A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma Part I : Metastasis-Associated Mortality

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 KaplaneMeier 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 KaplaneMeier 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 <0.001). 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; P <0.001) and cT4 (HR, 48.55; 95% CI, 12.86-183.27; P <0.001) compared with category cT1. Age, tumor laterality, and presence of heritable traits did not influence the incidence of metastatic disease. 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. (C) 2020 by the American Academy of Ophthalmology. This is an open access article under the CC BY-NC-ND licensePeer reviewe

Prevalence of, and risk factors for, dental sequelae in adolescents who underwent cancer therapy during childhood

Introduction: The increase in survival rates in children treated for cancer has been accompanied by a rise in sequelae in permanent teeth. The aim of the study was to correlate the type of cancer therapy administered to patients during early childhood and the dental sequelae recorded in survivors. Material and methods: Single-center retrospective cohort study carried out at the Children's University Hospital of Sant Joan de Déu in Barcelona, Spain. Hundred and nine patients who had received cancer treatment during early childhood were randomly examined and grouped according to diagnosis and cancer therapy received. The type of therapy was correlated with the number and severity of dental lesions that patients presented in adolescence. Results: Dental sequelae of some kind were present in 85.3% of patients. Microdontia was the most prevalent (52.3%). Treatment with alkylating agents had a relative risk of presenting moderate lesions of 3.36 (1.18-9.60), and one of 2.29 (1.07-4.91) of presenting severe lesions. Topoisomerase inhibitors and cytotoxic antibiotics presented relative risks of 1.6 (1.07-2.38) and 2.08 (1.02-4.26) of root alterations and agenesis, respectively. Conclusions: Treatment with alkylating agents together with cytotoxic antibiotics and topoisomerase inhibitors was associated with a higher relative risk of microdontia, agenesis, and root shortening

Recurrent somatic chromosomal abnormalities in relapsed extraocular retinoblastoma

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; ArgentinaFil: Francis, Jasmine H.. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: 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; ArgentinaFil: Gomez Gonzalez, Soledad. Hospital Sant Joan de Deu Barcelona; EspañaFil: Sampor, Claudia. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Zugbi, Santiago. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Ottaviani, Daniela. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Lemelle, Lauriane. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Mena, Marcela Daniela C. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Winter, Ursula Andrea. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Correa Llano, Genoveva. Hospital Sant Joan de Deu Barcelona; EspañaFil: Lamas, Gabriela. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Lubieniecki, Fabiana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Szijan, Irene. Universidad de Buenos Aires. Facultad de Farmacia y Bioquímica. Departamento de Microbiología, Inmunología y Biotecnología. Cátedra de Genética y Biología Molecular; ArgentinaFil: Mora, Jaume. Hospital Sant Joan de Deu Barcelona; EspañaFil: 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; ArgentinaFil: Doz, François. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Radvanyi, François. Universite de Paris; Francia. Institute Curie; Francia. Centre National de la Recherche Scientifique; FranciaFil: Abramson, David H.. Memorial Sloan-Kettering Cancer Center; Estados UnidosFil: 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; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Lavarino, Cinzia. Hospital Sant Joan de Deu Barcelona; EspañaFil: 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; Argentin

A Multicenter, International Collaborative Study for American Joint Committee on Cancer Staging of Retinoblastoma. Part II: Treatment Success and Globe Salvage

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: 2190 patients from 18 ophthalmic oncology centers from 13 countries over 6 continents.Methods: Patient-specific data fields for RB were designed by participating eye cancer specialists. All RB patients 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 the 2190 patients, the records of 2085 patients(95.2%) with 2905 eyes were complete. The median age at diagnosis was 17.0 months. 1260 (65.4%) had unilateral RB. Amongst the 2085 patients, tumor categories were cT1a in 55 (2.6%), cT1b 168 (8.1%), cT2a 197 (9.4%), cT2b 812 (38.9%), cT3 835 (40.0%) and cT4 in 18 (0.9%) patients. Of these, 1397 eyes in 1353 patients(48.1%) were treated with enucleation. One hundred and nine 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, respectively. Risk of metastasis increased with increasing cT (and pT) category(p < .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; p<0.001) and cT4 (HR, 48.55; 95% CI, 12.86-183.27; p< 0.001) compared to category cT1. Age, tumor laterality and presence of heritable trait did not influence the incidence of metastatic disease.Conclusion: 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, heterogenous RB patient population.Fil: Singh Tomar, Ankit. The New York Eye Cancer Center; Estados UnidosFil: Finger, Paul T.. The New York Eye Cancer Center; Estados UnidosFil: Gallie, Brenda. Princess Margaret Cancer Centre; CanadáFil: Mallipatna, Ashwin. University Of Toronto. Hospital For Sick Children; CanadáFil: Kivelä, Tero T.. University of Helsinki; FinlandiaFil: Zhang, Chengyue. Beijing Children's Hospital; ChinaFil: Zhao, Junyang. Beijing Children's Hospital; ChinaFil: Wilson, Matthew W.. University of Tennessee; Estados UnidosFil: Brenna, Rachel C.. University of Tennessee; Estados UnidosFil: Burges, Michala. University of Tennessee; Estados UnidosFil: Kim, Jonathan. The Vision Center at Children's Hospital Los Angeles; Estados UnidosFil: Khetan, Vikas. Sankara Nethralaya; IndiaFil: Ganesan, Suganeswari. Sankara Nethralaya; IndiaFil: Yarovoy, Andrey. The S.N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yarovaya, Vera. The S.N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Kotova, Elena. The S.N. Fyodorov Eye Microsurgery Federal State Institution; RusiaFil: Yousef, Yacoub A.. King Hussein Cancer Center; JordaniaFil: Nummi, Kalle. University of Helsinki; FinlandiaFil: Ushakova, Tatiana L.. N.N. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Yugay, Olga V.. N.N. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Polyakov, Vladimir G.. N.N. Blokhin National Medical Research Center Oncology of Russian Federation; RusiaFil: Ramirez Ortiz, Marco A.. Hospital Infantil de México Federico Gómez; MéxicoFil: Esparza Aguiar, Elizabeth. Hospital Infantil de México Federico Gómez; MéxicoFil: Chantada, Guillermo Luis. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Schaiquevich, Paula Susana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; Argentina. Consejo Nacional de Investigaciones Científicas y Técnicas; ArgentinaFil: Fandino, Adriana. Gobierno de la Ciudad de Buenos Aires. Hospital de Pediatría "Juan P. Garrahan"; ArgentinaFil: Yam, Jason C.. The Chinese University of Hong Kong; Hong KongFil: Lau, Winnie W.. The Chinese University of Hong Kong; Hong KongFil: Lam, Carol P.. The Chinese University of Hong Kong; Hong KongFil: Sharwood, Phillipa. University of Sydney; AustraliaFil: Moorthy, Sonia. KK Women’s and Children’s Hospital; SingapurFil: Long, Quah Boon. KK Women’s and Children’s Hospital; SingapurFil: Essuman, Vera Adobea. University of Ghana; GhanaFil: Renner, Lorna A.. University of Ghana; GhanaFil: Semenova, Ekaterina. The New York Eye Cancer Center; Estados UnidosFil: Català, Jaume. Hospital Sant Joan de Déu; EspañaFil: Correa Llano, Genoveva. Hospital Sant Joan de Déu; EspañaFil: Carreras, Elisa. Hospital Sant Joan de Déu; Españ

A high-risk retinoblastoma subtype with stemness features, dedifferentiated cone states and neuronal/ganglion cell gene expression

International audienceAbstract Retinoblastoma is the most frequent intraocular malignancy in children, originating from a maturing cone precursor in the developing retina. Little is known on the molecular basis underlying the biological and clinical behavior of this cancer. Here, using multi-omics data, we demonstrate the existence of two retinoblastoma subtypes. Subtype 1, of earlier onset, includes most of the heritable forms. It harbors few genetic alterations other than the initiating RB1 inactivation and corresponds to differentiated tumors expressing mature cone markers. By contrast, subtype 2 tumors harbor frequent recurrent genetic alterations including MYCN -amplification. They express markers of less differentiated cone together with neuronal/ganglion cell markers with marked inter- and intra-tumor heterogeneity. The cone dedifferentiation in subtype 2 is associated with stemness features including low immune and interferon response, E2F and MYC/MYCN activation and a higher propensity for metastasis. The recognition of these two subtypes, one maintaining a cone-differentiated state, and the other, more aggressive, associated with cone dedifferentiation and expression of neuronal markers, opens up important biological and clinical perspectives for retinoblastomas