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1. Diffuse pediatric high-grade glioma of methylation-based RTK2A and RTK2B subclasses present distinct radiological and histomolecular features including Gliomatosis cerebri phenotype

Author

Tauziède-Espariat, Arnault, Friker, Lea L., Nussbaumer, Gunther, Bison, Brigitte, Dangouloff-Ros, Volodia, Métais, Alice, Sumerauer, David, Zamecnik, Josef, Benesch, Martin, Perwein, Thomas, van Vuurden, Dannis, Wesseling, Pieter, La Madrid, Andrés Morales, Garrè, Maria Luisa, Antonelli, Manila, Giangaspero, Felice, Pietsch, Torsten, Sturm, Dominik, Jones, David T. W., Pfister, Stefan M., Grabovska, Yura, Mackay, Alan, Jones, Chris, Grill, Jacques, Ajlil, Yassine, von Bueren, André O., Karremann, Michael, Hoffmann, Marion, Kramm, Christof M., Kwiecien, Robert, Castel, David, Gielen, Gerrit H., and Varlet, Pascale

Published
2024
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2. Clinical and molecular study of radiation-induced gliomas

Author

Trkova, Katerina, Sumerauer, David, Bubenikova, Adela, Krskova, Lenka, Vicha, Ales, Koblizek, Miroslav, Zamecnik, Josef, Jurasek, Bruno, Kyncl, Martin, Malinova, Bela, Ondrova, Barbora, Jones, David T. W., Sill, Martin, Strnadova, Martina, Stolova, Lucie, Misove, Adela, Benes, III, Vladimir, and Zapotocky, Michal

Published
2024
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5. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author

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

Subjects
Rare Diseases, Pediatric, Cancer, Neurosciences, Pediatric Cancer, Genetics, 2.1 Biological and endogenous factors, Aetiology, Adolescent, Adult, B7-H1 Antigen, Biomarkers, Tumor, Child, DNA Repair, DNA Replication, Female, Germ-Line Mutation, Humans, Immune Checkpoint Inhibitors, Male, Neoplasms, Prospective Studies, Retrospective Studies, Survival Analysis, Tumor Microenvironment, Young Adult, Medical and Health Sciences, Immunology
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.

Published
2022

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

Author

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

Subjects
Cancer, Brain Disorders, Clinical Research, Digestive Diseases, Prevention, Brain Cancer, Rare Diseases, Adolescent, Adult, Brain Neoplasms, Child, Child, Preschool, Colorectal Neoplasms, DNA Mismatch Repair, DNA Repair Enzymes, Early Detection of Cancer, Female, Follow-Up Studies, Humans, Male, Neoplastic Syndromes, Hereditary, Population Surveillance, Prognosis, Prospective Studies, Survival Rate, United States, Young Adult, Clinical Sciences, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

PurposeConstitutional 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 methodsData 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.ResultsA 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.ConclusionSurveillance and early cancer detection are associated with improved OS for individuals with CMMRD.

Published
2021

9. Pattern of Relapse and Treatment Response in WNT-Activated Medulloblastoma

Author

Nobre, Liana, Zapotocky, Michal, Khan, Sara, Fukuoka, Kohei, Fonseca, Adriana, McKeown, Tara, Sumerauer, David, Vicha, Ales, Grajkowska, Wieslawa A, Trubicka, Joanna, Li, Kay Ka Wai, Ng, Ho-Keung, Massimi, Luca, Lee, Ji Yeoun, Kim, Seung-Ki, Zelcer, Shayna, Vasiljevic, Alexandre, Faure-Conter, Cécile, Hauser, Peter, Lach, Boleslaw, van Veelen-Vincent, Marie-Lise, French, Pim J, Van Meir, Erwin G, Weiss, William A, Gupta, Nalin, Pollack, Ian F, Hamilton, Ronald L, Rao, Amulya A Nageswara, Giannini, Caterina, Rubin, Joshua B, Moore, Andrew S, Chambless, Lola B, Vibhakar, Rajeev, Ra, Young Shin, Massimino, Maura, McLendon, Roger E, Wheeler, Helen, Zollo, Massimo, Ferruci, Veronica, Kumabe, Toshihiro, Faria, Claudia C, Sterba, Jaroslav, Jung, Shin, López-Aguilar, Enrique, Mora, Jaume, Carlotti, Carlos G, Olson, James M, Leary, Sarah, Cain, Jason, Krskova, Lenka, Zamecnik, Josef, Hawkins, Cynthia E, Tabori, Uri, Huang, Annie, Bartels, Ute, Northcott, Paul A, Taylor, Michael D, Yip, Stephen, Hansford, Jordan R, Bouffet, Eric, and Ramaswamy, Vijay

Subjects
Cancer, Clinical Research, Evaluation of treatments and therapeutic interventions, 5.1 Pharmaceuticals, Development of treatments and therapeutic interventions, 6.1 Pharmaceuticals, Adolescent, Antineoplastic Combined Chemotherapy Protocols, Biomarkers, Tumor, Cerebellar Neoplasms, Child, Cyclophosphamide, Female, Humans, Ifosfamide, Male, Medulloblastoma, Middle Aged, Neoplasm Recurrence, Local, Progression-Free Survival, medulloblastoma, WNT, genomics, cyclophosphamide, chemotherapy, prognosis, survival
Abstract

Over the past decade, wingless-activated (WNT) medulloblastoma has been identified as a candidate for therapy de-escalation based on excellent survival; however, a paucity of relapses has precluded additional analyses of markers of relapse. To address this gap in knowledge, an international cohort of 93 molecularly confirmed WNT MB was assembled, where 5-year progression-free survival is 0.84 (95%, 0.763-0.925) with 15 relapsed individuals identified. Maintenance chemotherapy is identified as a strong predictor of relapse, with individuals receiving high doses of cyclophosphamide or ifosphamide having only one very late molecularly confirmed relapse (p = 0.032). The anatomical location of recurrence is metastatic in 12 of 15 relapses, with 8 of 12 metastatic relapses in the lateral ventricles. Maintenance chemotherapy, specifically cumulative cyclophosphamide doses, is a significant predictor of relapse across WNT MB. Future efforts to de-escalate therapy need to carefully consider not only the radiation dose but also the chemotherapy regimen and the propensity for metastatic relapses.

Published
2020

10. Integrated genomic analysis reveals actionable targets in pediatric spinal cord low-grade gliomas

Author

Misove Adela, Vicha Ales, Broz Petr, Vanova Katerina, Sumerauer David, Stolova Lucie, Sramkova Lucie, Koblizek Miroslav, Zamecnik Josef, Kyncl Martin, Holubova Zuzana, Liby Petr, Taborsky Jakub, Benes Vladimir, Pernikova Ivana, Jones T. W. David, Sill Martin, Stancokova Terezia, Krskova Lenka, and Zapotocky Michal

Subjects
Spinal cord, Low-grade glioma, KIAA1549:BRAF fusion, NTRK fusion, Methylation profiling, Neurology. Diseases of the nervous system, RC346-429
Abstract

Abstract Gliomas are the most common central nervous tumors in children and adolescents. However, spinal cord low-grade gliomas (sLGGs) are rare, with scarce information on tumor genomics and epigenomics. To define the molecular landscape of sLGGs, we integrated clinical data, histology, and multi-level genetic and epigenetic analyses on a consecutive cohort of 26 pediatric patients. Driver molecular alteration was found in 92% of patients (24/26). A novel variant of KIAA1549:BRAF fusion (ex10:ex9) was identified using RNA-seq in four cases. Importantly, only one-third of oncogenic drivers could be revealed using standard diagnostic methods, and two-thirds of pediatric patients with sLGGs required extensive molecular examination. The majority (23/24) of detected alterations were potentially druggable targets. Four patients in our cohort received targeted therapy with MEK or NTRK inhibitors. Three of those exhibited clinical improvement (two with trametinib, one with larotrectinib), and two patients achieved partial response. Methylation profiling was implemented to further refine the diagnosis and revealed intertumoral heterogeneity in sLGGs. Although 55% of tumors clustered with pilocytic astrocytoma, other rare entities were identified in this patient population. In particular, diffuse leptomeningeal glioneuronal tumors (n = 3) and high-grade astrocytoma with piloid features (n = 1) and pleomorphic xanthoastrocytoma (n = 1) were present. A proportion of tumors (14%) had no match with the current version of the classifier. Complex molecular genetic sLGGs characterization was invaluable to refine diagnosis, which has proven to be essential in such a rare tumor entity. Moreover, identifying a high proportion of drugable targets in sLGGs opened an opportunity for new treatment modalities.

Published
2022
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11. ATRT–SHH comprises three molecular subgroups with characteristic clinical and histopathological features and prognostic significance

Author

Federico, Aniello, Thomas, Christian, Miskiewicz, Katarzyna, Woltering, Niklas, Zin, Francesca, Nemes, Karolina, Bison, Brigitte, Johann, Pascal D., Hawes, Debra, Bens, Susanne, Kordes, Uwe, Albrecht, Steffen, Dohmen, Hildegard, Hauser, Peter, Keyvani, Kathy, van Landeghem, Frank K. H., Lund, Eva Løbner, Scheie, David, Mawrin, Christian, Monoranu, Camelia-Maria, Parm Ulhøi, Benedicte, Pietsch, Torsten, Reinhard, Harald, Riemenschneider, Markus J., Sehested, Astrid, Sumerauer, David, Siebert, Reiner, Paulus, Werner, Frühwald, Michael C., Kool, Marcel, and Hasselblatt, Martin

Published
2022
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13. Spectrum and prevalence of genetic predisposition in medulloblastoma: a retrospective genetic study and prospective validation in a clinical trial cohort.

Author

Waszak, Sebastian M, Northcott, Paul A, Buchhalter, Ivo, Robinson, Giles W, Sutter, Christian, Groebner, Susanne, Grund, Kerstin B, Brugières, Laurence, Jones, David TW, Pajtler, Kristian W, Morrissy, A Sorana, Kool, Marcel, Sturm, Dominik, Chavez, Lukas, Ernst, Aurelie, Brabetz, Sebastian, Hain, Michael, Zichner, Thomas, Segura-Wang, Maia, Weischenfeldt, Joachim, Rausch, Tobias, Mardin, Balca R, Zhou, Xin, Baciu, Cristina, Lawerenz, Christian, Chan, Jennifer A, Varlet, Pascale, Guerrini-Rousseau, Lea, Fults, Daniel W, Grajkowska, Wiesława, Hauser, Peter, Jabado, Nada, Ra, Young-Shin, Zitterbart, Karel, Shringarpure, Suyash S, De La Vega, Francisco M, Bustamante, Carlos D, Ng, Ho-Keung, Perry, Arie, MacDonald, Tobey J, Hernáiz Driever, Pablo, Bendel, Anne E, Bowers, Daniel C, McCowage, Geoffrey, Chintagumpala, Murali M, Cohn, Richard, Hassall, Timothy, Fleischhack, Gudrun, Eggen, Tone, Wesenberg, Finn, Feychting, Maria, Lannering, Birgitta, Schüz, Joachim, Johansen, Christoffer, Andersen, Tina V, Röösli, Martin, Kuehni, Claudia E, Grotzer, Michael, Kjaerheim, Kristina, Monoranu, Camelia M, Archer, Tenley C, Duke, Elizabeth, Pomeroy, Scott L, Shelagh, Redmond, Frank, Stephan, Sumerauer, David, Scheurlen, Wolfram, Ryzhova, Marina V, Milde, Till, Kratz, Christian P, Samuel, David, Zhang, Jinghui, Solomon, David A, Marra, Marco, Eils, Roland, Bartram, Claus R, von Hoff, Katja, Rutkowski, Stefan, Ramaswamy, Vijay, Gilbertson, Richard J, Korshunov, Andrey, Taylor, Michael D, Lichter, Peter, Malkin, David, Gajjar, Amar, Korbel, Jan O, and Pfister, Stefan M

Subjects
Humans, Medulloblastoma, Cerebellar Neoplasms, Genetic Predisposition to Disease, Risk Factors, Retrospective Studies, Prospective Studies, Reproducibility of Results, Predictive Value of Tests, Gene Expression Profiling, Pedigree, DNA Mutational Analysis, DNA Methylation, Heredity, Phenotype, Germ-Line Mutation, Models, Genetic, Adolescent, Adult, Child, Child, Preschool, Infant, Female, Male, Young Adult, Genetic Testing, Transcriptome, Biomarkers, Tumor, Progression-Free Survival, Exome Sequencing, Brain Cancer, Genetics, Cancer, Human Genome, Pediatric, Pediatric Cancer, Rare Diseases, Brain Disorders, Aetiology, 2.1 Biological and endogenous factors, Oncology and Carcinogenesis, Oncology & Carcinogenesis
Abstract

BackgroundMedulloblastoma is associated with rare hereditary cancer predisposition syndromes; however, consensus medulloblastoma predisposition genes have not been defined and screening guidelines for genetic counselling and testing for paediatric patients are not available. We aimed to assess and define these genes to provide evidence for future screening guidelines.MethodsIn this international, multicentre study, we analysed patients with medulloblastoma from retrospective cohorts (International Cancer Genome Consortium [ICGC] PedBrain, Medulloblastoma Advanced Genomics International Consortium [MAGIC], and the CEFALO series) and from prospective cohorts from four clinical studies (SJMB03, SJMB12, SJYC07, and I-HIT-MED). Whole-genome sequences and exome sequences from blood and tumour samples were analysed for rare damaging germline mutations in cancer predisposition genes. DNA methylation profiling was done to determine consensus molecular subgroups: WNT (MBWNT), SHH (MBSHH), group 3 (MBGroup3), and group 4 (MBGroup4). Medulloblastoma predisposition genes were predicted on the basis of rare variant burden tests against controls without a cancer diagnosis from the Exome Aggregation Consortium (ExAC). Previously defined somatic mutational signatures were used to further classify medulloblastoma genomes into two groups, a clock-like group (signatures 1 and 5) and a homologous recombination repair deficiency-like group (signatures 3 and 8), and chromothripsis was investigated using previously established criteria. Progression-free survival and overall survival were modelled for patients with a genetic predisposition to medulloblastoma.FindingsWe included a total of 1022 patients with medulloblastoma from the retrospective cohorts (n=673) and the four prospective studies (n=349), from whom blood samples (n=1022) and tumour samples (n=800) were analysed for germline mutations in 110 cancer predisposition genes. In our rare variant burden analysis, we compared these against 53 105 sequenced controls from ExAC and identified APC, BRCA2, PALB2, PTCH1, SUFU, and TP53 as consensus medulloblastoma predisposition genes according to our rare variant burden analysis and estimated that germline mutations accounted for 6% of medulloblastoma diagnoses in the retrospective cohort. The prevalence of genetic predispositions differed between molecular subgroups in the retrospective cohort and was highest for patients in the MBSHH subgroup (20% in the retrospective cohort). These estimates were replicated in the prospective clinical cohort (germline mutations accounted for 5% of medulloblastoma diagnoses, with the highest prevalence [14%] in the MBSHH subgroup). Patients with germline APC mutations developed MBWNT and accounted for most (five [71%] of seven) cases of MBWNT that had no somatic CTNNB1 exon 3 mutations. Patients with germline mutations in SUFU and PTCH1 mostly developed infant MBSHH. Germline TP53 mutations presented only in childhood patients in the MBSHH subgroup and explained more than half (eight [57%] of 14) of all chromothripsis events in this subgroup. Germline mutations in PALB2 and BRCA2 were observed across the MBSHH, MBGroup3, and MBGroup4 molecular subgroups and were associated with mutational signatures typical of homologous recombination repair deficiency. In patients with a genetic predisposition to medulloblastoma, 5-year progression-free survival was 52% (95% CI 40-69) and 5-year overall survival was 65% (95% CI 52-81); these survival estimates differed significantly across patients with germline mutations in different medulloblastoma predisposition genes.InterpretationGenetic counselling and testing should be used as a standard-of-care procedure in patients with MBWNT and MBSHH because these patients have the highest prevalence of damaging germline mutations in known cancer predisposition genes. We propose criteria for routine genetic screening for patients with medulloblastoma based on clinical and molecular tumour characteristics.FundingGerman Cancer Aid; German Federal Ministry of Education and Research; German Childhood Cancer Foundation (Deutsche Kinderkrebsstiftung); European Research Council; National Institutes of Health; Canadian Institutes for Health Research; German Cancer Research Center; St Jude Comprehensive Cancer Center; American Lebanese Syrian Associated Charities; Swiss National Science Foundation; European Molecular Biology Organization; Cancer Research UK; Hertie Foundation; Alexander and Margaret Stewart Trust; V Foundation for Cancer Research; Sontag Foundation; Musicians Against Childhood Cancer; BC Cancer Foundation; Swedish Council for Health, Working Life and Welfare; Swedish Research Council; Swedish Cancer Society; the Swedish Radiation Protection Authority; Danish Strategic Research Council; Swiss Federal Office of Public Health; Swiss Research Foundation on Mobile Communication; Masaryk University; Ministry of Health of the Czech Republic; Research Council of Norway; Genome Canada; Genome BC; Terry Fox Research Institute; Ontario Institute for Cancer Research; Pediatric Oncology Group of Ontario; The Family of Kathleen Lorette and the Clark H Smith Brain Tumour Centre; Montreal Children's Hospital Foundation; The Hospital for Sick Children: Sonia and Arthur Labatt Brain Tumour Research Centre, Chief of Research Fund, Cancer Genetics Program, Garron Family Cancer Centre, MDT's Garron Family Endowment; BC Childhood Cancer Parents Association; Cure Search Foundation; Pediatric Brain Tumor Foundation; Brainchild; and the Government of Ontario.

Published
2018

14. A Hematogenous Route for Medulloblastoma Leptomeningeal Metastases

Author

Garzia, Livia, Kijima, Noriyuki, Morrissy, A Sorana, De Antonellis, Pasqualino, Guerreiro-Stucklin, Ana, Holgado, Borja L, Wu, Xiaochong, Wang, Xin, Parsons, Michael, Zayne, Kory, Manno, Alex, Kuzan-Fischer, Claudia, Nor, Carolina, Donovan, Laura K, Liu, Jessica, Qin, Lei, Garancher, Alexandra, Liu, Kun-Wei, Mansouri, Sheila, Luu, Betty, Thompson, Yuan Yao, Ramaswamy, Vijay, Peacock, John, Farooq, Hamza, Skowron, Patryk, Shih, David JH, Li, Angela, Ensan, Sherine, Robbins, Clinton S, Cybulsky, Myron, Mitra, Siddhartha, Ma, Yussanne, Moore, Richard, Mungall, Andy, Cho, Yoon-Jae, Weiss, William A, Chan, Jennifer A, Hawkins, Cynthia E, Massimino, Maura, Jabado, Nada, Zapotocky, Michal, Sumerauer, David, Bouffet, Eric, Dirks, Peter, Tabori, Uri, Sorensen, Poul HB, Brastianos, Priscilla K, Aldape, Kenneth, Jones, Steven JM, Marra, Marco A, Woodgett, James R, Wechsler-Reya, Robert J, Fults, Daniel W, and Taylor, Michael D

Subjects
Brain Cancer, Cancer, Neurosciences, Pediatric Cancer, Pediatric, Rare Diseases, Brain Disorders, Allografts, Animals, Cell Line, Tumor, Chemokine CCL2, Chromosomes, Human, Pair 10, Female, Humans, Male, Medulloblastoma, Meningeal Neoplasms, Mice, SCID, Neoplastic Cells, Circulating, Parabiosis, brain tumors, circulating tumor cells, medulloblastoma, metastases, pediatric cancer, Biological Sciences, Medical and Health Sciences, Developmental Biology
Abstract

While the preponderance of morbidity and mortality in medulloblastoma patients are due to metastatic disease, most research focuses on the primary tumor due to a dearth of metastatic tissue samples and model systems. Medulloblastoma metastases are found almost exclusively on the leptomeningeal surface of the brain and spinal cord; dissemination is therefore thought to occur through shedding of primary tumor cells into the cerebrospinal fluid followed by distal re-implantation on the leptomeninges. We present evidence for medulloblastoma circulating tumor cells (CTCs) in therapy-naive patients and demonstrate in vivo, through flank xenografting and parabiosis, that medulloblastoma CTCs can spread through the blood to the leptomeningeal space to form leptomeningeal metastases. Medulloblastoma leptomeningeal metastases express high levels of the chemokine CCL2, and expression of CCL2 in medulloblastoma in vivo is sufficient to drive leptomeningeal dissemination. Hematogenous dissemination of medulloblastoma offers a new opportunity to diagnose and treat lethal disseminated medulloblastoma.

Published
2018

15. Correction to: Integrated genomic analysis reveals actionable targets in pediatric spinal cord low-grade gliomas

Author

Misove, Adela, Vicha, Ales, Broz, Petr, Vanova, Katerina, Sumerauer, David, Stolova, Lucie, Sramkova, Lucie, Koblizek, Miroslav, Zamecnik, Josef, Kyncl, Martin, Holubova, Zuzana, Liby, Petr, Taborsky, Jakub, Benes, III, Vladimir, Pernikova, Ivana, Jones, David T. W., Sill, Martin, Stancokova, Terezia, Krskova, Lenka, and Zapotocky, Michal

Published
2022
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16. Gliomatosis cerebri in children: A poor prognostic phenotype of diffuse gliomas with a distinct molecular profile

Author

Nussbaumer, Gunther, primary, Benesch, Martin, additional, Grabovska, Yura, additional, Mackay, Alan, additional, Castel, David, additional, Grill, Jacques, additional, Alonso, Marta M, additional, Antonelli, Manila, additional, Bailey, Simon, additional, Baugh, Joshua N, additional, Biassoni, Veronica, additional, Blattner Johnson, Mirjam, additional, Broniscer, Alberto, additional, Carai, Andrea, additional, Colafati, Giovanna Stefania, additional, Colditz, Niclas, additional, Corbacioglu, Selim, additional, Crampsie, Shauna, additional, Entz-Werle, Natacha, additional, Eyrich, Matthias, additional, Friker, Lea L, additional, Frühwald, Michael C, additional, Garrè, Maria Luisa, additional, Gerber, Nicolas U, additional, Giangaspero, Felice, additional, Gil-da-Costa, Maria J, additional, Graf, Norbert, additional, Hargrave, Darren, additional, Hauser, Peter, additional, Herrlinger, Ulrich, additional, Hoffmann, Marion, additional, Hulleman, Esther, additional, Izquierdo, Elisa, additional, Jacobs, Sandra, additional, Karremann, Michael, additional, Kattamis, Antonis, additional, Kebudi, Rejin, additional, Kortmann, Rolf-Dieter, additional, Kwiecien, Robert, additional, Massimino, Maura, additional, Mastronuzzi, Angela, additional, Miele, Evelina, additional, Morana, Giovanni, additional, Noack, Claudia M, additional, Pentikainen, Virve, additional, Perwein, Thomas, additional, Pfister, Stefan M, additional, Pietsch, Torsten, additional, Roka, Kleoniki, additional, Rossi, Sabrina, additional, Rutkowski, Stefan, additional, Schiavello, Elisabetta, additional, Seidel, Clemens, additional, Štěrba, Jaroslav, additional, Sturm, Dominik, additional, Sumerauer, David, additional, Tacke, Anna, additional, Temelso, Sara, additional, Valentini, Chiara, additional, van Vuurden, Dannis, additional, Varlet, Pascale, additional, Veldhuijzen van Zanten, Sophie E M, additional, Vinci, Maria, additional, von Bueren, André O, additional, Warmuth-Metz, Monika, additional, Wesseling, Pieter, additional, Wiese, Maria, additional, Wolff, Johannes E A, additional, Zamecnik, Josef, additional, Morales La Madrid, Andrés, additional, Bison, Brigitte, additional, Gielen, Gerrit H, additional, Jones, David T W, additional, Jones, Chris, additional, and Kramm, Christof M, additional

Published
2024
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17. PATZ1 fusions define a novel molecularly distinct neuroepithelial tumor entity with a broad histological spectrum

Author

Alhalabi, Karam T., Stichel, Damian, Sievers, Philipp, Peterziel, Heike, Sommerkamp, Alexander C., Sturm, Dominik, Wittmann, Andrea, Sill, Martin, Jäger, Natalie, Beck, Pengbo, Pajtler, Kristian W., Snuderl, Matija, Jour, George, Delorenzo, Michael, Martin, Allison M., Levy, Adam, Dalvi, Nagma, Hansford, Jordan R., Gottardo, Nicholas G., Uro-Coste, Emmanuelle, Maurage, Claude-Alain, Godfraind, Catherine, Vandenbos, Fanny, Pietsch, Torsten, Kramm, Christof, Filippidou, Maria, Kattamis, Antonis, Jones, Chris, Øra, Ingrid, Mikkelsen, Torben Stamm, Zapotocky, Michal, Sumerauer, David, Scheie, David, McCabe, Martin, Wesseling, Pieter, Tops, Bastiaan B. J., Kranendonk, Mariëtte E. G., Karajannis, Matthias A., Bouvier, Nancy, Papaemmanuil, Elli, Dohmen, Hildegard, Acker, Till, von Hoff, Katja, Schmid, Simone, Miele, Evelina, Filipski, Katharina, Kitanovski, Lidija, Krskova, Lenka, Gojo, Johannes, Haberler, Christine, Alvaro, Frank, Ecker, Jonas, Selt, Florian, Milde, Till, Witt, Olaf, Oehme, Ina, Kool, Marcel, von Deimling, Andreas, Korshunov, Andrey, Pfister, Stefan M., Sahm, Felix, and Jones, David T. W.

Published
2021
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18. Gliomatosis cerebri in children:A poor prognostic phenotype of diffuse gliomas with a distinct molecul profile

Author

Nussbaumer, Gunther, Benesch, Martin, Grabovska, Yura, Mackay, Alan, Castel, David, Grill, Jacques, Alonso, Marta M., Antonelli, Manila, Bailey, Simon, Baugh, Joshua N., Biassoni, Veronica, Blattner-Johnson, Mirjam, Broniscer, Alberto, Carai, Andrea, Colafati, Giovanna Stefania, Colditz, Niclas, Corbacioglu, Selim, Crampsie, Shauna, Entz-Werle, Natacha, Eyrich, Matthias, Friker, Lea L., Frühwald, Michael C., Garrè, Maria Luisa, Gerber, Nicolas U., Giangaspero, Felice, Gil-Da-Costa, Maria J., Graf, Norbert, Hargrave, Darren, Hauser, Peter, Herrlinger, Ulrich, Hoffmann, Marion, Hulleman, Esther, Izquierdo, Elisa, Jacobs, Sandra, Karremann, Michael, Kattamis, Antonis, Kebudi, Rejin, Kortmann, Rolf Dieter, Kwiecien, Robert, Massimino, Maura, Mastronuzzi, Angela, Miele, Evelina, Morana, Giovanni, Noack, Claudia M., Pentikainen, Virve, Perwein, Thomas, Pfister, Stefan M., Pietsch, Torsten, Roka, Kleoniki, Rossi, Sabrina, Rutkowski, Stefan, Schiavello, Elisabetta, Seidel, Clemens, Štěrba, Jaroslav, Sturm, Dominik, Sumerauer, David, Tacke, Anna, Temelso, Sara, Valentini, Chiara, van Vuurden, Dannis, Varlet, Pascale, Veldhuijzen van Zanten, Sophie E.M., Vinci, Maria, von Bueren, André O., Warmuth-Metz, Monika, Wesseling, Pieter, Wiese, Maria, Wolff, Johannes E.A., Zamecnik, Josef, La Madrid, Andrés Morales, Bison, Brigitte, Gielen, Gerrit H., Jones, David T.W., Jones, Chris, Kramm, Christof M., Nussbaumer, Gunther, Benesch, Martin, Grabovska, Yura, Mackay, Alan, Castel, David, Grill, Jacques, Alonso, Marta M., Antonelli, Manila, Bailey, Simon, Baugh, Joshua N., Biassoni, Veronica, Blattner-Johnson, Mirjam, Broniscer, Alberto, Carai, Andrea, Colafati, Giovanna Stefania, Colditz, Niclas, Corbacioglu, Selim, Crampsie, Shauna, Entz-Werle, Natacha, Eyrich, Matthias, Friker, Lea L., Frühwald, Michael C., Garrè, Maria Luisa, Gerber, Nicolas U., Giangaspero, Felice, Gil-Da-Costa, Maria J., Graf, Norbert, Hargrave, Darren, Hauser, Peter, Herrlinger, Ulrich, Hoffmann, Marion, Hulleman, Esther, Izquierdo, Elisa, Jacobs, Sandra, Karremann, Michael, Kattamis, Antonis, Kebudi, Rejin, Kortmann, Rolf Dieter, Kwiecien, Robert, Massimino, Maura, Mastronuzzi, Angela, Miele, Evelina, Morana, Giovanni, Noack, Claudia M., Pentikainen, Virve, Perwein, Thomas, Pfister, Stefan M., Pietsch, Torsten, Roka, Kleoniki, Rossi, Sabrina, Rutkowski, Stefan, Schiavello, Elisabetta, Seidel, Clemens, Štěrba, Jaroslav, Sturm, Dominik, Sumerauer, David, Tacke, Anna, Temelso, Sara, Valentini, Chiara, van Vuurden, Dannis, Varlet, Pascale, Veldhuijzen van Zanten, Sophie E.M., Vinci, Maria, von Bueren, André O., Warmuth-Metz, Monika, Wesseling, Pieter, Wiese, Maria, Wolff, Johannes E.A., Zamecnik, Josef, La Madrid, Andrés Morales, Bison, Brigitte, Gielen, Gerrit H., Jones, David T.W., Jones, Chris, and Kramm, Christof M.

Abstract

Background: The term gliomatosis cerebri (GC), a radiology-defined highly infiltrating diffuse glioma, has been abandoned since molecular GC-associated features could not be established. Methods: We conducted a multinational retrospective study of 104 children and adolescents with GC providing comprehensive clinical and (epi-)genetic characterization. Results: Median overall survival (OS) was 15.5 months (interquartile range, 10.9–27.7) with a 2-year survival rate of 28%. Histopathological grading correlated significantly with median OS: CNS WHO grade II: 47.8 months (25.2–55.7); grade III: 15.9 months (11.4–26.3); grade IV: 10.4 months (8.8–14.4). By DNA methylation profiling (n = 49), most tumors were classified as pediatric-type diffuse high-grade glioma (pedHGG), H3-/IDH-wild-type (n = 31/49, 63.3%) with enriched subclasses pedHGG_RTK2 (n = 19), pedHGG_A/B (n = 6), and pedHGG_MYCN (n = 5), but only one pedHGG_RTK1 case. Within the pedHGG, H3-/IDH-wild-type subgroup, recurrent alterations in EGFR (n = 10) and BCOR (n = 9) were identified. Additionally, we observed structural aberrations in chromosome 6 in 16/49 tumors (32.7%) across tumor types. In the pedHGG, H3-/IDH-wild-type subgroup TP53 alterations had a significant negative effect on OS. Conclusions: Contrary to previous studies, our representative pediatric GC study provides evidence that GC has a strong predilection to arise on the background of specific molecular features (especially pedHGG_ RTK2, pedHGG_A/B, EGFR and BCOR mutations, chromosome 6 rearrangements).

Published
2024

19. Plerixafor combined with standard regimens for hematopoietic stem cell mobilization in pediatric patients with solid tumors eligible for autologous transplants: two-arm phase I/II study (MOZAIC)

Author

Morland, Bruce, Kepak, Tomas, Dallorso, Sandro, Sevilla, Julian, Murphy, Dermot, Luksch, Roberto, Yaniv, Isaac, Bader, Peter, Rößler, Jochen, Bisogno, Gianni, Maecker-Kolhoff, Britta, Lang, Peter, Zwaan, C. Michel, Sumerauer, David, Kriván, Gergely, Bernard, John, Liu, Qianying, Doyle, Eileen, and Locatelli, Franco

Published
2020
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20. Radiation-induced gliomas represent H3-/IDH-wild type pediatric gliomas with recurrent PDGFRA amplification and loss of CDKN2A/B

Author

Deng, Maximilian Y., Sturm, Dominik, Pfaff, Elke, Sill, Martin, Stichel, Damian, Balasubramanian, Gnana Prakash, Tippelt, Stephan, Kramm, Christof, Donson, Andrew M., Green, Adam L., Jones, Chris, Schittenhelm, Jens, Ebinger, Martin, Schuhmann, Martin U., Jones, Barbara C., van Tilburg, Cornelis M., Wittmann, Andrea, Golanov, Andrey, Ryzhova, Marina, Ecker, Jonas, Milde, Till, Witt, Olaf, Sahm, Felix, Reuss, David, Sumerauer, David, Zamecnik, Josef, Korshunov, Andrey, von Deimling, Andreas, Pfister, Stefan M., and Jones, David T. W.

Published
2021
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23. The molecular landscape of ETMR at diagnosis and relapse

Author

Lambo, Sander, Gröbner, Susanne N., Rausch, Tobias, Waszak, Sebastian M., Schmidt, Christin, Gorthi, Aparna, Romero, July Carolina, Mauermann, Monika, Brabetz, Sebastian, Krausert, Sonja, Buchhalter, Ivo, Koster, Jan, Zwijnenburg, Danny A., Sill, Martin, Hübner, Jens-Martin, Mack, Norman, Schwalm, Benjamin, Ryzhova, Marina, Hovestadt, Volker, Papillon-Cavanagh, Simon, Chan, Jennifer A., Landgraf, Pablo, Ho, Ben, Milde, Till, Witt, Olaf, Ecker, Jonas, Sahm, Felix, Sumerauer, David, Ellison, David W., Orr, Brent A., Darabi, Anna, Haberler, Christine, Figarella-Branger, Dominique, Wesseling, Pieter, Schittenhelm, Jens, Remke, Marc, Taylor, Michael D., Gil-da-Costa, Maria J., Łastowska, Maria, Grajkowska, Wiesława, Hasselblatt, Martin, Hauser, Peter, Pietsch, Torsten, Uro-Coste, Emmanuelle, Bourdeaut, Franck, Masliah-Planchon, Julien, Rigau, Valérie, Alexandrescu, Sanda, Wolf, Stephan, Li, Xiao-Nan, Schüller, Ulrich, Snuderl, Matija, Karajannis, Matthias A., Giangaspero, Felice, Jabado, Nada, von Deimling, Andreas, Jones, David T. W., Korbel, Jan O., von Hoff, Katja, Lichter, Peter, Huang, Annie, Bishop, Alexander J. R., Pfister, Stefan M., Korshunov, Andrey, and Kool, Marcel

Published
2019
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24. Diagnostics and treatment of diffuse intrinsic pontine glioma: where do we stand?

Author

El-Khouly, Fatma E., Veldhuijzen van Zanten, Sophie E. M., Santa-Maria Lopez, Vicente, Hendrikse, N. Harry, Kaspers, Gertjan J. L., Loizos, G., Sumerauer, David, Nysom, Karsten, Pruunsild, Kaie, Pentikainen, Virve, Thorarinsdottir, Halldora K., Rutkauskiene, Giedre, Calvagna, Victor, Drogosiewicz, Monika, Dragomir, Monica, Deak, Ladislav, Kitanovski, Lidija, von Bueren, Andre O., Kebudi, Rejin, Slavc, Irene, Jacobs, Sandra, Jadrijevic-Cvrlje, Filip, Entz-Werle, Natacha, Grill, Jacques, Kattamis, Antonis, Hauser, Peter, Pears, Jane, Biassoni, Veronica, Massimino, Maura, Lopez Aguilar, Enrique, Torsvik, Ingrid K., Joao Gil-da-Costa, Maria, Kumirova, Ella, Cruz-Martinez, Ofelia, Holm, Stefan, Bailey, Simon, Hayden, Tim, Thomale, Ulrich W., Janssens, Geert O. R., Kramm, Christof M., and van Vuurden, Dannis G.

Published
2019
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25. A multi-institutional retrospective pooled outcome analysis of molecularly annotated pediatric supratentorial ZFTA-fused ependymoma

Author

Ng, Chia Huan, primary, Obrecht, Denise, additional, Wells, Olivia, additional, Zapotocky, Michal, additional, Sumerauer, David, additional, Coltin, Hallie, additional, Khuong-Quang, Dong-Anh, additional, Eisenstat, David D, additional, Kinross, Kathryn M, additional, White, Christine L, additional, Algar, Elizabeth M, additional, Luck, Amanda, additional, Witt, Hendrik, additional, Schüller, Ulrich, additional, Mynarek, Martin, additional, Pietsch, Torsten, additional, Gerber, Nicolas U, additional, Benesch, Martin, additional, Warmuth-Metz, Monika, additional, Kortmann, Rolf, additional, Bison, Brigitte, additional, Taylor, Michael D, additional, Rutkowski, Stefan, additional, Pfister, Stefan M, additional, Jones, David T W, additional, Gottardo, Nicholas G, additional, von Hoff, Katja, additional, Pajtler, Kristian W, additional, Ramaswamy, Vijay, additional, and Hansford, Jordan R, additional

Published
2023
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27. A multi-institutional retrospective pooled outcome analysis of molecularly annotated pediatric supratentorial ZFTA-fused ependymoma

Author

Ng, Chia Huan, Obrecht, Denise, Wells, Olivia, Zapotocky, Michal, Sumerauer, David, Coltin, Hallie, Khuong-Quang, Dong-Anh, Eisenstat, David D; https://orcid.org/0000-0002-5976-0798, Kinross, Kathryn M, White, Christine L, Algar, Elizabeth M, Luck, Amanda, Witt, Hendrik, Schüller, Ulrich; https://orcid.org/0000-0002-8731-1121, Mynarek, Martin; https://orcid.org/0000-0003-3302-2719, Pietsch, Torsten, Gerber, Nicolas U, Benesch, Martin, Warmuth-Metz, Monika; https://orcid.org/0000-0002-3544-319X, Kortmann, Rolf, Bison, Brigitte, Taylor, Michael D, Rutkowski, Stefan, Pfister, Stefan M, Jones, David T W; https://orcid.org/0000-0002-2036-5141, Gottardo, Nicholas G; https://orcid.org/0000-0002-1082-6776, von Hoff, Katja; https://orcid.org/0000-0002-5669-8546, Pajtler, Kristian W; https://orcid.org/0000-0002-3562-6121, Ramaswamy, Vijay; https://orcid.org/0000-0002-6557-895X, Hansford, Jordan R; https://orcid.org/0000-0001-7733-383X, Ng, Chia Huan, Obrecht, Denise, Wells, Olivia, Zapotocky, Michal, Sumerauer, David, Coltin, Hallie, Khuong-Quang, Dong-Anh, Eisenstat, David D; https://orcid.org/0000-0002-5976-0798, Kinross, Kathryn M, White, Christine L, Algar, Elizabeth M, Luck, Amanda, Witt, Hendrik, Schüller, Ulrich; https://orcid.org/0000-0002-8731-1121, Mynarek, Martin; https://orcid.org/0000-0003-3302-2719, Pietsch, Torsten, Gerber, Nicolas U, Benesch, Martin, Warmuth-Metz, Monika; https://orcid.org/0000-0002-3544-319X, Kortmann, Rolf, Bison, Brigitte, Taylor, Michael D, Rutkowski, Stefan, Pfister, Stefan M, Jones, David T W; https://orcid.org/0000-0002-2036-5141, Gottardo, Nicholas G; https://orcid.org/0000-0002-1082-6776, von Hoff, Katja; https://orcid.org/0000-0002-5669-8546, Pajtler, Kristian W; https://orcid.org/0000-0002-3562-6121, Ramaswamy, Vijay; https://orcid.org/0000-0002-6557-895X, and Hansford, Jordan R; https://orcid.org/0000-0001-7733-383X

Abstract

BACKGROUND ZFTA-RELA (formerly known as c11orf-RELA) fused supratentorial ependymoma (ZFTAfus ST-EPN) has been recognized as a novel entity in the 2016 WHO classification of CNS tumors and further defined in the recent 2021 edition. ZFTAfus ST-EPN was reported to portend poorer prognosis when compared to its counterpart, YAP1 ST-EPN in some previously published series. The aim of this study was to determine the treatment outcome of molecularly confirmed and conventionally treated ZFTAfus ST-EPN patients treated in multiple institutions. METHODS We conducted a retrospective analysis of all pediatric patients with molecularly confirmed ZFTAfus ST-EPN patients treated in multiple institutions in 5 different countries (Australia, Canada, Germany, Switzerland, and Czechia). Survival outcomes were analyzed and correlated with clinical characteristics and treatment approaches. RESULTS A total of 108 patients were collated from multiple institutions in 5 different countries across three continents. We found across the entire cohort that the 5- and 10-year PFS were 65% and 63%, respectively. The 5- and 10-year OS of this cohort of patients were 87% and 73%. The rates of gross total resection (GTR) were high with 84 out of 108 (77.8%) patients achieving GTR. The vast majority of patients also received post-operative radiotherapy, 98 out of 108 (90.7%). Chemotherapy did not appear to provide any survival benefit in our patient cohort. CONCLUSION This is the largest study to date of contemporaneously treated molecularly confirmed ZFTAfus ST-EPN patients which identified markedly improved survival outcomes compared to previously published series. This study also re-emphasizes the importance of maximal surgical resection in achieving optimal outcomes in pediatric patients with supratentorial ependymoma.

Published
2023

29. Development of the SIOPE DIPG network, registry and imaging repository: a collaborative effort to optimize research into a rare and lethal disease

Author

Veldhuijzen van Zanten, Sophie E. M., Baugh, Joshua, Chaney, Brooklyn, De Jongh, Dennis, Sanchez Aliaga, Esther, Barkhof, Frederik, Noltes, Johan, De Wolf, Ruben, Van Dijk, Jet, Cannarozzo, Antonio, Damen-Korbijn, Carin M., Lieverst, Jan A., Colditz, Niclas, Hoffmann, Marion, Warmuth-Metz, Monika, Bison, Brigitte, Jones, David T. W., Sturm, Dominik, Gielen, Gerrit H., Jones, Chris, Hulleman, Esther, Calmon, Raphael, Castel, David, Varlet, Pascale, Giraud, Géraldine, Slavc, Irene, Van Gool, Stefaan, Jacobs, Sandra, Jadrijevic-Cvrlje, Filip, Sumerauer, David, Nysom, Karsten, Pentikainen, Virve, Kivivuori, Sanna-Maria, Leblond, Pierre, Entz-Werle, Natasha, von Bueren, Andre O., Kattamis, Antonis, Hargrave, Darren R., Hauser, Péter, Garami, Miklos, Thorarinsdottir, Halldora K., Pears, Jane, Gandola, Lorenza, Rutkauskiene, Giedre, Janssens, Geert O., Torsvik, Ingrid K., Perek-Polnik, Marta, Gil-da-Costa, Maria J., Zheludkova, Olga, Shats, Liudmila, Deak, Ladislav, Kitanovski, Lidija, Cruz, Ofelia, Morales La Madrid, Andres, Holm, Stefan, Gerber, Nicolas, Kebudi, Rejin, Grundy, Richard, Lopez-Aguilar, Enrique, Zapata-Tarres, Marta, Emmerik, John, Hayden, Tim, Bailey, Simon, Biassoni, Veronica, Massimino, Maura, Grill, Jacques, Vandertop, William P., Kaspers, Gertjan J. L., Fouladi, Maryam, Kramm, Christof M., van Vuurden, Dannis G., and on behalf of the members of the SIOPE DIPG Network

Published
2017
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31. Evaluation of the growth rates and related prognostic factors in radiation-induced meningiomas

Author

Entenmann, Christian Joachim, primary, Bubeníková, Adéla, additional, Blažková, Jana, additional, Zápotocký, Michal, additional, Kruseová, Jarmila, additional, Sumerauer, David, additional, Trková, Kateřina, additional, Sochová, Vladimíra, additional, Koblížek, Miroslav, additional, Kynčl, Martin, additional, Malinová, Běla, additional, Bradáč, Ondřej, additional, and Beneš, Vladimír, additional

Published
2022
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33. Genomic predictors of response to PD-1 inhibition in children with germline DNA replication repair deficiency

Author

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

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.

Published
2022

34. Hypertenze, na kterou enalapril nestačil, u chlapce s rekurencí akutní myokarditidy.

Author

Ulrich, Simona, Drahokoupilová, Eva, Sumerauer, David, Konopásek, Patrik, Slámová, Lucie, and Šrámková, Lucie

Subjects
ESSENTIAL hypertension, PARAGANGLIOMA, THERAPEUTICS, RETROPERITONEUM, HYPERTENSION, MYOCARDITIS
Abstract

Copyright of Pediatrie pro Praxi is the property of SOLEN sro and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

Published
2023
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35. NFB-13. Rhabdoid Tumor Predisposition Syndrome (RTPS) – Finding Evidence by systematic Analyses

Author

Nemes, Karolina, primary, Bens, Susanne, additional, Johann, Pascal D, additional, Steinbügl, Mona, additional, Gruhle, Miriam, additional, Kachanov, Denis, additional, Teleshova, Margarita, additional, Hauser, Peter, additional, Simon, Thorsten, additional, Tippelt, Stephan, additional, Eberl, Wolfgang, additional, Woessmann, Wilhelm, additional, Kratz, Christian, additional, Abbink, Floor, additional, Hernáiz-Driever, Pablo, additional, Eyrich, Matthias, additional, Sumerauer, David, additional, Milde, Till, additional, Reinhard, Harald, additional, Leipold, Alfred, additional, de Wetering, Marianne v, additional, Gil-da-Costa, Maria João, additional, Ebetsberger-Dachs, Georg, additional, Marques, Carmen Hernandez, additional, Bauer, Nina, additional, Biassoni, Veronica, additional, Meneses, Clarice Franco, additional, Knirsch, Stephanie, additional, Lauten, Melchior, additional, Gerber, Nicolas U, additional, Chada, Martin, additional, Kerl, Kornelius, additional, Lemmer, Andreas, additional, Heidrun, Boztug, additional, Kuhlen, Michaela, additional, Furtwängler, Rhoikos, additional, Kordes, Uwe, additional, Schneppenheim, Reiner, additional, Vokuhl, Christian, additional, Hasselblatt, Martin, additional, Kröncke, Thomas, additional, Bison, Brigitte, additional, Melchior, Patrick, additional, Timmermann, Beate, additional, Gerss, Joachim, additional, Siebert, Reiner, additional, and Frühwald, Michael C, additional

Published
2022
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36. SURG-05. Survival and functional outcomes in pediatric thalamic and thalamopeduncular low grade gliomas

Author

Benes, Vladimir, primary, Zapotocky, Michal, additional, Liby, Petr, additional, Taborsky, Jakub, additional, Blazkova Jr., Jana, additional, Blazkova Sr., Jana, additional, Sumerauer, David, additional, Misove, Adela, additional, Pernikova, Ivana, additional, Kyncl, Martin, additional, Krskova, Lenka, additional, Koblizek, Miroslav, additional, Zamecnik, Josef, additional, Bradac, Ondrej, additional, and Tichy, Michal, additional

Published
2022
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37. HGG-49. Gliomatosis cerebri in children: A collaborative report from the European Society for Pediatric Oncology (SIOPE)

Author

Nussbaumer, Gunther, primary, Benesch, Martin, additional, Gielen, Gerrit H, additional, Castel, David, additional, Grill, Jacques, additional, Alonso Roldán, Marta M, additional, Antonelli, Manila, additional, Bailey, Simon, additional, Baugh, Joshua N, additional, Biassoni, Veronica, additional, Carai, Andrea, additional, Colditz, Niclas, additional, Colefati, Giovanni Stefania, additional, Corbacioglu, Selim, additional, Crampsie, Shauna, additional, Entz-Werle, Natacha, additional, Eyrich, Matthias, additional, Frühwald, Michael C, additional, Garrè, Maria Luisa, additional, Gerber, Nicolas U, additional, Giangaspero, Felice, additional, Gil-da-Costa, Maria João, additional, Grabovska, Yura, additional, Graf, Norbert, additional, Hargrave, Darren, additional, Hauser, Peter, additional, Hoffmann, Marion, additional, Hulleman, Esther, additional, Jacobs, Sandra, additional, Karremann, Michael, additional, Kattamis, Antonis, additional, Kebudi, Rejin, additional, Kortmann, Rolf-Dieter, additional, Kwiecien, Robert, additional, Mackay, Alan, additional, Massimino, Maura, additional, Miele, Evelina, additional, Mastronuzzi, Angela, additional, Morana, Giovanni, additional, Noack, Claudia M, additional, Pentikainen, Virve, additional, Perwein, Thomas, additional, Pfister, Stefan M, additional, Pietsch, Torsten, additional, Roka, Kleoniki, additional, Rossi, Sabrina, additional, Rutkowski, Stefan, additional, Schiavello, Elisabetta, additional, Štěrba, Jaroslav, additional, Sturm, Dominik, additional, Sumerauer, David, additional, Temelso, Sara, additional, van Vuurden, Dannis, additional, Varlet, Pascale, additional, Veldhuijzen van Zanten, Sophie E M, additional, Vinci, Maria, additional, von Bueren, André O, additional, Warmuth-Metz, Monika, additional, Wesseling, Pieter, additional, Wiese, Maria, additional, Wolff, Johannes E A, additional, Zamecnik, Josef, additional, Jones, David T W, additional, Bison, Brigitte, additional, La Madrid, Andrés Morales, additional, Jones, Chris, additional, and Kramm, Christof M, additional

Published
2022
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39. Additional file 2 of Integrated genomic analysis reveals actionable targets in pediatric spinal cord low-grade gliomas

Author

Misove, Adela, Vicha, Ales, Broz, Petr, Vanova, Katerina, Sumerauer, David, Stolova, Lucie, Sramkova, Lucie, Koblizek, Miroslav, Zamecnik, Josef, Kyncl, Martin, Holubova, Zuzana, Liby, Petr, Taborsky, Jakub, Benes, Vladimir, Pernikova, Ivana, Jones, David T. W., Sill, Martin, Stancokova, Terezia, Krskova, Lenka, and Zapotocky, Michal

Abstract

Additional file 2: Table S2. Table showing the complete sLGGs cohort emphasizing the original histology before molecular pathology reevaluation, anatomical location, and molecular-biology data.

Published
2022
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40. Poorly differentiated chordoma with SMARCB1/INI1 loss: a distinct molecular entity with dismal prognosis

Author

Hasselblatt, Martin, Thomas, Christian, Hovestadt, Volker, Schrimpf, Daniel, Johann, Pascal, Bens, Susanne, Oyen, Florian, Peetz-Dienhart, Susanne, Crede, Yvonne, Wefers, Annika, Vogel, Hannes, Riemenschneider, Markus J., Antonelli, Manila, Giangaspero, Felice, Bernardo, Marie Christine, Giannini, Caterina, Ud Din, Nasir, Perry, Arie, Keyvani, Kathy, van Landeghem, Frank, Sumerauer, David, Hauser, Peter, Capper, David, Korshunov, Andrey, Jones, David T. W., Pfister, Stefan M., Schneppenheim, Reinhard, Siebert, Reiner, Frühwald, Michael C., and Kool, Marcel

Published
2016
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41. Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study

Author

von Hoff, Katja, Haberler, Christine, Schmitt-Hoffner, Felix, Schepke, Elizabeth, de Rojas, Teresa, Jacobs, Sandra, Zapotocky, Michal, Sumerauer, David, Perek-Polnik, Marta, Dufour, Christelle, van Vuurden, Dannis, Slavc, Irene, Gojo, Johannes, Pickles, Jessica C, Gerber, Nicolas U, Massimino, Maura, Gil-da-Costa, Maria Joao, Garami, Miklos, Kumirova, Ella, Sehested, Astrid, Scheie, David, Cruz, Ofelia, Moreno, Lucas, Cho, Jaeho, Zeller, Bernward, Bovenschen, Niels, Grotzer, Michael, Alderete, Daniel, Snuderl, Matija, Zheludkova, Olga, et al, University of Zurich, and von Hoff, Katja

Subjects
2728 Neurology (clinical), 10036 Medical Clinic, 610 Medicine & health, 2730 Oncology, 1306 Cancer Research
Published
2021
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43. Clinical evidence for a biological effect of epigenetically active decitabine in relapsed or progressive rhabdoid tumors

Author

Steinbügl, Mona, primary, Nemes, Karolina, additional, Johann, Pascal, additional, Kröncke, Thomas, additional, Tüchert, Stefanie, additional, da Costa, Maria Joao Gil, additional, Ebinger, Martin, additional, Schüller, Ulrich, additional, Sehested, Astrid, additional, Hauser, Peter, additional, Reinhard, Harald, additional, Sumerauer, David, additional, Hettmer, Simone, additional, Jakob, Marcus, additional, Hasselblatt, Martin, additional, Siebert, Reiner, additional, Witt, Olaf, additional, Gerss, Joachim, additional, Kerl, Kornelius, additional, and Frühwald, Michael C., additional

Published
2021
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44. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author

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

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

45. Survival Benefit for Individuals With Constitutional Mismatch Repair Deficiency Undergoing Surveillance

Author

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

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

46. Therapeutic implications of improved molecular diagnostics for rare CNS-embryonal tumor entities: results of an international, retrospective study

Author

Pathologie Groep Bovenschen, Infection & Immunity, Cancer, Pathologie Pathologen staf, Brain, von Hoff, Katja, Haberler, Christine, Schmitt-Hoffner, Felix, Schepke, Elizabeth, de Rojas, Teresa, Jacobs, Sandra, Zapotocky, Michal, Sumerauer, David, Perek-Polnik, Marta, Dufour, Christelle, van Vuurden, Dannis, Slavc, Irene, Gojo, Johannes, Pickles, Jessica C, Gerber, Nicolas U, Massimino, Maura, Gil-da-Costa, Maria Joao, Garami, Miklos, Kumirova, Ella, Sehested, Astrid, Scheie, David, Cruz, Ofelia, Moreno, Lucas, Cho, Jaeho, Zeller, Bernward, Bovenschen, Niels, Grotzer, Michael, Alderete, Daniel, Snuderl, Matija, Zheludkova, Olga, Golanov, Andrey, Okonechnikov, Konstantin, Mynarek, Martin, Juhnke, B Ole, Rutkowski, Stefan, Schüller, Ulrich, Pizer, Barry, Zezschwitz, Barbara V, Kwiecien, Robert, Wechsung, Maximilian, Konietschke, Frank, Hwang, Eugene I, Sturm, Dominik, Pfister, Stefan M, von Deimling, Andreas, Rushing, Elisabeth J, Ryzhova, Marina, Hauser, Peter, Łastowska, Maria, Wesseling, Pieter, Giangaspero, Felice, Hawkins, Cynthia, Figarella-Branger, Dominique, Eberhart, Charles, Burger, Peter, Gessi, Marco, Korshunov, Andrey, Jacques, Tom S, Capper, David, Pietsch, Torsten, Kool, Marcel, Pathologie Groep Bovenschen, Infection & Immunity, Cancer, Pathologie Pathologen staf, Brain, von Hoff, Katja, Haberler, Christine, Schmitt-Hoffner, Felix, Schepke, Elizabeth, de Rojas, Teresa, Jacobs, Sandra, Zapotocky, Michal, Sumerauer, David, Perek-Polnik, Marta, Dufour, Christelle, van Vuurden, Dannis, Slavc, Irene, Gojo, Johannes, Pickles, Jessica C, Gerber, Nicolas U, Massimino, Maura, Gil-da-Costa, Maria Joao, Garami, Miklos, Kumirova, Ella, Sehested, Astrid, Scheie, David, Cruz, Ofelia, Moreno, Lucas, Cho, Jaeho, Zeller, Bernward, Bovenschen, Niels, Grotzer, Michael, Alderete, Daniel, Snuderl, Matija, Zheludkova, Olga, Golanov, Andrey, Okonechnikov, Konstantin, Mynarek, Martin, Juhnke, B Ole, Rutkowski, Stefan, Schüller, Ulrich, Pizer, Barry, Zezschwitz, Barbara V, Kwiecien, Robert, Wechsung, Maximilian, Konietschke, Frank, Hwang, Eugene I, Sturm, Dominik, Pfister, Stefan M, von Deimling, Andreas, Rushing, Elisabeth J, Ryzhova, Marina, Hauser, Peter, Łastowska, Maria, Wesseling, Pieter, Giangaspero, Felice, Hawkins, Cynthia, Figarella-Branger, Dominique, Eberhart, Charles, Burger, Peter, Gessi, Marco, Korshunov, Andrey, Jacques, Tom S, Capper, David, Pietsch, Torsten, and Kool, Marcel

Published
2021

49. Enhancer hijacking activates GFI1 family oncogenes in medulloblastoma

Author

Northcott, Paul A., Lee, Catherine, Zichner, Thomas, Stütz, Adrian M., Erkek, Serap, Kawauchi, Daisuke, Shih, David J. H., Hovestadt, Volker, Zapatka, Marc, Sturm, Dominik, Jones, David T. W., Kool, Marcel, Remke, Marc, Cavalli, Florence M. G., Zuyderduyn, Scott, Bader, Gary D., VandenBerg, Scott, Esparza, Lourdes Adriana, Ryzhova, Marina, Wang, Wei, Wittmann, Andrea, Stark, Sebastian, Sieber, Laura, Seker-Cin, Huriye, Linke, Linda, Kratochwil, Fabian, Jäger, Natalie, Buchhalter, Ivo, Imbusch, Charles D., Zipprich, Gideon, Raeder, Benjamin, Schmidt, Sabine, Diessl, Nicolle, Wolf, Stephan, Wiemann, Stefan, Brors, Benedikt, Lawerenz, Chris, Eils, Jürgen, Warnatz, Hans-Jörg, Risch, Thomas, Yaspo, Marie-Laure, Weber, Ursula D., Bartholomae, Cynthia C., von Kalle, Christof, Turányi, Eszter, Hauser, Peter, Sanden, Emma, Darabi, Anna, Siesjö, Peter, Sterba, Jaroslav, Zitterbart, Karel, Sumerauer, David, van Sluis, Peter, Versteeg, Rogier, Volckmann, Richard, Koster, Jan, Schuhmann, Martin U., Ebinger, Martin, Grimes, Leighton H., Robinson, Giles W., Gajjar, Amar, Mynarek, Martin, von Hoff, Katja, Rutkowski, Stefan, Pietsch, Torsten, Scheurlen, Wolfram, Felsberg, Jörg, Reifenberger, Guido, Kulozik, Andreas E., von Deimling, Andreas, Witt, Olaf, Eils, Roland, Gilbertson, Richard J., Korshunov, Andrey, Taylor, Michael D., Lichter, Peter, Korbel, Jan O., Wechsler-Reya, Robert J., and Pfister, Stefan M.

Published
2014
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50. Therapeutic implications of improved molecular diagnostics for rare CNS embryonal tumor entities: results of an international, retrospective study

Author

von Hoff, Katja, primary, Haberler, Christine, additional, Schmitt-Hoffner, Felix, additional, Schepke, Elizabeth, additional, de Rojas, Teresa, additional, Jacobs, Sandra, additional, Zapotocky, Michal, additional, Sumerauer, David, additional, Perek-Polnik, Marta, additional, Dufour, Christelle, additional, van Vuurden, Dannis, additional, Slavc, Irene, additional, Gojo, Johannes, additional, Pickles, Jessica C, additional, Gerber, Nicolas U, additional, Massimino, Maura, additional, Gil-da-Costa, Maria Joao, additional, Garami, Miklos, additional, Kumirova, Ella, additional, Sehested, Astrid, additional, Scheie, David, additional, Cruz, Ofelia, additional, Moreno, Lucas, additional, Cho, Jaeho, additional, Zeller, Bernward, additional, Bovenschen, Niels, additional, Grotzer, Michael, additional, Alderete, Daniel, additional, Snuderl, Matija, additional, Zheludkova, Olga, additional, Golanov, Andrey, additional, Okonechnikov, Konstantin, additional, Mynarek, Martin, additional, Juhnke, Björn Ole, additional, Rutkowski, Stefan, additional, Schüller, Ulrich, additional, Pizer, Barry, additional, von Zezschwitz, Barbara, additional, Kwiecien, Robert, additional, Wechsung, Maximilian, additional, Konietschke, Frank, additional, Hwang, Eugene I, additional, Sturm, Dominik, additional, Pfister, Stefan M, additional, von Deimling, Andreas, additional, Rushing, Elisabeth J, additional, Ryzhova, Marina, additional, Hauser, Peter, additional, Łastowska, Maria, additional, Wesseling, Pieter, additional, Giangaspero, Felice, additional, Hawkins, Cynthia, additional, Figarella-Branger, Dominique, additional, Eberhart, Charles, additional, Burger, Peter, additional, Gessi, Marco, additional, Korshunov, Andrey, additional, Jacques, Tom S, additional, Capper, David, additional, Pietsch, Torsten, additional, and Kool, Marcel, additional

Published
2021
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