Research Into Visual Endpoints and RB Health Outcomes After Treatment: The RIVERBOAT Consortium

项目总结 这一努力的总体目标是组织第一个也是最大的国际多中心、多种族和民族 视网膜母细胞瘤(RB)幸存者协会研究健康结果并询问基因-表型 疾病表现的相关性。眼内RB在高收入国家几乎是100%可以治愈的， 因此，治疗的重点是抢救眼球，保留功能性视力，最大限度地减少急性和长期 长期不良后果。几十年来，RB一直可以通过眼球摘除或放射治疗治愈。然而， 眼球摘除、视力障碍、眼眶和面部畸形、心理社会和神经认知的发病率 损伤和较高的继发性恶性肿瘤发生率促使1990年代S静脉注射 局部眼科疗法(IVC)的化疗。高达40%的IVC患者的眼球挽救失败， 再加上全身毒性，导致自2008年以来动脉内化疗(IAC)的使用增加。IVC 和IAC被认为与以患者为中心的良好结局和较低的SMN发生率有关 摘除或放射。IVC可能与更多的全身毒性有关，而IAC与更多的局部毒性有关 毒性。因此，治疗方案在一定程度上取决于急性和长期毒性。治疗也必须 由治愈的可能性和视力决定的，这很大程度上受疾病的影响 外露，特别是玻璃体和视网膜下种子。然而，种子发育的生物学基础 在很大程度上仍不为人所知。这些知识可以为治疗的选择提供信息，并导致有针对性的发展 与改善疗效和毒性的平衡有关的治疗。没有一种有组织的系统的方法 评估IVC和IAC或生物决定因素的急性毒性和长期结果 积极的疾病表现，这推动了治疗决定，并反过来，健康结果。我们有 因此召集儿科肿瘤学和眼科研究人员组成视觉研究 终点和治疗后的RB健康结局(河船)联盟：1)定义急性毒性和 RB幸存者的视觉结果，并比较以患者为中心的心理社会和神经认知结果 具有标准数据和兄弟姐妹对照的幸存者；2)创建第一个临床注释的患者组织 分析基因相互作用以评估疾病的生物相关性并促进未来的研究：河船- 船长生物库；以及3)使用内河船船长生物库，确定 特定的RB1突变类型和附加修饰基因在确定驱动肿瘤表型中的作用 治疗决定。我们将通过以下方式积极影响RB的幸存者：1)评估以下方面的短期和长期结果 现代治疗；2)建立临床注释的基因组研究生物库；3) 探讨疾病表现的分子发病机制。这将解决RB管理的目标：Globe 并保留视力，无治疗相关不良后遗症。

PROJECT SUMMARY The overall goal of this effort is to organize the first and largest international multicenter, multi-racial and ethnic consortium of retinoblastoma (RB) survivors to study health outcomes and interrogate genotype-phenotype correlations of disease presentation. Intraocular RB is virtually 100% curable in high-income countries and treatment thus focuses on globe salvage with preservation of functional vision and minimizing acute and long- term adverse outcomes. RB has been curable for decades with enucleation or radiation therapy. However, the morbidity of eye removal, visual impairment, orbital and facial deformities, psychosocial and neurocognitive impairment and high subsequent malignant neoplasm (SMN) rates prompted in the 1990's the use of intravenous chemotherapy with local ophthalmic therapies (IVC). Failure of globe salvage in up to 40% of eyes with IVC, combined with systemic toxicities led to the increased use of intra-arterial chemotherapy (IAC) since 2008. IVC and IAC are believed to be associated with excellent patient centered outcomes and lower SMN rates than enucleation or radiation. IVC is potentially associated with more systemic toxicities, while IAC with greater local toxicity. Therapeutic options are thus, in part, determined by acute and long-term toxicities. Treatment must also be determined by likelihood of cure with globe and vision savage, which is heavily influenced by disease presentation, and in particular, vitreous and subretinal seeds. However, the biologic basis of seed development remains largely unknown. Such knowledge can inform choice of therapy and lead to development of targeted therapies associated with an improved balance of efficacy and toxicity. No organized systematic approach has been undertaken to assess acute toxicities and long-term outcomes of IVC and IAC or the biologic determinants of aggressive disease presentation, which drives therapeutic decisions, and in turn, health outcomes. We have therefore assembled pediatric oncology and ophthalmology investigators to form the Research Into Visual Endpoints and RB Health Outcomes After Treatment (RIVERBOAT) Consortium to: 1) define acute toxicity and visual outcomes in RB survivors and compare patient-centered psychosocial and neurocognitive outcomes in survivors with normative data and sibling controls; 2) create the first Clinically-Annotated Patient Tissues to Analyze gene INteractions to assess biologic correlates of disease and to facilitate future research: RIVERBOAT- CAPTAIN Biorepository; and 3) using the RIVERBOAT-CAPTAIN biorepository, determine the interplay between specific RB1 mutation type and the role of additional modifier genes in determining tumor phenotypes that drive treatment decisions. We will positively impact survivors of RB by: 1) assessing short and long-term outcomes of contemporary therapy; 2) establishing a clinically-annotated biorepository for genomic research; and 3) examining molecular pathogenesis of disease presentation. This will address the goal of RB management: globe and vision preservation without treatment-related adverse sequelae.