. Comfort First: an evaluation of a procedural pain management programme for children with cancer. Psychooncology 22, 775-82 (2013).

68. 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).

69. Xu, K. et al. Preimplantation genetic diagnosis for retinoblastoma: the first reported liveborn. Am J Ophthalmol 137, 18-23 (2004).

70. 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).

71. Kruizinga, R.C. et al. Calculating optimal surveillance for detection of von Hippel-Lindau-related manifestations. Endocr Relat Cancer 21, 63-71 (2014).

72. Durno, C.A. et al. Oncologic surveillance for subjects with biallelic mismatch repair gene mutations: 10 year follow-up of a kindred. Pediatr Blood Cancer 59, 652-6 (2012).

73. Shields, C.L. et al. Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy. Eye (Lond) 27, 253-64 (2013).

74. Abramson, D.H. et al. Presenting signs of retinoblastoma. J Pediatr 132, 505-8 (1998).

75. Abramson, D.H. et al. Presenting signs of retinoblastoma. J Pediatr 132, 505-8 (1998).

76. Shields, C.L. et al. Lesions simulating retinoblastoma (pseudoretinoblastoma) in 604 cases: results based on age at presentation. Ophthalmology 120, 311-6 (2013).

77. Eng, C. et al. Mortality from second tumors among long-term survivors of retinoblastoma. J Natl Cancer Inst 85, 1121-8 (1993).

78. MacCarthy, A. et al. Non-ocular tumours following retinoblastoma in Great Britain 1951 to 2004. Br J Ophthalmol 93, 1159-62 (2009).

79. Chantada, G. et al. SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries. Pediatr Blood Cancer 60, 719-27 (2013).

80. Dimaras, H. et al. Retinoblastoma. Lancet 379, 1436-46 (2012).

81. 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).

82. 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).

83. 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).

84. 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).

85. 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).

86. Francis, J.H. et al. Efficacy and Toxicity of Second-Course Ophthalmic Artery Chemosurgery for Retinoblastoma. Ophthalmology (2015).

87. Francis, J.H. et al. The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan. Ophthalmology (2015).

88. Chantada, G.L. et al. Outcome of patients with retinoblastoma and postlaminar optic nerve invasion. Ophthalmology 114, 2083-9 (2007).

89. 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).

90. 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).

91. Uusitalo, M.S. et al. Evaluation of chemoprophylaxis in patients with unilateral retinoblastoma with high-risk features on histopathologic examination. Arch Ophthalmol 119, 41-8 (2001).

92. Honavar, S.G. et al. Postenucleation adjuvant therapy in high-risk retinoblastoma. Arch Ophthalmol 120, 923-31 (2002).

93. 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).

94. Kim, J.W. Retinoblastoma: evidence for postenucleation adjuvant chemotherapy. Int Ophthalmol Clin 55, 77-96 (2015).

95. 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).

96. Shields, C.L. et al. The International Classification of Retinoblastoma predicts chemoreduction success. Ophthalmology 113, 2276-80 (2006).

97. 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).

98. 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).

99. Manjandavida, F.P., Honavar, S.G., Reddy, V.A. & Khanna, R. Management and outcome of retinoblastoma with vitreous seeds. Ophthalmology 121, 517-24 (2014).

100. 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).

101. 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).

102. Abouzeid, H. et al. (106)Ruthenium brachytherapy for retinoblastoma. Int J Radiat Oncol Biol Phys 71, 821-8 (2008).

103. 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).

104. 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).

105. 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).

106. Mouw, K.W. et al. Proton radiation therapy for the treatment of retinoblastoma. Int J Radiat Oncol Biol Phys 90, 863-9 (2014).

107. 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).

108. 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).

109. Abramson, D.H. & Schefler, A.C. Update on retinoblastoma. Retina 24, 828-48 (2004).

110. 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).

111. 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).

112. 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).

113. Schaiquevich, P. et al. Pharmacokinetic analysis of melphalan after superselective ophthalmic artery infusion in preclinical models and retinoblastoma patients. Invest Ophthalmol Vis Sci 53, 4205-12 (2012).

114. 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).

115. Shields, C.L. et al. Intravitreal melphalan for persistent or recurrent retinoblastoma vitreous seeds: preliminary results. JAMA Ophthalmol 132, 319-25 (2014).

116. Francis, J.H. et al. The Classification of Vitreous Seeds in Retinoblastoma and Response to Intravitreal Melphalan. Ophthalmology (in Press).

117. Munier, F.L. Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013. Ophthalmic Genet 35, 193-207 (2014).

118. 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).

119. Shome, D., Honavar, S.G., Raizada, K. & Raizada, D. Implant and prosthesis movement after enucleation: a randomized controlled trial. Ophthalmology 117, 1638-44 (2010).

120. 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).

121. 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).

122. Kaliki, S. et al. High-risk retinoblastoma based on international classification of retinoblastoma: analysis of 519 enucleated eyes. Ophthalmology 120, 997-1003 (2013).

123. Gallie, B.L. et al. Chemotherapy with focal therapy can cure intraocular retinoblastoma without radiotherapy. Arch Ophthalmol 114, 1321-8 (1996).

124. 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).

125. Chan, H.S. et al. Combining cyclosporin with chemotherapy controls intraocular retinoblastoma without requiring radiation. Clin Cancer Res 2, 1499-508 (1996).

126. Chan, H.S.L. (ClinicalTrials.gov, 2005).

127. Dunkel, I.J. et al. A phase II trial of carboplatin for intraocular retinoblastoma. Pediatr Blood Cancer (2007).

128. 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).

129. 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).

130. Draper, G.J., Sanders, B.M. & Kingston, J.E. Second primary neoplasms in patients with retinoblastoma. Br J Cancer 53, 661-71 (1986).

131. Gombos, D.S. et al. Secondary acute myelogenous leukemia in patients with retinoblastoma: is chemotherapy a factor? Ophthalmology 114, 1378-83 (2007).

132. Smith, M.A. et al. Secondary leukemia or myelodysplastic syndrome after treatment with epipodophyllotoxins. J Clin Oncol 17, 569-77 (1999).

133. 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).

134. 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).

135. 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).

136. 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).

137. Reese, A.B. Tumors of the Eye (Hoeber Med. Div. , New York, 1963).

138. Yamane, T., Kaneko, A. & Mohri, M. The technique of ophthalmic arterial infusion therapy for patients with intraocular retinoblastoma. Int J Clin Oncol 9, 69-73 (2004).

139. 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).

140. Shields, C.L. et al. Intra-arterial chemotherapy for retinoblastoma: report No. 1, control of retinal tumors, subretinal seeds, and vitreous seeds. Arch Ophthalmol 129, 1399-406 (2011).

141. 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).

142. Vajzovic, L.M. et al. Supraselective intra-arterial chemotherapy: evaluation of treatment-related complications in advanced retinoblastoma. Clinical ophthalmology 5, 171-6 (2011).

143. Dunkel, I.J. et al. Risk Factors for Severe Neutropenia following Intra-Arterial Chemotherapy for Intra-Ocular Retinoblastoma. PLoS One 9, e108692 (2014).

144. Munier, F.L. et al. Occurrence of sectoral choroidal occlusive vasculopathy and retinal arteriolar embolization after superselective ophthalmic artery chemotherapy for advanced intraocular retinoblastoma. Retina 31, 566-73 (2011).

145. Muen, W.J. et al. Efficacy and Complications of Super-selective Intra-ophthalmic Artery Melphalan for the Treatment of Refractory Retinoblastoma. Ophthalmology 119, 611-6 (2012).

146. Wilson, M.W. et al. Real-time ophthalmoscopic findings of superselective intraophthalmic artery chemotherapy in a nonhuman primate model. Arch Ophthalmol 129, 1458-65 (2011).

147. Brodie, S.E. et al. ERG monitoring of retinal function during systemic chemotherapy for retinoblastoma. Br J Ophthalmol 96, 877-80 (2012).

148. 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).

149. Mulvihill, A. et al. Ocular motility changes after subtenon carboplatin chemotherapy for retinoblastoma. Arch Ophthalmol 121, 1120-4 (2003).

150. Mallipatna, A.C., Dimaras, H., Chan, H.S., Heon, E. & Gallie, B.L. Periocular topotecan for intraocular retinoblastoma. Arch Ophthalmol 129, 738-45 (2011).

151. Ghassemi, F. & Amoli, F.A. Pathological findings in enucleated eyes after intravitreal melphalan injection. Int Ophthalmol 34, 533-40 (2014).

152. 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).

153. Malkin, D. Surveillance for children at genetic risk for cancer: are we ready? Pediatr Blood Cancer 61, 1337-8 (2014).

154. Statement on issues to be considered before new surgical technology is applied to the care of patients. Bulletin of the American College of Surgeons 80, 46-47 (1995).

155. Ferris, F.L. & Chew, E.Y. A new era for the treatment of retinoblastoma. Archives of Ophthalmology 114, 1412 (1996).

156. Mahida, J.P. et al. A synergetic screening approach with companion effector for combination therapy: application to retinoblastoma. PLoS ONE 8, e59156 (2013).

157. Taich, P. et al. Clinical pharmacokinetics of intra-arterial melphalan and topotecan combination in patients with retinoblastoma. Ophthalmology 121, 889-97 (2014).

158. 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).

159. 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).

160. Jockovich, M.E., Murray, T.G., Escalona-Benz, E., Hernandez, E. & Feuer, W. Anecortave acetate as single and adjuvant therapy in the treatment of retinal tumors of LH(BETA)T(AG) mice. Invest Ophthalmol Vis Sci 47, 1264-8 (2006).

161. Pina, Y. et al. Focal, periocular delivery of 2-deoxy-D-glucose as adjuvant to chemotherapy for treatment of advanced retinoblastoma. Invest Ophthalmol Vis Sci 51, 6149-56 (2010).

162. Laurent, V.E. et al. Detection of minimally disseminated disease in the cerebrospinal fluid of children with high-risk retinoblastoma by reverse transcriptase-polymerase chain reaction for GD2 synthase mRNA. Eur J Cancer 49, 2892-9 (2013).

163. Laurie, N.A. et al. Inactivation of the p53 pathway in retinoblastoma. Nature 444, 61-6 (2006).

164. 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).

165. Weintraub, N., Rot, I., Shoshani, N., Pe'er, J. & Weintraub, M. Participation in daily activities and quality of life in survivors of retinoblastoma. Pediatric blood & cancer 56, 590-4 (2011).

166. Rueegg, C.S. et al. Health-related quality of life in survivors of childhood cancer: the role of chronic health problems. J Cancer Surviv 7, 511-22 (2013).

167. Darcy, L., Bjork, M., Enskar, K. & Knutsson, S. The process of striving for an ordinary, everyday life, in young children living with cancer, at six months and one year post diagnosis. Eur J Oncol Nurs 18, 605-12 (2014).

168. Li, H.C., Chung, O.K., Ho, K.Y., Chiu, S.Y. & Lopez, V. A descriptive study of the psychosocial well-being and quality of life of childhood cancer survivors in Hong Kong. Cancer Nurs 35, 447-55 (2012).

169. 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).

170. 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).

171. 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).

172. 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).

173. 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).

174. 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).

175. 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).

176. van Dijk, J. et al. Behavioural functioning of retinoblastoma survivors. Psychooncology 18, 87-95 (2009).

177. van Dijk, J. et al. Coping strategies of retinoblastoma survivors in relation to behavioural problems. Psychooncology 18, 1281-9 (2009).

178. 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).

179. van der Kolk, B. Developmental Trauma Disorder. Psychiatric Annuals, 401-408 (2005).

180. 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).

181. Buchbinder, D. et al. Psychological outcomes of siblings of cancer survivors: a report from the Childhood Cancer Survivor Study. Psychooncology 20, 1259-68 (2011).

182. Gold, J.I. in RESEARCHLA Blog [online].

183. Care, C.o.H. & Council, C.L. Child life services. Pediatrics 133, e1471-8 (2014).

184. 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).

185. 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).

186. 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).

187. 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).

188. O'Callaghan, C., Sexton, M. & Wheeler, G. Music therapy as a non-pharmacological anxiolytic for paediatric radiotherapy patients. Australas Radiol 51, 159-62 (2007).

189. Post-White, J. et al. Massage therapy for children with cancer. J Pediatr Oncol Nurs 26, 16-28 (2009).

190. Sposito, A.M. et al. Coping Strategies Used by Hospitalized Children With Cancer Undergoing Chemotherapy. J Nurs Scholarsh (2015).

191. 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).

192. Olteanu, C. & Dimaras, H. Enucleation Refusal for Retinoblastoma: A Global Study. Ophthalmic Genet, 1-7 (2014).

193. Brink, A., Correa, Z.M., Geller, J., Abruzzo, T. & Augsburger, J.J. Managing the consequences of aggressive conservative treatment for refractory retinoblastoma with vitreous seeding. Arquivos Brasileiros de Oftalmologia 77 (2014).

194. White, A. & Gallie, B.L. in 46th World Congress of the International Society of Paediatric Oncology (Toronto, Canada, 2014).

195. Miller, V.A., Cousino, M., Leek, A.C. & Kodish, E.D. Hope and persuasion by physicians during informed consent. J Clin Oncol 32, 3229-35 (2014).

196. White, A. in 1st meeting of One Retinoblastoma World (London England, 2012).

197. MacCarthy, A. et al. Second and subsequent tumours among 1927 retinoblastoma patients diagnosed in Britain 1951-2004. Br J Cancer 108, 2455-63 (2013).

198. 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).

199. 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).

200. 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).

201. Rowland, E. & Metcalfe, A. Communicating inherited genetic risk between parent and child: a meta-thematic synthesis. Int J Nurs Stud 50, 870-80 (2013).

202. 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).

203. 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).

204. van Dijk, J. et al. Restrictions in daily life after retinoblastoma from the perspective of the survivors. Pediatr Blood Cancer 54, 110-5 (2010).

205. 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).

206. van Dijk, J. et al. Quality of life of adult retinoblastoma survivors in the Netherlands. Health Qual Life Outcomes 5, 30 (2007).

· web viewretinoblastoma. helen dimaras, tim corson, david cobrinik, abby white, junyang zhao,...

Documents