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RetinoblastomaHelen Dimaras1, Timothy W. Corson2, David Cobrinik3, Abby White4, Junyang Zhao5, Francis L.Munier6, David Abramson7, Carol Shields8, Guillermo Chantada9, Festus Njuguna10 and Brenda L. Gallie11[Au: Please ensure all names are as you would like them fo1| Department of Ophthalmology & Vision Sciences, The Hospital for Sick Children& University of Toronto, Toronto, Canada2| Eugene and Marilyn Glick Eye Institute, Departments of Ophthalmology, Biochemistry and Molecular Biology, and Pharmacology and Toxicology, and Simon Cancer Center,Indiana University, Indianapolis, USA3| The Vision Center and The Saban Research Institute Children's Hospital Los Angeles, Los Angeles, CA USA; and Department of Ophthalmology, Department of Biochemistry and Molecular Biology, The USC Eye Institute, and Norris Comprehensive Cancer Center, Keck School of Medicine of the University of Southern California, Los Angeles, CA USA4| Daisy's Eye Cancer Fund, Oxford, UK5| Beijing Tongren Eye Centre, Beijing, China6| Jules-Gonin Eye Hospital, Lausanne, Switzerland7| Memorial Sloan Kettering Cancer Center, New York, USA8| Wills Eye Hospital, Philadelphia, USA9| Hospital JP Garrahan, Buenos Aires, Argentina10| Moi Teaching & Referral Hospital, Eldoret, Kenya11| Department of Ophthalmology & Vision Sciences, The Hospital for Sick Children& University of Toronto, Hospital for Sick Children, 5525 University Ave, Toronto, Ontario M5G1X8, Canada[Au: Please check and update affiliations. Every affiliation should contain the Department (which needs to be updated for all authors), Institution, City, State and Country. Only the corresponding author has to supply the full postal address.]Abstract 173228/200[Au: Abstracts have no line/paragraph breaks]The genetic basis of human malignancy was determined through the study of retinoblastoma, a rare cancer of infant retina. Tumours form when both RB1 alleles mutate in a susceptible retinal cell, likely a cone photoreceptor precursor. The tumour suppressor functions of the retinoblastoma protein, pRB, r?,arelikelyrelated to cell division and genomic stability, but the key biochemical functions and molecular basis for of tissue specificity remain unknown. Retinoblastoma is diagnosed in 8,000 c[]children each year worldwide[Au: globally?], yet patient survival is >95% in high-income countries, but <30% globally, dependings on the socio-economical context; it is as high as>95% in high-income countries,but<30% globally[Au: Do you mean overall survival, or survival of the affected eye?]. Collaborations ofStakeholders collaboration is are improving outcomes, by increasing awareness for earlier diagnosis, sharing expertise, and developing guidelines. Intra-arterial and intra-vitreal chemotherapy have emergedthave emerged as a promising wayo salvage eyes with retinoblastoma, with dramatic responses. Two new therapies have emerged to salvage eyes with retinoblastoma: intra-arterial and intra-vitreal chemotherapy, to which the disease can respond dramatically.Ongoing iInternational collaboration is ongoing towill replace the multiple different classifications of eye involvement with standardized clear definitions, to that will facilitate rigorous assessment of eligibility, efficacy and safety of treatments. Heritable retinoblastoma survivors are at risk for second cancers; defining the molecular basis of RB1 retinal specificity may explain tissue specificity of second cancers, opening the path and lead to cancer prevention. In this Primer, we describe the current molecular understanding of retinoblastoma, and describe advances in the sociomedical aspects of the disease, including internet-based initiatives such to provide global,retinoblastoma-specific medical records. ]Keywordsretinoblastoma, pediatric oncology, pediatric ophthalmology, tumour suppressor gene, MYCN oncogene, Intra-arterial chemotherapy, Intra-vitreal chemotherapy, Cone photoreceptor, Cancer therapy, Global healthCompeting interests[Au: Please insert the competing interest statement for each author here, or in the online submission form with your revised manuscript.][Au: Pleasemakesureofficialnomenclatureisusedforprotein(Uniprot)andgene(Hugoanditalics)namesandthattheyarestyledaccordingtospecies(capitalsforhumans,onlyfirstlettercapitalformice). Also make sure that abbreviations are consistently used throughout the manuscript (N-Myc, MYCN, etc.)][Au: I’ve inserted HX notations at all the headings to indicate the level of heading, three of which are allowed.][H1] Introduction(BLG)3192211/300Retinoblastoma is a rare cancer initiated by biallelic mutation of the retinoblastoma gene (RB1) in a specific[Au: by ‘specific’ do you mean a single cell (cell of origin)?]single susceptible developing retinal cell type. SinceInheritance of onea mutant RB1 allele strongly predisposes to retinoblastomatumours that form when the second RB1 allele is mutated. ADDIN EN.CITE <EndNote><Cite><Author>Knudson</Author><Year>2001</Year><RecNum>22274</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>22274</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1429979318">22274</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Knudson, A. G.</author></authors></contributors><auth-address>Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. ag_knudson@fccc.edu</auth-address><titles><title>Two genetic hits (more or less) to cancer</title><secondary-title>Nat Rev Cancer</secondary-title><alt-title>Nature reviews. Cancer</alt-title></titles><periodical><full-title>Nat Rev Cancer</full-title></periodical><pages>157-62</pages><volume>1</volume><number>2</number><keywords><keyword>Adult</keyword><keyword>Age of Onset</keyword><keyword>Aneuploidy</keyword><keyword>Animals</keyword><keyword>Carcinogens/adverse effects</keyword><keyword>Cell Transformation, Neoplastic/*genetics</keyword><keyword>Child</keyword><keyword>Chromosome Aberrations</keyword><keyword>Female</keyword><keyword>Forecasting</keyword><keyword>Genes, Retinoblastoma</keyword><keyword>Genes, Tumor Suppressor</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Male</keyword><keyword>*Models, Genetic</keyword><keyword>Mutagens/adverse effects</keyword><keyword>Mutation</keyword><keyword>Neoplasms/epidemiology/genetics</keyword><keyword>Oncogenes</keyword><keyword>Retinoblastoma/epidemiology/genetics</keyword></keywords><dates><year>2001</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1474-175X (Print)
1474-175X (Linking)</isbn><accession-num>11905807</accession-num><urls><related-urls><url> Although RB1 loss initiates cancer in specific susceptible tissues, it is lost with progression in almost all human cancers. ADDIN EN.CITE <EndNote><Cite><Author>Hanahan</Author><Year>2000</Year><RecNum>16157</RecNum><DisplayText><style face="superscript">2</style></DisplayText><record><rec-number>16157</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1313535298">16157</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hanahan, D.</author><author>Weinberg, R. A.</author></authors></contributors><auth-address>Department of Biochemistry, Hormone Research Institute, University of California at San Francisco, 94143, USA.</auth-address><titles><title>The hallmarks of cancer</title><secondary-title>Cell</secondary-title><alt-title>Cell</alt-title></titles><periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></periodical><alt-periodical><full-title>Cell</full-title><abbr-1>Cell</abbr-1></alt-periodical><pages>57-70</pages><volume>100</volume><number>1</number><edition>2000/01/27</edition><keywords><keyword>Animals</keyword><keyword>Apoptosis</keyword><keyword>Cell Transformation, Neoplastic</keyword><keyword>Gene Expression Regulation, Neoplastic</keyword><keyword>Humans</keyword><keyword>*Neoplasms/blood supply/etiology/genetics/pathology</keyword><keyword>*Neoplasms, Experimental/blood supply/genetics/pathology</keyword><keyword>Neovascularization, Pathologic</keyword></keywords><dates><year>2000</year><pub-dates><date>Jan 7</date></pub-dates></dates><isbn>0092-8674 (Print)
0092-8674 (Linking)</isbn><accession-num>10647931</accession-num><work-type>Research Support, U.S. Gov't, Non-P.H.S.
Research Support, U.S. Gov't, P.H.S.
Review</work-type><urls><related-urls><url> REF,The principals discovered by study of retinoblastoma led to characterization of familial cases has contributed tothe recognition that all altered genes broadly underlie all cancer initiation and progression. cancer is initiated and progresses, by altered genes[Au: please cite a reference(s). Also, if biallelic mutation is needed, that inheritance of ‘a’ (i.e., single) mutant allele also predisposes is unclear]. ADDIN EN.CITE <EndNote><Cite><Author>Knudson</Author><Year>2001</Year><RecNum>22274</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>22274</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1429979318">22274</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Knudson, A. G.</author></authors></contributors><auth-address>Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. ag_knudson@fccc.edu</auth-address><titles><title>Two genetic hits (more or less) to cancer</title><secondary-title>Nat Rev Cancer</secondary-title><alt-title>Nature reviews. Cancer</alt-title></titles><periodical><full-title>Nat Rev Cancer</full-title></periodical><pages>157-62</pages><volume>1</volume><number>2</number><keywords><keyword>Adult</keyword><keyword>Age of Onset</keyword><keyword>Aneuploidy</keyword><keyword>Animals</keyword><keyword>Carcinogens/adverse effects</keyword><keyword>Cell Transformation, Neoplastic/*genetics</keyword><keyword>Child</keyword><keyword>Chromosome Aberrations</keyword><keyword>Female</keyword><keyword>Forecasting</keyword><keyword>Genes, Retinoblastoma</keyword><keyword>Genes, Tumor Suppressor</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Male</keyword><keyword>*Models, Genetic</keyword><keyword>Mutagens/adverse effects</keyword><keyword>Mutation</keyword><keyword>Neoplasms/epidemiology/genetics</keyword><keyword>Oncogenes</keyword><keyword>Retinoblastoma/epidemiology/genetics</keyword></keywords><dates><year>2001</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1474-175X (Print)
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ADDIN EN.CITE.DATA 3 An intraretinal white tumour develops after genomic changes lead to uncontrolled proliferation — the tumour is visible through the pupil (the most common first sign) (Figures 3, 9) or blocks vision and impedes central visual fixation (the second most common sign)[Au: reference?]. ADDIN EN.CITE <EndNote><Cite><Author>Dimaras</Author><Year>2012</Year><RecNum>17755</RecNum><DisplayText><style face="superscript">4</style></DisplayText><record><rec-number>17755</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1335495654">17755</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dimaras, H.</author><author>Kimani, K.</author><author>Dimba, E. A.</author><author>Gronsdahl, P.</author><author>White, A.</author><author>Chan, H. S.</author><author>Gallie, B. L.</author></authors></contributors><auth-address>Division of Haematology/Oncology, The Hospital for Sick Children, Toronto, ON, Canada.</auth-address><titles><title>Retinoblastoma</title><secondary-title>Lancet</secondary-title><alt-title>Lancet</alt-title></titles><periodical><full-title>Lancet</full-title></periodical><alt-periodical><full-title>Lancet</full-title></alt-periodical><pages>1436-46</pages><volume>379</volume><number>9824</number><edition>2012/03/15</edition><dates><year>2012</year><pub-dates><date>Apr 14</date></pub-dates></dates><isbn>1474-547X (Electronic)
0140-6736 (Linking)</isbn><accession-num>22414599</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>(11)61137-9
doi:10.1016/S0140-6736(12)61446-9
</electronic-resource-num><language>eng</language></record></Cite></EndNote>4 Ifthese signs areWhen noticed early, prompt treatment is often usually cures. Later diagnosis can lead to ative. If notdiagnosed incurable late,the cancer can invadeinvasion of the optic nerve and brain ,which is usually incurable,or or can metastasis, ze, particularly to the bone marrow, whichcanis sometimes be curablecured with by extensive medical intervention.Rigorous clinical trials in retinoblastoma are difficult for multiple reasons: there aretoo few patients in high-income countries; the disease can haveoften has a complex presentation (two eyes withdiffering severity); the disease is too raretoo few patients to interest the pharmaceutical industry; multidisciplinary collaboration is needed to make progresrequireds; and there ishigh societal value on eyes and vision that maysomtimes imposess considerations beyond curing the cancer. New technologies showing a dramatic primary response in the intraocular tumour have been quickly embraced, despite absence of rigorous clinical trials. for eye salvage.[Au: Sentence about survival deleted to minimize overlap.]The Internet has opened many avenues for retinoblastoma: parents make the diagnosis themselves; colleagues discuss and share patients around the globe; centres of retinoblastoma excellence can be mapped (Table Figure 21)[Au: I assume this is a callout to Table 2 (which should be changed to Table 1).]; and a common database for all children no matter where they live is within sightreach. These developments could empower a learning health system to achieve an evidence base for retinoblastoma care. In this Primer, we review retinoblastoma at a time when new science, new ideas, new therapies and global collaboration are unprecedented. [H1] Epidemiology (HD,GC, JZ, FN) 914762/500[H2] Globalpatients, resources and outcomes[Au: edited to fit within a 42 character limit (which includes white spaces)]The expected number of patients with retinoblastoma annually per country can be calculated by multiplying the[Au: global?] global retinoblastoma incidence (1 in 16,000-18,000 live births) by forecast births (Table 2).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaXZlbGE8L0F1dGhvcj48WWVhcj4yMDA5PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 5-7 This predicts approximately 8,000 new cases each year.Patient distribution is such thatOf all affected children, 11% reside in high-income, 69% in middle-income and 20% in low-income countries. Although the incidence prevalence is higher in middle- to low-income countries, most retinoblastoma treatment centres are in middle- and high-income countries, creating a gap in healthcare access (Figure 2). Consistent with income being a surrogate for non-economic measures of quality of lifestandard of living, retinoblastoma in low-income countries is associated with low patient survival (~30%PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5OeWF3aXJhPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 11-13 Without timely diagnosis and appropriate treatment, difficult-to-cure metastatic disease may occur. Fortunately, with early diagnosis, many eyes can be safely treated to support a lifetime of good vision, pointing to key elements to for global focus on globally: awareness, collaboration, and affordable expert care. [H2] Solutions for global retinoblastomaA number of initiatives have addressed the inequality in retinoblastoma treatment between the developing and the developed worlds. In 2009, the Canadian National Rb Strategy (NRbS) published the first-ever retinoblastoma clinical practice guidelines, ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Year>2009</Year><RecNum>12485</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>12485</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1254258597">12485</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>National Retinoblastoma Strategy Canadian Guidelines for Care / Stratégie thérapeutique du rétinoblastome guide clinique canadien</title><secondary-title>Can J Ophthalmol</secondary-title></titles><periodical><full-title>Can J Ophthalmol</full-title><abbr-1>Canadian journal of ophthalmology</abbr-1></periodical><pages>S1-88</pages><volume>44</volume><number>Supp 2</number><dates><year>2009</year></dates><urls><related-urls><url> adapted by the Kenyan National Retinoblastoma Strategy (KNRbS) and published in 2014 in partnership with the Kenyan Department of Health. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Year>2014</Year><RecNum>21413</RecNum><DisplayText><style face="superscript">14</style></DisplayText><record><rec-number>21413</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1424896242">21413</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors></contributors><titles><title>Kenya national retinoblastoma strategy: Best practice guidelines</title></titles><dates><year>2014</year></dates><urls><related-urls><url>health.go.ke/images/downloads/Best-Practice-September-2014.pdf</url></related-urls></urls></record></Cite></EndNote>14.?T The KNRbS achieved standardization of pathology processing and reporting that to supports treatment decisions and discussion of prognosis with families. Adoption of upfront (first-line) enucleation with implants and immediate prosthetic eyes (sourced from India), parent to parent interactions to allay uninformed fears, and standardization of information provided to parents has reduced the rate of non-compliance with treatment. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Year>2014</Year><RecNum>21413</RecNum><DisplayText><style face="superscript">14, 15</style></DisplayText><record><rec-number>21413</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1424896242">21413</key></foreign-keys><ref-type name="Government Document">46</ref-type><contributors></contributors><titles><title>Kenya national retinoblastoma strategy: Best practice guidelines</title></titles><dates><year>2014</year></dates><urls><related-urls><url>health.go.ke/images/downloads/Best-Practice-September-2014.pdf</url></related-urls></urls></record></Cite><Cite><Author>Dimaras</Author><Year>2008</Year><RecNum>15650</RecNum><record><rec-number>15650</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1304997001">15650</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Generic">13</ref-type><contributors><authors><author>Dimaras, H</author><author>White, A</author><author>Gallie, B.L.</author></authors></contributors><titles><title>The Kenyan National Retinoblastoma Strategy: Building local capacity in the diagnosis and management of pediatric eye cancer in Kenya</title><secondary-title>Ophthalmology Rounds</secondary-title></titles><volume>6</volume><number>4</number><dates><year>2008</year><pub-dates><date>July/August 2008</date></pub-dates></dates><pub-location>Toronto</pub-location><urls><related-urls><url><style face="underline" font="default" size="100%">, 15 In 2013, the Paediatric Oncology in Developing Countries Committee of the SIOP (International Society of Paediatric Oncology) published a consensus guideline for the management of retinoblastoma in countries with limited resources ADDIN EN.CITE <EndNote><Cite><Author>Chantada</Author><Year>2013</Year><RecNum>18862</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>18862</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1364496460">18862</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chantada, G.</author><author>Luna-Fineman, S.</author><author>Sitorus, R. S.</author><author>Kruger, M.</author><author>Israels, T.</author><author>Leal-Leal, C.</author><author>Bakhshi, S.</author><author>Qaddoumi, I.</author><author>Abramson, D. H.</author><author>Doz, F.</author></authors></contributors><auth-address>Hospital de Pediatria SAMIC Prof Dr Juan P Garrahan, Buenos Aires, Argentina; St Jude Children's Research Hospital, Memphis, Tennessee. gchantada@.</auth-address><titles><title>SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries</title><secondary-title>Pediatr Blood Cancer</secondary-title><alt-title>Pediatric blood & cancer</alt-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><pages>719-27</pages><volume>60</volume><number>5</number><edition>2013/01/22</edition><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1545-5017 (Electronic)
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ADDIN EN.CITE.DATA 17 and the Brazilian SOBOPE (Brazilian Society of Pediatric Oncology) ADDIN EN.CITE <EndNote><Cite><Author>de Castro Junior</Author><Year>2011</Year><RecNum>21806</RecNum><DisplayText><style face="superscript">18</style></DisplayText><record><rec-number>21806</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426971255">21806</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>de Castro Junior, C. G.</author><author>Macedo, C. R.</author></authors></contributors><auth-address>President of Brazilian Society of Pediatric Oncology, Pediatric Oncology Service, Hospital de Clinicas de Porto Alegre, RS, Brazil.</auth-address><titles><title>Brazilian Society of Pediatric Oncology - SOBOPE: 30 years of history, a lot in the present, full of the future</title><secondary-title>Rev Bras Hematol Hemoter</secondary-title><alt-title>Revista brasileira de hematologia e hemoterapia</alt-title></titles><periodical><full-title>Rev Bras Hematol Hemoter</full-title><abbr-1>Revista brasileira de hematologia e hemoterapia</abbr-1></periodical><alt-periodical><full-title>Rev Bras Hematol Hemoter</full-title><abbr-1>Revista brasileira de hematologia e hemoterapia</abbr-1></alt-periodical><pages>326-7</pages><volume>33</volume><number>5</number><dates><year>2011</year></dates><isbn>1806-0870 (Electronic)
1516-8484 (Linking)</isbn><accession-num>23049330</accession-num><urls><related-urls><url> guidelines are also applicable at a national level with governmental support for treatment. ]Peer-to-peer collaborations and twinning programmes have built a framework for knowledge and expertise exchange, filling gaps in specialized training, and source donations of equipment and resources with the ultimate aim of sustainable local capacity. ADDIN EN.CITE <EndNote><Cite><Author>Naseripour</Author><Year>2012</Year><RecNum>21411</RecNum><DisplayText><style face="superscript">19</style></DisplayText><record><rec-number>21411</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1424896241">21411</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Naseripour, M.</author></authors></contributors><auth-address>Eye Research Center, Rassoul Akram Hospital, Tehran University of Medical Sciences, Niayesh Avenue, Sattar-khan Street, Tehran, Iran.</auth-address><titles><title>"Retinoblastoma survival disparity": The expanding horizon in developing countries</title><secondary-title>Saudi J Ophthalmol</secondary-title><alt-title>Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society</alt-title></titles><periodical><full-title>Saudi J Ophthalmol</full-title><abbr-1>Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society</abbr-1></periodical><alt-periodical><full-title>Saudi J Ophthalmol</full-title><abbr-1>Saudi journal of ophthalmology : official journal of the Saudi Ophthalmological Society</abbr-1></alt-periodical><pages>157-61</pages><volume>26</volume><number>2</number><dates><year>2012</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1319-4534 (Print)
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ADDIN EN.CITE.DATA 17and between the Institut Curie and a centre in Bamako, Mali.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5UcmFvcmU8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 22 The Central American Association of Pediatric Hematology Oncology (AHOPCA) created a cooperative group and implemented multicentre protocols for retinoblastoma treatment,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdW5hLUZpbmVtYW48L0F1dGhvcj48WWVhcj4yMDEyPC9Z
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Tm90ZT4A
ADDIN EN.CITE.DATA 21, 23, 24 a major achievement, not yet paralleled in developed countries. The AHOPCA funding is now 90% local. Twinning programme sbenefit from strong participation of both non-governmental and governmental organizations. However, where government may prove volatile and unpredictable, sustainable local capacity is a challenge. Less formal cooperation between developed and less developed countries can also result in highly efficient programmes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XYWRkZWxsPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA 25, 26A successful national strategy has also been developed in China. About 1,100 newly diagnosed cases are forecasted annually, scattered over 32 provinces, and iI mposing high travel costs related to travel. Before 2005, enucleation was the only available treatment available for most children. For better treatment options and follow-up, multiple centres classified by expertise and resources were established in 28 hospitals covering 25 provinces (over 90% of the population) ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Year>2015</Year><RecNum>22259</RecNum><DisplayText><style face="superscript">27</style></DisplayText><record><rec-number>22259</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1429979272">22259</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors></contributors><titles><title>One Retinoblastoma World</title></titles><pages>One Retinoblastoma World is a global network with the bold idea that all children with retinoblastoma can have equal opportunity to optimal care. We aim for global collaboration to deliver coordinated, evidence-based retinoblastoma care.</pages><number>April 22 2015</number><dates><year>2015</year></dates><pub-location>Toronto</pub-location><urls><related-urls><url> ( HYPERLINK "" ). The improved efficiency and collaboration from 2006 to 2014 has led to standardized classification and treatment of 2,097 newly diagnosed patients with retinoblastoma on common protocols from 2006 to 2014 with improvements gains in of survival (unpublished data). In Argentina, a single centre with high expertise coordinates affiliated retinoblastoma clinics . This collaboration between governmental hospitals, local and international NGO’s with prospective protocols has significantly improved survival in two decades with prospective protocols.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2h2YXJ0em1hbjwvQXV0aG9yPjxZZWFyPjE5OTY8L1ll
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ADDIN EN.CITE.DATA 29, 30In a rapidly changing world, Finally, Internet based strategies are now opening up global collaboration globally. including The One Retinoblastoma World map (Figure 2) leads families to the nearest centre with known expertise.REFurlshows…….etc . REF url?? and The retinoblastoma-specific point-of-care database (eCancerCareRB, eCCRB) summarizes the medical record for retinoblastoma for each child (Figures 3, 4 and 9). eCCRB is now on a cloud serveron the Internet is, freely accessible to every retinoblastoma centre with local ethics and privacy approvals. The Disease-specific, electronic Patient Illustrated Clinical Timeline (DePICT) is language-independent, well understood by parents, and supports fully informed care choices. ADDIN EN.CITE <EndNote><Cite><Author>Chiu</Author><Year>In Press</Year><RecNum>21787</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>21787</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426869795">21787</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chiu, Hannah H. </author><author>Dimaras, Helen</author><author>Downie, Rob </author><author>Gallie, Brenda</author></authors></contributors><titles><title>Breaking down barriers to communicating complex retinoblastoma information: can graphics be the solution?</title><secondary-title>Canadian Journal of Ophthalmology</secondary-title></titles><periodical><full-title>Can J Ophthalmol</full-title><abbr-1>Canadian journal of ophthalmology</abbr-1></periodical><dates><year>In Press</year></dates><urls></urls></record></Cite></EndNote>31 With guardian consent from every guardian, fully identified data including images is accessible to allthose in the circle of care of theeach child. Ultimately, the de-identified data will be fuel for a learning health system. The graphical timeline is language-independent, well understood by parents, and has been used to supports fully informed care choices. ADDIN EN.CITE <EndNote><Cite><Author>Chiu</Author><Year>In Press</Year><RecNum>21787</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>21787</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426869795">21787</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chiu, Hannah H. </author><author>Dimaras, Helen</author><author>Downie, Rob </author><author>Gallie, Brenda</author></authors></contributors><titles><title>Breaking down barriers to communicating complex retinoblastoma information: can graphics be the solution?</title><secondary-title>Canadian Journal of Ophthalmology</secondary-title></titles><periodical><full-title>Can J Ophthalmol</full-title><abbr-1>Canadian journal of ophthalmology</abbr-1></periodical><dates><year>In Press</year></dates><urls></urls></record></Cite></EndNote>31 the retinoblastoma-specific point-of-care database (eCancerCareRB, eCCRB) provide worldwide accessible information for patients, parents and health care providers. . [H1] Mechanisms/pathophysiology (TWC, DC, BLG) 1574/1500T The search for the genetic basis of retinoblastoma provided the two-hit model of tumor suppressor gene inactivation. In 19712, Knudson discovered that the distribution of age of diagnosis of retinoblastoma sat which patients are diagnosed withretinoblastomasis consistent with one rate-limiting event in bilaterally affected patients (who usually always have heritable disease), and withvsand two such events in unilaterally affected patients with no family history (which is usually non-heritable condition).{Knudson, 1971 #591} Based on these results, Comingsit wasOthers proposed that heritable retinoblastomas result from a germline mutation (‘first hit’) and an acquired somatic mutation (‘second hit’) in heritable cases, and non-heritable retinoblastomas arise when from two somatic mutations in the same transformation suppressor gene in in a susceptible cell non-heritable cases (Figure 4).{Comings, 1973 #21098} [H2] Driver gene mutations[Au: Title inserted. OK?]Deleted because it seems superfluous hereThetwo-hit model guided the search for the retinoblastoma gene, RB1. Chromosomal deletions in some patients led investigatorspointed to a chromosome 13q14 locus. Loss of heterozygosity of 13q14 polymorphic markers in 70% of retinoblastoma tumours{Cavenee, 1983 #62;Dryja, 1986 #10404} implied that the second hit, somatic mutation involved the same genetic region, consistent with the two-hit modellocus. The breakthrough came when one retinoblastoma was missing the sequence of a 13q DNA clone,Eventually, Southern blotting showed loss from a tumour of a 13q segment{Dryja, 1986 #10404} that turned out to be a conserved, exonic sequence of RB1.{Dryja, 1986 #10404;Friend, 1986 #4934;Lee, 1987 #333;Friend, 1986 #4934;Fung, 1987 #21743}RB1 is a large (190 kb) gene with 27 exons, encoding a 4.7 kb mRNA andthat translatesd into a 928 amino acid protein, pRB. Many different modifications impair its pRB function, including point mutations, promoter methylation, and small and large deletions..{Lohmann, 1999 #4359}RB1 encodes a 4.7 kb mRNA, translated into the 928 amino acid protein, RB. The A/B “pocket” region ADDIN EN.CITE <EndNote><Cite><Author>Dick</Author><Year>2013</Year><RecNum>10937</RecNum><DisplayText><style face="superscript">40</style></DisplayText><record><rec-number>10937</rec-number><foreign-keys><key app="EN" db-id="saep2xxtw9repceffx0pfze85vzp0eattzaa" timestamp="1425486951">10937</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dick, F. A.</author><author>Rubin, S. M.</author></authors></contributors><auth-address>London Regional Cancer Program, Children's Health Research Institute, and Department of Biochemistry, Western University, London, Ontario N6A 4L6, Canada. fdick@uwo.ca</auth-address><titles><title>Molecular mechanisms underlying RB protein function</title><secondary-title>Nat Rev Mol Cell Biol</secondary-title><alt-title>Nature reviews. Molecular cell biology</alt-title></titles><periodical><full-title>Nat Rev Mol Cell Biol</full-title></periodical><pages>297-306</pages><volume>14</volume><number>5</number><keywords><keyword>Animals</keyword><keyword>Apoptosis/genetics</keyword><keyword>Cell Cycle/genetics</keyword><keyword>Genomic Instability</keyword><keyword>Humans</keyword><keyword>Retinoblastoma Protein/*genetics/*metabolism</keyword></keywords><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1471-0080 (Electronic)
1471-0072 (Linking)</isbn><accession-num>23594950</accession-num><urls><related-urls><url> is best characterized and harbours most of the RB1 missense mutations.,although N-terminal mutations are also found (Goodrich 2003). The A/B pocket is conserved in two other RB family members, p107 (RBL1) and p130 (RBL2). These proteins are rarely mutated in cancer, although a large 16q region containing p130 is lost in some retinoblastoma and other cancers. TThe pRB functions that normally suppress retinoblastoma within the retina remain unknown. pRB is best known as a cell cycle regulator that binds to E2F transcription factors to repress cell proliferation-related genes. Hyperphosphorylation of pRB by cyclin-dependent kinases in response to mitogenic signals normally relieves repression and promotes the G1 to S phase transition. pRB loss relieves this suppression in the absence of mitogenic signals to enable tumourigenesis. It Notably, two other RB family members, p107 and p130, regulate distinct E2Fs and cell cycle genes, suggesting that the few genes uniquely regulated by RB have special importance.{Hurford, 1997 #11388}It is tempting to speculate that pRB is primarily needed to suppress E2F.In addition to E2F suppression, RB can up-regulate p27, and is implicated in cell differentiation, apoptosis, and genomic integrity.{Dick, 2013 #10937;}RB seems unlikely to be required in order to sustain high p27 levels, since increasing RB is associated with decreasing p27 during cone precursor maturation.{Lee, 2006 #11229} It is therefore tempting to speculate that RB is primarily needed to suppress E2F. However, Sseveral “low penetrance” RB1 mutations encode proteins with minimal ability to bind E2F, butand predispose carriers to fewer retinoblastomas at a far lower rate than RB1 null alleles.{Lohmann, 1994 #10195} {Lohmann, 1994 #10195}(0-2 tumours insteadof ~ 6 tumours).{Munier, 1994 #19241}[can cite Lohmann ref 38 here instead] Such defective E2F-binding alleles may suppress the additional retinoblastomasfunction to block retinoblastoma development through an E2F-independent mechanism. In addition to E2F suppression, pRB can also up-regulates p27, and is implicated in cell differentiation, apoptosis, and genomic integrity. ADDIN EN.CITE <EndNote><Cite><Author>Dick</Author><Year>2013</Year><RecNum>10937</RecNum><DisplayText><style face="superscript">40</style></DisplayText><record><rec-number>10937</rec-number><foreign-keys><key app="EN" db-id="saep2xxtw9repceffx0pfze85vzp0eattzaa" timestamp="1425486951">10937</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dick, F. A.</author><author>Rubin, S. M.</author></authors></contributors><auth-address>London Regional Cancer Program, Children's Health Research Institute, and Department of Biochemistry, Western University, London, Ontario N6A 4L6, Canada. fdick@uwo.ca</auth-address><titles><title>Molecular mechanisms underlying RB protein function</title><secondary-title>Nat Rev Mol Cell Biol</secondary-title><alt-title>Nature reviews. Molecular cell biology</alt-title></titles><periodical><full-title>Nat Rev Mol Cell Biol</full-title></periodical><pages>297-306</pages><volume>14</volume><number>5</number><keywords><keyword>Animals</keyword><keyword>Apoptosis/genetics</keyword><keyword>Cell Cycle/genetics</keyword><keyword>Genomic Instability</keyword><keyword>Humans</keyword><keyword>Retinoblastoma Protein/*genetics/*metabolism</keyword></keywords><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1471-0080 (Electronic)
1471-0072 (Linking)</isbn><accession-num>23594950</accession-num><urls><related-urls><url> In the developing retina, RB seems unlikely to be required to sustain high p27 levels, since Increasing pRB expression is associated with decreasing p27 during cone precursor maturation.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 3 Further genetic or epigenetic changes are likely needed for malignant transformation. ADDIN EN.CITE <EndNote><Cite><Author>Theriault</Author><Year>2014</Year><RecNum>10406</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>10406</rec-number><foreign-keys><key app="EN" db-id="saep2xxtw9repceffx0pfze85vzp0eattzaa" timestamp="1425486615">10406</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Theriault, B. L.</author><author>Dimaras, H.</author><author>Gallie, B. L.</author><author>Corson, T. W.</author></authors></contributors><auth-address>Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.</auth-address><titles><title>The genomic landscape of retinoblastoma: a review</title><secondary-title>Clin Experiment Ophthalmol</secondary-title><alt-title>Clinical & experimental ophthalmology</alt-title></titles><periodical><full-title>Clin Experiment Ophthalmol</full-title></periodical><pages>33-52</pages><volume>42</volume><number>1</number><edition>2014/01/18</edition><keywords><keyword>cytogenetics</keyword><keyword>epigenetics</keyword><keyword>microRNA</keyword><keyword>retinoblastoma</keyword><keyword>single nucleotide polymorphism</keyword></keywords><dates><year>2014</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>1442-9071 (Electronic)
1442-6404 (Linking)</isbn><accession-num>24433356</accession-num><work-type>Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url> Comparative genomic hybridization studies identified common regions of DNA gain that led to several candidate retinoblastoma oncogenes: the mitotic kinesin KIF14 and p53 regulator MDM4 (1q32), transcription factors E2F3 and DEK (6p22), and the onco-miR clusters miR-106b~25 (7q22.1) and miR-17~92 (13q31). In addition, Consistent loss of 16q22 losses led to identification of cadherin-11 (CDH11) as a tumour suppressor gene;, while whole-genome sequencing identified inactivating mutations in the transcriptional corepressor BCOR.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 48 Besides SYK, many other genes and microRNAs show altered expression in retinoblastoma compared to normal retina. ADDIN EN.CITE <EndNote><Cite><Author>Theriault</Author><Year>2014</Year><RecNum>10406</RecNum><DisplayText><style face="superscript">47</style></DisplayText><record><rec-number>10406</rec-number><foreign-keys><key app="EN" db-id="saep2xxtw9repceffx0pfze85vzp0eattzaa" timestamp="1425486615">10406</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Theriault, B. L.</author><author>Dimaras, H.</author><author>Gallie, B. L.</author><author>Corson, T. W.</author></authors></contributors><auth-address>Campbell Family Cancer Research Institute, Ontario Cancer Institute, Princess Margaret Cancer Centre, Toronto, Ontario, Canada.</auth-address><titles><title>The genomic landscape of retinoblastoma: a review</title><secondary-title>Clin Experiment Ophthalmol</secondary-title><alt-title>Clinical & experimental ophthalmology</alt-title></titles><periodical><full-title>Clin Experiment Ophthalmol</full-title></periodical><pages>33-52</pages><volume>42</volume><number>1</number><edition>2014/01/18</edition><keywords><keyword>cytogenetics</keyword><keyword>epigenetics</keyword><keyword>microRNA</keyword><keyword>retinoblastoma</keyword><keyword>single nucleotide polymorphism</keyword></keywords><dates><year>2014</year><pub-dates><date>Jan-Feb</date></pub-dates></dates><isbn>1442-9071 (Electronic)
1442-6404 (Linking)</isbn><accession-num>24433356</accession-num><work-type>Research Support, N.I.H., Extramural
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ADDIN EN.CITE.DATA 51 While RB1+/+MYCNA retinoblastomas share certain secondary genomic changes with RB1-/-tumours, they are diagnosed at a much younger age than unilateral RB1-/- tumoursshow very early onset and have a distinct histology, reflecting a unique subtype. RB1+/+MYCNA retinoblastomas are diagnosed at a much younger age than RB1-/- tumours. The trend of increasing MYCN copy number with age at diagnosis, and the very young age of presentation of very large tumours, suggests thatplaces the cell of origin of RB1+/+MYCNA tumours is earlier in developmentally earlier than that of RB1-/-tumours.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5SdXNobG93PC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 51 To date, aAnother 1.5% of patients with unilateral non-familial retinoblastomas seemto have apparently normal both RB1and MYCN (?)genes; their tumours may be driven by an unidentified factor or be caused by unknown mechanism to may inactivate pRBRB1.[H2] Cone-precursor circuitry sensitizes to RB1 lossor - The retinoblastoma cell of originSince pRB is expressed in most if not all cells, in the body the retina’s unique sensitivity to pRB loss is perplexing. Cell type-specificIntracellular sSignaling circuitry specific to the retinoblastoma cell-of-origin and which collaborating collaborateswithlost RB1 inactivation in the retinoblastoma cell-of-origin could provide a basis forexplain the retinal tropism. In EarlystudiesDetection of diverse retinal cell type markers and RNAs in retinoblastomas pointed to a pleuripotent cell, detection of diverse retinal cell type markers in retinoblastoma suggested that the tumours might derive from a cell able to give rise to multiple cell typesa multipotent[Au: what is meant by ‘multipotent’ in this context?]cell-of-origin, yet but could could also represent normal RB1+/+ RB-positive cells, or aberrant expression within the tumourof oncogenic transformation.{Xu, 2009 #14691;} {McEvoy, 2011 #16182} Moreover, the co-expression of RNAs characteristic of diverse retinal cell types bysingle retinoblastoma cells ADDIN EN.CITE <EndNote><Cite><Author>McEvoy</Author><Year>2011</Year><RecNum>16182</RecNum><DisplayText><style face="superscript">49</style></DisplayText><record><rec-number>16182</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1316481812">16182</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>McEvoy, J.</author><author>Flores-Otero, J.</author><author>Zhang, J.</author><author>Nemeth, K.</author><author>Brennan, R.</author><author>Bradley, C.</author><author>Krafcik, F.</author><author>Rodriguez-Galindo, C.</author><author>Wilson, M.</author><author>Xiong, S.</author><author>Lozano, G.</author><author>Sage, J.</author><author>Fu, L.</author><author>Louhibi, L.</author><author>Trimarchi, J.</author><author>Pani, A.</author><author>Smeyne, R.</author><author>Johnson, D.</author><author>Dyer, M. A.</author></authors></contributors><auth-address>Department of Developmental Neurobiology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.</auth-address><titles><title>Coexpression of normally incompatible developmental pathways in retinoblastoma genesis</title><secondary-title>Cancer Cell</secondary-title><alt-title>Cancer Cell</alt-title></titles><periodical><full-title>Cancer Cell</full-title><abbr-1>Cancer cell</abbr-1></periodical><alt-periodical><full-title>Cancer Cell</full-title><abbr-1>Cancer cell</abbr-1></alt-periodical><pages>260-75</pages><volume>20</volume><number>2</number><edition>2011/08/16</edition><dates><year>2011</year><pub-dates><date>Aug 16</date></pub-dates></dates><isbn>1878-3686 (Electronic)
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ADDIN EN.CITE.DATA 53 and express different retinal markers, and may not extrapolate to humans. ADDIN EN.CITE <EndNote><Cite><Author>Cobrinik</Author><Year>2013</Year><RecNum>21036</RecNum><DisplayText><style face="superscript">54</style></DisplayText><record><rec-number>21036</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1424050717">21036</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Cobrinik, D.</author></authors><secondary-authors><author>Martinez-Murillo, R.</author><author>Martinez, A.</author></secondary-authors></contributors><titles><title>Learning about retinoblastoma from mouse models that missed</title><secondary-title>Animal Models of Brain Tumors</secondary-title><short-title>Learning about retinoblastoma from mouse models that missed</short-title></titles><pages>141-152</pages><dates><year>2013</year></dates><pub-location>New York</pub-location><publisher>Springer</publisher><urls></urls></record></Cite></EndNote>54Apart from the detection of cone markers that could bemight have beenadoptedinduced during transformation], ADDIN EN.CITE <EndNote><Cite><Author>Bogenmann</Author><Year>1988</Year><RecNum>114</RecNum><DisplayText><style face="superscript">55, 56</style></DisplayText><record><rec-number>114</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">114</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Bogenmann, E.</author><author>Lochrie, M. A.</author><author>Simon, M. I.</author></authors></contributors><titles><title>Cone cell-specific genes expressed in retinoblastoma</title><secondary-title>Science</secondary-title></titles><periodical><full-title>Science</full-title><abbr-1>Science (New York, N.Y</abbr-1></periodical><pages>76-8</pages><volume>240</volume><number>4848</number><dates><year>1988</year></dates><label>1613</label><urls></urls></record></Cite><Cite><Author>Hurwitz</Author><Year>1990</Year><RecNum>1504</RecNum><record><rec-number>1504</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">1504</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Hurwitz, R. L.</author><author>Bogenmann, E.</author><author>Font, R. L.</author><author>Holcombe, V.</author><author>Clark, D.</author></authors></contributors><titles><title>Expression of the functional cone phototransduction cascade in retinoblastoma</title><secondary-title>J Clin Invest</secondary-title><alt-title>Journal Of Clinical Investigation.</alt-title></titles><periodical><full-title>J Clin Invest</full-title><abbr-1>The Journal of clinical investigation</abbr-1></periodical><pages>1872-8</pages><volume>85</volume><number>6</number><dates><year>1990</year></dates><urls><related-urls><url>, 56tThe first suggestion that retinoblastomas originate in cone precursors came from evidence that emerging tumourshave a topographic distribution that mimics the horizontal visual streak characteristic of red and green cones . ADDIN EN.CITE <EndNote><Cite><Author>Munier</Author><Year>1994</Year><RecNum>19241</RecNum><DisplayText><style face="superscript">44</style></DisplayText><record><rec-number>19241</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1377295457">19241</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Munier, F. L.</author><author>Balmer, A.</author><author>van Melle, G.</author><author>Gailloud, C.</author></authors></contributors><auth-address>Hopital Ophtalmique Jules Gonin, Lausanne, Switzerland.</auth-address><titles><title>Radial asymmetry in the topography of retinoblastoma. Clues to the cell of origin</title><secondary-title>Ophthalmic Genet</secondary-title><alt-title>Ophthalmic genetics</alt-title></titles><periodical><full-title>Ophthalmic Genet</full-title><abbr-1>Ophthalmic genetics</abbr-1></periodical><alt-periodical><full-title>Ophthalmic Genet</full-title><abbr-1>Ophthalmic genetics</abbr-1></alt-periodical><pages>101-6</pages><volume>15</volume><number>3-4</number><edition>1994/09/01</edition><keywords><keyword>Eye Neoplasms/genetics/*pathology</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Male</keyword><keyword>Ophthalmoscopy</keyword><keyword>Retina/pathology</keyword><keyword>Retinal Cone Photoreceptor Cells/pathology</keyword><keyword>Retinoblastoma/genetics/*pathology</keyword></keywords><dates><year>1994</year><pub-dates><date>Sep-Dec</date></pub-dates></dates><isbn>1381-6810 (Print)
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ADDIN EN.CITE.DATA 57; all these changes typically occurduringcone precursor maturation .PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MZWU8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 42 These features suggest that RB is needed to counter an oncogenic programme associated with cone precursor maturation. Notably,early smalltumours detected via optical coherence tomography (OCT) appeared to be centred in the inner nuclear layer of the retina, not the outer nuclear layer where mature cones reside.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb290bWFuPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 58 However, they also extended into the outer nuclear layer, and the smallest tumour detected to date had a significant outer nuclear layer presence (Figure 5c).The apparent growth of early tumours within the inner nuclear layerPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Sb290bWFuPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 58 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 tumours, and promote retinoblastoma cell growth in vitro.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 61, 62Many other lines exist ADDIN EN.CITE <EndNote><Cite><Author>Gallie</Author><Year>1999</Year><RecNum>9610</RecNum><DisplayText><style face="superscript">63</style></DisplayText><record><rec-number>9610</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">9610</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Gallie, B. L.</author><author>Trogadis, J.</author><author>Han, L-P.</author></authors><secondary-authors><author>John Masters</author></secondary-authors></contributors><titles><title>Retinoblastoma</title><secondary-title>Human Cell Culture</secondary-title></titles><pages>361-374</pages><volume>2</volume><dates><year>1999</year></dates><urls></urls></record></Cite></EndNote>63 and but require further characterization. Primary retinoblastoma cellscan be implanted asxenografts in immunodeficient micePEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxsaWU8L0F1dGhvcj48WWVhcj4xOTc3PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 48However, caution is needed, becausexenografts implanted subretinallyor on the vitreous membrane (collagen layer separating the vitreous humour from the rest of the eye)intravitreallycan have a different anatomy relative to the eye’s natural barriers, potentially affecting drug distribution and limiting translation to the patients. Genetically engineered mouse models can also be used to assess novel treatments. ADDIN EN.CITE <EndNote><Cite><Author>Pacal</Author><Year>2006</Year><RecNum>5968</RecNum><DisplayText><style face="superscript">65</style></DisplayText><record><rec-number>5968</rec-number><foreign-keys><key app="EN" db-id="saep2xxtw9repceffx0pfze85vzp0eattzaa" timestamp="1425482969">5968</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pacal, M.</author><author>Bremner, R.</author></authors></contributors><auth-address>Toronto Western Research Institute, University Health Network, 399 Bathurst Street, Room Mc6-424, Toronto, Ontario, M5T 2S8 Canada.</auth-address><titles><title>Insights from animal models on the origins and progression of retinoblastoma</title><secondary-title>Curr Mol Med</secondary-title><alt-title>Current molecular medicine</alt-title></titles><periodical><full-title>Curr Mol Med</full-title></periodical><pages>759-81</pages><volume>6</volume><number>7</number><keywords><keyword>Animals</keyword><keyword>*Cell Transformation, Neoplastic</keyword><keyword>*Disease Models, Animal</keyword><keyword>Disease Progression</keyword><keyword>Humans</keyword><keyword>Retinoblastoma Protein/genetics/*metabolism</keyword></keywords><dates><year>2006</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1566-5240 (Print)</isbn><accession-num>17100602</accession-num><urls><related-urls><url> </url></related-urls></urls><language>eng</language></record></Cite></EndNote>65 While Rb1+/- mice do not develop retinoblastoma, retinal deletion of Rb1 (using Pax6a, Nestin, or Chx10 promoters) in systemicp107, p130 or p27knockout micemutant backgrounds achieves retinal tumour formation. ADDIN EN.CITE <EndNote><Cite><Author>Cobrinik</Author><Year>2013</Year><RecNum>21036</RecNum><DisplayText><style face="superscript">54</style></DisplayText><record><rec-number>21036</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1424050717">21036</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Cobrinik, D.</author></authors><secondary-authors><author>Martinez-Murillo, R.</author><author>Martinez, A.</author></secondary-authors></contributors><titles><title>Learning about retinoblastoma from mouse models that missed</title><secondary-title>Animal Models of Brain Tumors</secondary-title><short-title>Learning about retinoblastoma from mouse models that missed</short-title></titles><pages>141-152</pages><dates><year>2013</year></dates><pub-location>New York</pub-location><publisher>Springer</publisher><urls></urls></record></Cite></EndNote>54 These models have been used to examine genetic interactions in vivo, such as the role of microRNA miR-17~92 overexpression in Pax6a-Cre;Rb1lox/lox; p107-/- mice.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db25rcml0ZTwvQXV0aG9yPjxZZWFyPjIwMTE8L1llYXI+
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ADDIN EN.CITE.DATA 66 However, since the mouse tumours require different collaborating mutations and may not originate from the same retinal cell type, their ability to predict human retinoblastoma treatment responses is not certain. Viral oncoproteins can promote murine retinoblastoma development, such as adenovirus E1A expressed in retinas of p53-/- mice, and Simian Virus 40 T-antigen expressed in developing Müller cellsdirected by the transgene insertion site.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaW5kbGU8L0F1dGhvcj48WWVhcj4xOTkwPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 67, 68 Subconjunctivaltopotecan was tested in this latter model and is now in the clinic, and Cdh11 was confirmed as a tumour suppressor by crossing a knockout into this model. ADDIN EN.CITE <EndNote><Cite><Author>Marchong</Author><Year>2010</Year><RecNum>7442</RecNum><DisplayText><style face="superscript">69</style></DisplayText><record><rec-number>7442</rec-number><foreign-keys><key app="EN" db-id="saep2xxtw9repceffx0pfze85vzp0eattzaa" timestamp="1425483885">7442</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Marchong, M. N.</author><author>Yurkowski, C.</author><author>Ma, C.</author><author>Spencer, C.</author><author>Pajovic, S.</author><author>Gallie, B. L.</author></authors></contributors><auth-address>Campbell Family Institute for Cancer Research, Ontario Cancer Institute/Princess Margaret Hospital, University Health Network, Toronto, Ontario, Canada.</auth-address><titles><title>Cdh11 acts as a tumor suppressor in a murine retinoblastoma model by facilitating tumor cell death</title><secondary-title>PLos Genetics</secondary-title><alt-title>PLoS Genet</alt-title></titles><periodical><full-title>PLoS genetics</full-title></periodical><alt-periodical><full-title>PLoS Genet</full-title></alt-periodical><pages>e1000923</pages><volume>6</volume><number>4</number><edition>2010/04/28</edition><keywords><keyword>Animals</keyword><keyword>*Apoptosis</keyword><keyword>Cadherins/*genetics</keyword><keyword>Female</keyword><keyword>*Genes, Tumor Suppressor</keyword><keyword>Male</keyword><keyword>Mice</keyword><keyword>Mice, Inbred Strains</keyword><keyword>Mice, Knockout</keyword><keyword>Mutation</keyword><keyword>Retinoblastoma/genetics/*metabolism</keyword></keywords><dates><year>2010</year></dates><isbn>1553-7404 (Electronic)
1553-7390 (Linking)</isbn><accession-num>20421947</accession-num><work-type>Research Support, N.I.H., Extramural</work-type><urls><related-urls><url> Thus, much may be learned and translated to the bedside with available systems while awaiting models that more precisely simulate retinoblast ADDIN EN.CITE <EndNote><Cite><Author>Knudson</Author><Year>2001</Year><RecNum>22274</RecNum><DisplayText><style face="superscript">1</style></DisplayText><record><rec-number>22274</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1429979318">22274</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Knudson, A. G.</author></authors></contributors><auth-address>Fox Chase Cancer Center, Philadelphia, Pennsylvania 19111, USA. ag_knudson@fccc.edu</auth-address><titles><title>Two genetic hits (more or less) to cancer</title><secondary-title>Nat Rev Cancer</secondary-title><alt-title>Nature reviews. Cancer</alt-title></titles><periodical><full-title>Nat Rev Cancer</full-title></periodical><pages>157-62</pages><volume>1</volume><number>2</number><keywords><keyword>Adult</keyword><keyword>Age of Onset</keyword><keyword>Aneuploidy</keyword><keyword>Animals</keyword><keyword>Carcinogens/adverse effects</keyword><keyword>Cell Transformation, Neoplastic/*genetics</keyword><keyword>Child</keyword><keyword>Chromosome Aberrations</keyword><keyword>Female</keyword><keyword>Forecasting</keyword><keyword>Genes, Retinoblastoma</keyword><keyword>Genes, Tumor Suppressor</keyword><keyword>Genetic Predisposition to Disease</keyword><keyword>Humans</keyword><keyword>Kinetics</keyword><keyword>Male</keyword><keyword>*Models, Genetic</keyword><keyword>Mutagens/adverse effects</keyword><keyword>Mutation</keyword><keyword>Neoplasms/epidemiology/genetics</keyword><keyword>Oncogenes</keyword><keyword>Retinoblastoma/epidemiology/genetics</keyword></keywords><dates><year>2001</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1474-175X (Print)
1474-175X (Linking)</isbn><accession-num>11905807</accession-num><urls><related-urls><url> pathogenesis.[H1] Diagnosis, screening and prevention(HD, GC, BLG) 1720/1500Diagnosis is usually clear from presenting signs ADDIN EN.CITE <EndNote><Cite><Author>Abramson</Author><Year>1998</Year><RecNum>8122</RecNum><DisplayText><style face="superscript">70</style></DisplayText><record><rec-number>8122</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">8122</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abramson, D. H.</author><author>Frank, C. M.</author><author>Susman, M.</author><author>Whalen, M. P.</author><author>Dunkel, I. J.</author><author>Boyd, N. W. rd</author></authors></contributors><titles><title>Presenting signs of retinoblastoma</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>505-8</pages><volume>132</volume><number>3 Pt 1</number><keywords><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Human</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Retinal Neoplasms/*diagnosis/genetics/physiopathology</keyword><keyword>Retinoblastoma/*diagnosis/genetics/physiopathology</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>1998</year></dates><urls><related-urls><url> and clinical examination. Biopsies are not performed on presumed intraocular retinoblastoma due to risk of seeding tumour outside of the eye.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJjaW9nbHU8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFy
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ADDIN EN.CITE.DATA 74[H2] Clinical DiagnosisDiagnosis is usually clear from presenting signs ADDIN EN.CITE <EndNote><Cite><Author>Abramson</Author><Year>1998</Year><RecNum>8122</RecNum><DisplayText><style face="superscript">70</style></DisplayText><record><rec-number>8122</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">8122</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abramson, D. H.</author><author>Frank, C. M.</author><author>Susman, M.</author><author>Whalen, M. P.</author><author>Dunkel, I. J.</author><author>Boyd, N. W. rd</author></authors></contributors><titles><title>Presenting signs of retinoblastoma</title><secondary-title>J Pediatr</secondary-title></titles><periodical><full-title>J Pediatr</full-title></periodical><pages>505-8</pages><volume>132</volume><number>3 Pt 1</number><keywords><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Human</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Retinal Neoplasms/*diagnosis/genetics/physiopathology</keyword><keyword>Retinoblastoma/*diagnosis/genetics/physiopathology</keyword><keyword>Retrospective Studies</keyword></keywords><dates><year>1998</year></dates><urls><related-urls><url> clinical examinationThe most common first sign of retinoblastoma is leukocoria (white pupil), which is caused by light reflecting directly off the tumour(Figure 6) Often parents notice leukocoria, but cannot convince their health advisors that there is a problem. The second most common sign is strabismus, or misaligned eyes, due to tumour blocking central vision. Signs of advanced disease include change in iris colour, enlarged eye due to glaucoma, and orbital cellulitis, a dangerous eye infection. ADDIN EN.CITE <EndNote><Cite><Author>Mullaney</Author><Year>1998</Year><RecNum>22266</RecNum><DisplayText><style face="superscript">75</style></DisplayText><record><rec-number>22266</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1429979278">22266</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mullaney, P. B.</author><author>Karcioglu, Z. A.</author><author>Huaman, A. M.</author><author>al-Mesfer, S.</author></authors></contributors><auth-address>King Khaled Eye Specialist Hospital, Riyadh, Kingdom of Saudi Arabia.</auth-address><titles><title>Retinoblastoma associated orbital cellulitis</title><secondary-title>Br J Ophthalmol</secondary-title><alt-title>The British journal of ophthalmology</alt-title></titles><periodical><full-title>Br J Ophthalmol</full-title></periodical><pages>517-21</pages><volume>82</volume><number>5</number><keywords><keyword>Cellulitis/*etiology/radiography</keyword><keyword>Child, Preschool</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Male</keyword><keyword>Orbital Diseases/*etiology/radiography</keyword><keyword>Paraneoplastic Syndromes/*etiology/radiography</keyword><keyword>Retinal Neoplasms/*complications/pathology/radiography</keyword><keyword>Retinoblastoma/*complications/pathology/radiography</keyword><keyword>Tomography, X-Ray Computed</keyword></keywords><dates><year>1998</year><pub-dates><date>May</date></pub-dates></dates><isbn>0007-1161 (Print)
0007-1161 (Linking)</isbn><accession-num>9713058</accession-num><urls><related-urls><url>[?]Proptosis (protrusion of the eye from the socket)[?]ispresents very late, but commonly,in regions countries where awareness and resources are poor. Importantly, as awareness efforts are being implemented globally, advanced retinoblastoma is declining.Unlike most cancers for whichpathology provides definitive diagnosis, diagnosis of retinoblastoma is wholly clinical; biopsy incurs high risk of metastasis.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LYXJjaW9nbHU8L0F1dGhvcj48WWVhcj4yMDAyPC9ZZWFy
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ADDIN EN.CITE.DATA 71-73Observation of leukocoria necessitates rapid referral to an expert. A dilated eye exam (dilation of the pupil) with indirect ophthalmoscope (retinal camera) is performed to provide a clear view of the retina, macula and optic nerve. ?The OPTOS? (Optos, UK) ],a non-mydriatic, wide field camera of 200°, might be useful for a rapid view of the retina, with minimal intrusion on the awake child.?Calcification, a typical characteristic of retinoblastoma , is easily detected by ultrasonography(b-scan) . MRI is used to detect infiltration of the optic nerve and trilateral tumours (intracranial tumours associated with RB1 mutations such as pinealoblastoma and primitive neuroectodermaltumou][.. CT scansshould beavoided if possible owingto oncogenic toxicity of radiation in these children. Differential diagnosis for Coats disease, persistent fetal vasculature, and vitreous haemorrhage is needed.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGllbGRzPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48
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ADDIN EN.CITE.DATA 76and OCT can discover invisible tumours in infants with familial disease (Figures 5). ADDIN EN.CITE <EndNote><Cite><Author>Rootman</Author><Year>2012</Year><RecNum>18558</RecNum><DisplayText><style face="superscript">77</style></DisplayText><record><rec-number>18558</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1354547972">18558</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Rootman, D. B.</author><author>Gonzalez, E.</author><author>Mallipatna, A.</author><author>Vandenhoven, C.</author><author>Hampton, L.</author><author>Dimaras, H.</author><author>Chan, H. S.</author><author>Gallie, B. L.</author><author>Heon, E.</author></authors></contributors><auth-address>The Hospital for Sick Children, Toronto, Canada.</auth-address><titles><title>Hand-held high-resolution spectral domain optical coherence tomography in retinoblastoma: clinical and morphologic considerations</title><secondary-title>Br J Ophthalmol</secondary-title><alt-title>The British journal of ophthalmology</alt-title></titles><periodical><full-title>Br J Ophthalmol</full-title></periodical><edition>2012/10/30</edition><dates><year>2012</year><pub-dates><date>Oct 26</date></pub-dates></dates><isbn>1468-2079 (Electronic)
0007-1161 (Linking)</isbn><accession-num>23104902</accession-num><urls><related-urls><url> fluorescein angiogram with the RetCam?can evaluate vascular abnormalities, suspicious residual or recurrent tumour, new vessel activity in scars, and areas of non-perfusion. Very tiny intra-retinal tumours not yet vascularized are better discovered with OCT. Imaging supports eye classification and cancer staging, documents treatment responses, supports consultation with colleagues, and helps parents understand treatment options. [H2] Classification and StagingThe Reese-Ellsworth classification ADDIN EN.CITE <EndNote><Cite><Author>Reese</Author><Year>1963</Year><RecNum>906</RecNum><DisplayText><style face="superscript">78</style></DisplayText><record><rec-number>906</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">906</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Reese, A. B.</author><author>Ellsworth, R. M.</author></authors></contributors><titles><title>The evaluation and current concept of retinoblastoma therapy.</title><secondary-title>Trans Am Acad Ophthalmol-Otolaryngol</secondary-title></titles><periodical><full-title>Trans Am Acad Ophthalmol-Otolaryngol</full-title></periodical><pages>164-172</pages><keywords><keyword>RB, treatment</keyword></keywords><dates><year>1963</year></dates><urls></urls></record></Cite></EndNote>78for intraocular retinoblastoma predicted outcomes of external beam radiation. When intravenous chemotherapy, (IVC)systemic chemotherapy andfocal therapy became the common primary treatment to salvage eyes, new schemes were developed (Figure 7, Extended Data 2). An international collaboration, led byMurphree, developedthe International Classification of Intraocular Retinoblastoma (IIRC) which better predicted responses to IVC than did the Reese-Ellsworth classification . ADDIN EN.CITE <EndNote><Cite><Author>Murphree</Author><Year>2005</Year><RecNum>22178</RecNum><DisplayText><style face="superscript">79</style></DisplayText><record><rec-number>22178</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1428421047">22178</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murphree, A. L.</author></authors></contributors><titles><title>Intraocular retinoblastoma: the case for a new group classification</title><secondary-title>Ophthalmology Clinics of North America</secondary-title></titles><periodical><full-title>Ophthalmol Clin North Am</full-title><abbr-1>Ophthalmology clinics of North America</abbr-1></periodical><pages>41-53</pages><volume>18</volume><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>79Eyes are classified by the IIRC with groups ranging from A to E, with E being the most severe. However, subsequent modifications of the IIRC group definitions without an overt change to the Classification Scheme name (Figure 7).The subsequent Shields version of the IIRC(IRC) PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGllbGRzPC9BdXRob3I+PFllYXI+MjAwNjwvWWVhcj48
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ADDIN EN.CITE.DATA 80, 81 results in discrepant classification of 25% of the most severely involved eyes when compared to the original IIRC definitions (Figure 7).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ob3ZldHNreTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA 82, 83Subsequently, the Children’s Oncology Group (COG) used a variation ADDIN EN.CITE <EndNote><Cite><Author>Group</Author><Year>2011</Year><RecNum>21798</RecNum><DisplayText><style face="superscript">84</style></DisplayText><record><rec-number>21798</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426956253">21798</key></foreign-keys><ref-type name="Web Page">12</ref-type><contributors><authors><author>Children's Oncology Group</author></authors></contributors><titles><title>Newly diagnosed with retinoblastoma with COG RB Classification page 2</title></titles><volume>2015</volume><number>2/21/2015</number><dates><year>2011</year></dates><urls><related-urls><url> with minor measurement differences with the IIRC (Figure 7).Similarly, for extraocular retinoblastoma, a number of staging systems co-exist and none has gained uniform acceptance. The St Jude Staging System, reported decades ago, is still used, especially in Latin America. In a coordinated action with the originalMurphreeinternationalIIRC ADDIN EN.CITE <EndNote><Cite><Author>Murphree</Author><Year>2005</Year><RecNum>22178</RecNum><DisplayText><style face="superscript">79</style></DisplayText><record><rec-number>22178</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1428421047">22178</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murphree, A. L.</author></authors></contributors><titles><title>Intraocular retinoblastoma: the case for a new group classification</title><secondary-title>Ophthalmology Clinics of North America</secondary-title></titles><periodical><full-title>Ophthalmol Clin North Am</full-title><abbr-1>Ophthalmology clinics of North America</abbr-1></periodical><pages>41-53</pages><volume>18</volume><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>79collaboration, the International Retinoblastoma Staging System focused on the overall staging of cancer including [retinoblastoma (Extended Data 2). ADDIN EN.CITE <EndNote><Cite><Author>Chantada</Author><Year>2006</Year><RecNum>14007</RecNum><DisplayText><style face="superscript">85</style></DisplayText><record><rec-number>14007</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1275245296">14007</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chantada, G.</author><author>Doz, F.</author><author>Antoneli, C. B.</author><author>Grundy, R.</author><author>Clare Stannard, F. F.</author><author>Dunkel, I. J.</author><author>Grabowski, E.</author><author>Leal-Leal, C.</author><author>Rodriguez-Galindo, C.</author><author>Schvartzman, E.</author><author>Popovic, M. B.</author><author>Kremens, B.</author><author>Meadows, A. T.</author><author>Zucker, J. M.</author></authors></contributors><auth-address>Department of Hematology-Oncology, Hospital JP Garrahan, Buenos Aires, Argentina. gchantada@.ar</auth-address><titles><title>A proposal for an international retinoblastoma staging system</title><secondary-title>Pediatr Blood Cancer</secondary-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><pages>801-5</pages><volume>47</volume><number>6</number><edition>2005/12/17</edition><keywords><keyword>Humans</keyword><keyword>Neoplasm Staging/*standards</keyword><keyword>Retinal Neoplasms/*classification/*diagnosis/pathology</keyword><keyword>Retinoblastoma/*classification/*diagnosis/pathology</keyword></keywords><dates><year>2006</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1545-5009 (Print)
1545-5009 (Linking)</isbn><accession-num>16358310</accession-num><urls><related-urls><url> The American Joint Committee on Cancer (AJCC)/International Union Against Cancer (UICC) staging system (TNM, defined by primary tumour (T), lymph node extension (N), and distant metastasis (M))for retinoblastoma ADDIN EN.CITE <EndNote><Cite><Author>Finger</Author><Year>2010</Year><RecNum>11539</RecNum><DisplayText><style face="superscript">86</style></DisplayText><record><rec-number>11539</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1237945664">11539</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Finger, P. T.</author><author>Harbour, J. W.</author><author>Murphree, A. L.</author><author>Karcioglu, Z. A.</author><author>Seregard, S.</author><author>Albert, D.</author><author>Augsburger, J. J.</author><author>Chevez-Barrios, P.</author><author>Coupland, S. E.</author><author>Eagle, R. C., Jr.</author><author>Deward, D.</author><author>Gallie, B. L.</author><author>Haik, B. G.</author><author>Harocopos, G. J.</author><author>Hungerford, J. L.</author><author>Kivela, T.</author><author>Milman, T.</author><author>Rootman, J.</author></authors><secondary-authors><author>Edge, S. B, </author><author>Byrd, D. R.</author><author>Carducci, M. A.</author><author>Compton, C. C.</author></secondary-authors></contributors><titles><title>Retinoblastoma</title><secondary-title>AJCC Cancer Staging Manual. </secondary-title></titles><pages>561-568</pages><volume> 7th ed</volume><section>52</section><dates><year>2010</year></dates><pub-location>New York, NY</pub-location><publisher>Springer</publisher><urls></urls></record></Cite></EndNote>86 is not widely used.There is a strong need for a single, collaborative, consensus classification of eyes and cancer staging.[H2] Pathology Retinoblastomas are consist of small, and round cells that stain blueon haematoxylin staining. Well-differentiated regions form rosette structures: Flexner-Wintersteiner rosettes, virtually exclusive forhighly indicative of retinoblastoma; and Homer Wright rosettes, common in diverse neural cancers (Figure 4)[. ADDIN EN.CITE <EndNote><Cite><Author>Eagle</Author><Year>2013</Year><RecNum>11382</RecNum><DisplayText><style face="superscript">87</style></DisplayText><record><rec-number>11382</rec-number><foreign-keys><key app="EN" db-id="saep2xxtw9repceffx0pfze85vzp0eattzaa" timestamp="1425487371">11382</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Eagle, R. C., Jr.</author></authors></contributors><auth-address>Department of Pathology, Wills Eye Institute, Philadelphia, PA 19107, USA. reagle@</auth-address><titles><title>The pathology of ocular cancer</title><secondary-title>Eye (Lond)</secondary-title><short-title>The pathology of ocular cancer</short-title></titles><periodical><full-title>Eye (Lond)</full-title></periodical><pages>128-36</pages><volume>27</volume><number>2</number><keywords><keyword>Eye Neoplasms/*pathology</keyword><keyword>Humans</keyword><keyword>Melanoma/pathology</keyword><keyword>Organ Sparing Treatments/methods</keyword><keyword>Retinal Neoplasms/pathology</keyword><keyword>Retinoblastoma/*pathology</keyword><keyword>Uveal Neoplasms/pathology</keyword></keywords><dates><year>2013</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1476-5454 (Electronic) 0950-222X (Linking)</isbn><accession-num>23154492</accession-num><urls><related-urls><url> feature more differentiated photoreceptor-like clusters of cells termed fleurettes (Figure 4).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5EaW1hcmFzPC9BdXRob3I+PFllYXI+MjAwODwvWWVhcj48
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ADDIN EN.CITE.DATA 3Histological study of the enucleated eye is the only way to evaluate high-risk features (tumour 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)and establish pathological staging. []PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5XaWxzb248L0F1dGhvcj48WWVhcj4yMDExPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 90using Shields classification, and 15% Group D and 50% Group E ADDIN EN.CITE <EndNote><Cite><Author>Wilson</Author><Year>2011</Year><RecNum>15944</RecNum><DisplayText><style face="superscript">88</style></DisplayText><record><rec-number>15944</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1306969913">15944</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Wilson, M. W.</author><author>Qaddoumi, I.</author><author>Billups, C.</author><author>Haik, B. G.</author><author>Rodriguez-Galindo, C.</author></authors></contributors><auth-address>Hamilton Eye Institute, Memphis, TN 38163, USA. mwilson5@uthsc.edu</auth-address><titles><title>A clinicopathological correlation of 67 eyes primarily enucleated for advanced intraocular retinoblastoma</title><secondary-title>The British journal of ophthalmology</secondary-title><alt-title>Br J Ophthalmol</alt-title></titles><alt-periodical><full-title>Br J Ophthalmol</full-title></alt-periodical><pages>553-8</pages><volume>95</volume><number>4</number><edition>2010/08/10</edition><keywords><keyword>Child, Preschool</keyword><keyword>Combined Modality Therapy</keyword><keyword>Eye Enucleation</keyword><keyword>Female</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Intraocular Pressure/physiology</keyword><keyword>Male</keyword><keyword>Retinal Neoplasms/*pathology/surgery</keyword><keyword>Retinoblastoma/*pathology/surgery</keyword><keyword>Retrospective Studies</keyword><keyword>Treatment Outcome</keyword></keywords><dates><year>2011</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1468-2079 (Electronic)
0007-1161 (Linking)</isbn><accession-num>20693555</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url> the Murphree classification. ADDIN EN.CITE <EndNote><Cite><Author>Murphree</Author><Year>2005</Year><RecNum>22178</RecNum><DisplayText><style face="superscript">79</style></DisplayText><record><rec-number>22178</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1428421047">22178</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murphree, A. L.</author></authors></contributors><titles><title>Intraocular retinoblastoma: the case for a new group classification</title><secondary-title>Ophthalmology Clinics of North America</secondary-title></titles><periodical><full-title>Ophthalmol Clin North Am</full-title><abbr-1>Ophthalmology clinics of North America</abbr-1></periodical><pages>41-53</pages><volume>18</volume><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>79 The documentation of high-risk pathological features is important to recognize need foradjuvant systemic chemotherapy to reduce risk of metastatic relapse. ADDIN EN.CITE <EndNote><Cite><Author>Kim</Author><Year>2015</Year><RecNum>21573</RecNum><DisplayText><style face="superscript">93</style></DisplayText><record><rec-number>21573</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1425913801">21573</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kim, J. W.</author></authors></contributors><titles><title>Retinoblastoma: evidence for postenucleation adjuvant chemotherapy</title><secondary-title>Int Ophthalmol Clin</secondary-title><alt-title>International ophthalmology clinics</alt-title></titles><periodical><full-title>Int Ophthalmol Clin</full-title><abbr-1>International ophthalmology clinics</abbr-1></periodical><alt-periodical><full-title>Int Ophthalmol Clin</full-title><abbr-1>International ophthalmology clinics</abbr-1></alt-periodical><pages>77-96</pages><volume>55</volume><number>1</number><dates><year>2015</year><pub-dates><date>Winter</date></pub-dates></dates><isbn>1536-9617 (Electronic)
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ADDIN EN.CITE.DATA 86, 92Still, too frequently retrospective examination finds a previously unnoticed risk after metastatic disease is diagnosed. Highly retinoblastoma-specific stains such as staining for the cone-rod homeobox transcription factor (CRX; not normally seen outside the eye) ADDIN EN.CITE <EndNote><Cite><Author>Torbidoni</Author><Year>In press</Year><RecNum>21747</RecNum><DisplayText><style face="superscript">95</style></DisplayText><record><rec-number>21747</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426677057">21747</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Torbidoni, A.V.</author><author>Laurent, V. E.</author><author>Sampor, C.</author><author>Ottaviani, D.</author><author>Vazquez, V.</author><author>Gabri, M.</author><author>Rossi, J.</author><author>de Dávila, M. T. G.</author><author>Alonso, C.</author><author>Alonso, D. F.</author><author>Chantada, G. L. </author></authors></contributors><titles><title>The cone-rod homeobox transcription factor (CRX) mRNA as a molecular marker in metastatic retinoblastoma</title><secondary-title>JAMA Ophthalmology</secondary-title></titles><periodical><full-title>JAMA Ophthalmol</full-title><abbr-1>JAMA ophthalmology</abbr-1></periodical><dates><year>In press</year></dates><urls></urls></record></Cite></EndNote>95 and N-glycosylated ganglioside (NeuGc-GM3) ADDIN EN.CITE <EndNote><Cite><Author>Torbidoni</Author><Year>2014</Year><RecNum>21690</RecNum><DisplayText><style face="superscript">96</style></DisplayText><record><rec-number>21690</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426493480">21690</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Torbidoni, A. V.</author><author>Scursoni, A.</author><author>Camarero, S.</author><author>Segatori, V.</author><author>Gabri, M.</author><author>Alonso, D.</author><author>Chantada, G.</author><author>de Davila, M. T.</author></authors></contributors><auth-address>Department of Hemato-Oncology, Pediatric Hospital "Prof. Dr. Juan P. Garrahan", Buenos Aires, Argentina.</auth-address><titles><title>Immunoreactivity of the 14F7 Mab raised against N-Glycolyl GM3 Ganglioside in retinoblastoma tumours</title><secondary-title>Acta Ophthalmol</secondary-title><alt-title>Acta ophthalmologica</alt-title></titles><periodical><full-title>Acta Ophthalmol</full-title></periodical><alt-periodical><full-title>Acta Ophthalmol Suppl</full-title><abbr-1>Acta ophthalmologica</abbr-1></alt-periodical><dates><year>2014</year><pub-dates><date>Nov 17</date></pub-dates></dates><isbn>1755-3768 (Electronic)
1755-375X (Linking)</isbn><accession-num>25403557</accession-num><urls><related-urls><url> mayplay facilitate observation of a few tumours cells lurking in a high-risk location.[H2] Genetic DiagnosisThe majority (94%) of patients withretinoblastoma are the first individuals to be diagnosed in a family, only141 out of 2,141 patients(6%) indicated thatone or more family members were previously diagnosed with retinoblastomawhen tested for RB1 mutations,(data from Impact Genetics, January 2015). Approximately 50% of people with retinoblastoma carry one RB1 mutation in their constitutional cells (100% ofbilateral and 15% of unilateral patients). ADDIN EN.CITE <EndNote><Cite><Author>Gallie</Author><Year>2004</Year><RecNum>9770</RecNum><DisplayText><style face="superscript">97</style></DisplayText><record><rec-number>9770</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">9770</key></foreign-keys><ref-type name="Book Section">5</ref-type><contributors><authors><author>Gallie, BL</author><author>Erraguntla, V</author><author>Heon, E</author><author>Chan, HSL</author></authors><secondary-authors><author>D. Taylor</author><author>C. Hoyt</author></secondary-authors></contributors><titles><title>Retinoblastoma.</title><secondary-title>Pediatric Ophthalmology and Strabismus</secondary-title></titles><pages>486-504</pages><section>50</section><dates><year>2004</year></dates><publisher>ELSEVIER</publisher><urls></urls></record></Cite></EndNote>97The remaining unilateral retinoblastomas arise by somatic mutational events (biallelicRB1 loss or somatic amplification of the MYCN oncogene) with no additional cancer risks.Knowledge of the patient’sRB1mutation enables precise screening of relatives and subsequent generations. The mutation can be detected prenatally from DNA in amniotic fluid when amniocentesis can be safely performed during pregnancy, and, if necessary, labour can be induced near term to detect and treat retinoblastoma tumours early. Without genetic testing, it is recommended that children who are at risk( already one eye affected ,and/or positive family history) continue to undergo multiple exams under anaesthesia.After Whengenetic tests canconfirm that no faulty mutant RB1 gene was inherited , 85% of patients with unilateral retinoblastoma will test negative with <1% residual risk for undetectable low level mosaicism, which informs the decision to reducetheintensity of surveillance and accurate determination of cancer risks of family members. ADDIN EN.CITE <EndNote><Cite ExcludeAuth="1"><Year>2009</Year><RecNum>12485</RecNum><DisplayText><style face="superscript">10</style></DisplayText><record><rec-number>12485</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1254258597">12485</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors></contributors><titles><title>National Retinoblastoma Strategy Canadian Guidelines for Care / Stratégie thérapeutique du rétinoblastome guide clinique canadien</title><secondary-title>Can J Ophthalmol</secondary-title></titles><periodical><full-title>Can J Ophthalmol</full-title><abbr-1>Canadian journal of ophthalmology</abbr-1></periodical><pages>S1-88</pages><volume>44</volume><number>Supp 2</number><dates><year>2009</year></dates><urls><related-urls><url> genetic diagnosis offers the family the option to selectunaffected embryoswhen the mutation ina parent is identified.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5YdTwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+PFJlY051
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ADDIN EN.CITE.DATA 101and CRX expression. ADDIN EN.CITE <EndNote><Cite><Author>Torbidoni</Author><Year>In press</Year><RecNum>21747</RecNum><DisplayText><style face="superscript">95</style></DisplayText><record><rec-number>21747</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426677057">21747</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Torbidoni, A.V.</author><author>Laurent, V. E.</author><author>Sampor, C.</author><author>Ottaviani, D.</author><author>Vazquez, V.</author><author>Gabri, M.</author><author>Rossi, J.</author><author>de Dávila, M. T. G.</author><author>Alonso, C.</author><author>Alonso, D. F.</author><author>Chantada, G. L. </author></authors></contributors><titles><title>The cone-rod homeobox transcription factor (CRX) mRNA as a molecular marker in metastatic retinoblastoma</title><secondary-title>JAMA Ophthalmology</secondary-title></titles><periodical><full-title>JAMA Ophthalmol</full-title><abbr-1>JAMA ophthalmology</abbr-1></periodical><dates><year>In press</year></dates><urls></urls></record></Cite></EndNote>95Best outcomes in familial retinoblastoma depend on the effectiveness of the healthcare team to identify and counsel families. Parentsneed appropriate genetic counselling and understanding of the risks and actions for each at-risk pregnancy. Alarmingly, a study of retinoblastoma in several developing countries observed that familial cases were diagnosed later than non-familial probands.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFudGFkYTwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA 103[H2] Screening [H3] Screening througheye examination[Au: edits OK? Dashes are not allowed]To detect retinoblastoma as early as possible,vision screening and eye examination have been developed. General recommendations for childhood vision screening with effective training to detect signs of retinoblastoma do occasionally identify a child with retinoblastoma . However, onenegativechildhood screening test doesnot mean this child will remain tumour-free since a tumourmight appear later, or may have been in the periphery and not visible (false negative) Leukocoria is most often first noted by parents (Figure 6), rarely first by physicians.Too often health workers fail to take the parent’s complaint seriously, due to lack of awareness[Au: reference?]. Photoleukocoria refers to the appearance of leukocoria on flash photographs (Figure 6). Awareness campaigns bring children to attention, but are lose effectiveness with time. An innovative study called PhotoRed in India trained healthcare professionals to used flash photography to identify childhood eye diseases, including retinoblastoma. ADDIN EN.CITE <EndNote><Cite><Author>Patel</Author><Year>2012</Year><RecNum>21658</RecNum><DisplayText><style face="superscript">104</style></DisplayText><record><rec-number>21658</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426111726">21658</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Patel, Tirth</author><author>Mallipatna, Ashwin</author><author>Merchant, Alefia</author><author>Battu, Ravindra</author><author>Nischal, K</author><author>Arnold, Robert</author><author>Naresh, Vasudha</author><author>Matalia, Jyoti</author><author>Dimaras, H</author><author>Gallie, B </author></authors></contributors><titles><title>Consumer Digital Cameras: A feasible strategy for the early detection of childhood blindness</title><secondary-title>Association for Research in Vision and Ophthalmology (ARVO)</secondary-title></titles><num-vols>Pediatric Ophthalmology</num-vols><dates><year>2012</year><pub-dates><date>May 10, 2012</date></pub-dates></dates><urls></urls></record></Cite></EndNote>104Another pioneering project is developing software to enable cameras to detect photoleukocoria.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYmRvbHZhaGFiaTwvQXV0aG9yPjxZZWFyPjIwMTM8L1ll
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ADDIN EN.CITE.DATA 106 Surveillance screening for second cancers is a pressing need in the opinion of retinoblastoma survivors. The first study to evaluate annual whole body MRI surveillance for individuals with predisposing RB1 mutation showed it was feasible to detect second cancers but with modest sensitivity(5 out of 25 patients screened).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmllZG1hbjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
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ADDIN EN.CITE PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmllZG1hbjwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
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ADDIN EN.CITE.DATA 107 This is an important area for further research so that early intervention can reduce mortality from second cancers, as has been demonstrated in Li-Fraumeni syndrome.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5WaWxsYW5pPC9BdXRob3I+PFllYXI+MjAxMTwvWWVhcj48
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ADDIN EN.CITE.DATA 70, 109[Au: Subsequent sentence moved to the diagnosis section.][H2] Intraocular retinoblastoma[Au: Only 43 characters allowed so extra level introduced; OK?][Au: EBRT is not discussed, but mentioned quite often in the manuscript; consider adding a short paragraph. Stem cell therapy is also mentioned in one of the figure legends, without explanation. Worthwhile to mention?][H3] Primary TreatmentChoice of primary treatment is based on likelihood of cure (is determined on the basis ofpatient survival), followed byeye salvage and ultimate visual potentialion– both weighed against short term and long term complications of treatment. ADDIN EN.CITE <EndNote><Cite><Author>Shields</Author><Year>2013</Year><RecNum>21554</RecNum><DisplayText><style face="superscript">109</style></DisplayText><record><rec-number>21554</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1425525188">21554</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Shields, C. L.</author><author>Fulco, E. M.</author><author>Arias, J. D.</author><author>Alarcon, C.</author><author>Pellegrini, M.</author><author>Rishi, P.</author><author>Kaliki, S.</author><author>Bianciotto, C. G.</author><author>Shields, J. A.</author></authors></contributors><auth-address>Ocular Oncology Service, Wills Eye Institute, Thomas Jefferson University, Philadelphia, PA 19107, USA. carol.shields@</auth-address><titles><title>Retinoblastoma frontiers with intravenous, intra-arterial, periocular, and intravitreal chemotherapy</title><secondary-title>Eye (Lond)</secondary-title><alt-title>Eye</alt-title></titles><periodical><full-title>Eye (Lond)</full-title></periodical><alt-periodical><full-title>Eye</full-title></alt-periodical><pages>253-64</pages><volume>27</volume><number>2</number><keywords><keyword>Antineoplastic Agents/*administration & dosage</keyword><keyword>Humans</keyword><keyword>Injections, Intra-Arterial</keyword><keyword>Injections, Intraocular</keyword><keyword>Injections, Intravenous</keyword><keyword>Intravitreal Injections</keyword><keyword>Retinal Neoplasms/diagnosis/*drug therapy</keyword><keyword>Retinoblastoma/diagnosis/*drug therapy</keyword></keywords><dates><year>2013</year><pub-dates><date>Feb</date></pub-dates></dates><isbn>1476-5454 (Electronic)
0950-222X (Linking)</isbn><accession-num>22995941</accession-num><urls><related-urls><url> In order of approximate frequency of global use globally, primary treatmentsoptions for intraocular disease include enucleation, intravenous chemotherapy (IVC) with focal therapy (laser, cryotherapy), intra-arterial chemotherapy (IAC) with focal therapy, and focal therapy whentumours aresmall at diagnosis. External beam radiotherapy (EBRTT)[Au: EBRT instead of EBR; OK?]is no longer recommended for primary intraocular retinoblastoma, since radiation incurs a very high risk of second cancers on persons carrying an RB1mutation, especially in the first year of life.and is 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.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Fbmc8L0F1dGhvcj48WWVhcj4xOTkzPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 110, 111The preferred primary treatment option depends on the severity of disease of each affectedeye(Figure 8).[Au: Since the management section is over the agreed word count at present and to reduce overlap, I have added some of the information to the figure legend 8 and to the separate sections discussing the techniques (indicated in green), but this will need shortening (see the legend at the end of the document).]Bilateral retinoblastoma in much of the developing 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.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5DaGFudGFkYTwvQXV0aG9yPjxZZWFyPjIwMTM8L1llYXI+
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ADDIN EN.CITE.DATA 115 repeated systemic chemotherapy,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HdW5kdXo8L0F1dGhvcj48WWVhcj4yMDA0PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 125and Group E ADDIN EN.CITE <EndNote><Cite><Author>Murphree</Author><Year>2005</Year><RecNum>22178</RecNum><DisplayText><style face="superscript">79</style></DisplayText><record><rec-number>22178</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1428421047">22178</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murphree, A. L.</author></authors></contributors><titles><title>Intraocular retinoblastoma: the case for a new group classification</title><secondary-title>Ophthalmology Clinics of North America</secondary-title></titles><periodical><full-title>Ophthalmol Clin North Am</full-title><abbr-1>Ophthalmology clinics of North America</abbr-1></periodical><pages>41-53</pages><volume>18</volume><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>79eyes treated with neo-adjuvant systemic chemotherapy before enucleation have significant risk for death from retinoblastoma. ADDIN EN.CITE <EndNote><Cite><Author>Zhao</Author><Year>2011</Year><RecNum>15639</RecNum><DisplayText><style face="superscript">126</style></DisplayText><record><rec-number>15639</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1302183192">15639</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Zhao, J.</author><author>Dimaras, H.</author><author>Massey, C.</author><author>Xu, X.</author><author>Huang, D.</author><author>Li, B.</author><author>Chan, H. S.</author><author>Gallie, B. L.</author></authors></contributors><auth-address>Beijing Tongren Eye Centre, Beijing Tongren Hospital, Capital Medical University, Beijing, China.</auth-address><titles><title>Pre-enucleation chemotherapy for eyes severely affected by retinoblastoma masks risk of tumor extension and increases death from metastasis</title><secondary-title>Journal of clinical oncology : official journal of the American Society of Clinical Oncology</secondary-title><alt-title>J Clin Oncol</alt-title></titles><alt-periodical><full-title>J Clin Oncol</full-title></alt-periodical><pages>845-51</pages><volume>29</volume><number>7</number><edition>2011/02/02</edition><dates><year>2011</year><pub-dates><date>Mar 1</date></pub-dates></dates><isbn>1527-7755 (Electronic)
0732-183X (Linking)</isbn><accession-num>21282531</accession-num><work-type>Research Support, Non-U.S. Gov't</work-type><urls><related-urls><url>[Au:OK?]Prior to the advent of IAC,Of Group D eyes treated with systemic chemotherapy and focal therapy 53% failed (required salvage EBRT and/or enucleation). ADDIN EN.CITE <EndNote><Cite><Author>Berry</Author><Year>2013</Year><RecNum>18819</RecNum><DisplayText><style face="superscript">121</style></DisplayText><record><rec-number>18819</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1363747288">18819</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Berry, J. L.</author><author>Jubran, R.</author><author>Kim, J. W.</author><author>Wong, K.</author><author>Bababeygy, S. R.</author><author>Almarzouki, H.</author><author>Lee, T. C.</author><author>Murphree, A. L.</author></authors></contributors><auth-address>Doheny Eye Institute, Los Angeles, California. jesse.berrymd@.</auth-address><titles><title>Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage</title><secondary-title>Pediatr Blood Cancer</secondary-title><alt-title>Pediatric blood & cancer</alt-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><pages>688-93</pages><volume>60</volume><number>4</number><edition>2012/09/22</edition><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1545-5017 (Electronic)
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ADDIN EN.CITE.DATA 112, 131, 132Despite advances in the conservative managementeye-salvage therapiesfor[Au: as in chemoreduction and focal therapy? Please specify explicitly]of advanced retinoblastoma, the major cause of failure has remainedsthe persistence or recurrence of vitreous seeding. Pharmacokinetic studies have shownshow poor vitreous levels of drugs administered by either systemic chemotherapy or IAC.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TY2hhaXF1ZXZpY2g8L0F1dGhvcj48WWVhcj4yMDEyPC9Z
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ADDIN EN.CITE.DATA 133 The highest drug bioavailability in the vitreous is achieved by IViC using a safety-enhanced injection technique in carefully selected eligible eyes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdW5pZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 134 Following control of the source of seeds, IViC achieved two-year Kaplan-Meier estimates of 98.5% control of target seeds and 90.4% event-free survival for target seeds and ocular survivall, respectively.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdW5pZXI8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 134-136The number of IViC treatments to attain control of vitreous seeds is dependent on the type and extent of seeding. ADDIN EN.CITE <EndNote><Cite><Author>Francis</Author><Year>2015</Year><RecNum>21457</RecNum><DisplayText><style face="superscript">134</style></DisplayText><record><rec-number>21457</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1425058363">21457</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Francis, J. H.</author><author>Abramson, D.H.</author><author>Gaillard, M. C.</author><author>Marr, B. P.</author><author>Beck-Popovic, M.</author><author>Munier, F. L. </author></authors></contributors><titles><title>The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan</title><secondary-title>Ophthalmology</secondary-title></titles><periodical><full-title>Ophthalmology</full-title></periodical><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>134The efficacy of IViC has eliminated the need for EBRT, and decreased patient exposure to salvage systemic or intra-arterial chemotherapyIAC. The toxicity of IViC is limited to technique-dependent localized peripheral salt-and-pepper retinopathy, the extent of which is technique-dependent. ADDIN EN.CITE <EndNote><Cite><Author>Munier</Author><Year>2014</Year><RecNum>21464</RecNum><DisplayText><style face="superscript">137</style></DisplayText><record><rec-number>21464</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1425058365">21464</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Munier, F. L.</author></authors></contributors><auth-address>Retinoblastoma Clinic, Jules-Gonin Eye Hospital , Lausanne , Switzerland.</auth-address><titles><title>Classification and management of seeds in retinoblastoma. Ellsworth Lecture Ghent August 24th 2013</title><secondary-title>Ophthalmic Genet</secondary-title><alt-title>Ophthalmic genetics</alt-title></titles><periodical><full-title>Ophthalmic Genet</full-title><abbr-1>Ophthalmic genetics</abbr-1></periodical><alt-periodical><full-title>Ophthalmic Genet</full-title><abbr-1>Ophthalmic genetics</abbr-1></alt-periodical><pages>193-207</pages><volume>35</volume><number>4</number><dates><year>2014</year><pub-dates><date>Dec</date></pub-dates></dates><isbn>1744-5094 (Electronic)
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ADDIN EN.CITE.DATA 138, 139. Since the majority of children with intraocular retinoblastoma have Group D or E diseaseat diagnosis, and more than 50% have unilateral disease with other eye unaffected, cure can be achieved with enucleation (Figures 3 and 8). All IIRC ADDIN EN.CITE <EndNote><Cite><Author>Murphree</Author><Year>2005</Year><RecNum>22178</RecNum><DisplayText><style face="superscript">79</style></DisplayText><record><rec-number>22178</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1428421047">22178</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murphree, A. L.</author></authors></contributors><titles><title>Intraocular retinoblastoma: the case for a new group classification</title><secondary-title>Ophthalmology Clinics of North America</secondary-title></titles><periodical><full-title>Ophthalmol Clin North Am</full-title><abbr-1>Ophthalmology clinics of North America</abbr-1></periodical><pages>41-53</pages><volume>18</volume><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>79 Group E eyes require enucleationbecause,by definition, they carry risk of extraocular extension; however, this can only be confirmed by thepathological assessment of the enucleated eye. 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. ADDIN EN.CITE <EndNote><Cite><Author>Mourits</Author><Year>2015</Year><RecNum>21745</RecNum><DisplayText><style face="superscript">140</style></DisplayText><record><rec-number>21745</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426636935">21745</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mourits, D. L.</author><author>Hartong, D. T.</author><author>Bosscha, M. I.</author><author>Kloos, R. J.</author><author>Moll, A. C.</author></authors></contributors><auth-address>Department of Ophthalmology, VU University Medical Center, Amsterdam, the Netherlands.
Department of Ophthalmology, Academic Medical Center, Amsterdam, the Netherlands.</auth-address><titles><title>Worldwide enucleation techniques and materials for treatment of retinoblastoma: an international survey</title><secondary-title>PLoS One</secondary-title><alt-title>PloS one</alt-title></titles><periodical><full-title>PLoS ONE</full-title></periodical><alt-periodical><full-title>PLoS ONE</full-title></alt-periodical><pages>e0121292</pages><volume>10</volume><number>3</number><dates><year>2015</year></dates><isbn>1932-6203 (Electronic)
1932-6203 (Linking)</isbn><accession-num>25767872</accession-num><urls><related-urls><url> Comparative studies have shown enhanced prosthetic eye motility with the myoconjunctival approach, which is affordable world-wide.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaG9tZTwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 141, 142Complex 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, ADDIN EN.CITE <EndNote><Cite><Author>Vincent</Author><Year>2002</Year><RecNum>10471</RecNum><DisplayText><style face="superscript">143</style></DisplayText><record><rec-number>10471</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">10471</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Vincent, A. L.</author><author>Webb, M. C.</author><author>Gallie, B. L.</author><author>Heon, E.</author></authors></contributors><auth-address>Department of Ophthalmology, The Hospital for Sick Children, Toronto, Ontario, Canada.</auth-address><titles><title>Prosthetic conformers: a step towards improved rehabilitation of enucleated children</title><secondary-title>Clin Experiment Ophthalmol</secondary-title></titles><periodical><full-title>Clin Experiment Ophthalmol</full-title></periodical><pages>58-9</pages><volume>30</volume><number>1</number><keywords><keyword>Eye Enucleation/psychology/*rehabilitation</keyword><keyword>*Eye, Artificial</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Orbital Implants</keyword><keyword>Prosthesis Implantation</keyword><keyword>Research Support, Non-U.S. Gov't</keyword><keyword>Vision/physiology</keyword></keywords><dates><year>2002</year><pub-dates><date>Feb</date></pub-dates></dates><accession-num>11887800</accession-num><urls><related-urls><url> </url></related-urls></urls></record></Cite></EndNote>143 observed in Kenya to help the closefamily accept enucleation for their child.[H3] Intravenous chemotherapy and focal therapy Since 1996 first-line therapy to control IIRC Groups B, C and D diseasehas been IVC with different combinations, doses, schedules, and durations of carboplatin, etoposide and vincristine (CEV) followed by focal therapy to consolidate the chemotherapy responses(Table 3).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5HYWxsaWU8L0F1dGhvcj48WWVhcj4xOTk2PC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 146, 147Eyes in groups B and C do well with CEV and focal therapy. With follow-up of 54 months, 47% of IIRC ADDIN EN.CITE <EndNote><Cite><Author>Murphree</Author><Year>2005</Year><RecNum>22178</RecNum><DisplayText><style face="superscript">79</style></DisplayText><record><rec-number>22178</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1428421047">22178</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murphree, A. L.</author></authors></contributors><titles><title>Intraocular retinoblastoma: the case for a new group classification</title><secondary-title>Ophthalmology Clinics of North America</secondary-title></titles><periodical><full-title>Ophthalmol Clin North Am</full-title><abbr-1>Ophthalmology clinics of North America</abbr-1></periodical><pages>41-53</pages><volume>18</volume><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>79Group D eyes ADDIN EN.CITE <EndNote><Cite><Author>Berry</Author><Year>2013</Year><RecNum>18819</RecNum><DisplayText><style face="superscript">121</style></DisplayText><record><rec-number>18819</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1363747288">18819</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Berry, J. L.</author><author>Jubran, R.</author><author>Kim, J. W.</author><author>Wong, K.</author><author>Bababeygy, S. R.</author><author>Almarzouki, H.</author><author>Lee, T. C.</author><author>Murphree, A. L.</author></authors></contributors><auth-address>Doheny Eye Institute, Los Angeles, California. jesse.berrymd@.</auth-address><titles><title>Long-term outcomes of Group D eyes in bilateral retinoblastoma patients treated with chemoreduction and low-dose IMRT salvage</title><secondary-title>Pediatr Blood Cancer</secondary-title><alt-title>Pediatric blood & cancer</alt-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><pages>688-93</pages><volume>60</volume><number>4</number><edition>2012/09/22</edition><dates><year>2013</year><pub-dates><date>Apr</date></pub-dates></dates><isbn>1545-5017 (Electronic)
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ADDIN EN.CITE.DATA 81Fundamental principles for systemic cancer therapy apply to retinoblastoma: optimized outcomes are achieved by high dose intensity and combination of several agents with complementary mechanisms of action.This is illustrated by the reduced effectiveness of single agent, low dose carboplatin for retinoblastoma. ADDIN EN.CITE <EndNote><Cite><Author>Dunkel</Author><Year>2007</Year><RecNum>10798</RecNum><DisplayText><style face="superscript">148</style></DisplayText><record><rec-number>10798</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">10798</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Dunkel, I. J.</author><author>Lee, T. C.</author><author>Shi, W.</author><author>Beaverson, K. L.</author><author>Novetsky, D.</author><author>Lyden, D.</author><author>Finlay, J. L.</author><author>McCormick, B.</author><author>Abramson, D. H.</author></authors></contributors><auth-address>Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York.</auth-address><titles><title>A phase II trial of carboplatin for intraocular retinoblastoma</title><secondary-title>Pediatr Blood Cancer</secondary-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><dates><year>2007</year><pub-dates><date>Feb 14</date></pub-dates></dates><isbn>1545-5009 (Print)</isbn><accession-num>17301956</accession-num><urls><related-urls><url> </url><url> Acute toxicities of IVC for retinoblastoma are as for other paediatric cancers, including short-term transient pancytopenia (reduction in red blood cells, white blood cells and platelets), hair loss, vincristine-induced neurotoxicity, and infections. Long term toxicities include carboplatin-induced ototoxicity (toxicity to the ear),PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KZWhhbm5lPC9BdXRob3I+PFllYXI+MjAwOTwvWWVhcj48
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ADDIN EN.CITE.DATA 158, 159Foveal involvement with tumour or subretinal fluid at presentation contribute to poor vision. There is no documented local toxicity of IVC to the eye. [H3] Intra-arterial chemotherapy Intra-arterial chemotherapy [Au: IViC deleted since it is not discussed in this section; OK?]has had a great impact on retinoblastoma management as it enables saving of eyes that were previously deemed unsalvageable.IAC is usually performed by ophthalmic artery chemosurgery (OAC, also called superselective ophthalmic artery infusion)[Au: OK?]whereby, after the patient has been administered heparin,a micro-catheter isinserted into the femoral artery and passed up to the orifice of the ophthalmic artery (but not into the artery) where drugs or combination of drugs (typically melphalan, carboplatin, and [Au:OK?]topotecan) areinfused in a pulsatile fashion over many minutes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYnJhbXNvbjwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+
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ADDIN EN.CITE.DATA 160Alternatively, a catheter with an inflatable balloon near the tip can be used to ensure selective treatment to the eye.During the procedure, theinternal carotid artery is temporarily occluded by inflating the tip and melphalan is injected over a few seconds below the balloon with the intention of having the drug directedinto the ophthalmic artery(so-called selective ophthalmic treatment). ADDIN EN.CITE <EndNote><Cite><Author>Suzuki</Author><Year>2011</Year><RecNum>16292</RecNum><DisplayText><style face="superscript">131</style></DisplayText><record><rec-number>16292</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1320094277">16292</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Suzuki, S.</author><author>Yamane, T.</author><author>Mohri, M.</author><author>Kaneko, A.</author></authors></contributors><auth-address>Division of Ophthalmic Oncology, National Cancer Center Hospital, Tokyo, Japan.</auth-address><titles><title>Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis</title><secondary-title>Ophthalmology</secondary-title><alt-title>Ophthalmology</alt-title></titles><periodical><full-title>Ophthalmology</full-title></periodical><alt-periodical><full-title>Ophthalmology</full-title></alt-periodical><pages>2081-7</pages><volume>118</volume><number>10</number><edition>2011/07/01</edition><dates><year>2011</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1549-4713 (Electronic)
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ADDIN EN.CITE.DATA 161Also, tandem therapy in which both eyes are treatedin the same, one hour session has successfully been performed (so-called tandem therapy).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYnJhbXNvbjwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+
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ADDIN EN.CITE.DATA 129 However, death from metastatic diseasecan occur more than five years after any treatment. The longest follow-up study described forselective ophthalmic treatmentin Japan (including death from metastatic retinoblastoma and second cancers) showedan overall survival of 95% at 15 years. ADDIN EN.CITE <EndNote><Cite><Author>Suzuki</Author><Year>2011</Year><RecNum>16292</RecNum><DisplayText><style face="superscript">131</style></DisplayText><record><rec-number>16292</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1320094277">16292</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Suzuki, S.</author><author>Yamane, T.</author><author>Mohri, M.</author><author>Kaneko, A.</author></authors></contributors><auth-address>Division of Ophthalmic Oncology, National Cancer Center Hospital, Tokyo, Japan.</auth-address><titles><title>Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis</title><secondary-title>Ophthalmology</secondary-title><alt-title>Ophthalmology</alt-title></titles><periodical><full-title>Ophthalmology</full-title></periodical><alt-periodical><full-title>Ophthalmology</full-title></alt-periodical><pages>2081-7</pages><volume>118</volume><number>10</number><edition>2011/07/01</edition><dates><year>2011</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1549-4713 (Electronic)
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ADDIN EN.CITE.DATA 79, 80, 84 (Figure 7, Extended Data 2), which prevents a clear-cut comparison of the results between centres, especially regarding Group D and E cases. We need a universally endorsed single classification in order to avoid confusion regarding eligibility and salvage rates for new treatments. Ocular survival with the selective ophthalmic treatment65% for Group C and45% for Group D in one Japanese study [Au:OK?]. ADDIN EN.CITE <EndNote><Cite><Author>Suzuki</Author><Year>2011</Year><RecNum>16292</RecNum><DisplayText><style face="superscript">131</style></DisplayText><record><rec-number>16292</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1320094277">16292</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Suzuki, S.</author><author>Yamane, T.</author><author>Mohri, M.</author><author>Kaneko, A.</author></authors></contributors><auth-address>Division of Ophthalmic Oncology, National Cancer Center Hospital, Tokyo, Japan.</auth-address><titles><title>Selective ophthalmic arterial injection therapy for intraocular retinoblastoma: the long-term prognosis</title><secondary-title>Ophthalmology</secondary-title><alt-title>Ophthalmology</alt-title></titles><periodical><full-title>Ophthalmology</full-title></periodical><alt-periodical><full-title>Ophthalmology</full-title></alt-periodical><pages>2081-7</pages><volume>118</volume><number>10</number><edition>2011/07/01</edition><dates><year>2011</year><pub-dates><date>Oct</date></pub-dates></dates><isbn>1549-4713 (Electronic)
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ADDIN EN.CITE.DATA 165 The most common reason for second-line [Au:OK?]enucleation of eyes with retinoblastoma in developed countries has always been the presence of extensive vitreous seeding. ADDIN EN.CITE <EndNote><Cite><Author>Abramson</Author><Year>2005</Year><RecNum>11240</RecNum><DisplayText><style face="superscript">166</style></DisplayText><record><rec-number>11240</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1226968127">11240</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Abramson, D. H.</author></authors></contributors><auth-address>Ophthalmic Oncology Service, Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, NY 10023, USA. abramsod@</auth-address><titles><title>Retinoblastoma in the 20th century: past success and future challenges the Weisenfeld lecture</title><secondary-title>Invest Ophthalmol Vis Sci</secondary-title></titles><periodical><full-title>Invest Ophthalmol Vis Sci</full-title><abbr-1>Investigative ophthalmology & visual science</abbr-1></periodical><pages>2683-91</pages><volume>46</volume><number>8</number><edition>2005/07/27</edition><keywords><keyword>*Awards and Prizes</keyword><keyword>Child, Preschool</keyword><keyword>Florida</keyword><keyword>History, 21st Century</keyword><keyword>Humans</keyword><keyword>Infant</keyword><keyword>Ophthalmology/*history</keyword><keyword>Retinal Neoplasms/*pathology</keyword><keyword>Retinoblastoma/*pathology</keyword><keyword>Societies, Scientific</keyword></keywords><dates><year>2005</year><pub-dates><date>Aug</date></pub-dates></dates><isbn>0146-0404 (Print)</isbn><accession-num>16043839</accession-num><urls><related-urls><url> [pii]
10.1167/iovs.04-1462</electronic-resource-num><language>eng</language></record></Cite></EndNote>166 Only 20% of such eyes can be salvaged with EBRT.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYnJhbXNvbjwvQXV0aG9yPjxZZWFyPjIwMDQ8L1llYXI+
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ADDIN EN.CITE.DATA 112, 129, 130With the selective ophthalmic treatment, 58% of children with foveal tumours retained a visual acuity of >0.01[Au: unit necessary? Earlier in the article, the 20/20 etc scale was used for acuity. Please be consistent with which scale you use to avoid confusion] and for those without foveal tumours 51% retained visual acuity of >0.5 with 36% >1.0 (2). Electroretinographic[Au: OK?]monitoring of OAC patientsPEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYnJhbXNvbjwvQXV0aG9yPjxZZWFyPjIwMDg8L1llYXI+
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AG==
ADDIN EN.CITE.DATA 172[Au: Paragraph in Green moved up.]Complications following OAC are currently few and include both short-term and long-term effects.In an analysis of 198 catheterizations of the ophthalmic[Au: OAC technique?]artery in 70 consecutive eyes with retinoblastoma, minor transient complications included transient eyelid oedema (5%), blepharoptosis (5%), and forehead hyperaemia (2%).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGllbGRzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA 129Lasting complications included vitreous haemorrhage (2%), branch retinal artery obstruction (1%), ophthalmic artery spasm with reperfusion (2%), ophthalmic artery obstruction (2%), partial choroidalischaemia (2%), and optic neuropathy (< 1%).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5TaGllbGRzPC9BdXRob3I+PFllYXI+MjAxNDwvWWVhcj48
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ADDIN EN.CITE.DATA 173, 174Although this procedure has been performed in children as young as three weeks of age, most centrres withhold cannulation until the patient is at least 3 months of age and 6-7 kg in weight because of concerns about repeated puncture of the femoral artery. As a result, these very young children are given single agent (carboplatin) IVC in modest doses (18.7 mg/kg) as an outpatient until they attain the 6-7 kg/3 month goal when they are suitable for OAC. This approach is called “bridge therapy” and 94.7% of such eyes (Kaplan-Meier) have been salvaged without the need of radiotherapy.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Hb2JpbjwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 175[H3] Focal therapy [Au: Please add references to this section.]Focal therapy is the local application of anti-cancer therapy – thermo-, cryo-, radio-, or chemotherapy – to the eye, under direct visualization through the pharmacologically dilated pupil. This approach is useful for primary treatment of IIRC Group A cancersand consolidation therapy for residual or recurrent small-volume, active tumours after systemic or IAC. In general, focal therapy is repeated monthly until the tumour is completely atrophic or calcified. Transpupillary thermotherapyinvolves laser treatment through the dilated pupil. Photocoagulation treatment with 532 nm, 810 nm or continuous wave 1064 nm laser is directly applied by multiple short (0.7 s) burns to small volume active or suspicious tumour, starting at a sub-coagulation power intensity and increasing to attain white, opaque coagulation. Both laser treatments are repeated monthly until the tumour is flat, atrophic or calcified.Cryotherapy is performed to freezethetumour through the sclera with a nitrous oxide probe; the tumour is directly visualized and duration of freeze judged to completely eliminatethe tumour. Since tumour cells die when thawing, one minute is allowed for each thaw between freezing cycles. Cryotherapy effectively destroys small primary tumour(s) or recurrences in the periphery of the retina.Plaque radiotherapy involves the position of a radioactive probe on the eye to delivertrans-scleral radiotherapy withan apex dose of 35 Gy over 4-7 days.[Au: edits OK?]Plaque focal radiation has not been associated with second primary tumours and is effective for treatment of a single primary or recurrenttumour in a location that will not compromise vision. Paraocularchemotherapy has been usefulunder conjunctiva or in tenon’s capsule for small volume recurrences and vitreous seeds.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5BYnJhbXNvbjwvQXV0aG9yPjxZZWFyPjE5OTk8L1llYXI+
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ADDIN EN.CITE.DATA 176-178[H3] Intravitreal ChemotherapyVitreous seeds are the major cause of failure (enucleationor 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.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5GcmFuY2lzPC9BdXRob3I+PFllYXI+MjAxNTwvWWVhcj48
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ADDIN EN.CITE.DATA 134, 135, 137, 179, 180[Au: Sentence in green moved up]The procedure involves lowering theintraocular pressure with an anterior chamber paracentesis or by digital massage after induction of anesthesia.Intravitrealmelphalanis injected through the conjunctival, sclera, and pars plana with a small-gauge needle. On needle withdrawal, the injection site is sealed and sterilized with cryotherapy and the eye is shaken gently to distribute the drug though the vitreous. Three classes of vitreous seeds have been identified with significantly different median times to regression, mean number of injections and cumulative and mean melphalan dose. ADDIN EN.CITE <EndNote><Cite><Author>Francis</Author><Year>2015</Year><RecNum>21457</RecNum><DisplayText><style face="superscript">135</style></DisplayText><record><rec-number>21457</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1425058363">21457</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Francis, J. H.</author><author>Abramson, D.H.</author><author>Gaillard, M. C.</author><author>Marr, B. P.</author><author>Beck-Popovic, M.</author><author>Munier, F. L. </author></authors></contributors><titles><title>The classification of vitreous seeds in retinoblastoma and response to intravitreal melphalan</title><secondary-title>Ophthalmology</secondary-title></titles><periodical><full-title>Ophthalmology</full-title></periodical><dates><year>2015</year></dates><urls></urls></record></Cite></EndNote>135Ultrasound biomicroscopy[Au:OK?]may be used to evaluate the otherwise hidden ciliary region behind the iris,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Nb3VsaW48L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxS
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ADDIN EN.CITE.DATA 76 to confirm that the injection site is tumour-free prior to IViC treatment.[H2] Extraocular retinoblastoma[H3] Extraocular at presentationRetinoblastoma 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 anthracyclines. ADDIN EN.CITE <EndNote><Cite><Author>Chantada</Author><Year>2013</Year><RecNum>18862</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>18862</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1364496460">18862</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chantada, G.</author><author>Luna-Fineman, S.</author><author>Sitorus, R. S.</author><author>Kruger, M.</author><author>Israels, T.</author><author>Leal-Leal, C.</author><author>Bakhshi, S.</author><author>Qaddoumi, I.</author><author>Abramson, D. H.</author><author>Doz, F.</author></authors></contributors><auth-address>Hospital de Pediatria SAMIC Prof Dr Juan P Garrahan, Buenos Aires, Argentina; St Jude Children's Research Hospital, Memphis, Tennessee. gchantada@.</auth-address><titles><title>SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries</title><secondary-title>Pediatr Blood Cancer</secondary-title><alt-title>Pediatric blood & cancer</alt-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><pages>719-27</pages><volume>60</volume><number>5</number><edition>2013/01/22</edition><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1545-5017 (Electronic)
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ADDIN EN.CITE.DATA 126, 132 Bone marrow metastasis without central nervous system involvementhas potential for cure with extensive therapy including stem cell transplant. However, extension of retinoblastoma into the brain has a very low likelihood of cure.[H2] Palliation [Au: should this be a subheading under ‘Management’ in general, or under ‘Extraocular retinoblastoma’? I think the former, but wasn’t certain] Palliation includes pain management, symptom relief, nutritional support, and psychosocial support for the child and families. ADDIN EN.CITE <EndNote><Cite><Author>Chantada</Author><Year>2013</Year><RecNum>18862</RecNum><DisplayText><style face="superscript">16</style></DisplayText><record><rec-number>18862</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1364496460">18862</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chantada, G.</author><author>Luna-Fineman, S.</author><author>Sitorus, R. S.</author><author>Kruger, M.</author><author>Israels, T.</author><author>Leal-Leal, C.</author><author>Bakhshi, S.</author><author>Qaddoumi, I.</author><author>Abramson, D. H.</author><author>Doz, F.</author></authors></contributors><auth-address>Hospital de Pediatria SAMIC Prof Dr Juan P Garrahan, Buenos Aires, Argentina; St Jude Children's Research Hospital, Memphis, Tennessee. gchantada@.</auth-address><titles><title>SIOP-PODC recommendations for graduated-intensity treatment of retinoblastoma in developing countries</title><secondary-title>Pediatr Blood Cancer</secondary-title><alt-title>Pediatric blood & cancer</alt-title></titles><periodical><full-title>Pediatr Blood Cancer</full-title></periodical><pages>719-27</pages><volume>60</volume><number>5</number><edition>2013/01/22</edition><dates><year>2013</year><pub-dates><date>May</date></pub-dates></dates><isbn>1545-5017 (Electronic)
1545-5009 (Linking)</isbn><accession-num>23335388</accession-num><urls><related-urls><url> retinoblastoma is highly sensitive to most chemotherapy agents. Children presenting with orbital retinoblastoma are usually in severe pain and discomfort that may be alleviated with judicious use of anticancer therapy even when no curative intent is pursued. These children often 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. 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. EBRT and chemotherapy are useful for pain control in palliation but are often unavailable in low-income countries.[Au: references?][H1] Quality of life(AW, HD, BLG) 881/500[Au: I think this section would benefit from a short introduction that outlines what the major QOL issues in retinoblastoma survivors are. For example, radiotherapy on a young brain can lead to developmental issues, cognitive decline, etc. This will set up the rest of the section nicely and need only be a sentence or two.]“Quality of life” describes the level of physical, emotional and psychological wellbeing experienced by an individual. Cancer, its treatment and effects on the developing body, brain and mind can significantly decrease Quality of Life, with implications for treatment decisions, supportive and long-term follow up care.[H2] Measured life-long impact Analysis of the life-long treatment impact of retinoblastoma and its various treatmentsshows that surprising results[Au: what exactly is surprising?].PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA 182 However, studyverbal IQ of age-matched persons with the early infancy form of retinoblastoma was significantly above[Au: Explanation for the higher IQ?]normal sighted and non-retinoblastoma blind persons. ADDIN EN.CITE <EndNote><Cite><Author>Tobin</Author><Year>2010</Year><RecNum>22060</RecNum><DisplayText><style face="superscript">183</style></DisplayText><record><rec-number>22060</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1427257372">22060</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tobin, M.</author><author>Hill, E.</author><author>Hill, J.</author></authors></contributors><titles><title>Retinoblastoma and superior verbal IQ scores?</title><secondary-title>British Journal of Visual Impairment</secondary-title></titles><periodical><full-title>British Journal of Visual Impairment</full-title></periodical><pages>7-18</pages><volume>28</volume><number>1</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>183No explanation has been identified for this finding, though hypotheses of a genetic cause have been proposed. There is altered development of visual, auditory and multisensory brain morphology in adults who lost one eye to retinoblastoma in early life, suggesting that the remaining eye acquired increased contralateral visual cortical connections.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LZWxseTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 181 However, study IQ of age-matched persons with the early infancy form of retinoblastoma was significantly above[Au: Explanation for the higher IQ?]normal sighted and non-retinoblastoma blind persons. ADDIN EN.CITE <EndNote><Cite><Author>Tobin</Author><Year>2010</Year><RecNum>22060</RecNum><DisplayText><style face="superscript">182</style></DisplayText><record><rec-number>22060</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1427257372">22060</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Tobin, M.</author><author>Hill, E.</author><author>Hill, J.</author></authors></contributors><titles><title>Retinoblastoma and superior verbal IQ scores?</title><secondary-title>British Journal of Visual Impairment</secondary-title></titles><periodical><full-title>British Journal of Visual Impairment</full-title></periodical><pages>7-18</pages><volume>28</volume><number>1</number><dates><year>2010</year></dates><urls></urls></record></Cite></EndNote>182There is clinical and animal evidence that repeated anaesthesia of young children may impair neurocognitive development.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Jbmc8L0F1dGhvcj48WWVhcj4yMDEyPC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 138, 186, 187Repeat anaesthesia is necessary in eye salvage and in very young children to discover and treat small tumours. Going forward, one outcome to record in retinoblastoma clinical studies is number of examinations under anaesthesiaandage.[H2] Direct insight from survivors[Au: This section contains 22 references. Please try to delete some, since the reference list needs to be cut to 200 references. ]Most important are insights from the retinoblastoma survivors themselves. Social media brings retinoblastoma parents and survivorsinto peer-support communities. Research processes that deepen understanding of quality of lifefollowing retinoblastoma are needed to learn from these valuable evidence sources.[H3] Coping during treatmentand psychosocial outcomesA mother describes her son’s response to radiotherapy aged 16 months: “In the beginning he was extremely combative. At the end of the treatment course, he was a broken child, withdrawn and passively accepting what was happening to him. The long term damage caused took years of therapy to start to heal"[Au: source reference?].Children’s perception of pain and medical interventions changes over time.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5LaGluIEhsYTwvQXV0aG9yPjxZZWFyPjIwMTQ8L1llYXI+
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ADDIN EN.CITE.DATA 188-194Repeated procedures cause anticipation anxiety and intolerance of even minimally invasive experiences and mild pain. The child’s initial strong emotions may be suppressed as the child gives up, and re-emerge as depression, post-traumatic stress or developmental trauma disorder.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gRGlqazwvQXV0aG9yPjxZZWFyPjIwMDk8L1llYXI+
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ADDIN EN.CITE.DATA 113, 195-201Programmes such as 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(Figure 11).PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Db21taXR0ZWUgb24gSG9zcGl0YWw8L0F1dGhvcj48WWVh
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ADDIN EN.CITE.DATA 5, 106, 202-211 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, manydescribe acute fear of their mouth and nose being covered. One adult describes how the scent and taste of strawberries makes her nauseous – her mask was always coated with strawberry scent.Extended isolation during therapy may impact social functioning. While most adult survivors perform well socially, many report low confidence and intense anxiety, especially in large groups and crowded environments. Most survivors are high cognitive performers.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA 181 However, reduced vision causes some children to become frustrated by their inability to keep up with peers, damaging self-esteem and confidence.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj52YW4gRGlqazwvQXV0aG9yPjxZZWFyPjIwMTA8L1llYXI+
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ADDIN EN.CITE.DATA 212-214[H2] Radiotherapy late effectsWhile radiotherapy is now rarely used for retinoblastoma, thousands of adult survivors live with its long-term effects. Many feel neglected and demoralized by lack of follow up and prospective management. Facial deformity causes low self-confidence and social anxiety. Reconstructive surgery is a painful process that may impact remaining vision, but its cosmetic effects can dramatically improve quality of lie. Dry eye is very painful, and corneal vascularization reduces already limited vision. Use of ocular lubricants may prevent complications, and should be started early before pain and vision loss occur.Chronic primary headaches, hormone dysfunction and seizures also impact quality of lifeafter radiotherapy.[Au: reference?][H2] Second cancer riskIndividuals at risk of second primary cancers require life-long oncology follow up.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NYWNDYXJ0aHk8L0F1dGhvcj48WWVhcj4yMDEzPC9ZZWFy
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ADDIN EN.CITE.DATA 150, 215, 216Lack of agreed protocols causes confusion, frustration and fear as adults struggle to access informed follow up care, compounded by primary doctors who are not awareof late effects and lifelong implications of RB1 mutation.Full information about the patient’scancer history, genetic status and life-long risks will empower survivors to be advocates for their own and their children’s health.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Gb3JkPC9BdXRob3I+PFllYXI+MjAxMzwvWWVhcj48UmVj
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ADDIN EN.CITE.DATA 217-220[H2] Psychosocial outcomes[Au: I would merge this paragraph with the ‘coping’ section to eliminate overlap]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, manydescribe acute fear of their mouth and nose being covered. One adult describes how the scent and taste of strawberries makes her nauseous – her mask was always coated with strawberry scent.Extended isolation during therapy may impact social functioning. While most adult survivors perform well socially, many report low confidence and intense anxiety, especially in large groups and crowded environments. Most survivors are high cognitive performers.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5Ccmlua21hbjwvQXV0aG9yPjxZZWFyPjIwMTU8L1llYXI+
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ADDIN EN.CITE.DATA 211-213[H2] Family planning Many adult survivors have little knowledge of retinoblastoma genetics, genetic counselling or testing, their status, or of options for their baby. Cost and availability of genetic testing and pre-implantation genetic diagnosis is often prohibitive.Lack of an agreed screening protocol for at-risk babies causes anxiety among survivor-parents. Profound anger and guilt about somehow being responsible for the child’s cancer is amplified when diagnosis is delayed by inadequate screening. Agreed screening protocols for at-risk children will reduce survivor-parent anxiety and enhance early diagnosis to achieve minimally invasive therapy.[H1] Outlook(All) 1332/1000Retinoblastoma is curable if diagnosed early. We propose that within 10 years retinoblastoma can be azero-death cancer. Our anti-retinoblastoma arsenal will consist not only of curative treatments, but also measures to prevent development of disease in predisposed individuals. To achieve this vision, critical efforts are needed to build upon the current state-of-the-art for retinoblastoma as presented in this Primer.Now, we dream big with key action items, responding to the immediate obvious targets for improvements, and setting the stage for innovative discoveries in retinoblastoma.[H2] Patient-centered, global research focus[Au:OK?]Retinoblastoma will benefit from clinical science at the level that has achieved dramatic change for pediatric cancer. Because most centres have too few affected children, or many children and inadequate resources to study them, we have lagged behind in systematic accumulation of evidence on which to base therapy. [Au: Deleted description of AHOPCA to avoid repetition]Today we are faced with sweeping change in treatment of eyes with retinoblastoma to usingIAC and salvage of unresponsive vitreous seeds by IViC. However, we do not have full data on which to judge eligibility, long-term effectiveness or outcomes.We have opportunities now to learn from initiatives and innovations everywhere, and to listen carefully to the patient’s voice to become a trulyn inclusive, participatory global network to advance evidence. The growing voice of the pPatients and families, empowered by social media, will be heard in the research approaches. Patient-informed research direction and methods will be, making them relevant, ethical, and appropriate. Stakeholders from low-and-middle income countries will be active innovators, assuring that protocols will beare feasible and acceptable. For example, AHOPCA created and implemented multicentre protocols for retinoblastoma treatment,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5MdW5hLUZpbmVtYW48L0F1dGhvcj48WWVhcj4yMDEyPC9Z
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ADDIN EN.CITE.DATA 21, 23, 24 a major achievement not yet paralleled in developed countries. Equality for retinoblastoma will come by education (Internet access), with shared collaborative care coordinated online. Local rRetinoblastoma expertise will be developed locally (proportional to the local burden of retinoblastoma) but derived globally, with best practices drawing on rigorous molecular and clinical research. Retinoblastoma clinical trialswill be true collaborative, high patient numberenrolment studies. Effective innovations will include all outcomes and sustainability (cost, uptake by health ministries, social acceptability of therapy, etc.). The global burden of retinoblastoma shows the inherent inequity in how patients are diagnosed and cared for around the world. Documentation of human and material resources required for optimal retinoblastoma care, drawn from established clinical care guidelines, represent the first step in the path towards achieving health equity. National strategies in areas currently underrepresented in the retinoblastoma literature are poised to fill the knowledge gap with new approaches and evidence. Progress in retinoblastoma therapy is critically dependent on achieving consensus on a standard classification of intraocular disease. The ongoing AJCC/UICC international survey of features of eyes at diagnosis, treatments given and outcomes will be used to derive one evidence-based classification and replace the current clinical staging schemes that confuse analysis or eligibility or outcomes.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5NdXJwaHJlZTwvQXV0aG9yPjxZZWFyPjIwMDU8L1llYXI+
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ADDIN EN.CITE.DATA 79, 80, 86We are poised to collect uniform data on all children with retinoblastoma. The eCCRB point-of-care database summarizes the health record from diagnosis, including features of eyes and patient, treatments, complications, and outcomes, and is available to all retinoblastoma centres. eCCRB also supports the caregivers by graphic display of information otherwise out of reach, ensuring high motivation for good data quality. The next phase of this Internet project (aiming at 2020) will combine the 1RBW map with eCCRB de-identified data. “Real-time” analysis of outcomes is planned to feedback to treating doctors, a “learning health system”, ADDIN EN.CITE <EndNote><Cite><Author>Grossmann</Author><Year>2013</Year><RecNum>22061</RecNum><DisplayText><style face="superscript">221</style></DisplayText><record><rec-number>22061</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1427403922">22061</key></foreign-keys><ref-type name="Book">6</ref-type><contributors><authors><author>Grossmann, Claudia </author><author>Sanders, Julia </author><author>English, Rebecca A. </author></authors></contributors><titles><title>KNOWLEDGE GENERATION IN A LEARNING HEALTH SYSTEM: Workshop Summary</title></titles><dates><year>2013</year></dates><pub-location>Washington, DC 20001</pub-location><publisher>National Academies Press</publisher><isbn>978-0-309-28911-5</isbn><urls><related-urls><url> to assist in selection of evidence-based care for the next affected child affected by retinoblastoma.[H2] Cause of every death from retinoblastomaWe propose to determine the most likely cause and key risk factors of every death from retinoblastoma.This Similar in concept to the groundbreaking Million Death Study,PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5KaGE8L0F1dGhvcj48WWVhcj4yMDA2PC9ZZWFyPjxSZWNO
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ADDIN EN.CITE.DATA 222 this information will guide us to target preventable deaths quickly, by simply developing awareness of the disease, clinical research, and strengthening of health systems. ADDIN EN.CITE <EndNote><Cite><Author>Farmer</Author><Year>2015</Year><RecNum>22117</RecNum><DisplayText><style face="superscript">223</style></DisplayText><record><rec-number>22117</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1427745698">22117</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Farmer, Paul</author></authors></contributors><titles><title>Who Lives and Who Dies?</title><secondary-title>Medical Examiner</secondary-title></titles><periodical><full-title>Medical Examiner</full-title></periodical><edition>15 march 2015</edition><dates><year>2015</year><pub-dates><date>15 march 2015</date></pub-dates></dates><urls><related-urls><url> map documents staff, equipment [Au:OK?], and spaces, and provides an alternative system of global collaboration, perhaps unique to small neglected diseases that fall through the cracks even in the most developed health care system.Implementation of this knowledge science can help tostreamlinereferral and the speed of pathology reporting.[H2TargetedNewtherapies A vast body of scientific work is steadily increasing oOur knowledge of the retinoblastoma cell of origin and its unique sensitivities is steadily increasing, which, and may reveal strategies to prevent tumorigenesis. Moreover, ongoing work to define molecular lesions in retinoblastoma will continue to yield novel therapeutic targets for therapy. Advances in therapeutic development and prevention depend on these molecular studies, but we do not yet have preclinical models that accurately reflect retinoblastoma pathogenesis and treatment. One of the earliest targeted therapies developed for retinoblastoma that was, based on preclinical information generated by transgenic mice,were thewasNutlin-3s. ADDIN EN.CITE <EndNote><Cite><Author>Laurie</Author><Year>2006</Year><RecNum>10712</RecNum><DisplayText><style face="superscript">224</style></DisplayText><record><rec-number>10712</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="0">10712</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Laurie, N. A.</author><author>Donovan, S. L.</author><author>Shih, C. S.</author><author>Zhang, J.</author><author>Mills, N.</author><author>Fuller, C.</author><author>Teunisse, A.</author><author>Lam, S.</author><author>Ramos, Y.</author><author>Mohan, A.</author><author>Johnson, D.</author><author>Wilson, M.</author><author>Rodriguez-Galindo, C.</author><author>Quarto, M.</author><author>Francoz, S.</author><author>Mendrysa, S. M.</author><author>Guy, R. K.</author><author>Marine, J. C.</author><author>Jochemsen, A. G.</author><author>Dyer, M. A.</author></authors></contributors><auth-address>Department of Developmental Neurobiology, St Jude Children's Research Hospital, Memphis, Tennessee 38105, USA.</auth-address><titles><title>Inactivation of the p53 pathway in retinoblastoma</title><secondary-title>Nature</secondary-title><alt-title>Nature</alt-title></titles><periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></periodical><alt-periodical><full-title>Nature</full-title><abbr-1>Nature</abbr-1></alt-periodical><pages>61-6</pages><volume>444</volume><number>7115</number><dates><year>2006</year><pub-dates><date>Nov 2</date></pub-dates></dates><isbn>1476-4687 (Electronic)</isbn><accession-num>17080083</accession-num><urls><related-urls><url> 
 Nutlin-3 targets the negative regulation of p53 by MDM2/MDM4X, resulting in p53-mediated apoptotic cell death. Nutlin-3 showed promising activity in combination with topotecan for retinoblastoma control in preclinical models. This drug combination is currently undergoing evaluation in a prospective study in combination with local chemotherapy.Based upon information obtained fromAs mentioned, gene expression and epigenetic analyses of retinoblastomastumours identified, the spleen tyrosine kinase (SYK), an upregulated proto-oncogene required for as required for retinoblastoma cell survival has been identified as a potential new target.PEVuZE5vdGU+PENpdGU+PEF1dGhvcj5aaGFuZzwvQXV0aG9yPjxZZWFyPjIwMTI8L1llYXI+PFJl
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ADDIN EN.CITE.DATA 48Although the SYK antagonist R406was considered a promising candidate based onpreclinical studies, its ocular pharmacokinetic profile following peri-ocular administration rendered it not unfavourable for clinical use. ADDIN EN.CITE <EndNote><Cite><Author>Pritchard</Author><Year>2014</Year><RecNum>21452</RecNum><DisplayText><style face="superscript">225</style></DisplayText><record><rec-number>21452</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1425058354">21452</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Pritchard, E. M.</author><author>Stewart, E.</author><author>Zhu, F.</author><author>Bradley, C.</author><author>Griffiths, L.</author><author>Yang, L.</author><author>Suryadevara, P. K.</author><author>Zhang, J.</author><author>Freeman, B. B., 3rd</author><author>Guy, R. K.</author><author>Dyer, M. A.</author></authors></contributors><auth-address>Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.</auth-address><titles><title>Pharmacokinetics and efficacy of the spleen tyrosine kinase inhibitor r406 after ocular delivery for retinoblastoma</title><secondary-title>Pharm Res</secondary-title><alt-title>Pharmaceutical research</alt-title></titles><periodical><full-title>Pharm Res</full-title><abbr-1>Pharmaceutical research</abbr-1></periodical><alt-periodical><full-title>Pharm Res</full-title><abbr-1>Pharmaceutical research</abbr-1></alt-periodical><pages>3060-72</pages><volume>31</volume><number>11</number><dates><year>2014</year><pub-dates><date>Nov</date></pub-dates></dates><isbn>1573-904X (Electronic)
0724-8741 (Linking)</isbn><accession-num>24906597</accession-num><urls><related-urls><url> Preclinical studies have sought to identify new molecular targets and new agents to block the drivers of tumourigenesis in retinoblastoma, and to evaluate pharmacokinetics of new agents alone or in combination ADDIN EN.CITE <EndNote><Cite><Author>Mahida</Author><Year>2013</Year><RecNum>18827</RecNum><DisplayText><style face="superscript">226</style></DisplayText><record><rec-number>18827</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1364352736">18827</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Mahida, J. P.</author><author>Antczak, C.</author><author>Decarlo, D.</author><author>Champ, K. G.</author><author>Francis, J. H.</author><author>Marr, B.</author><author>Polans, A. S.</author><author>Albert, D. M.</author><author>Abramson, D. H.</author><author>Djaballah, H.</author></authors></contributors><auth-address>HTS Core Facility, Molecular Pharmacology and Chemistry Program, Memorial Sloan Kettering Cancer Center, New York, New York, United States of America.</auth-address><titles><title>A synergetic screening approach with companion effector for combination therapy: application to retinoblastoma</title><secondary-title>PLoS ONE</secondary-title><alt-title>PloS one</alt-title></titles><periodical><full-title>PLoS ONE</full-title></periodical><alt-periodical><full-title>PLoS ONE</full-title></alt-periodical><pages>e59156</pages><volume>8</volume><number>3</number><edition>2013/03/26</edition><dates><year>2013</year></dates><isbn>1932-6203 (Electronic)
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ADDIN EN.CITE.DATA 232Improved understanding of retinoblastoma pathogenesis (Figure 1) as well as high-throughput drug screening could yield additional agents that with appropriate clinical evaluation may significantly change future treatment.[Au: QoL section deleted to remove overlap.]Display Item Legends Box 1: [Au: Please consider including a box with explanations for the specialist terms.]Complex integrated implantsEBRT and tantalum ring localizationbrachytherapymyoconjunctival approachoraserrataorbital retinoblastomasalt and pepper retinopathyScleral depressionStem cell therapy?proton beam radiotherapyBox 2: Outstanding research questions [Au: Titles OK?]Patient-centered, global research focusAddress the "reluctance of healthworkers to confer the true risks"(i.e.such as in Jordan where doctors do not want to destroy families) and choice of families who know and /understand the risks but choose not to follow-through because of the same stigma.Define treatment success: cure (life), salvage of vision (one eye), slavage salvage of eye (vision and cosmetic), fewest examinations under anaesthesia (cumulative toxicitiy[Au: toxicity?]of anaesthesia)Meta-analysis of all children treated primarily with IAC.Develop a “retinoblastoma index” relating levels of awareness, access to centres with the necessary resources and expertise, and application of evidence-based care, as predictors of outcome. PathogenesisWhat is the genomic progression post RB1 loss?What molecular changes promote (early) metastasis? Are there other RB1+/+ subtypes beyond MYCN-amplified retinoblastoma?What dictates the tissue specificity of RB1 loss leading to cancer?What are the unique molecular features of second RB1-related cancers in RB1 mutation carriers? Figure 1| Progression of retinoblastoma. a) Biallelic loss of RB1 may block differentiation of a cone precursor cell, as itfails to localize normally in XXX layer. b) Genomic instability might leadto an intraretinalbenign retinoma. Inset: a small retinoblastoma visualized by optical coherence tomography[Au: OK? Or do RB1-/- cells always form retinomas.] [Au: Which kind of scan is shown in the insert? Please add information to the legend.] . c) This tumourcan progresses to form a retinoblastoma if additional mutations are acquired [Au:OK? Or do all the retinomas progress to retinoblastomas], and seeds under the retina and into the vitreous membrane; d) invades past the lamina cribrosa of the optic nerve, uvea, or sclera to constitute high risk pathologic features. e) Finally, the tumor mightextend extraocularly into orbit, brain (direct or subarachnoid to CSF) or metastasizes to bone marrow.[Au: Can we add percentages of to the figure, showing how many % of patients will progress to the next stage – if data are available? How many % of RB1 carriers, for example, will progress to develop retinoblastoma?][Au: It would be great if we could have an extra panel, preferably panel A, showing the normal eye anatomy, with labels for all the relevant anatomical terms mentioned in this legend, or the manuscript. ]Figure 2 | Global Retinoblastoma Prevalence. Heat Map of estimated distribution of the global retinoblastoma patient population as assembled by the One Retinoblastoma World (1RBW) initiative. The majority of cases reside in low and middle income countries. The 1RBW Map of Treatment Centers ( HYPERLINK "" ) connects affected families to expert care close to home, providing rich global data for anyone to use. Without prior awareness of retinoblastoma, parents now commonly self-diagnose on the Internet, and the 1RBW map connects them to experts without delays. Images from HYPERLINK "" .[Au: I think only panel A should be sufficient. It is quite clear that most cases are in the middle/lower income countries.]Figure 3 | Triplets with retinoblastoma tumours.[Au: Paragraph in green moved from the epidemiology section]The retinoblastoma-specific point-of-care database (eCancerCareRB, eCCRB) summarizes the medical record for retinoblastoma for each child. eCCRB is now on a cloud server, freely accessible to every retinoblastoma centre with local ethics and privacy approvals. With consent from every guardian, fully identified data including images is accessible to all in the circle of care of the child. The graphical timeline is language-independent, well understood by parents, and has been used to support fully informed care choices. ADDIN EN.CITE <EndNote><Cite><Author>Chiu</Author><Year>In Press</Year><RecNum>21787</RecNum><DisplayText><style face="superscript">31</style></DisplayText><record><rec-number>21787</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1426869795">21787</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Chiu, Hannah H. </author><author>Dimaras, Helen</author><author>Downie, Rob </author><author>Gallie, Brenda</author></authors></contributors><titles><title>Breaking down barriers to communicating complex retinoblastoma information: can graphics be the solution?</title><secondary-title>Canadian Journal of Ophthalmology</secondary-title></titles><periodical><full-title>Can J Ophthalmol</full-title><abbr-1>Canadian journal of ophthalmology</abbr-1></periodical><dates><year>In Press</year></dates><urls></urls></record></Cite></EndNote>31 thisThese triplets developed retinoblastomas in all six eyes illustrating the full expressivity and penetrance of the RB1-/- germline mutations that result in no protein, such as the mutation carried by each triplet. The eCCRB timelines reveal that all eyes had individualized therapy, with choices considering the overall impact on each child. Each child has lost one eye, and each has a normal vision eye with disease control in less than one year. The number of eye exams under anaesthesia was least for the child who had primary enucleation. OD, right eye; OS, left eye. Eye involvement at diagnosis is indicated in the International Intraocular classification; ADDIN EN.CITE <EndNote><Cite><Author>Murphree</Author><Year>2005</Year><RecNum>22178</RecNum><DisplayText><style face="superscript">79</style></DisplayText><record><rec-number>22178</rec-number><foreign-keys><key app="EN" db-id="d9serdrv0tw09per5zaxr0ppxav09pzwwat2" timestamp="1428421047">22178</key><key app="ENWeb" db-id="">0</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Murphree, A. L.</author></authors></contributors><titles><title>Intraocular retinoblastoma: the case for a new group classification</title><secondary-title>Ophthalmology Clinics of North America</secondary-title></titles><periodical><full-title>Ophthalmol Clin North Am</full-title><abbr-1>Ophthalmology clinics of North America</abbr-1></periodical><pages>41-53</pages><volume>18</volume><dates><year>2005</year></dates><urls></urls></record></Cite></EndNote>79 the eye labelled “Group 0” had no tumour at initial diagnosis but develop a tumour 6 weeks later..[Au: Is this an original figure, or do we need a reference? Also, because these patients are identifiable, we need to obtain consent to publish their images. I would argue that including their photographs is not essential to understanding the key information in the figureand remove the photograph.]Figure 4| Genetic origins of retinoblastoma. Three genetic subtypes of retinoblastoma are known. Heritable retinoblastoma patients have a constitutive[Au: inactivating?YES]inactivatingmutation (M1) in the RB1tumor suppressor gene in all cells of their body. A second, somatic mutation (M2) in a susceptible retinal cell can lead to benign retinoma. Further genetic and/or epigenetic events (M3…Mn) are required to transition to retinoblastoma. Non-heritable, RB1 mutant retinoblastomas follow a similar progression, except both M1 and M2 occur in a susceptible retinal cell. MYCN-amplified (MYCNA) retinoblastoma is a rare, non-heritable retinoblastoma subtype driven by amplification of MYCN with normal RB1; other changes in these tumours remain uncharacterized.Retinoma histology shows distinct photoreceptor-like fleurettes, while RB1-/- retinoblastoma can show Flexner-Wintersteiner (indicated) and Homer Wright rosettes. Conversely, MYCNAretinoblastoma show a distinct histology with rounded nuclei and prominent nucleoli.[Au: Can you please provide a short explanation for the histological images?]Figure 5 |[Au: Please provide a short title.]Retinal origin of retinoblastoma tumorsa, The retina has a complex structure and contains multiple cell types. Haematoxylin and eosin staining of post-fertilization week 19 retinashowsthree post-mitotic nuclear layers in the central retina in the vicinity of near the fovea (left) and two nuclear layers in the less mature periphery of the same histologic section (right).Cell types in each layer are indicated.b, Cone precursors normally have high expression of RB. Immunofluorescence staining of post-fertilization week 19 retina showsespecially strong RB signal (red) in maturing cone precursors in the central retina (left, counterstained for cone arrestin, green) and in retinal progenitor cells in the peripheral retina of the same histologic section (right).RB staining is less intense in DAPI-stained nuclei (blue) in other retinal cell types.c, Early retinoblastoma appearing toextend from the inner nuclear layer to the outer nuclear layer. Optical coherence tomography of an invisible tiny retinoblastoma tumor in a 2.5 month old infant appearing toextend from the inner nuclear layer to the outer nuclear layer. The tumorwho has his family’s RB1 mutant allele?has an uncertain?epicentre?making it difficult to infer the retinal layer from which the tumor arose.[Au: Isn’t it visible in the right panel?]This layer-of-origin may be further resolveddefinedin the future with more images of higher resolution OCT of retina in very young children carrying an inherited germline RB1 mutation. Abbreviations: ONL, outer nuclear layer; INL, inner nuclear layer; GCL, ganglion cell layer; NBL, neuroblastic layer; RPE, retinal pigment epithelium. [Au: Where should this text go? Please take into account that legends should not exceed 200 words.]Retinoblastomas are thought to originate in developing retinal cells that have biallelicRB1 inactivation. The prominent expression of cone-specific proteins in retinoblastoma cells combined with high-level pRB, MYCN, and MDM2 in cone precursors and the proliferative response of RB1-depleted cone precursors have provided compelling evidence of a cone precursor origin34,38,39.Although cone precursors are among the earliest post-mitotic retinal cell types produced, they lie dormant for several weeks to months prior to expressing pRB, cone phototransduction proteins, and the oncoproteins that may sensitize to pRB loss. 34,39Hence, retinoblastomas have been proposed to arise following cell cycle re-entry of this normally post-mitotic retinal cell type. 38The figure displays the locations of maturing cone precursors relative to other cell types in the developing retina. Because the retina develops in a central-to-peripheral direction, the central retina is developmentally far more advanced than the periphery, and different retinal cell maturation states can be viewed in a single histologic section. Panels (a) and (b) display the different histologic appearance and pRB expression patterns in the relatively mature and post-mitotic central retina (left) and in the immature far periphery (right).In the central retina, postmitotic cone precursors in the outer nuclear layer highly express pRB (red) and cone arrestin (green).However, in the immature peripheral retina, pRB is most highly expressed in the retinal progenitor cells in the neuroblastic layer, but neither pRB nor cone arrestin is detected in immature post-mitotic cone precursors. 39Despite that maturing cone precursors but not other retinal cell types proliferate in response to pRB depletion38, and that cone precursors are located in the outer nuclear layer, the smallest and presumably earliest retinoblastomas that have been detected in infants using optical coherence tomography have been centered in the inner nuclear layer (c).This poses a challenge to the cone precursor origin model, yet might be consistent with a migration of RB1-deficient cone precursors from the outer nuclear layer to the inner nuclear layer, where they could interact with astrocytes and blood vessels that enable tumorigenesis.41Figure 6 | a,Photoleukocoria led the parents to diagnose retinoblastoma using the Internet (a). The right left eye was enucleated. The other eye was normal at diagnosis and developed later a small tumour treated with only laser. b, Subsequent MRI discovered revealed thathe also had trilateral retinoblastoma. He was treated with a; following systemic chemotherapy, and intrathecal(given directly into the cerebro-spinal fluid) [Au: This has not been discussed in the management section as a potential therapy for RB so a short explanation might be required.]chemotherapy and high dose chemotherapy with hematopoietic stem cell transplant[Au: bone marrow transplant, or stem cells in the eye?]t, c,The child is disease-free at age 8 years (insert).d, His treatment summary is illustrated in the DePICT view of eCancerCareretinoblastoma.[Au: Similar to Figure 3, I would suggest removing the insert. For the photo of the baby, we can just show his eyes making identification impossible.]Figure 7 | Many different classification schemes for intraocular retinoblastoma confound comparison of outcomes.The features listed determine the overall classification, ranging from small tumours not threatening vision (“A”) to tumours clinically noted to have features suggesting potential spread outside the eye (“E”). Most importantly, size of tumour alone does not make an eye dangerous by Murphree, Children’s Oncology Group (COG), or TNM classification; but any eye with tumour >50% of eye volume is E (advanced-stage disease)by Shields classification.The consequence is widespread confusion in the literature undermining clinical research, since studies using the different classifications cannot be compared for outcomes. Additionally the term “tumour touching lens” in the Murphree International Classification of Intraocular Retinoblastoma (IIRCfor Group E, is broadly misunderstood to include tumor pushing retina forward to touch lens; more accurately the wording “tumour directly touching lens”,is used toclarify that only tumor cells actually on the back of the lens (in front of the anterior hyaloid) would be Group E, and at risk for extraocular spread.[Au: Has this figure been published before? If so, please add a reference. You will also need to fill in some paperwork to request permission of the original publisher. I will send this after the peer review process.]Extended Data 2 | Pdf of classification and staging schemes[Au: This wasn’t attached in the submission, so I cannot assess if it’s necessary. However, Figure 7 already contains detailed information, at least for the scope of the primer.]Figure 8 | Primary treatment choices for each eye based on the International Intraocular Retinoblastoma Classification IIRC (Murphree)classification. Treatment depends on the combined severity of each of the affected eyes (Eye 1 / Eye 2); the preferred option for each eye is depicted in the blue boxes. [Au: Explanation of the figure OK?]Group A eyes can be treated with laser or cryo focal therapy(focal therapy) alone., but might be preceded by systemic chemotherapy if the other eye is Group B, C or D. Group B and C eyes require several cycles of several systemic or intra-arterial chemotherapy cycles followed by focal laser or cryotherapytherapy(for Group B) and intravitrealchemotherapy(IViC) with melphalan(in Ggroup C). Isolated single tumours inGroup B or C eyes with one tumour may occasionally be appropriate for primary radioactive plaque therapy. In general, Ffor safety of the child, it is important that all eyes with features suggesting imminent extraocular extension E eyes be removed, to enable accurate pathological examination to determine which eyes posed aif risk oflife metastasisthreat that could be mitigated byrequires adjuvant chemotherapy.Figure 9 | Good rResponses to intravenous chemotherapy(IVC;treatment courses in eCCRB timeline)..a,Before (Left) 4 cycles of carboplatin, etoposide and vincristine (CEV) + cyclosporine (CSA) chemotherapy and laser consolidation for Group B/ D[Au: Please specify what the rows are: upper row: B level eye and lower row: D level eye?]; and after (Right) showing good response and recovering fovea at edge of calcificationum.b, Before (Left) 4 cycles of CEV + CSA chemotherapy and laser consolidation for Group D/ D; and after (Right) showing good response with minimal focal therapy (15 years follow-up).Figure 10 | Resolution of retinoblastoma with intra-arterial chemotherapy (IAC).a, Before (Left) and after (Right) IAC for a retinoblastoma eye with extensive retinal detachment; b, Before (Left) and after (Right) IAC for a retinoblastoma eye with extensive vitreous seeding; c,Before (Left) and after (Right) IAC treatment of an eye with macular tumour.Figure 11 | Child Life promotes effective coping through play, preparation, education, positive-touch and self-expression activities, based on natural child development. Child Life helps children and their families cope with challenging healthcare issues, hospitalization and therapeutic interventions. Even in palliation, play is the job of a child. These children play doctor and nurse, wearing gloves and, stethoscopes while they examine Puppet Kevin who had one eye removed for retinoblastoma. Play (medical play and just general play) promotes a sense of mastery for children within their medical experience. Photo taken at the Sally Test Pediatric Centre, Moi Teaching and Referral Hospital, Eldoret, Kenya.TablesTable 2: Estimated Global Distribution of RetinoblastomaForecast births were calculated using most recent data (2012) for population, birth rate and mortality rate (World Bank ( HYPERLINK "" ] accessed on 5 February 2015. Low (1:18,000 live births) and high estimates (1:16,000 live births) calculated, following the example of Kivela. ADDIN EN.CITE <EndNote><Cite ExcludeYear="1"><Author>Kivela</Author><Year>2009</Year><RecNum>7293</RecNum><DisplayText><style face="superscript">5</style></DisplayText><record><rec-number>7293</rec-number><foreign-keys><key app="EN" db-id="saep2xxtw9repceffx0pfze85vzp0eattzaa" timestamp="1425483770">7293</key></foreign-keys><ref-type name="Journal Article">17</ref-type><contributors><authors><author>Kivela, T.</author></authors></contributors><titles><title>The epidemiological challenge of the most frequent eye cancer: retinoblastoma, an issue of birth and death</title><secondary-title>Br J Ophthalmol</secondary-title></titles><periodical><full-title>Br J Ophthalmol</full-title></periodical><pages>1129-31</pages><volume>93</volume><number>9</number><edition>2009/08/26</edition><keywords><keyword>Adolescent</keyword><keyword>Child</keyword><keyword>Child, Preschool</keyword><keyword>Humans</keyword><keyword>Retinal Neoplasms/*epidemiology</keyword><keyword>Retinoblastoma/*epidemiology</keyword><keyword>Survival Analysis</keyword></keywords><dates><year>2009</year><pub-dates><date>Sep</date></pub-dates></dates><isbn>1468-2079 (Electronic)
0007-1161 (Linking)</isbn><accession-num>19704035</accession-num><urls><related-urls><url> [pii]
10.1136/bjo.2008.150292</electronic-resource-num><language>eng</language></record></Cite></EndNote>5[Au: it might also be useful to list in the table footnote which countries are included in the different categories.]CategoryPopulation, total[Au: approximations might be better: 7.0 billion; 1.3 billion; 250 million]Birth rate, crude (per 1,000 people)Mortality rate, infant (per 1,000 live births)Forecast Live Birthstotal[Au: approximations might be better total[Au: approximations might be better]Retinoblastoma Cases (High) 1:16,000Retinoblastoma Cases (Low) 1:18000% of World Retinoblastoma[Au: is this based on the high or low approximations?]World7,043,105,59119.434.6131,629,8628,2277,313100%High income1,299,489,52011.65.514,941,32093483011.4%High income: nonOECD249,927,99413.810.33,418,872214190High income: OECD1,049,561,52611.04.411,518,845720640Low & middle income5,743,616,07121.138.1116,699,2037,2946,48388.7%Middle income4,913,580,79719.233.791,300,5465,7065,07269.4%Upper middle income2,390,210,77414.816.334,737,3172,1711,93026.4%Lower middle income2,523,370,02323.445.356,490,3883,5313,13842.9%Low income830,035,27432.354.525,373,8901,5861,41019.3%Table 1. Availability of treatment and imaging at retinoblastoma centres worldwide.Retinoblastoma centres worldwide were surveyed (up to March 25, 2015) and featured on the One Retinoblastoma World Map (). Information is available for 54 countries (22 High-Income countries, 28 Middle-Income countries and 4 Low-Income countries, following World Bank Classification).The estimate of availability of intra-arterial chemotherapy was drawn from Grigorovskiet al's study.[Au: Only the percentages would be sufficient.]CountriesTotal centres Enucleation (#, %)Laser therapy (#, %)Cryo-therapy (#, %)IVC (#, %)Retcam imaging (#, %)High Income 4747 (100%)43 (91%)42 (89%)40 (85%)42 (89%)Middle Income 7575 (100%)68 (91%)68 (91%)52 (69%)47 (63%)Low Income1010 (100%)5 (50%)2 (20%)5 (50%)3 (30%)Total 132132 (100%)116 (88%)112 (85%)97 (73%)92 (70%)Supplementary informationAcknowledgementsTWC: NIH NCATS KL2TR001106, Research to Prevent Blindness, Inc. Can contain grant and contribution numbers. Should be brief, and should not include thanks to anonymous referees and editors, inessential words, or effusive comments.Author contributionsIntroduction (B.G.); Epidemiology (B.G., H.D.); Mechanisms/pathophysiology (B.G., T.C., D.C.); Diagnosis, screening and prevention (B.G., H.D., J.Z.); Management (B.G., F.M., D.A., C.S., G.C.); Quality of life (B.G., A.W.); Outlook (B.G., H.D., T.C., D.C., F.M.); overview of Primer (B.G.).[Au: I noticed some discrepancies between the information in the online submission system and the manuscript – with regard to author contributions. I took the info of the submission system. Please check very carefully and make changes (with tracked changes on) so that I can update the submission system. Also, Festus Njuguna does not have any contributions in the submission system; please add information here.]Competing interestsIn the interests of transparency, the Nature Clinical Reviews journals have a competing financial interests policy. 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