Search

Limited survival data for the six Global Initiative for Childhood Cancer (GICC) priority cancers are available in Africa. Management of pediatric malignancies in Africa is challenging due to lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment. Reporting of outcome data is problematic due to the lack of registries. With the aim of evaluating the feasibility of baseline outcomes for the six index cancers, we present a descriptive analysis of respective survival rates in Africa. The survival rates were between 18% (lower middle-income countries) to 82.3% (upper middle-income countries) for acute lymphoblastic leukemia, between 26.9% (low-income countries) to 77.9% (upper middle-income countries) for nephroblastoma, between 23% (low-income countries) to 100% (upper middle-income countries), for retinoblastoma, 45% (low-income countries) to 95% (upper middle-income countries) for Hodgkin lymphoma and 28% (low-income countries) to 76% (upper middle-income countries) for Burkitt lymphoma. Solutions to improve survival rates and reported outcomes include establishing and funding sustainable registries, training and to actively include all countries in consortia from different African regions.HighlightsContinental differences in childhood cancer management such lack of resources, setting-specific comorbidities, high rates of late presentation and treatment abandonment, present challenges to the achievement of Global Initiative for Childhood Cancer goals.The available data registries do not adequately inform on the true incidences and outcomes of childhood cancers in Africa.The pathophysiology of some childhood cancers in Africa are associated with high-risk prognostic factors.Outcomes can be improved by greater regional collaboration to manage childhood cancer based on local resources and tumor characteristics.Some individual countries have reached the Global Initiative for Childhood Cancer goals for single cancers and it should be possible for more African countries to follow suit.

Objective To investigate in a large global sample of patients with retinoblastoma whether sex predilection exists for this childhood eye cancer. Methods A cross-sectional analysis including 4351 treatment-naive retinoblastoma patients from 153 countries who presented to 278 treatment centers across the world in 2017. The sex ratio (male/female) in the sample was compared to the sex ratio at birth by means of a two-sided proportions test at global level, country economic grouping, continent, and for selected countries. Results For the entire sample, the mean retinoblastoma sex ratio, 1.20, was higher than the weighted global sex ratio at birth, 1.07 (p n = 1940), 1.23 vs. 1.07 (p = 0.019); Asia (n = 2276), 1.28 vs. 1.06 (p n = 558), 1.52 vs. 1.11 (p = 0.008). Sensitivity analysis, excluding data from India, showed that differences remained significant for the remaining sample (χ2 = 6.925, corrected p = 0.025) and for Asia (χ2 = 5.084, corrected p = 0.036). Excluding data from Asia, differences for the remaining sample were nonsignificant (χ2 = 2.205, p = 0.14). Conclusions No proof of sex predilection in retinoblastoma was found in the present study, which is estimated to include over half of new retinoblastoma patients worldwide in 2017. A high male to female ratio in Asian countries, India in specific, which may have had an impact on global-level analysis, is likely due to gender discrimination in access to care in these countries, rather than a biological difference between sexes.

Purpose To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels. Design International, multicenter, registry-based retrospective case series. Participants Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents. Methods Multicenter registry-based data were pooled from retinoblastoma patients enrolled between January 2001 and December 2013. Adequate data to allow American Joint Committee on Cancer staging, eighth edition, and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects, and included high-income countries (HICs), upper middle-income countries (UMICs), and lower middle-income countries (LMICs). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes. Main Outcome Measures Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy). Results Most (60%) study patients resided in UMICs and LMICs. The global median age at diagnosis was 17.0 months and higher in UMICs (20.0 months) and LMICs (20.0 months) than HICs (14.0 months; P Conclusions This international, multicenter, registry-based analysis of retinoblastoma management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure, and lower globe salvage.

BACKGROUND: Although mortality due to COVID-19 has been reportedly low among children with cancer, changes in health-care services due to the pandemic have affected cancer care delivery. This study aimed to assess the effect of the COVID-19 pandemic on childhood cancer care worldwide. METHODS: A cross-sectional survey was distributed to paediatric oncology providers worldwide from June 22 to Aug 21, 2020, through the St Jude Global Alliance and International Society for Paediatric Oncology listservs and regional networks. The survey included 60 questions to assess institution characteristics, the number of patients diagnosed with COVID-19, disruptions to cancer care (eg, service closures and treatment abandonment), adaptations to care, and resources (including availability of clinical staff and personal protective equipment). Surveys were included for analysis if respondents answered at least two thirds of the items, and the responses were analysed at the institutional level. FINDINGS: Responses from 311 health-care professionals at 213 institutions in 79 countries from all WHO regions were included in the analysis. 187 (88%) of 213 centres had the capacity to test for SARS-CoV-2 and a median of two (range 0-350) infections per institutution were reported in children with cancer. 15 (7%) centres reported complete closure of paediatric haematology-oncology services (median 10 days, range 1-75 days). Overall, 2% (5 of 213) of centres were no longer evaluating new cases of suspected cancer, while 43% (90 of 208) of the remaining centers described a decrease in newly diagnosed paediatric cancer cases. 73 (34%) centres reported increased treatment abandonment (ie, failure to initiate cancer therapy or a delay in care of 4 weeks or longer). Changes to cancer care delivery included: reduced surgical care (153 [72%]), blood product shortages (127 [60%]), chemotherapy modifications (121 [57%]), and interruptions to radiotherapy (43 [28%] of 155 institutions that provided radiotherapy before the pandemic). The decreased number of new cancer diagnoses did not vary based on country income status (p=0·14). However, unavailability of chemotherapy agents (p=0·022), treatment abandonment (p

Cure4Kids is a free web-based knowledge platform for professionals providing care for children with cancer and hematologic diseases, offering its users a comprehensive suite of learning opportunities. It has been a resource for the pediatric oncology community across the world for the past two decades, with 60,107 users having logged in 1,412,514 times with 22,045,553 content hits. A transformation of Cure4Kids is being planned and will include an improved user interface, increased interactivity, and more content.

Purpose To evaluate the ability of the American Joint Committee on Cancer (AJCC) 8th edition to predict local tumor control and globe salvage for children with retinoblastoma (RB). Design International, multicenter, registry-based retrospective case series. Participants A total of 2854 eyes of 2097 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. Methods International, multicenter, registry-based data were pooled from patients enrolled between January 2001 and December 2013. All RB eyes with adequate records to allow tumor staging by the AJCC 8th edition criteria and follow-up to ascertain treatment outcomes were included. Main Outcome Measures Globe-salvage rates were estimated by AJCC clinical (cTNMH) categories and tumor laterality. Local treatment failure was defined as use of enucleation or external beam radiation therapy (EBRT), with or without plaque brachytherapy or intra-arterial chemotherapy (IAC). Results Unilateral RB occurred in 1340 eyes (47%). Among the 2854 eyes, tumor categories were cT1 to cT4 in 696 eyes (24%), 1334 eyes (47%), 802 eyes (28%), and 22 eyes (1%), respectively. Of these, 1275 eyes (45%) were salvaged, and 1179 eyes (41%) and 400 eyes (14%) underwent primary and secondary enucleation, respectively. The 2- and 5-year Kaplan–Meier cumulative globe-salvage rates without the use of EBRT by cTNMH categories were 97% and 96% for category cT1a tumors, 94% and 88% for cT1b tumors, 68% and 60% for cT2a tumors, 66% and 57% for cT2b tumors, and 32% and 25% for cT3 tumors, respectively. Risk of local treatment failure increased with increasing cT category (P Conclusions Multicenter, international, internet-based data sharing validated the 8th edition AJCC RB staging to predict globe-salvage in a large, heterogeneous, real-world patient population with RB.

Purpose To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma (RB). Design International, multicenter, registry-based retrospective case series. Participants A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents. Methods Patient-specific data fields for RB were designed and selected by subcommittee. All patients with RB with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied. Main Outcome Measures Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the Kaplan–Meier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait. Results Of 2190 patients, the records of 2085 patients (95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. A total of 1260 patients (65.4%) had unilateral RB. Among the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b in 168 (8.1%), cT2a in 197 (9.4%), cT2b in 812 (38.9%), cT3 in 835 (40.0%), and cT4 in 18 (0.9%). Of these, 1397 eyes in 1353 patients (48.1%) were treated with enucleation. A total of 109 patients (5.2%) developed metastases and died. The median time (n = 92) from diagnosis to metastasis was 9.50 months. The 5-year Kaplan–Meier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval [CI], 97–99) for cT1b and cT2a, 96% (95% CI, 95–97) for cT2b, 89% (95% CI, 88–90) for cT3 tumors, and 45% (95% CI, 31–59) for cT4 tumors. Risk of metastasis increased with increasing cT (and pT) category (P Conclusions Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real-life, heterogeneous patient population with RB.

Intraocular retinoblastoma treatment has changed radically over the last decade, leading to a notable improvement in ocular survival. However, eyes that relapse remain difficult to treat, as few alternative active drugs are available. More challenging is the scenario of central nervous system (CNS) metastasis, in which almost no advancements have been made. Both clinical scenarios represent an urgent need for new drugs. Using an integrated multidisciplinary approach, we developed a decision process for prioritizing drug selection for local (intravitreal [IVi], intrathecal/intraventricular [IT/IVt]), systemic, or intra-arterial chemotherapy (IAC) treatment by means of high-throughput pharmacological screening of primary cells from two patients with intraocular tumor and CNS metastasis and a thorough database search to identify clinical and biopharmaceutical data. This process identified 169 compounds to be cytotoxic; only 8 are FDA-approved, lack serious toxicities and available for IVi administration. Four of these agents could also be delivered by IT/IVt. Twelve FDA-approved drugs were identified for systemic delivery as they are able to cross the blood-brain barrier and lack serious adverse events; four drugs are of oral usage and six compounds that lack vesicant or neurotoxicity could be delivered by IAC. We also identified promising compounds in preliminary phases of drug development including inhibitors of survivin, antiapoptotic Bcl-2 family proteins, methyltransferase, and kinesin proteins. This systematic approach may be applied more broadly to prioritize drugs to be repurposed or to identify novel hits for use in retinoblastoma treatment.

Retinoblastoma survivors in low- and middle-income countries are exposed to high-intensity treatments that potentially place them at higher risk of early subsequent malignant neoplasms (SMNs).We followed 714 (403 [56.4%] nonhereditary and 311 [43.5%] hereditary) retinoblastoma survivors diagnosed from August 1987 to December 2016, up to the age of 16 years. We quantified risk of SMNs with cumulative incidence (CI) and standardized incidence ratios (SIR) analysis. Multivariate regression Cox model was used to determine the association of treatments and risk of SMNs.Median follow-up was of 9 years (range: 0.18-16.9) and 24 survivors (3.36%) developed 25 SMNs (n = 22 hereditary, n = 2 nonhereditary). SMNs included sarcomas (osteosarcomas, Ewing sarcomas, rhabdomyosarcomas; n = 12), leukemias (n = 5), and central nervous system tumors (CNS; n = 3). All cases of acute myeloid leukemia (AML) and most of Ewing sarcomas occurred within 5 years of retinoblastoma diagnosis. The type of SMN was the main indicator of mortality (five of five patients with leukemias, six of 12 with sarcomas, and zero of three with CNS tumors died). Compared to the general population, radiation increased the risk of Ewing sarcoma in hereditary survivors by 700-fold (95% CI = 252-2422.6) and chemotherapy increased the risk of AML by 140-fold (95% CI = 45.3-436). The CI of SMNs for hereditary survivors was 13.7% (95% CI = 8.4-22.1) at 15 years.Retinoblastoma survivors from Argentina are at higher risk of developing SMNs early in life compared to the general Argentinean population, especially those treated with radiation plus chemotherapy. AML and Ewing sarcoma presented within 5 years of retinoblastoma diagnosis are associated with chemotherapy and radiation exposure.

The ongoing coronavirus 2019 disease (COVID-19) pandemic strained medical systems worldwide. We report on the impact on pediatric oncology care in Latin American (LATAM) during its first year.Four cross-sectional surveys were electronically distributed among pediatric onco-hematologists in April/June/October 2020, and April/2021 through the Latin American Society of Pediatric Oncology (SLAOP) email list and St Jude Global regional partners.Four hundred fifty-three pediatric onco-hematologists from 20 countries responded to the first survey, with subsequent surveys response rates above 85%. More than 95% of participants reported that treatment continued without interruption for new and active ongoing patients, though with disruptions in treatment availability. During the first three surveys, respondents reported suspensions of outpatient procedures (54.2%), a decrease in oncologic surgeries (43.6%), radiotherapy (28.4%), stem cell transplants (SCT) (69.3%), and surveillance consultations (81.2%). Logistic regression analysis showed that at the beginning of the first wave, participants from countries with healthcare expenditure below 7% were more likely to report a decrease in outpatient procedures (odds ratio [OR]: 1.84, 95% CI: 1.19-2.8), surgeries (OR: 3, 95% CI: 1.9-4.6) and radiotherapy (OR: 6, 95% CI: 3.5-10.4). Suspension of surveillance consultations was higher in countries with COVID-19 case fatality rates above 2% (OR: 3, 95% CI: 1.4-6.2) and SCT suspensions in countries with COVID-19 incidence rate above 100 cases per 100,000 (OR: 3.48, 95% CI: 1.6-7.45). Paradoxically, at the beginning of the second wave with COVID-19 cases rising exponentially, most participants reported improvements in cancer services availability.Our data show the medium-term collateral effects of the pandemic on pediatric oncology care in LATAM, which might help delineate oncology care delivery amid current and future challenges posed by the pandemic.

Tumor boards are part of standard care of patients with complex cancers, but appropriate multidisciplinary expertise and infrastructure are often not available in low- and middle-income countries (LMIC) for pediatric cancers, such as neuroblastoma. Our goal was to review results of a Global Neuroblastoma Network (GNN) tumor board accessible to LMIC.De-identified clinical cases presented via internet conference during a weekly GNN virtual tumor board from 2010 through 2020 were evaluated in a standardized format, including diagnostic imaging, pathology, therapy information, resource limitations, and questions for discussion. Information summarized included the presentations, a survey of the impact on care, and a resource questionnaire.Registered GNN participants included 575 individuals from 77 countries, with a median of 39 participants per session. Total 412 cases were presented from 32 countries, including 351 unique neuroblastoma patients, 52 follow-up cases, and nine non-neuroblastoma diagnoses. Twenty-eight educational sessions were presented. Limited critical resources for diagnostics and staging of cases included MYCN analysis (54.7%), metaiodobenzylguanidine (MIBG) scans (38.7%), and International Neuroblastoma Pathology Classification (49%). Therapies were also limited, with markedly decreased use of radiation and autologous stem cell transplant for high-risk cases, and no availability of anti-GD2 antibody in LMIC. Limited sampling with a post-presentation survey showed that 100% found the GNN helpful, and 70% altered the care plan based on the discussion.This report shows the utility of an international tumor board for LMIC focused on a challenging solid tumor where local expertise may be limited, with international multidisciplinary expert participation and educational sessions.

IMPORTANCE: High-risk histopathologic features of retinoblastoma are useful to assess the risk of systemic metastasis. In this era of globe salvage treatments for retinoblastoma, the definition of high-risk retinoblastoma is evolving. OBJECTIVE: To evaluate variations in the definition of high-risk histopathologic features for metastasis of retinoblastoma in different ocular oncology practices around the world. DESIGN, SETTING, AND PARTICIPANTS: An electronic web-based, nonvalidated 10-question survey was sent in December 2020 to 52 oncologists and pathologists treating retinoblastoma at referral retinoblastoma centers. INTERVENTION: Anonymized survey about the definition of high-risk histopathologic features for metastasis of retinoblastoma. MAIN OUTCOMES AND MEASURES: High-risk histopathologic features that determine further treatment with adjuvant systemic chemotherapy to prevent metastasis. RESULTS: Among the 52 survey recipients, the results are based on the responses from 27 individuals (52%) from 24 different retinoblastoma practices across 16 countries in 6 continents. The following were considered to be high-risk features: postlaminar optic nerve infiltration (27 [100%]), involvement of optic nerve transection (27 [100%]), extrascleral tissue infiltration (27 [100%]), massive (=3 mm) choroidal invasion (25 [93%]), microscopic scleral infiltration (23 [85%]), ciliary body infiltration (20 [74%]), trabecular meshwork invasion (18 [67%]), iris infiltration (17 [63%]), anterior chamber seeds (14 [52%]), laminar optic nerve infiltration (13 [48%]), combination of prelaminar and laminar optic nerve infiltration and minor choroidal invasion (11 [41%]), minor (

Background Patients with single‐ventricle physiology who undergo the Fontan procedure are at risk for thrombotic events associated with significant morbidity and mortality. The UNIVERSE Study evaluated the efficacy and safety of a novel liquid rivaroxaban formulation, using a body weight–adjusted dosing regimen, versus acetylsalicylic acid (ASA) in children post‐Fontan. Methods and Results The UNIVERSE Study was a randomized, multicenter, 2‐part, open‐label study of rivaroxaban, in children who had undergone a Fontan procedure, to evaluate its dosing regimen, safety, and efficacy. Part A was the single‐arm part of the study that determined the pharmacokinetics/pharmacodynamics and safety of rivaroxaban in 12 participants before proceeding to part B, whereby 100 participants were randomized 2:1 to open‐label rivaroxaban versus ASA. The study period was 12 months. A total of 112 participants were enrolled across 35 sites in 10 countries. In part B, for safety outcomes, major bleeding occurred in one participant on rivaroxaban (epistaxis that required transfusion). Clinically relevant nonmajor bleeding occurred in 6% of participants on rivaroxaban versus 9% on ASA. Trivial bleeding occurred in 33% of participants on rivaroxaban versus 35% on ASA. For efficacy outcomes, 1 participant on rivaroxaban in part B had a pulmonary embolism (2% overall event rate); and for ASA, 1 participant had ischemic stroke and 2 had venous thrombosis (9% overall event rate). Conclusions In this study, participants who received rivaroxaban for thromboprophylaxis had a similar safety profile and fewer thrombotic events, albeit not statistically significant, compared with those in the ASA group. Registration URL: https://www.clinicaltrials.gov . Identifier: NCT02846532.

Introduction: Hematopoietic stem cell transplantation (HSCT) in children is associated with severe complications that need admission to critical care units. Mortality in this group of patients remains high with reported survival that ranges between 38 and 71%. Goals: To analyze the predictive factors of mortality of pediatric patients who received HSCT and were admitted to the pediatric intensive care unit (PICU) Material and methods: Retrospective review and analysis of a population of children and adolescents who underwent hematopoietic stem cell transplantation from 12/01/2008 to 11/30/2018 and were admitted to the pediatric intensive care unit (PICU) of a university hospital. Results: Of 248 patients subjected to the analysis, 109 patients were admitted. Overall mortality was 29% (n=32). After univariate analysis, the type of transplant (unrelated), baseline disease (malignant vs non-malignant), febrile neutropenia, cytomegalovirus (CMV) infection, multiorgan failure, respiratory failure, graft versus host disease (GVHD), conditioning regimen with myeloablative chemotherapy and pre-transplant malnutrition were associated with higher mortality. After the Multivariate Analysis of Logistic Regression, the variables GVHD (OR 2, 23 95% CI: 1.92 a 2, 98), need of mechanical ventilation ( OR 2.47,95% CI 1.39 a 5.73) unrelated allogeneic transplants (OR 1.58, 95% CI 1.14 a 2.17) and previous malnutrition (OR: 1.78, 95% CI 1,223-3.89) were statistically associated with mortality. Conclusion: In our population two of three children receiving HSCT and admitted to PICU survived. Graft vs. host disease, need of mechanical ventilation, unrelated transplantation and previous malnutrition were predictors of mortality.

Targeted therapies with MAPK inhibitors have proven to modulate the clinical manifestations of patients with Langerhans cell histiocytosis (LCH). We explored the presence of BRAFV600E mutation in our cohort of patients with LCH and cholestasis, sclerosing cholangitis, or liver fibrosis that presented resistance to chemotherapy. The BRAFV600E mutation was detected either in the diagnosis (skin and bone) or liver biopsy in our cohort of 13 patients. Thus, we observed a high incidence of BRAFV600E mutation in 100% either in diagnostic biopsy (skin and bone) or liver biopsy in patients with progressive liver disease, sequela, or liver transplant requirement.

Targeted therapies with MAPK inhibitors have proven to modulate the clinical manifestations of patients with Langerhans cell histiocytosis (LCH). We explored the presence of BRAF

Chemotherapy; Childhood cancer; Radiotherapy Quimioterapia; Cáncer infantil; Radioterapia Quimioteràpia; Càncer infantil; Radioteràpia Introduction Advanced intraocular retinoblastoma can be cured by enucleation, but spread of retinoblastoma cells beyond the natural limits of the eye is related to a high mortality. Adjuvant therapy after enucleation has been shown to prevent metastasis in children with risk factors for extraocular retinoblastoma. However, histological criteria and adjuvant treatment regimens vary and there is no unifying consensus on the optimal choice of treatment. Method Data on guidelines for adjuvant treatment in European retinoblastoma referral centres were collected in an online survey among all members of the European Retinoblastoma Group (EURbG) network. Extended information was gathered via personal email communication. Results Data were collected from 26 centres in 17 countries. Guidelines for adjuvant treatment were in place at 92.3% of retinoblastoma centres. There was a consensus on indication for and intensity of adjuvant treatment among more than 80% of all centres. The majority of centres use no adjuvant treatment for isolated focal choroidal invasion or prelaminar optic nerve invasion. Patients with massive choroidal invasion or postlaminar optic nerve invasion receive adjuvant chemotherapy, while microscopic invasion of the resection margin of the optic nerve or extension through the sclera are treated with combined chemo- and radiotherapy. Conclusion Indications and adjuvant treatment regimens in European retinoblastoma referral centres are similar but not uniform. Further biomarkers in addition to histopathological risk factors could improve treatment stratification. The high consensus in European centres is an excellent foundation for a common European study with prospective validation of new biomarkers. Open access funding enabled and organized by Projekt DEAL.

Standardized guidelines for assessing tumor response to therapy are essential for designing and conducting clinical trials. The Response Evaluation Criteria In Solid Tumors (RECIST) provide radiological standards for assessment of solid tumors. However, no such guidelines exist for the evaluation of intraocular cancer, and ocular oncology clinical trials have largely relied on indirect measures of therapeutic response-such as progression-free survival-to evaluate the efficacy of treatment agents. Herein, we propose specific criteria for evaluating treatment response of retinoblastoma, the most common pediatric intraocular cancer, and emphasize a multimodal imaging approach for comprehensive assessment of retinoblastoma tumors in clinical trials.

Most reports about copy number alterations (CNA) in retinoblastoma relate to patients with intraocular disease and features of children with extraocular relapse remain unknown, so we aimed to describe the CNA in this population. We evaluated 23 patients and 27 specimens from 4 centers. Seventeen cases had extraocular relapse after initial enucleation and six cases after an initial preservation attempt. We performed an analysis of CNA and BCOR gene alteration by SNP array (Single Nucleotide Polymorfism array), whole-exome sequencing, IMPACT panel and CGH array (Array-based comparative genomic hybridization). All cases presented CNA at a higher prevalence than those reported in previously published studies for intraocular cases. CNA previously reported for intraocular retinoblastoma were found at a high frequency in our cohort: gains in 1q (69.5%), 2p (60.9%) and 6p (86.9%), and 16q loss (78.2%). Other, previously less-recognized, CNA were found including loss of 11q (34.8%), gain of 17q (56.5%), loss of 19q (30.4%) and BCOR alterations were present in 72.7% of our cases. A high number of CNA including 11q deletions, 17q gains, 19q loss, and BCOR alterations, are more common in extraocular retinoblastoma. Identification of these features may be correlated with a more aggressive tumor warranting consideration for patient management. Fil: Aschero, María del Rosario. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Francis, Jasmine H.. Memorial Sloan-Kettering Cancer Center; Estados Unidos Fil: Ganiewich, Daiana. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Gomez Gonzalez, Soledad. Hospital Sant Joan de Deu Barcelona; España Fil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Zugbi, Santiago. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Ottaviani, Daniela. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; Francia Fil: Lemelle, Lauriane. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; Francia Fil: Mena, Marcela Daniela C. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Winter, Ursula Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Correa Llano, Genoveva. Hospital Sant Joan de Deu Barcelona; España Fil: Lamas, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Lubieniecki, Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Szijan, Irene. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; Argentina Fil: Mora, Jaume. Hospital Sant Joan de Deu Barcelona; España Fil: Podhajcer, Osvaldo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Doz, François. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; Francia Fil: Radvanyi, François. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; Francia Fil: Abramson, David H.. Memorial Sloan-Kettering Cancer Center; Estados Unidos Fil: Llera, Andrea Sabina. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones Bioquímicas de Buenos Aires. Fundación Instituto Leloir. Instituto de Investigaciones Bioquímicas de Buenos Aires; Argentina Fil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Lavarino, Cinzia. Hospital Sant Joan de Deu Barcelona; España Fil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina

The COVID-19 pandemic quickly led to an abundance of publications and recommendations, despite a paucity of information on how COVID-19 affects children with cancer. This created a dire need for a trusted resource with curated information and a space for the pediatric oncology community to share experiences. The Global COVID-19 Observatory and Resource Center for Childhood Cancer was developed, launched, and maintained by the International Society of Pediatric Oncology and St. Jude Children's Research Hospital. The three components (Resource Library, Global Registry, and Collaboration Space) complement each other, establishing a mechanism to generate and transfer knowledge rapidly throughout the community. Fil: Moreira, Daniel C.. St. Jude Children's Research Hospital; Estados Unidos Fil: Sniderman, Elizabeth. St. Jude Children's Research Hospital; Estados Unidos Fil: Mukkada, Sheena. St. Jude Children's Research Hospital; Estados Unidos Fil: Chantada, Guillermo Luis. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; Argentina Fil: Bhakta, Nickhill. St. Jude Children's Research Hospital; Estados Unidos Fil: Foster, Whitney. St. Jude Children's Research Hospital; Estados Unidos Fil: Avula, Meghana. St. Jude Children's Research Hospital; Estados Unidos Fil: Homsi, Maysam R.. St. Jude Children's Research Hospital; Estados Unidos Fil: Faughnan, Lane. St. Jude Children's Research Hospital; Estados Unidos Fil: Happ, Brooke. St. Jude Children's Research Hospital; Estados Unidos Fil: Andujar, Allyson. St. Jude Children's Research Hospital; Estados Unidos Fil: Sonnenfelt, Jason. St. Jude Children's Research Hospital; Estados Unidos Fil: Dalvi, Rashmi. Bombay Hospital And Medical Research Centre; India Fil: Frazier, A. Lindsay. No especifíca; Fil: Hessissen, Laila. Universite Mohammed V. Rabat; Otros paises de África Fil: Kearns, Pamela R.. No especifíca; Fil: Luna Fineman, Sandra. No especifíca; Fil: Moreno, Arturo. Hospital Universitario de Puebla; México Fil: Saghir Khan, Muhammad. No especifíca; Fil: Sullivan, Michael. Royal Children's Hospital, Melbourne; Australia Fil: Devidas, Meenakshi. St. Jude Children's Research Hospital; Estados Unidos Fil: Santana, Victor. St. Jude Children's Research Hospital; Estados Unidos Fil: Caniza, Miguela. St. Jude Children's Research Hospital; Estados Unidos Fil: Pritchard Jones, Kathy. University College London; Estados Unidos Fil: Rodriguez Galindo, Carlos. St. Jude Children's Research Hospital; Estados Unidos

Retinoblastoma is the most common paediatric ocular malignancy. Its disease-free survival rate in developed countries is higher than 95%, but in the developing world this tumour presents with advanced disease leading to poorer outcome. Late diagnosis and problems with compliance for treatment affect the outcome in that setting. Retinoblastoma may occur in children with germline mutations of the RB1 gene, who usually present with bilateral heritable disease. In those with somatic mutations, it always presents as unilateral and non-hereditable disease. The former have a higher susceptibility for secondary malignancies occurring later in life. Enucleation of the affected eyeball is often curative when the disease presents intraocularly, but conservative therapies have evolved from conventional external photon-beam radiotherapy, which was associated with severe long-term toxicity, to chemotherapy plus local treatments. Recently, local intra-arterial and intravitreal chemotherapy has been more intensively used, leading to higher preservation rates.

Hematopoietic stem cell transplantation (HSCT) in children is a procedure that is not exempt of severe complications. Admission to the pediatric intensive care unit (PICU) is associated with a high mortality rate. Objectives: To analyze survival and predictors of mortality among children who received a HSCT and were admitted to the PICU, and to develop a mortality prediction model in this population.Retrospective review of children and adolescents who received a HSCT between January 1st, 2005 and December 31st, 2019 and were admitted to the PICU of a tertiary care teaching hospital.Out of 264 children receiving the transplant, 114 were admitted to the PICU. The overall mortality rate was 29% (n = 34). The type of transplant, underlying disease, febrile neutropenia event, cytomegalovirus infection, respiratory failure, graft versus host disease (GVHD), myeloablative chemotherapy, and previous malnutrition were associated with higher mortality rates. In the multivariate analysis, GVHD (odds ratio [OR]: 2.23; 95% confidence interval [CI]: 1.92-2.98), need for mechanical ventilation (OR: 2.47; 95% CI: 1.39- 5.73), alternative donor transplant (OR: 1.58; 95% CI: 1.14-2.17), and previous malnutrition (OR: 1.78; 95% CI: 1.22-3.89) were associated with a higher mortality rate.In the studied population, 2 out of 3 children who received a HSCT and were admitted to the PICU survived. GVHD, mechanical ventilation, alternative donor transplant, and previous malnutrition were predictors of mortality.Introducción: El trasplante de células progenitoras hematopoyéticas (TPH) en niños es un procedimiento no exento de complicaciones graves. El ingreso de esta población a unidades de cuidados intensivos pediátricos (UCIP) se asocia con elevada mortalidad. Objetivos: Analizar la sobrevida y los factores predictivos de la mortalidad en niños que recibieron TPH e ingresaron a la UCIP y elaborar un modelo predictivo de mortalidad en esta población. Materiales y métodos: Revisión retrospectiva de niños y adolescentes que recibieron un TPH entre el 01/01/2005 y el 31/12/2019 e ingresaron a la UCIP de un hospital universitario de alta complejidad. Resultados: De un total de 264 niños que recibieron el trasplante, 114 ingresaron a la UCIP. La mortalidad general fue del 29% (n = 34). El tipo de trasplante, enfermedad basal, evento de neutropenia febril, infección por citomegalovirus, insuficiencia respiratoria, enfermedad de injerto contra huésped (EICH), quimioterapia mieloablativa y desnutrición previa se asociaron con tasas de mortalidad más elevadas. En el análisis multivariado, la EICH (razón de posibilidades [OR, por su sigla en inglés]: 2,23; intervalo de confianza del 95% [IC 95%]: 1,92-2,98), la necesidad de ventilación mecánica invasiva (OR: 2,47; IC95%: 1,39-5,73), el trasplante de donante alternativo (OR: 1,58; IC 95%: 1,14-2,17) y la desnutrición previa (OR: 1,78; IC 95%: 1,223-3,89) se asociaron con mayor mortalidad. Conclusión: En la población estudiada, dos de cada tres niños que recibieron TPH e ingresaron a la UCIP sobrevivieron. La EICH, ventilación mecánica, trasplante de donante alternativo y desnutrición previa fueron factores predictivos de mortalidad.

To compare metastasis-related mortality, local treatment failure, and globe salvage after retinoblastoma in countries with different national income levels.International, multicenter, registry-based retrospective case series.Two thousand one hundred ninety patients, 18 ophthalmic oncology centers, and 13 countries on 6 continents.Multicenter registry-based data were pooled from retinoblastoma patients enrolled between January 2001 and December 2013. Adequate data to allow American Joint Committee on Cancer staging, eighth edition, and analysis for the main outcome measures were available for 2085 patients. Each country was classified by national income level, as defined by the 2017 United Nations World Population Prospects, and included high-income countries (HICs), upper middle-income countries (UMICs), and lower middle-income countries (LMICs). Patient survival was estimated with the Kaplan-Meier method. Logistic and Cox proportional hazards regression models were used to determine associations between national income and treatment outcomes.Metastasis-related mortality and local treatment failure (defined as use of secondary enucleation or external beam radiation therapy).Most (60%) study patients resided in UMICs and LMICs. The global median age at diagnosis was 17.0 months and higher in UMICs (20.0 months) and LMICs (20.0 months) than HICs (14.0 months; P0.001). Patients in UMICs and LMICs reported higher rates of disease-specific metastasis-related mortality and local treatment failure. As compared with HICs, metastasis-related mortality was 10.3-fold higher for UMICs and 9.3-fold higher for LMICs, and the risk for local treatment failure was 2.2-fold and 1.6-fold higher, respectively (all P0.001).This international, multicenter, registry-based analysis of retinoblastoma management revealed that lower national income levels were associated with significantly higher rates of metastasis-related mortality, local treatment failure, and lower globe salvage.

Although previous studies have suggested that the complications and mortality rate related to COVID-19 are substantially lower in the paediatric population,1 it is reasonable to consider that children with underlying conditions such as cancer will be at increased risk of severe disease... Fil: Vasquez, Liliana. Universidad de San Martín de Porres; Perú. Organización Panamericana de la Salud; Perú Fil: Sampor, Claudia. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina Fil: Villanueva, Gabriela. Fundacion Hospital de Pediatria Professor Dr. Juan P. Garrahan; Argentina Fil: Maradiegue, Essy. Instituto Nacional de Enfermedades Neoplasicas; Perú Fil: Garcia Lombardi, Mercedes. Gobierno de la Ciudad de Buenos Aires. Hospital General de Niños "Ricardo Gutiérrez"; Argentina Fil: Gomez García, Wendy. Hospital Infantil Dr. Robert Reid Cabral; República Dominicana Fil: Moreno, Florencia. Ministerio de Salud. Instituto Nacional del Cáncer; Argentina Fil: Diaz, Rosdali. Instituto Nacional de Enfermedades Neoplasicas; Perú Fil: Cappellano, Andrea M.. Universidade Federal de Sao Paulo; Brasil Fil: Portilla, Carlos Andres. Universidad del Valle; Colombia Fil: Salas, Beatriz. Hospital del Niño Manuel Ascencio Villarroel; Bolivia Fil: Nava, Evelinda. Hospital de Niños Jesus Garcia Coello; Venezuela Fil: Brizuela, Silvia. Instituto de Previsión Social ; Paraguay Fil: Jimenez, Soledad. Hospital Solca Núcleo de Loja; Ecuador Fil: Espinoza, Ximena. Hospital de Niños Dr. Roberto del Río; Chile Fil: Gassant, Pascale Yola. Hôpital Saint-Damien; Haití Fil: Quintero, Karina. Children's Hospital Dr Jose Renan Esquivel; Panamá Fil: Fuentes Alabi, Soad. Hospital Nacional de Niños Benjamin Bloom; El Salvador Fil: Velasquez, Thelma. No especifíca; Fil: Fu, Ligia. Hospital Escuela de Tegucigalpa; Honduras Fil: Gamboa, Yessika. National Children's Hospital; Costa Rica Fil: Quintana, Juan. Clinica Las Condes; Chile Fil: Castiglioni, Mariela. Hospital Pereira Rossell; Uruguay Fil: Nuñez, Cesar. Children's Cancer Hospital; Estados Unidos Fil: Moreno, Arturo. Hospital Universitario de Puebla; México Fil: Luna Fineman, Sandra. State University of Colorado at Boulder; Estados Unidos Fil: Luciani, Silvana. Pan American Health Organization; Estados Unidos Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Hospital Sant Joan de Deu Barcelona; España

BackgroundThe travel distance from home to a treatment centre, which may impact the stage at diagnosis, has not been investigated for retinoblastoma, the most common childhood eye cancer. We aimed to investigate the travel burden and its impact on clinical presentation in a large sample of patients with retinoblastoma from Africa and Europe.MethodsA cross-sectional analysis including 518 treatment-naïve patients with retinoblastoma residing in 40 European countries and 1024 treatment-naïve patients with retinoblastoma residing in 43 African countries.ResultsCapture rate was 42.2% of expected patients from Africa and 108.8% from Europe. African patients were older (95% CI −12.4 to −5.4, pConclusionsFewer than half the expected number of patients with retinoblastoma presented to African referral centres in 2017, suggesting poor awareness or other barriers to access. Despite the relatively shorter distance travelled by African patients, they presented with later-stage disease. Health education about retinoblastoma is needed for carers and health workers in Africa in order to increase capture rate and promote early referral.

To evaluate the ability of the American Joint Committee on Cancer (AJCC) 8th edition to predict local tumor control and globe salvage for children with retinoblastoma (RB).International, multicenter, registry-based retrospective case series.A total of 2854 eyes of 2097 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents.International, multicenter, registry-based data were pooled from patients enrolled between January 2001 and December 2013. All RB eyes with adequate records to allow tumor staging by the AJCC 8th edition criteria and follow-up to ascertain treatment outcomes were included.Globe-salvage rates were estimated by AJCC clinical (cTNMH) categories and tumor laterality. Local treatment failure was defined as use of enucleation or external beam radiation therapy (EBRT), with or without plaque brachytherapy or intra-arterial chemotherapy (IAC).Unilateral RB occurred in 1340 eyes (47%). Among the 2854 eyes, tumor categories were cT1 to cT4 in 696 eyes (24%), 1334 eyes (47%), 802 eyes (28%), and 22 eyes (1%), respectively. Of these, 1275 eyes (45%) were salvaged, and 1179 eyes (41%) and 400 eyes (14%) underwent primary and secondary enucleation, respectively. The 2- and 5-year Kaplan-Meier cumulative globe-salvage rates without the use of EBRT by cTNMH categories were 97% and 96% for category cT1a tumors, 94% and 88% for cT1b tumors, 68% and 60% for cT2a tumors, 66% and 57% for cT2b tumors, and 32% and 25% for cT3 tumors, respectively. Risk of local treatment failure increased with increasing cT category (P0.001). Cox proportional hazards regression analysis confirmed a higher risk of local treatment failure in categories cT1b (hazard ratio [HR], 3.5; P = 0.004), cT2a (HR, 15.1; P0.001), cT2b (HR, 16.4; P0.001), and cT3 (HR, 45.0; P0.001) compared with category cT1a. Use of plaque brachytherapy and IAC improved local tumor control in categories cT1a (P = 0.031) and cT1b (P0.001).Multicenter, international, internet-based data sharing validated the 8th edition AJCC RB staging to predict globe-salvage in a large, heterogeneous, real-world patient population with RB.

To evaluate the ability of the 8th edition of the American Joint Committee on Cancer (AJCC) Cancer Staging Manual to estimate metastatic and mortality rates for children with retinoblastoma (RB).International, multicenter, registry-based retrospective case series.A total of 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents.Patient-specific data fields for RB were designed and selected by subcommittee. All patients with RB with adequate records to allow tumor staging by the AJCC criteria and follow-up for metastatic disease were studied.Metastasis-related 5- and 10-year survival data after initial tumor staging were estimated with the Kaplan-Meier method depending on AJCC clinical (cTNM) and pathological (pTNM) tumor, node, metastasis category and age, tumor laterality, and presence of heritable trait.Of 2190 patients, the records of 2085 patients (95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. A total of 1260 patients (65.4%) had unilateral RB. Among the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b in 168 (8.1%), cT2a in 197 (9.4%), cT2b in 812 (38.9%), cT3 in 835 (40.0%), and cT4 in 18 (0.9%). Of these, 1397 eyes in 1353 patients (48.1%) were treated with enucleation. A total of 109 patients (5.2%) developed metastases and died. The median time (n = 92) from diagnosis to metastasis was 9.50 months. The 5-year Kaplan-Meier cumulative survival estimates by clinical tumor categories were 100% for category cT1a, 98% (95% confidence interval [CI], 97-99) for cT1b and cT2a, 96% (95% CI, 95-97) for cT2b, 89% (95% CI, 88-90) for cT3 tumors, and 45% (95% CI, 31-59) for cT4 tumors. Risk of metastasis increased with increasing cT (and pT) category (P0.001). Cox proportional hazards regression analysis confirmed a higher risk of metastasis in category cT3 (hazard rate [HR], 8.09; 95% CI, 2.55-25.70; P0.001) and cT4 (HR, 48.55; 95% CI, 12.86-183.27; P0.001) compared with category cT1. Age, tumor laterality, and presence of heritable traits did not influence the incidence of metastatic disease.Multicenter, international, internet-based data sharing facilitated analysis of the 8th edition AJCC RB Staging System for metastasis-related mortality and offered a proof of concept yielding quantitative, predictive estimates per category in a large, real-life, heterogeneous patient population with RB.

BACKGROUND: . Intravitreal administration of topotecan shows activity against tumor vitreous seeding in the conservative treatment of retinoblastoma, a malignant tumor originated in the retina of small children. Adequate storage of the intravitreal topotecan solution would allow immediate availability for patients at health care institutions. The goal of the work was to address the stability of the intravitreal topotecan formulation upon reconstitution. MATERIALS AND METHODS: . Intravitreal topotecan solutions were reconstituted (at a concentration of 0.2 mg topotecan in 1 mL saline solution vehicle, aliquoted in 1 mL plastic syringes) and stored either frozen or at room temperature for different times. Topotecan content was analyzed at time zero and at different conditions using a high performance liquid chromatography method to quantify topotecan lactone (active) and to detect its pH-dependent hydrolysis product, the open carboxylate. RESULTS: . We found that intravitreal topotecan syringes remained stable at room temperature at least for 24 h, at least for 167 days upon stored frozen at -20°C, and up to 8 h after thawing at day 6. The degradation carboxylate product did not appear in the analyzed thawed samples during the whole study. CONCLUSIONS: . This study confirms the stability of frozen intravitreal topotecan syringes and will help optimize the use of this chemotherapy modality at institutions with low resources. Storage of aliquots will also help reduce personnel exposure to chemotherapy at hospital pharmacies.

Importance: Comprehensive understanding of the genomic and gene-expression differences between retinoblastoma tumors from patients with bilateral disease may help to characterize risk and optimize treatment according to individual tumor characteristics. Objective: To compare the genomic features between each eye and a specimen from an orbital relapse in patients with bilateral retinoblastoma. Design, Setting, and Participants: In this case, 2 patients with retinoblastoma underwent upfront bilateral enucleation. Tumor samples were subjected to genomic and gene-expression analysis. Primary cell cultures were established from both of the tumors of 1 patient and were used for gene-expression studies. Main Outcomes and Measures: Whole-exome sequencing was performed on an Illumina platform for fresh tumor samples and DNA arrays (CytoScan or OncoScan) were used for paraffin-embedded samples and cell lines. Gene-expression analysis was performed using Agilent microarrays. Germinal and somatic alterations, copy number alterations, and differential gene expression were assessed. Results: After initial bilateral enucleation, patient 1 showed massive choroidal and laminar optic nerve infiltration, while patient 2 showed choroidal and laminar optic nerve invasion. Patient 1 developed left-eye orbital recurrence and bone marrow metastasis less than 1 year after enucleation. Both ocular tumors showed gains on 1q and 6p but presented other distinct genomic alterations, including an additional gain in 2p harboring the N-myc proto-oncogene (MYCN) in the left tumor and orbital recurrence. Similar copy number alterations between the orbital recurrence and the left eye supported the origin of the relapse, with an additional 11q loss only detected in the orbital relapse. Specimens from patient 2 showed common copy number gains and losses, but further evolution rendered a 2p gain spanningMYCNin the left tumor. For this patient, microarray expression analysis showed differential expression of theMYCNand the forkhead box protein G1 (FOXG1) gene pathways between the left and right tumors. Conclusions and Relevance: Differential genomic and gene expression features were observed between tumors in 2 patients with bilateral disease, confirming intereye heterogeneity that might be considered if targeted therapies are used in such patients. Chromosomal alteration profile supported the origin of the orbital recurrence from the homolateral eye in 1 patient. Loss in chromosome 11q may have been associated with extraocular relapse in this patient., Centro de Investigaciones Inmunológicas Básicas y Aplicadas

Retinoblastoma is lethal by metastasis if left untreated, so the primary goal of therapy is to preserve life, with ocular survival, visual preservation and quality of life as secondary aims. Historically, enucleation was the first successful therapeutic approach to decrease mortality, followed over 100 years ago by the first eye salvage attempts with radiotherapy. This led to the empiric delineation of a window for conservative management subject to a "state of metastatic grace" never to be violated., Over the last two decades, conservative management of retinoblastoma witnessed an impressive acceleration of improvements, culminating in two major paradigm shifts in therapeutic strategy. Firstly, the introduction of systemic chemotherapy and focal treatments in the late 1990s enabled radiotherapy to be progressively abandoned. Around 10 years later, the advent of chemotherapy in situ, with the capitalization of new routes of targeted drug delivery, namely intra-arterial, intravitreal and now intracameral injections, allowed significant increase in eye preservation rate, definitive eradication of radiotherapy and reduction of systemic chemotherapy., Here we intend to review the relevant knowledge susceptible to improve the conservative management of retinoblastoma in compliance with the "state of metastatic grace", with particular attention to (i) reviewing how new imaging modalities impact the frontiers of conservative management, (ii) dissecting retinoblastoma genesis, growth patterns, and intraocular routes of tumor propagation, (iii) assessing major therapeutic changes and trends, (iv) proposing a classification of relapsing retinoblastoma, (v) examining treatable/preventable disease-related or treatment-induced complications, and (vi) appraising new therapeutic targets and concepts, as well as liquid biopsy potentiality.

Carriers of germline DICER1 mutations are predisposed to a rare cancer syndrome, the DICER1 syndrome, associated with tumours such as pleuropulmonary blastoma (PPB), ovarian Sertoli-Leydig cell tumours (SLCT), multinodular goiter (MNG), cystic nephroma (CN), embryonal rhabdomyosarcoma (ERMS) and others. Germline mutations in DICER1 cause an alteration in miRNAs processing, deregulating target oncogenes and leading to elevated risk of tumorigenesis. In most reported cases, there is a heterozygous germline mutation and a somatic second hit mutation. Aim: Analyze the presence of germline and somatic alterations in the DICER1 gene in 6 patients with paediatric tumours associated with DICER1 spectrum. Methods: Automated sequencing of DICER1 gene from gDNA extracted from blood and formalin-fixed, paraffin-embedded tumour tissues of affected subjects and relatives. Cases: 5 girls (P1-P5) and 1 boy (P6), (P1: bilateral SLCT, P2 and P3: SLCT and MNG, P4: MNG and uterine myosarcoma, P5: vaginal rhabdomyosarcoma, and P6: CN). Chronological age at diagnostic was 5, 12, 15, 16, 13 y 2, respectively. Results: We detected 5 novel heterozygous mutations: p.Trp1098* in P1, p.Phe351fs*1 in P2, p.Arg1596Glyfs*24 in P4, c.3269+1G>A in P5, p.Asp244Glyfs*27 in P6, and one previously described heterozygous deletion p.Asp1437Metfs*16 in P3.These mutations (P1-P4 and P6) predict the presence of a truncated protein losing its essential domains for the enzymatic activity and, in one P5 an alteration in the splicing process. The tissue analysis revealed p.Asp1709Glu in MNG and p.Glu1705Lys in SLCT in P2, and p.Glu1705Lys in MNG in P3,previously described as hotspot somatic mutations. Conclusions: We report five novel germinal mutations in DICER1 gene and two somatic hotspot mutations in MNG and SLCT tissue samples. These findings confirm that a second hit event is involved in the mechanism of MNG and SLCT development. Molecular analysis of DICER1 gene allows to perform genetic counselling about familial recurrence risk.

To review preclinical and clinical pharmacokinetic studies of the three most important chemotherapy drugs used for intraocular retinoblastoma and the contribution of the reported results to optimize treatment.Systemic review of pharmacokinetic studies identified by a literature search at Pubmed using the keywords carboplatin, melphalan, topotecan, intravitreal, ophthalmic artery chemosurgery, pharmacokinetics, and retinoblastoma.A total of 21 studies were reviewed for assessing the preclinical and clinical pharmacokinetics of carboplatin, topotecan, and melphalan delivered by intravenous, periocular, ophthalmic artery, and intravitreal routes. Some preclinical studies were done before translation to the clinics. Others, despite encouraging preclinical data as reported for periocular topotecan did not correlate with clinical use. In addition, as was the case for melphalan after ophthalmic artery chemosurgery and despite nonfavorable preclinical information, some routes of drug delivery are clinically effective. Besides topotecan, complete knowledge of the pharmacokinetics of melphalan and carboplatin is still lacking.Pharmacokinetic knowledge of chemotherapy may aid to guide retinoblastoma treatment in favor of safety and efficacy. Nonetheless, results obtained in preclinical models should be translated with care to the clinics.

The authors regret that Science Direct is not formatted to display the full content of the paper synopsis. This is now fixed with the publication of this corrigendum. List of contents 1. Introduction2. Epidemiology 2.1. Incidence2.2. Prevalence2.3. Predisposing factors for sporadic retinoblastoma3. Diagnosis 3.1. Presenting features3.2. Clinical examination and ancillary testing 3.2.1. Fundus documentation and fluorescein angiography3.2.2. Ultrasonic biomicroscopy (UBM)3.2.3. Optic coherence tomography (OCT)3.2.4. Magnetic Resonance Imaging (MRI)3.3. Classifications 3.3.1. Grouping of the eye at presentation (RE, IIRC, ICRB, COG, TNMH)3.3.2. Patient staging at presentation (IRSS, TNMH)3.3.3. Classification of retinoblastoma at relapse (RSU classification)3.4. Differential diagnosis3.5. Prenatal diagnosis of retinoblastoma3.6. Trilateral retinoblastoma 3.6.1. Incidence, early detection and screening3.6.2. Influence of the retinoblastoma treatment on the incidence of trilateral retinoblastoma3.6.3. Improved treatment of trilateral retinoblastoma: high-dose chemotherapy3.6.4. Differential diagnosis: pineal cysts3.7. Metastatic retinoblastoma 3.7.1. Diagnosis of metastatic retinoblastoma3.7.2. Treatment of metastatic retinoblastoma3.7.3. Influence of conservative retinoblastoma treatment in the occurrence of metastasis3.8. Second primary neoplasms 3.8.1. Incidence and mortality of second primary neoplasms3.8.2. Characteristics of secondary primary neoplasms3.8.3. Factors influencing the risk of secondary primary neoplasms 3.8.3.1. Genetic predisposition3.8.3.2. Influence of therapy3.8.3.2.1. Radiotherapy3.8.3.2.2. Chemotherapy3.8.4. Long-term follow-up in heritable retinoblastoma survivors 4. Retinoblastoma genesis 4.1. Mutational inactivation of the RB1 gene initiates retinoblastoma tumorigenesis4.2. Most retinoblastomas show more than two-hits4.3. RB1 mutations initiate tumorigenesis in the retinoblastoma cell-of-origin 4.3.1. First hints pointing towards a photoreceptor cell-of-origin4.3.2. Efforts to identify the retinoblastoma origin using genetically engineered mice4.3.3. Circumstantial and direct evidence for a cone precursor cell-of-origin4.3.4. Reconciling the cone precursor cell-of-origin with apparently contradictory observations4.4. Collaboration between RB1 inactivation and the cell-of-origin circuitry5. Retinoblastoma genetics and genetic counseling 5.1. Genetic presentations of retinoblastoma 5.1.1. Inherited heritable retinoblastoma (familial retinoblastoma) 5.1.1.1. Familial retinoblastoma with complete retinoblastoma5.1.1.2. Familial retinoblastoma with incomplete penetrance5.1.2. Isolated heritable retinoblastoma 5.1.2.1. Isolated bilateral retinoblastoma (full expressivity)5.1.2.2. Isolated retinoblastoma with genomic 13q14 deletion (reduced expressivity)5.1.3. Mosaic retinoblastoma5.1.4. Non-heritable retinoblastoma 5.1.4.1. Isolated unilateral retinoblastoma with somatic biallelic RB1 mutation5.1.4.2. Retinoblastoma without alterations of the RB1 gene 5.2. Genetic counseling and testing 5.2.1. Familial retinoblastoma5.2.2. Isolated bilateral retinoblastoma5.2.3. Isolated unilateral retinoblastoma 6. Clinical growth and seeding patterns 6.1. Retinoblastoma growth patterns 6.1.1. Classic growth patterns of primary retinoblastoma: endophytic, exophytic, mixed growth6.1.2. Rare variants of retinoblastoma 6.1.2.1. Cavitary retinoblastoma6.1.2.2. Diffuse infiltrating retinoblastoma6.1.2.3. Diffuse anterior retinoblastoma 6.2. Intra-ocular seeding 6.2.1. Vitreous seeding6.2.2. Retrohyaloid seeding6.2.3. Subretinal seeding6.2.4. Aqueous seeding 6.2.4.1. Prevalence of anterior chamber seeding6.2.4.2. Prevalence of anterior uvea invasion6.2.4.3. Invasion mechanisms of the aqueous humor 6.3. Retinoma/retinocytoma and phthisis bulbi 6.3.1. Prevalence and relationship with retinoblastoma6.3.2. Clinical features and risk of malignant transformation. 7. Conservative management of intraocular retinoblastoma 7.1. Pharmacokinetics 7.1.1. Intravenous drug delivery7.1.2. Intra-arterial drug delivery 7.1.2.1. Intraocular distribution of intra-arterial melphalan and topotecan7.1.2.2. Systemic adverse effects of intra-arterial delivered drugs7.1.3. Intravitreal drug delivery 7.1.3.1. Intraocular distribution of intravitreal melphalan7.1.3.2. Intraocular distribution of intravitreal topotecan7.1.4. Intracameral drug delivery7.1.5. Periocular drug delivery7.1.6. Suprachoroidal drug delivery7.2. Treatment modalities 7.2.1. Intravenous chemotherapy 7.2.1.1. Drug regimen and number of cycles7.2.1.2. Indications 7.2.1.2.1. Current indications7.2.1.2.2. Potential future indications 7.2.2. Treatment outcomes of intravenous chemotherapy 7.2.2.1. Relapse rate and role of consolidation by focal treatments7.2.2.2. Eye preservation without external beam radiotherapy7.2.3. Chemotherapy-related toxicity of intravenous chemotherapy 7.2.3.1. Expected toxicities7.2.3.2. Long-term toxicities7.2.4. Intra-arterial chemotherapy 7.2.4.1. Drug regimen and number of cycles7.2.4.2. Indications 7.2.4.2.1. Current indications7.2.4.2.2. Potential future indications7.2.4.3. Treatment outcomes 7.2.4.3.1. Recurrence rate and salvage therapy7.2.4.3.2. Eye preservation without external beam radiotherapy7.2.4.4. Adverse effects7.2.5. Intravitreal chemotherapy 7.2.5.1. Drug regimen and number of injections7.2.5.2. Safety7.2.5.3. Treatment outcomes7.2.5.4. Adverse effects7.2.6. Intracameral chemotherapy 7.2.6.1. Treatment outcomes7.2.6.2. Treatment-related adverse effects7.2.6.3. Potential alternatives to intracameral chemotherapy for aqueous seeding7.2.7. Periocular chemotherapy7.2.8. Focal treatments 7.2.8.1. Cryotherapy7.2.8.2. Hyperthermia7.2.8.3. Photocoagulation7.2.8.4. Brachytherapy 7.3. Disease and treatment-related complications 7.3.1. Amblyopia7.3.2. Cataract 7.3.2.1. Incidence7.3.2.2. Cataract surgery7.3.3. Rhegmatogenous retinal detachment 7.3.3.1. Incidence7.3.3.2. Surgical repair7.3.4. Secondary neovascularization7.3.5. Chorioretinal complications 7.3.5.1. Intravitreal melphalan-induced chorioretinopathy 7.3.5.1.1. Clinical presentation, classification system and incidence7.3.5.1.2. Risk factors associated with intravitreal melphalan-induced chorioretinopathy 7.3.5.1.2.1. Intravitreal concentration7.3.5.1.2.2. Para-vitreal injections7.3.5.1.2.3. Intraocular pigmentation7.3.5.1.2.4. Concomitant drug interactions 7.3.5.2. Choroidal occlusive vasculopathy 7.3.5.2.1. Clinical presentation, classification system and incidence.7.3.5.2.2. Factors associated with choroidal occlusive vasculopathy 7.4. Evaluation of quality of life8. Future directions and conclusion 8.1. Animal models8.2. Gene therapy8.3. Cell-of-origin targeted therapy8.4. Personalized therapy and liquid biopsy8.5. New drugs or combinations of drugs8.6. New Galenic formulation of known drugs8.7. Conclusion

Fil: Zugbi, Santiago. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Winter, Ursula Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Castañon, Agustina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina

Patients with retinoblastoma and central nervous system (CNS) involvement are rarely curable with available treatments. We designed a high-dose intra-arterial regimen targeting the ophthalmic artery and chiasm combined with intrathecal chemotherapy to treat a 4-year-old patient with retinoblastoma metastasized to the CNS. After three cycles of this regimen, including carboplatin, melphalan, and intrathecal topotecan, a partial response of the orbital tumor mass and chiasmatic lesion, and complete response in the cerebrospinal fluid and bone marrow were achieved. This new treatment strategy may be explored as a treatment component for patients with overt extraocular retinoblastoma and CNS dissemination. Fil: Rodriguez, Anabel. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Zugbi, Santiago. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Unidad de Farmacocinética Clínica. Laboratorio Farmacia; Argentina Fil: Requejo, Flavio. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Deu, Alejandra. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Unidad de Farmacocinética Clínica. Laboratorio Farmacia; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Sgroi, Mariana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Bosaleh, Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Fandiño, Adriana Cristina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina Fil: Schaiquevich, Paula Susana. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan". Unidad de Farmacocinética Clínica. Laboratorio Farmacia; Argentina Fil: Chantada, Guillermo Luis. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina

In this retrospective study of patients with overt orbital retinoblastoma, we evaluated minimally disseminated disease (MDD) in bone marrow and cerebrospinal fluid (CSF) using CRX and/or GD2 synthase as markers. Ten patients were evaluated-five (50%) at diagnosis and five upon relapse. MDD was detected in four cases (one in the bone marrow, two in the CSF, and in one case in both sites). All patients received chemotherapy and four received orbital radiotherapy. Seven patients relapsed or progressed and all of them died. Three patients remain in complete remission. There was no apparent correlation between MDD and the outcome.