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1. Retinoblastoma with and without Extraocular Tumor Extension

Author

Swathi Kaliki, MD, Vijitha S. Vempuluru, MD, Ido Didi Fabian, MD, Elhassan Abdallah, MD, Shehu U. Abdullahi, MD, Rula A. Abdulqader, MD, Aminatu A. Abdulrahaman, MD, Sherif Abouelnaga, MD, Dupe S. Ademola-Popoola, FMCOph, FWACS, Adedayo Adio, FWACS, Mahmoud A. Afifi, MD, Armin R. Afshar, MD, Priyanka Aggarwal, MD, Ada E. Aghaji, FMCOph MSc, Alia Ahmad, MRCPCH UK, Marliyanti N.R. Akib, MD, Adeseye M. Akinsete, MBBS, Lamis Al Harby, MD, Saleh A. Al Mesfer, MD, Mouroge H. Al Ani, MD, Silvia Alarcón Portabella, MD, Safaa A.F. Al-Badri, MD, Ana Patricia A. Alcasabas, MD, Saad A. Al-Dahmash, MD, Amanda Alejos, MD, Ernesto Alemany-Rubio, MD, Amadou I. Alfa Bio, MD, Yvania Alfonso Carreras, MD, Christiane E. Al-Haddad, MD, Hamoud H.Y. Al-Hussaini, MD, MSc, Amany M. Ali, MD, Donjeta B. Alia, MD, Mazin F. Al-Jadiry, MD, Usama Al-Jumaly, MD, Hind M. Alkatan, MD, Charlotta All-Eriksson, MD, PhD, Ali A.R.M. Al-Mafrachi, FIBMS, Argentino A. Almeida, MD, Khalifa M. Alsawidi, MD, Athar A.S.M. Al-Shaheen, MD, Entissar H. Al-Shammary, MD, Doreen Amankwaa-Frempong, MBChB, Primawita O. Amiruddin, MD, Inggar Armytasari, MD, Nicholas J. Astbury, FRCS, FRCOphth, Hatice T. Atalay, MD, Eda Ataseven, MD, La-ongsri Atchaneeyasakul, MD, Rose Atsiaya, OCO, Rudolf Autrata, MD, PhD, Julia Balaguer, MD, PhD, Ruhengiz Balayeva, PhD, Honorio Barranco, MD, PhD, Paulina Bartoszek, MD, Katarina Bartuma, MD, PhD, Covadonga Bascaran, MD, MSc, Nikolaos E. Bechrakis, MD, Maja Beck Popovic, MD, Ainura S. Begimkulova, MD, Sarra Benmiloud, MD, Rokia C. Berete, MD, PhD, Jesse L. Berry, MD, Anirban Bhaduri, MD, Sunil Bhat, MBBS, MD, Arpita Bhattacharyya, MD, Eva M. Biewald, MD, Elaine Binkley, MD, Sharon Blum, MD, Nadia Bobrova, MD, H. Culver Boldt, MD, Maria Teresa B.C. Bonanomi, MD, PhD, Gabrielle C. Bouda, MD, Hédi Bouguila, MD, PhD, Rachel C. Brennan, MD, Bénédicte G. Brichard, MD, PhD, Jassada Buaboonnam, MD, Aléine Budiongo, MD, Matthew Burton, FRCOphth, Patricia Calderón-Sotelo, MD, Doris A. Calle Jara, MD, Jayne E. Camuglia, FRANZCO, Miriam R. Cano, MD, MSc, Michael Capra, FRCPI, Shani Caspi, MD, Nathalie Cassoux, MD, PhD, Guilherme Castela, MD, Luis Castillo, MD, Jaume Català-Mora, MD, PhD, Isabel Caviedes, MD, Arthika Chandramohan, MD, Guillermo L. Chantada, MD, PhD, Shabana Chaudhry, MD, Bhavna Chawla, MD, Wensi Chen, MD, Faraja S. Chiwanga, MSc, Tsengelmaa Chuluunbat, MD, PhD, Krzysztof Cieslik, MD, Antony Clark, FRANZCO, Ruellyn L. Cockcroft, MB ChB , M Med Paed, Codruta Comsa, MD, Maria G. Correa Llano, MD, Timothy W. Corson, PhD, Line Couitchere, MD, Kristin E. Cowan-Lyn, MD, MBBS, Monika Csóka, MD, PhD, Wantanee Dangboon, MD, Anirban Das, MD, Pranab Das, MD, Sima Das, MS, Jacquelyn M. Davanzo, BSN, BSPH, Alan Davidson, MBChB, MPhil, Sonia De Francesco, MD, Patrick De Potter, MD, PhD, Karina Q. Delgado, MD, PhD, Hakan Demirci, MD, Laurence Desjardins, MD, Rosdali Y. Diaz Coronado, MD, Helen Dimaras, PhD, Andrew J. Dodgshun, M Phil, Carla R. Donato Macedo, MD, Monica D. Dragomir, MD, PhD, Yi Du, MD, Magritha Du Bruyn, MD, Johannes P. Du Plessis, MMed (Paed), Gagan Dudeja, MBBS, MS, Katrin Eerme, MD, I Wayan Eka Sutyawan, MD, Asmaa El Kettani, MD, Amal M. Elbahi, MD, James E. Elder, MBBS, Alaa M. Elhaddad, MD, PhD, Moawia M.A. Elhassan, MD, Mahmoud M. Elzembely, MD, Connor Ericksen, MD, Vera A. Essuman, FWACS, Ted Grimbert A. Evina, MD, Ifeoma R. Ezegwui, FMCOph, FWACS, FAEH, Zehra Fadoo, MBBS, Adriana C. Fandiño, MD, Mohammad Faranoush, MD, Oluyemi Fasina, FWACS, Delia D.P.G. Fernández, MSc, Ana Fernández-Teijeiro, MD, PhD, Allen Foster, FRCOphth, Shahar Frenkel, MD, PhD, Ligia D. Fu, MD, Soad L. Fuentes-Alabi, MD, MPH, Juan L. Garcia, MSc, David García Aldana, MD, Henry N. Garcia Pacheco, MD, Jennifer A. Geel, MBChB, MMed, Fariba Ghassemi, MD, Ana V. Girón, MD, Marco A. Goenz, MD, Aaron S. Gold, OD, Hila Golberg, MD, Glen A. Gole, MD, FRANZCO, Nir Gomel, MD, Efren Gonzalez, MD, Graciela Gonzalez Perez, MD, Liudmira González-Rodríguez, MD, Malka Gorfine, PhD, Jaime Graells, MD, Pernille A. Gregersen, MD, Nathalia D.A.K. Grigorovski, MD, Koffi M. Guedenon, MD, D Sanjeeva Gunasekera, MD, Ahmet K. Gündüz, MD, Himika Gupta, MD, Sanjiv Gupta, MS, Vineeta Gupta, MD, Theodora Hadjistilianou, MD, Patrick Hamel, MD, Syed A. Hamid, FCPS, Norhafizah Hamzah, MSc, Eric D. Hansen, MD, J William Harbour, MD, M. Elizabeth Hartnett, MD, Murat Hasanreisoglu, MD, Sadiq Hassan, MD, FWACS, Shadab Hassan, FRCS, FCPS, Wojciech Hautz, MD, Huda A. Haydar, CHD, Stanislava Hederova, MD, Laila Hessissen, MD, Hoby Lalaina, MD, Suradej Hongeng, MD, Diriba F. Hordofa, MD, G. Baker Hubbard, MD, Marlies Hummlen, MD, Kristina Husakova, MD, Allawi N. Hussein Al-Janabi, MD, Affiong A. Ibanga, MB.BCh, FMCOph, Russo Ida, MD, Vesna R. Ilic, MD, Ziyavuddin Islamov, MD, Vivekaraj Jairaj, DNB, Teyyeb A. Janjua, MD, FCPS, FRCSEd, Irfan Jeeva, FRCOphth, Xunda Ji, MD, Dong Hyun Jo, MD, PhD, Michael M. Jones, MD, PhD, FRANZCO, Theophile B. Amani Kabesha, MD, PhD, Rolande L. Kabore, MD, Abubakar Kalinaki, MD, Pius Kamsang, MD, Mehmet Kantar, MD, Noa Kapelushnik, MD, Tamar Kardava, PhD, Rejin Kebudi, MD, Jonny Keomisy, MD, Tomas Kepak, MD, Petra Ketteler, MD, Zohora J. Khan, MD, Hussain A. Khaqan, MD, Vikas Khetan, FRCS, FACS, Alireza Khodabande, MD, Zaza Khotenashvili, MD, Jonathan W. Kim, MD, Jeong Hun Kim, MD, PhD, Hayyam Kiratli, MD, Tero T. Kivelä, MD, Artur Klett, MD, PhD, Irem Koç, MD, Jess Elio Kosh Komba Palet, MD, Dalia Krivaitiene, MD, PhD, Mariana Kruger, Mmed Paed, PhD, Kittisak Kulvichit, MD, Mayasari W. Kuntorini, MD, Alice Kyara, BA, Geoffrey C. Lam, FRANZCO, Scott A. Larson, MD, Slobodanka Latinović, MD, PhD, Kelly D. Laurenti, MD, Yotam Lavi, MD, PhD, Alenka Lavric Groznik, MD, Amy A. Leverant, MD, Cairui Li, MD, Kaijun Li, MD, Ben Limbu, MD, Chun-Hsiu Liu, MD, Quah Boon Long, FRCS (Ed), MMed ( Ophth), FAMS, Juan P. López, MD, Robert M. Lukamba, MD, Sandra Luna-Fineman, MD, Delfitri Lutfi, MD, Lesia Lysytsia, MD, Shiran Madgar, MD, George N. Magrath, MD, Amita Mahajan, MD, Puja Maitra, MD, Erika Maka, MD, Emil K. Makimbetov, MD, Azza M.Y. Maktabi, MD, Carlos Maldonado, MD, Ashwin Mallipatna, MD, Rebecca Manudhane, MD, Lyazat Manzhuova, MD, Nieves Martín Begue, MD, PhD, Sidra Masud, MBBS, Ibrahim O. Matende, MD, M. Med (Oph), Clarissa C.D.S. Mattosinho, MD, Marchelo Matua, BAPH, Ismail Mayet, MD, Freddy B. Mbumba, MD, MMed Paed, John D. McKenzie, MD, Azim Mehrvar, MD, Aemero A. Mengesha, MD, Vikas Menon, MD, Gary John V.D.D. Mercado, MD, Marilyn B. Mets, MD, Edoardo Midena, MD, PhD, Audra Miller, MD, Divyansh K.C. Mishra, DNB, Furahini G. Mndeme, MD, Ahmed A. Mohamedani, FRCPath, Mona T. Mohammad, MD, FRCS, Annette C. Moll, MD, PhD, Margarita M. Montero, MD, Claude Moreira, MD, PhD, Prithvi Mruthyunjaya, MD, MHS, Mchikirwa S. Msina, MMed Ophth, Gerald Msukwa, MMed Ophth, Sangeeta S. Mudaliar, DNB Pediatric, Hassan Muhammad, MD, Kangwa I. Muma, MMed Ophth, FCOphth, Francis L. Munier, MD, Timothy G. Murray, MD, MBA, Kareem O. Musa, FWACS, FMCOphth, FICO, Asma Mushtaq, MD, Anne A. Musika, MD, Hamzah Mustak, MD, Tajudeen Mustapha, MBBS, FWACS, Okwen M. Muyen, MD, Khumo H. Myezo, Msc, Gita Naidu, MMed Paed, PhD, Natasha Naidu, MBCHB, FCS Ophthalmol, Akshay Gopinathan Nair, MD, Sundaram Natarajan, FRCS, Larisa Naumenko, MD, PhD, Paule Aïda Ndoye Roth, MD PhD, Yetty M. Nency, MD, Vladimir Neroev, MD, PhD, Yvonne Ng, MBChB ( Auckland) , FRANZCO, Marina Nikitovic, MD, PhD, Elizabeth D. Nkanga, FMCOph, Henry E. Nkumbe, MD, Marcel N. Numbi, MD, Kalle Nummi, MD, Murtuza Nuruddin, FRCS, Mutale Nyaywa, MD, MMed Ophth, FCOphth, Chinsisi Nyirenda, MD, Ghislaine Obono-Obiang, MD, Scott C.N. Oliver, MD, Joaquin Ooporto, MD, Miriam Ortega-Hernández, MD, Alexander Oscar, MD, Diego Ossandon, MD, Halimah Pagarra, MD, PhD, Vivian Paintsil, FWACP, Luisa Paiva, MD, Mahesh Shanmugam Palanivelu, FRCSED, Ruzanna Papyan, MD, Raffaele Parrozzani, MD, PhD, Claudia R. Pascual Morales, MD, Katherine E. Paton, MD, FRCSC, Jacob Pe'er, MD, Jesús Peralta Calvo, MD, Sanja Perić, MD, PhD, Chau T.M. Pham, MD, Remezo Philbert, MD, David A. Plager, MD, Pavel Pochop, MD, PhD, Rodrigo A. Polania, MD, Vladimir Polyakov, MD, Jimena Ponce, MD, Ali O. Qadir, MD, Seema Qayyum, FCPS, Jiang Qian, MD, Ardizal Rahman, MD, Purnima Rajkarnikar, MD, Rajesh Ramanjulu, MD, Aparna Ramasubramanian, MD, Marco A. Ramirez-Ortiz, MD, MPH, Jasmeen K. Randhawa, BA, Léa Raobela, MD, Riffat Rashid, MS, M. Ashwin Reddy, FRCOphth, Lorna A. Renner, FRCPCH (UK), David Reynders, MD, Dahiru Ribadu, FMCOph, Petra Ritter-Sovinz, MD, Anna Rogowska, MD, Duangnate Rojanaporn, MD, Livia Romero, MD, Soma R. Roy, DCO, Raya H. Saab, MD, Svetlana Saakyan, MD, PhD, Ahmed H. Sabhan, MD, Mandeep S. Sagoo, FRCS (Ed), Azza M.A. Said, MD, Rohit Saiju, MD, Beatriz Salas, MD, Sonsoles San Román Pacheco, MD, Gissela L. Sánchez, MD, Alma Janeth Sanchez Orozco, MD, Phayvanh Sayalith, MD, Trish A. Scanlan, MRCPI, MSc, Christoph Schwab, MD, Ahad Sedaghat, MD, Rachna Seth, DNB MNAMS, Mariana Sgroi, MD, Ankoor S. Shah, MD, PhD, Shawkat A. Shakoor, MS, Manoj K. Sharma, MD, Sadik T. Sherief, MD, Carol L. Shields, MD, David Sia, MB ChB, FRANZCO, Sorath Noorani Siddiqui, MD, Sidi Sidi cheikh, MD, PhD, Sónia Silva, MD, Arun D. Singh, MD, Usha Singh, MS, Penny Singha, MD, Rita S. Sitorus, MD, PhD, Alison H. Skalet, MD, PhD, Hendrian D. Soebagjo, MD, PhD, Tetyana Sorochynska, MD, PhD, Grace Ssali, MD, Andrew W. Stacey, MD, Sandra E. Staffieri, PhD, Erin D. Stahl, MD, David M. Steinberg, PhD, David K. Stones, MBChB, FCPaed, Caron Strahlendorf, MD, Maria Estela Coleoni Suarez, MD, Sadia Sultana, FCPS, Xiantao Sun, MD, Rosanne Superstein, MD, Eddy Supriyadi, MD, PhD, Supawan Surukrattanaskul, MD, Shigenobu Suzuki, MD, PhD, Karel Svojgr, MD, PhD, Fatoumata Sylla, MD, Gevorg Tamamyan, MD, PhD, Deborah Tan, MBBS, Alketa Tandili, MD, PhD, Jing Tang, MD, Fanny F. Tarrillo Leiva, MD, Maryam Tashvighi, MD, Bekim Tateshi, MD, PhD, Kok Hoi Teh, MD, Edi S. Tehuteru, MD, Luiz F. Teixeira, MD, Manca Tekavcic Pompe, MD, PhD, Abdullah Dahan M. Thawaba, MD, Tuyisabe Theophile, MSc, Helen Toledano, MBChB, Doan L. Trang, MD, Fousseyni Traoré, MD, Devjyoti Tripathy, MD, Samuray Tuncer, MD, Harba Tyau-Tyau, MD, Ali B. Umar, MD, FMCPath, Emel Unal, MD, Ogul E. Uner, BA, Steen F. Urbak, MD, PhD, Tatiana L. Ushakova, MD, Rustam H. Usmanov, MD, Sandra Valeina, MD, Paola Valente, MD, Milo van Hoefen Wijsard, MD, Jacqueline Karina Vasquez Anchaya, MD, Leon O. Vaughan, FRCS (Ed), Nevyana V. Veleva-Krasteva, MD, PhD, Nishant Verma, MD, Andi A. Victor, MD, PhD, Maris Viksnins, MD, Edwin G. Villacís Chafla, MD, Victor M. Villegas, MD, Victoria Vishnevskia-Dai, MD, Keith Waddell, DM, FRCP, FRCS, FRCOphth, Amina H. Wali, MD, FMCOph Nigeria, Yi-Zhuo Wang, MD, Nutsuchar Wangtiraumnuay, MD, FICO, Julie A. Wetter, MMed Rad Onc, FCRad Onc, Widiarti P. Riono, MD, Matthew W. Wilson, MD, Amelia D.C. Wime, MD, Atchareeya Wiwatwongwana, MD, Damrong Wiwatwongwana, MD, Charlotte Wolley Dod, MD, Emily S. Wong, FCOphth HK, FHKAM, Phanthipha Wongwai, MD, PhD, Si-qi Wu, MSc, Daoman Xiang, MD, PhD, Yishuang Xiao, MSc, Bing Xu, MD, Kang Xue, MD, Antonio Yaghy, MD, Jason C. Yam, FRCSEd, Huasheng Yang, MD, Jenny M. Yanga, MD, Muhammad A. Yaqub, MD, FCPS, FRCSEd, Vera A. Yarovaya, MD, Andrey A. Yarovoy, MD, PhD, Huijing Ye, MD, Roberto I. Yee, MD, Yacoub A. Yousef, MD, Putu Yuliawati, MD, Arturo M. López, MD, Ekhtelbenina Zein, MD, Yi Zhang, MD, PhD, Katsiaryna Zhilyaeva, MD, Nida Zia, MBBS, MCPS, Othman A.O. Ziko, MD, PhD, Marcia Zondervan, MBA, Sabrina Schlüter, MD, and Richard Bowman, FRCOphth

Subjects
External beam radiotherapy, Extraocular extension, Multimodal treatment, Retinoblastoma, Tumor, Ophthalmology, RE1-994
Abstract

Purpose: To study the treatment and outcomes of children with retinoblastoma (RB) with extraocular tumor extension (RB-EOE) and compare them with RB without extraocular tumor extension (RB-w/o-EOE). Design: Multicenter intercontinental collaborative prospective study from 2017 to 2020. RB-EOE cases included those with overt orbital tumor extension in treatment-naive patients. Cases with microscopic orbital extension detected postenucleation were excluded from the study. Participants: A total of 319 children with RB-EOE and 3116 children with RB-w/o-EOE. Intervention: Chemotherapy, enucleation, exenteration, radiotherapy. Main Outcome Measures: Systemic metastasis and death. Results: Of the 3435 RB patients included in this study, 309 (9%) were from low-income countries (LIC), 1448 (42%) from lower-middle income, 1012 (29%) from upper-middle income, and 666 (19%) patients from high-income countries. There was an inverse relationship between the percentage of RB-EOE and national income level, with 96 (31%) patients from LIC, 197 (6%) lower-middle income, 20 (2%) upper-middle income, and 6 (1%) patients from high-income countries (P = 0.0001). The outcomes were statistically significant for RB-EOE compared with RB-w/o-EOE: systemic metastasis (32% vs. 4% respectively; P = 0.0001) and metastasis-related death (63% vs. 6% respectively; P = 0.0001). Multimodal treatment was the most common form of treatment (n = 177; 54%) for RB-EOE, with most cases undergoing a combination of intravenous chemotherapy and enucleation (n = 97; 30%). Adjuvant external beam radiotherapy (EBRT) after surgery (enucleation/orbital exenteration) was given in only 68 (21%) cases. Kaplan–Meier analysis for systemic metastasis and metastasis-related death in RB-EOE was 28% and 57% at 1 year, 29% and 60% at 2 years, and 29% and 61% at 3 years, respectively. Cox regression analysis revealed that the risk of death from RB-EOE was greater in patients aged >4 years than

Published
2025
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2. Cutaneous Adverse Events to Targeted Therapies and Immuno­therapies in Children: A Retrospective Study of 103 Patients from Two Tertiary Haemato-Oncology Referral Centres

Author

Ayelet Ollech, Michal Yalon, Gadi Abebe-Campino, Vered Molho-Pessach, Eve Finklestein, Hodaya Cohen, Aviv Barzilai, Shani Caspi, and Shoshana Greenberger

Subjects
drug cutaneous adverse events, targeted therapies, immunotherapies, paediatrics, oncology, Dermatology, RL1-803
Abstract

Targeted medications and immunotherapies are being developed to specifically target the pathways involved in tumours. There is limited experience with these new medications and their cutaneous side-effects in the paediatric population. A retrospective study of all paediatric oncological patients treated with targeted therapies and immunotherapies between 1 January 2013 and 1 August 2020 was carried out in 2 haemato-oncological referral centres. A total of 103 children were included in the study. The median (interquartile range) age was 13 years (8.4–16.9), male:female ratio 1.5:1, median (interquartile range) follow-up was 7 months (2–18). Fifty (48%) of the children developed cutaneous adverse events. Treatment was discontinued in only 3 (6%) cases and was altered in only (2%) 1 case due to a cutaneous adverse event. When targeted therapies and immunotherapies for tumours in children are used, there is an increased incidence of cutaneous adverse events. Nevertheless, treatment modification or discontinuation due to cutaneous side-effects is rarely needed.

Published
2021
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3. Supplementary Table S1 from Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Author

Chris Jones, David T.W. Jones, Thomas S. Jacques, David W. Ellison, Sergey Popov, David Capper, Maria Vinci, Andrea Carai, Angela Mastronuzzi, Suzanne J. Baker, Felix Sahm, Stefan M. Pfister, Christof M. Kramm, Andreas von Deimling, Lynley V. Marshall, Fernando Carceller, Darren R. Hargrave, Kristian Aquilina, Matthias A. Karajannis, David S. Ziegler, Mark J. Cowley, Maria Tsoli, Stephen P. Lowis, Timothy E.G. Hassall, Andrew S. Moore, Simon Bailey, Francesca Diomedi-Camassei, Giovanna Stefania Colafati, Evelina Miele, Clare Mitchell, Tabitha Bloom, Olaf Witt, Marc Zuckermann, Dominik Sturm, Barbara C. Worst, Lotte Hiddingh, Andrey Korshunov, Pablo Hernáiz Driever, Felipe Andreiuolo, Torsten Pietsch, Simone Hettmer, Kornelius Kerl, Winand N.M. Dinjens, Martin Ebinger, Martin U. Schuhmann, Jens Schittenhelm, Michael Karremann, Michael Capra, Jane B. Cryan, Michael Farrell, Petter Brandal, Thale Kristin Olsen, David A. Solomon, Monika Ashok Davare, Lissa Baird, Matthew D. Wood, Barbara Faganel Kotnik, Mara Popović, Shani Caspi, Ho-Keung Ng, Roger Packer, Irene Slavc, Christine Haberler, Matthias Preusser, Tobey J. Macdonald, Paula Z. Proszek, Debbie Hughes, Marc K. Rosenblum, Stephen W. Gilheeney, Ira J. Dunkel, Martin Sill, Simon P. Robinson, Jessica K.R. Boult, Rachael Natrajan, Claire Cairns, Bassel Zebian, Christopher Chandler, Safa Al-Sarraj, Lawrence J. Doey, Andrew J. Martin, Leslie Bridges, Matija Snuderl, David E. Kram, Uwe Kordes, Ulrich Schüller, Jeffrey Knipstein, Stephen Crosier, Mellissa Maybury, Catherine Rowe, Kathreena M. Kurian, Michael Hubank, Ji Wen, Wilda Orisme, James D. Dalton, Kelly Haupfear, Mark Kristiansen, Jane Chalker, Aimee Avery, Amy R. Fairchild, Alex Virasami, Louise Howell, Anna Burford, Valeria Molinari, Diana M. Carvalho, Sara Temelso, Elisa Izquierdo, Iris Stoler, Tejus A. Bale, Scott Newman, Ruth G. Tatevossian, Jessica C. Pickles, Britta Ismer, Alan Mackay, and Matthew Clarke

Abstract

Supplementary Table S1

Published
2023
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4. Supplementary Data from Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Author

Chris Jones, David T.W. Jones, Thomas S. Jacques, David W. Ellison, Sergey Popov, David Capper, Maria Vinci, Andrea Carai, Angela Mastronuzzi, Suzanne J. Baker, Felix Sahm, Stefan M. Pfister, Christof M. Kramm, Andreas von Deimling, Lynley V. Marshall, Fernando Carceller, Darren R. Hargrave, Kristian Aquilina, Matthias A. Karajannis, David S. Ziegler, Mark J. Cowley, Maria Tsoli, Stephen P. Lowis, Timothy E.G. Hassall, Andrew S. Moore, Simon Bailey, Francesca Diomedi-Camassei, Giovanna Stefania Colafati, Evelina Miele, Clare Mitchell, Tabitha Bloom, Olaf Witt, Marc Zuckermann, Dominik Sturm, Barbara C. Worst, Lotte Hiddingh, Andrey Korshunov, Pablo Hernáiz Driever, Felipe Andreiuolo, Torsten Pietsch, Simone Hettmer, Kornelius Kerl, Winand N.M. Dinjens, Martin Ebinger, Martin U. Schuhmann, Jens Schittenhelm, Michael Karremann, Michael Capra, Jane B. Cryan, Michael Farrell, Petter Brandal, Thale Kristin Olsen, David A. Solomon, Monika Ashok Davare, Lissa Baird, Matthew D. Wood, Barbara Faganel Kotnik, Mara Popović, Shani Caspi, Ho-Keung Ng, Roger Packer, Irene Slavc, Christine Haberler, Matthias Preusser, Tobey J. Macdonald, Paula Z. Proszek, Debbie Hughes, Marc K. Rosenblum, Stephen W. Gilheeney, Ira J. Dunkel, Martin Sill, Simon P. Robinson, Jessica K.R. Boult, Rachael Natrajan, Claire Cairns, Bassel Zebian, Christopher Chandler, Safa Al-Sarraj, Lawrence J. Doey, Andrew J. Martin, Leslie Bridges, Matija Snuderl, David E. Kram, Uwe Kordes, Ulrich Schüller, Jeffrey Knipstein, Stephen Crosier, Mellissa Maybury, Catherine Rowe, Kathreena M. Kurian, Michael Hubank, Ji Wen, Wilda Orisme, James D. Dalton, Kelly Haupfear, Mark Kristiansen, Jane Chalker, Aimee Avery, Amy R. Fairchild, Alex Virasami, Louise Howell, Anna Burford, Valeria Molinari, Diana M. Carvalho, Sara Temelso, Elisa Izquierdo, Iris Stoler, Tejus A. Bale, Scott Newman, Ruth G. Tatevossian, Jessica C. Pickles, Britta Ismer, Alan Mackay, and Matthew Clarke

Abstract

Supplementary Figures and Legends

Published
2023
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5. Data from Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Author

Chris Jones, David T.W. Jones, Thomas S. Jacques, David W. Ellison, Sergey Popov, David Capper, Maria Vinci, Andrea Carai, Angela Mastronuzzi, Suzanne J. Baker, Felix Sahm, Stefan M. Pfister, Christof M. Kramm, Andreas von Deimling, Lynley V. Marshall, Fernando Carceller, Darren R. Hargrave, Kristian Aquilina, Matthias A. Karajannis, David S. Ziegler, Mark J. Cowley, Maria Tsoli, Stephen P. Lowis, Timothy E.G. Hassall, Andrew S. Moore, Simon Bailey, Francesca Diomedi-Camassei, Giovanna Stefania Colafati, Evelina Miele, Clare Mitchell, Tabitha Bloom, Olaf Witt, Marc Zuckermann, Dominik Sturm, Barbara C. Worst, Lotte Hiddingh, Andrey Korshunov, Pablo Hernáiz Driever, Felipe Andreiuolo, Torsten Pietsch, Simone Hettmer, Kornelius Kerl, Winand N.M. Dinjens, Martin Ebinger, Martin U. Schuhmann, Jens Schittenhelm, Michael Karremann, Michael Capra, Jane B. Cryan, Michael Farrell, Petter Brandal, Thale Kristin Olsen, David A. Solomon, Monika Ashok Davare, Lissa Baird, Matthew D. Wood, Barbara Faganel Kotnik, Mara Popović, Shani Caspi, Ho-Keung Ng, Roger Packer, Irene Slavc, Christine Haberler, Matthias Preusser, Tobey J. Macdonald, Paula Z. Proszek, Debbie Hughes, Marc K. Rosenblum, Stephen W. Gilheeney, Ira J. Dunkel, Martin Sill, Simon P. Robinson, Jessica K.R. Boult, Rachael Natrajan, Claire Cairns, Bassel Zebian, Christopher Chandler, Safa Al-Sarraj, Lawrence J. Doey, Andrew J. Martin, Leslie Bridges, Matija Snuderl, David E. Kram, Uwe Kordes, Ulrich Schüller, Jeffrey Knipstein, Stephen Crosier, Mellissa Maybury, Catherine Rowe, Kathreena M. Kurian, Michael Hubank, Ji Wen, Wilda Orisme, James D. Dalton, Kelly Haupfear, Mark Kristiansen, Jane Chalker, Aimee Avery, Amy R. Fairchild, Alex Virasami, Louise Howell, Anna Burford, Valeria Molinari, Diana M. Carvalho, Sara Temelso, Elisa Izquierdo, Iris Stoler, Tejus A. Bale, Scott Newman, Ruth G. Tatevossian, Jessica C. Pickles, Britta Ismer, Alan Mackay, and Matthew Clarke

Abstract

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management.Significance:Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype.See related video: https://vimeo.com/438254885See related commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890

Published
2023
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6. Hypothalamic-pituitary-gonadal function, pubertal development, and fertility outcomes in male and female medulloblastoma survivors: a single-center experience

Author

Eve Stern, Michal Ben-Ami, Noah Gruber, Amos Toren, Shani Caspi, Gadi Abebe-Campino, Michal Lurye, Michal Yalon, and Dalit Modan-Moses

Subjects
Cancer Research, Oncology, Neurology (clinical)
Abstract

BackgroundEndocrine deficiencies, including hypothalamic-pituitary-gonadal axis (HPGA) impairment, are common in survivors of childhood and adolescent medulloblastoma. Still, data regarding pubertal development and fecundity are limited, and few studies assessed HPGA function in males. We aimed to describe HPGA function in a large cohort of patients with medulloblastoma.MethodsA retrospective study comprising all 62 medulloblastoma patients treated in our center between 1987 and 2021, who were at least 2 years from completion of therapy. HPGA function was assessed based on clinical data, biochemical markers, and questionnaires.ResultsOverall, 76% of female patients had clinical or biochemical evidence of HPGA dysfunction. Biochemical evidence of diminished ovarian reserve was seen in all prepubertal girls (n = 4). Among the males, 34% had clinical or biochemical evidence of gonadal dysfunction, 34% had normal function, and 29% were age-appropriately clinically and biochemically prepubertal. The difference between males and females was significant (P = .003). Cyclophosphamide-equivalent dose was significantly associated with HPGA function in females, but not in males. There was no association between HPGA dysfunction and other endocrine deficiencies, length of follow-up, weight status, and radiation treatment protocol. Two female and 2 male patients achieved successful pregnancies, resulting in 6 live births.ConclusionsHPGA dysfunction is common after treatment for childhood medulloblastoma. This is seen more in females, likely due to damage to the ovaries from spinal radiotherapy. Our findings may assist in counseling patients and their families regarding risk to future fertility and need for fertility preservation.

Published
2023
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7. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author

Lee Yi Yen, Melyssa Aronson, Carol J. Swallow, Cynthia Hawkins, Lara Reichman, Rebecca C. Luiten, Sumita Roy, Michal Zapotocky, Patrick Tomboc, Christian Kratz, Michael Osborn, Junne Kamihara, Ayse Bahar Ercan, Jamie L. Maciaszek, Vanessa Bianchi, Benjamin Oshrine, Hagit N. Baris, Ossama M. Maher, Mohsin Rashid, Sara Rhode, Sharon Gardner, Annika Bronsema, David S. Ziegler, An Van Damme, Monica Newmark, Mithra Ghalibafian, Heather Hampel, Jordan R. Hansford, Vahid Fallah Azad, Michael P. Link, Simon C. Ling, Marc Remke, Shayna Zelcer, Deborah T. Blumenthal, Isabelle Scheers, Rebecca Loret De Mola, Syed Ahmer Hamid, Vanan MagimairajanIssai, Kim E. Nichols, Saunders Hsu, Catherine Goudie, Naureen Mushtaq, Ira Winer, Abeer Al-Battashi, Garth Nicholas, Roula Farah, Kami Wolfe Schneider, Rejin Kebudi, Jan Rapp, Gregory Thomas, Helen Toledano, Alvaro Lassaletta, Anne Bendel, Jeffrey Knipstein, Musa Alharbi, Gadi Abebe-Campino, Rose B. McGee, Anirban Das, Uri Tabori, Donald Basel, Alyssa Reddy, Melissa Edwards, Scott Lindhorst, Craig Harlos, Bailey Gallinger, Elizabeth Cairney, Anita Villani, Valerie Larouche, Rachel Pearlman, Maude Blundell, Gary Mason, David Sumerauer, Magnus Sabel, Aghiad Chamdin, Leslie Taylor, David Malkin, William D. Foulkes, Maura Massimino, Catherine Gilpin, Eric Bouffet, Miriam Bornhorst, Carol Durno, Enrico Opocher, Nobuko Hijiya, Zehavit Frenkel, David Samuel, Michal Lurye, Stefanie Zimmermann, Shani Caspi, Stefano Chiaravalli, David Gass, Eshetu G. Atenafu, Shlomi Constantini, Shay Ben-Shachar, Michal Yalon, Rina Dvir, Daniel Pettee, Bruce Crooks, Santanu Sen, Carl Koschmann, Raymond Bedgood, Theodore Nicolaides, Duncan Stearns, Yael Goldberg, Melissa Galati, Gabriel Robbins, UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique, and UCL - SSS/IREC/PEDI - Pôle de Pédiatrie

Subjects
Adult, Male, 0301 basic medicine, Oncology, Cancer Research, medicine.medical_specialty, Adolescent, MEDLINE, DNA Mismatch Repair, Young Adult, 03 medical and health sciences, 0302 clinical medicine, Neoplastic Syndromes, Hereditary, Internal medicine, medicine, Humans, Prospective Studies, Child, Early Detection of Cancer, Hematology, Brain Neoplasms, business.industry, Cancer predisposition, Prognosis, United States, Survival Rate, DNA Repair Enzymes, 030104 developmental biology, Survival benefit, Child, Preschool, Population Surveillance, 030220 oncology & carcinogenesis, MISMATCH REPAIR DEFICIENCY, Female, Colorectal Neoplasms, business, Follow-Up Studies
Abstract

PURPOSE Constitutional mismatch repair deficiency syndrome (CMMRD) is a lethal cancer predisposition syndrome characterized by early-onset synchronous and metachronous multiorgan tumors. We designed a surveillance protocol for early tumor detection in these individuals. PATIENTS AND METHODS Data were collected from patients with confirmed CMMRD who were registered in the International Replication Repair Deficiency Consortium. Tumor spectrum, efficacy of the surveillance protocol, and malignant transformation of low-grade lesions were examined for the entire cohort. Survival outcomes were analyzed for patients followed prospectively from the time of surveillance implementation. RESULTS A total of 193 malignant tumors in 110 patients were identified. Median age of first cancer diagnosis was 9.2 years (range: 1.7-39.5 years). For patients undergoing surveillance, all GI and other solid tumors, and 75% of brain cancers were detected asymptomatically. By contrast, only 16% of hematologic malignancies were detected asymptomatically ( P < .001). Eighty-nine patients were followed prospectively and used for survival analysis. Five-year overall survival (OS) was 90% (95% CI, 78.6 to 100) and 50% (95% CI, 39.2 to 63.7) when cancer was detected asymptomatically and symptomatically, respectively ( P = .001). Patient outcome measured by adherence to the surveillance protocol revealed 4-year OS of 79% (95% CI, 54.8 to 90.9) for patients undergoing full surveillance, 55% (95% CI, 28.5 to 74.5) for partial surveillance, and 15% (95% CI, 5.2 to 28.8) for those not under surveillance ( P < .0001). Of the 64 low-grade tumors detected, the cumulative likelihood of transformation from low-to high-grade was 81% for GI cancers within 8 years and 100% for gliomas in 6 years. CONCLUSION Surveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Published
2021
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8. Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes

Author

Michael Karremann, Olaf Witt, Tabitha Bloom, Winand N.M. Dinjens, Felipe Andreiuolo, Michael Farrell, Scott Newman, Simone Hettmer, James Dalton, Leslie R. Bridges, Jens Schittenhelm, Martin Ebinger, Thomas S. Jacques, Francesca Diomedi-Camassei, Dominik Sturm, Jane Chalker, Matija Snuderl, David W. Ellison, Paula Proszek, Irene Slavc, Matthias A. Karajannis, Giovanna Stefania Colafati, Louise Howell, Christine Haberler, Simon Bailey, Barbara C. Worst, David A. Solomon, Andrew J. Martin, Stefan M. Pfister, Maria Vinci, Ho Keung Ng, Kelly Haupfear, Mellissa Maybury, Stephen Gilheeney, Bassel Zebian, Martin Sill, David T.W. Jones, Pablo Hernáiz Driever, Martin U. Schuhmann, Angela Mastronuzzi, Jessica K.R. Boult, Matthew Clarke, Rachael Natrajan, Kornelius Kerl, Lawrence Doey, Alex Virasami, Andrey Korshunov, Christof M. Kramm, Jane Cryan, David E. Kram, Timothy E.G. Hassall, Debbie Hughes, Claire Mitchell, Chris Jones, Monika A. Davare, Evelina Miele, Safa Al-Sarraj, Sara Temelso, Catherine Rowe, Suzanne J. Baker, Sergey Popov, Torsten Pietsch, Matthew D. Wood, Roger J. Packer, Lynley V. Marshall, Michael Capra, Valeria Molinari, Diana Carvalho, Marc Zuckermann, Andreas von Deimling, Uwe Kordes, Kathreena M Kurian, Shani Caspi, Ira J. Dunkel, Wilda Orisme, Ulrich Schüller, Claire Cairns, Matthias Preusser, Kristian Aquilina, Petter Brandal, Stephen Lowis, Iris Stoler, Christopher Chandler, Lissa C. Baird, Marc K. Rosenblum, Ji Wen, Felix Sahm, Barbara Faganel Kotnik, Stephen Crosier, Mara Popović, Andrea Carai, Lotte Hiddingh, Thale Kristin Olsen, Fernando Carceller, Simon P. Robinson, Maria Tsoli, Ruth G. Tatevossian, Anna Burford, Mike Hubank, Elisa Izquierdo, Tejus Bale, David Capper, Andrew S. Moore, David S. Ziegler, Amy R Fairchild, Aimee Avery, Alan Mackay, Jessica C Pickles, Mark Kristiansen, Jeffrey Knipstein, Darren Hargrave, Mark J. Cowley, Tobey J. MacDonald, Britta Ismer, and Pathology

Subjects
0301 basic medicine, Oncology, Disease specific, medicine.medical_specialty, Population, Genome, Article, 03 medical and health sciences, 0302 clinical medicine, Text mining, Proto-Oncogene Proteins, Internal medicine, ROS1, medicine, Humans, education, Grading (tumors), Gene, Exome sequencing, education.field_of_study, business.industry, Receptor Protein-Tyrosine Kinases, Infant, Glioma, Protein-Tyrosine Kinases, Prognosis, 030104 developmental biology, Treatment Outcome, 030220 oncology & carcinogenesis, Gene Fusion, Neoplasm Grading, business
Abstract

Infant high-grade gliomas appear clinically distinct from their counterparts in older children, indicating that histopathologic grading may not accurately reflect the biology of these tumors. We have collected 241 cases under 4 years of age, and carried out histologic review, methylation profiling, and custom panel, genome, or exome sequencing. After excluding tumors representing other established entities or subgroups, we identified 130 cases to be part of an “intrinsic” spectrum of disease specific to the infant population. These included those with targetable MAPK alterations, and a large proportion of remaining cases harboring gene fusions targeting ALK (n = 31), NTRK1/2/3 (n = 21), ROS1 (n = 9), and MET (n = 4) as their driving alterations, with evidence of efficacy of targeted agents in the clinic. These data strongly support the concept that infant gliomas require a change in diagnostic practice and management. Significance: Infant high-grade gliomas in the cerebral hemispheres comprise novel subgroups, with a prevalence of ALK, NTRK1/2/3, ROS1, or MET gene fusions. Kinase fusion–positive tumors have better outcome and respond to targeted therapy clinically. Other subgroups have poor outcome, with fusion-negative cases possibly representing an epigenetically driven pluripotent stem cell phenotype. See related video: https://vimeo.com/438254885 See related commentary by Szulzewsky and Cimino, p. 904. This article is highlighted in the In This Issue feature, p. 890

Published
2020
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9. Adjuvant therapy of histopathological risk factors of retinoblastoma in Europe: A survey by the European Retinoblastoma Group (EURbG)

Author

Angelika Eggert, Nadezhda Fedorovna Bobrova, Madlen Reschke, Doris Hadjistilianou, Hatice Tuba Atalay, Annette C. Moll, Martin Ebinger, Eva Biewald, Katarzyna Pawinska-Wasikowska, Catriona Duncan, Hayyam Kiratli, Karel Svojgr, David Garcia Aldana, François Doz, Ines B Brecht, Francis L. Munier, Constantino Sábado Álvarez, Erika Maka, Yelena Diarra, Floor Abbink, Nikolaos E. Bechrakis, Beate Timmermann, Nathalie Cassoux, Tomáš Kepák, Maja Beck Popovic, Petra Ritter-Sovinz, Vicktoria Vishnevskia-Dai, Shani Caspi, Guillermo Chantada, Guilherme Castela, Artur Klett, Olga Rutynowska-Pronicka, Enrico Opocher, Ida Russo, Sabine Dittner-Moormann, Jelena Rascon, Isabelle Aerts, Helen Jenkinson, Petra Ketteler, Sonsoles San Roman Pacheco, Pediatric surgery, CCA - Cancer Treatment and quality of life, Ophthalmology, APH - Quality of Care, APH - Health Behaviors & Chronic Diseases, ACS - Diabetes & metabolism, Institut Català de la Salut, [Dittner-Moormann S] Department of Pediatric Hematology and Oncology, University Duisburg-Essen, University Hospital Essen, Essen, Germany. [Reschke M] Department of Pediatric Oncology and Hematology, Charité - Universitätsmedizin Berlin, Berlin, Germany. [Abbink FCH] Amsterdam UMC, Location VU University Medical Centre, Amsterdam, The Netherlands. [Aerts I] Institut Curie, PSL Research University and University of Paris, Paris, France. [Atalay HT] Gazi University School of Medicine, Ankara, Turkey. [Fedorovna Bobrova N] Filatov Eye Institute Odessa, Odessa, Ukraine. [Sábado Álvarez C] Servei d’Oncologia i Hematologia Pediàtriques, Vall d’Hebron Hospital Universitari, Barcelona, Spain, and Vall d'Hebron Barcelona Hospital Campus

Subjects
Investigative Techniques::Epidemiologic Methods::Data Collection::Surveys and Questionnaires [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Oncology, genetic structures, medicine.medical_treatment, Medizin, childhood cancer, chemotherapy, terapéutica::tratamiento combinado [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], metastasis, 0302 clinical medicine, Risk Factors, Surveys and Questionnaires, Antineoplastic Combined Chemotherapy Protocols, biomarker, Child, Retinoblastoma, Extraocular Retinoblastoma, Hematology, Prognosis, Combined Modality Therapy, RB1 gene, 3. Good health, Europe, Chemotherapy, Adjuvant, Child, Preschool, 030220 oncology & carcinogenesis, Resection margin, neoplasias::neoplasias::neoplasias::neoplasias::neoplasias por localización::neoplasias del ojo::neoplasias de la retina::retinoblastoma [ENFERMEDADES], Adjuvant, medicine.medical_specialty, Retinal Neoplasms, Enucleation, técnicas de investigación::métodos epidemiológicos::estadística como asunto::probabilidad::riesgo::factores de riesgo [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], Enquestes, Intraocular Retinoblastoma, Eye Enucleation, 03 medical and health sciences, Internal medicine, medicine, Adjuvant therapy, Humans, Neoplasms::Neoplasms::Neoplasms::Neoplasms::Neoplasms by Site::Eye Neoplasms::Retinal Neoplasms::Retinoblastoma [DISEASES], radiotherapy, Retina - Càncer - Radioteràpia, business.industry, técnicas de investigación::métodos epidemiológicos::recopilación de datos::encuestas y cuestionarios [TÉCNICAS Y EQUIPOS ANALÍTICOS, DIAGNÓSTICOS Y TERAPÉUTICOS], medicine.disease, eye diseases, Retina - Càncer - Quimioteràpia, Therapeutics::Combined Modality Therapy [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], Radiation therapy, Pediatrics, Perinatology and Child Health, Radiotherapy, Adjuvant, sense organs, Investigative Techniques::Epidemiologic Methods::Statistics as Topic::Probability::Risk::Risk Factors [ANALYTICAL, DIAGNOSTIC AND THERAPEUTIC TECHNIQUES, AND EQUIPMENT], business, 030215 immunology
Abstract

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.

Published
2021
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10. Mutation and Microsatellite Burden Predict Response to PD-1 Inhibition in Children with Germline DNA Replication Repair Deficiency

Author

Uri Tabori, Magnus Sabel, Alexander Lossos, Annika Bronsema, Lauren Sambira, David Gass, Vanan Magimairajan, Gary Mason, Melissa Edwards, Vanja Cabric, Simone Stone, David Malkin, Isabelle Scheers, Ben George, Anita Villani, Deborah T. Blumenthal, An Van Damme, Rose B. McGee, Lee Yen, Sandra Luna-Fineman, John M. Maris, David Sumerauer, Charlotta Fröjd, Sumedha Sudhaman, Michael D. Taylor, Enrico Opocher, Yosef E. Maruvka, Oz Mordechai, Jeffrey Knipstein, Rebecca Loret De Mola, Melyssa Aronson, Shlomi Constantini, Abhaya Kulkarni, Daniel A. Morgenstern, Rina Dvir, Trevor J. Pugh, Patrick Tomboc, Ted Laetsch, Noor Alsafwani, Vanessa Bianchi, Kim E. Nichols, Jordan R. Hansford, Manohar Shroff, Peter B. Dirks, Shani Caspi, Anirban Das, Stefano Chiaravalli, Valerie Larouche, Eric Bouffet, Adam Shlien, Gad Getz, Maura Massimino, Alyssa Reddy, Michal Yalon, Gadi Campino, Anne Bendel, Cynthia Hawkins, Michal Zapotocky, Derek Tsang, Jiil Chung, Tomasz Sarosiek, Lindsey Hoffman, Daniel C. Bowers, Ailish Coblentz, Kristina A. Cole, Stefanie Zimmermann, Scott Lindhorst, Nobuko Hijaya, Michael Osborn, David S. Ziegler, Liana Nobre, Carol Durno, David Samuel, and Pamela Ohashi

Subjects
Genetics, Replication (statistics), Mutation (genetic algorithm), Microsatellite, Biology, Germline
Abstract

Cancers arising from germline DNA mismatch-repair or polymerase-proofreading deficiencies (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion/deletion (MS-indel) burden in humans and are lethal due to inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICI) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI in these patients. ICI treatment of 45 progressive/recurrent tumours from 38 patients revealed durable objective responses in the majority, culminating in 3-year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations/Mb) enriched for combined MMRD+PPD, while MS-indels predicted response in MMRD tumours with lower mutation burden (10-100 mutations/Mb). Further, both mechanisms were associated with increased immune infiltration even in “immunologically-cold” tumours such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and associated with immune activation in both the tumour microenvironment and systemically. Further, patients with flare continuing ICI treatment achieved durable responses. Our study demonstrates improved survival for patients with tumours not previously known to respond to ICI, including CNS and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained responses to immunotherapy.

Published
2021
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11. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author

Anirban Das, Sumedha Sudhaman, Daniel Morgenstern, Ailish Coblentz, Jiil Chung, Simone C. Stone, Noor Alsafwani, Zhihui Amy Liu, Ola Abu Al Karsaneh, Shirin Soleimani, Hagay Ladany, David Chen, Matthew Zatzman, Vanja Cabric, Liana Nobre, Vanessa Bianchi, Melissa Edwards, Lauren C, Sambira Nahum, Ayse B. Ercan, Arash Nabbi, Shlomi Constantini, Rina Dvir, Michal Yalon-Oren, Gadi Abebe Campino, Shani Caspi, Valerie Larouche, Alyssa Reddy, Michael Osborn, Gary Mason, Scott Lindhorst, Annika Bronsema, Vanan Magimairajan, Enrico Opocher, Rebecca Loret De Mola, Magnus Sabel, Charlotta Frojd, David Sumerauer, David Samuel, Kristina Cole, Stefano Chiaravalli, Maura Massimino, Patrick Tomboc, David S. Ziegler, Ben George, An Van Damme, Nobuko Hijiya, David Gass, Rose B. McGee, Oz Mordechai, Daniel C. Bowers, Theodore W. Laetsch, Alexander Lossos, Deborah T. Blumenthal, Tomasz Sarosiek, Lee Yi Yen, Jeffrey Knipstein, Anne Bendel, Lindsey M. Hoffman, Sandra Luna-Fineman, Stefanie Zimmermann, Isabelle Scheers, Kim E. Nichols, Michal Zapotocky, Jordan R. Hansford, John M. Maris, Peter Dirks, Michael D. Taylor, Abhaya V. Kulkarni, Manohar Shroff, Derek S. Tsang, Anita Villani, Wei Xu, Melyssa Aronson, Carol Durno, Adam Shlien, David Malkin, Gad Getz, Yosef E. Maruvka, Pamela S. Ohashi, Cynthia Hawkins, Trevor J. Pugh, Eric Bouffet, Uri Tabori, UCL - SSS/IREC/PEDI - Pôle de Pédiatrie, and UCL - (SLuc) Service de gastro-entérologie et hépatologie pédiatrique

Subjects
Adult, DNA Replication, Male, Adolescent, DNA Repair, Pediatric Cancer, Immunology, Cancer immunotherapy, Medical and Health Sciences, General Biochemistry, Genetics and Molecular Biology, B7-H1 Antigen, Article, Paediatric cancer, Tumour biomarkers, Young Adult, Rare Diseases, Neoplasms, Genetics, Biomarkers, Tumor, Tumor Microenvironment, 2.1 Biological and endogenous factors, Humans, Prospective Studies, Aetiology, Child, Immune Checkpoint Inhibitors, Cancer genetics, Germ-Line Mutation, Cancer, Retrospective Studies, Pediatric, Tumor, Neurosciences, General Medicine, Survival Analysis, CNS cancer, Female, Biomarkers
Abstract

Cancers arising from germline DNA mismatch repair deficiency or polymerase proofreading deficiency (MMRD and PPD) in children harbour the highest mutational and microsatellite insertion–deletion (MS-indel) burden in humans. MMRD and PPD cancers are commonly lethal due to the inherent resistance to chemo-irradiation. Although immune checkpoint inhibitors (ICIs) have failed to benefit children in previous studies, we hypothesized that hypermutation caused by MMRD and PPD will improve outcomes following ICI treatment in these patients. Using an international consortium registry study, we report on the ICI treatment of 45 progressive or recurrent tumors from 38 patients. Durable objective responses were observed in most patients, culminating in a 3 year survival of 41.4%. High mutation burden predicted response for ultra-hypermutant cancers (>100 mutations per Mb) enriched for combined MMRD + PPD, while MS-indels predicted response in MMRD tumors with lower mutation burden (10–100 mutations per Mb). Furthermore, both mechanisms were associated with increased immune infiltration even in ‘immunologically cold’ tumors such as gliomas, contributing to the favorable response. Pseudo-progression (flare) was common and was associated with immune activation in the tumor microenvironment and systemically. Furthermore, patients with flare who continued ICI treatment achieved durable responses. This study demonstrates improved survival for patients with tumors not previously known to respond to ICI treatment, including central nervous system and synchronous cancers, and identifies the dual roles of mutation burden and MS-indels in predicting sustained response to immunotherapy., Hypermutation and microsatellite burden determine responses and long-term survival following PD-1 blockade in children and young adults with refractory cancers resulting from germline DNA replication repair deficiency.

Published
2021

12. Evaluation of Toxicity and Effect on Growth and Sexual Development in Children with MAPK Pathway Driven Tumors Treated with BRAF and MEK Inhibitors -- A Single Center Experience

Author

Michalle Soudack, Michael Kinori, Eve Stern, Shani Caspi, Gadi Abebe Campino, Michal Lurye, Dalit Modan-Moses, Shoshana Greenberger, Amos Toren, Michal Yalon, Talya Finke, Ariel Hirchorn, Michal Golan, Sharon Armarnik, Uriel Katz, Michal Ben-Ami, and Renana Gross

Subjects
Erythema nodosum, MAPK/ERK pathway, Oncology, medicine.medical_specialty, business.industry, MEK inhibitor, medicine.disease, Rash, Tolerability, Internal medicine, Toxicity, medicine, medicine.symptom, business, Prospective cohort study, Adverse effect
Abstract

Background The MAPK pathway, is a signal transduction pathway involved in the oncogenesis of a variety of pediatric tumors. The clinical use of BRAF inhibitors and MEK inhibitors is increasingly used in oncology practice. The toxicity profile of these drugs in the pediatric population, particularly in relation to development, growth and sexual maturation remains insufficiently studied. Procedure This study includes 22 pediatric patients with molecularly confirmed MAPK pathway driven tumors treated with MEK or BRAF between August 2014 and March 2020. Throughout treatment they underwent regular laboratory, endocrine, cardiac, ophthalmic and dermatologic evaluation. Toxicity was recorded and evaluated according to CTCA v4. Results Overall an adverse event frequency of 86% was encountered. Dermatological disorders accounted for 68% of the adverse events. Overall 8 patients suffered from severe adverse events including Erythema Nodosum, PLEVA-like rash, osteoporosis, Sarcoid-like massive lymphadenopathy, retinal toxicity and elevated liver enzymes & CPK. Four patients discontinued treatment as a result of adverse events. In this cohort we did not encounter any treatment-related abnormalities of sexual maturation or gonadal function nor statistically significant growth retardation, however a slower than expected growth rate was observed in one patient. In addition dose-dependent, non-symptomatic and within normal range for age decreased cardiac SF% was noted in two patients treated with MEK inhibitor. Conclusion Treatment with BRAF and MEK inhibitors was shown to be generally safe, we report drug tolerability of 82%. However, further prospective studies should be preformed to are characterize the full scope of side effects in the pediatric population.

Published
2020
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13. Cutaneous Adverse Events to Targeted Therapies and Immuno­therapies in Children: A Retrospective Study of 103 Patients from Two Tertiary Haemato-Oncology Referral Centres

Author

Shoshana Greenberger, Hodaya Cohen, Shani Caspi, Gadi Abebe-Campino, Vered Molho-Pessach, Ayelet Ollech, Aviv Barzilai, Eve Finklestein, and Michal Yalon

Subjects
Male, Pediatrics, medicine.medical_specialty, Referral, Dermatology, paediatrics, New medications, Interquartile range, medicine, Humans, Molecular Targeted Therapy, Child, Adverse effect, Referral and Consultation, Retrospective Studies, Skin, business.industry, Incidence (epidemiology), drug cutaneous adverse events, Infant, Retrospective cohort study, General Medicine, immunotherapies, targeted therapies, Discontinuation, RL1-803, oncology, Female, Immunotherapy, business, Paediatric population
Abstract

Targeted medications and immunotherapies are being developed to specifically target the pathways involved in tumours. There is limited experience with these new medications and their cutaneous side-effects in the paediatric population. A retrospective study of all paediatric oncological patients treated with targeted therapies and immunotherapies between 1 January 2013 and 1 August 2020 was carried out in 2 haemato-oncological referral centres. A total of 103 children were included in the study. The median (interquartile range) age was 13 years (8.4–16.9), male:female ratio 1.5:1, median (interquartile range) follow-up was 7 months (2–18). Fifty (48%) of the children developed cutaneous adverse events. Treatment was discontinued in only 3 (6%) cases and was altered in only (2%) 1 case due to a cutaneous adverse event. When targeted therapies and immunotherapies for tumours in children are used, there is an increased incidence of cutaneous adverse events. Nevertheless, treatment modification or discontinuation due to cutaneous side-effects is rarely needed.

Published
2021
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14. Gliomas in the context of Li-Fraumeni syndrome: An international cohort

Author

Anne Naumer, Sarah Leary, Shayna Zelcer, Orli Michaeli, Thomas P. Slavin, Kara N. Maxwell, Shani Caspi, Uri Tabori, Allison F. O'Neill, Joshua D. Schiffman, Claire Forde, Wendy Kohlmann, Kim E. Nichols, D. Gareth Evans, Miriam Bornhorst, Shannon Stasi, David Malkin, Anita Villani, Surya P. Rednam, and Lindsey M. Hoffman

Subjects
Cancer Research, Tumor suppressor gene, business.industry, Cancer predisposition, Context (language use), medicine.disease, 03 medical and health sciences, 0302 clinical medicine, Germline mutation, Oncology, Li–Fraumeni syndrome, 030220 oncology & carcinogenesis, Cohort, Cancer research, Medicine, business, 030215 immunology
Abstract

1517 Background: Li-Fraumeni syndrome (LFS) is a cancer predisposition syndrome associated with germline mutation in the TP53 tumor suppressor gene. As a result of increased awareness and surveillance imaging, more asymptomatic low-grade brain lesions are being identified, raising important questions regarding the management of those patients. Sporadic low-grade gliomas (LGG) in the pediatric age rarely transform to malignant lesions, whereas the prognosis of high-grade gliomas (HGG) is grim in all age groups. Although HGG is a hallmark of LFS, little is known of the natural history of these lesions in this syndrome. Methods: For this multi-institutional retrospective study, anonymized clinicopathologic data from TP53 mutation carriers with gliomas were collected and analysed. Results: Our cohort included 61 patients, of whom 71% (n = 45) were children or young adults (age < 25 years). 39% of patients with known family history of cancer had a close relative with a brain tumor. Of 31 patients with low grade lesions at presentation, 83% (n = 26) were identified through surveillance. Five-year progression free survival (PFS) for these patients was 48%, though two patients progressed later. Furthermore, at 5 years 25% of these patients had biopsy proven malignant transformation to HGG. This “transformation free survival” rate did not plateau, as at 7 years 56% of patients transformed. When considering death from a brain tumor, the 5- and 10- year overall survival (OS) for the LGG group was 100% and 83%, respectively. Additional 3 patients succumbed to other LFS related malignancies. For the HGG group, consisting of 30 patients, the 5 year OS was 35% (median follow-up 19.5 months), comparing favorably with the sporadic HGG population as reported in the literature. Almost all of these patients presented with clinical symptoms. Notably, 12 (40%) of them had a prior malignancy. Conclusions: Our analysis suggests that the risk of transformation of LGG in the setting of LFS is high and warrants ongoing surveillance. Interestingly, there are a considerable number of long- term survivors in our HGG group, although the median follow up is still short. Further study to examine potential genotype- phenotype correlations in germline TP53 mutation carriers will inform strategies to identify those patients at highest risk of glioma progression.

Published
2019
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