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Arafah O, Maher E, Mosaab A, Naguib E, Refaat A, Ahmed S, Taha H, El-Beltagy M, El-Ayadi M. High-grade glioma in infants and very young children: characteristics, treatment, and outcomes. Childs Nerv Syst 2024; 40:2667-2675. [PMID: 38943024 DOI: 10.1007/s00381-024-06501-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/01/2024] [Accepted: 06/10/2024] [Indexed: 06/30/2024]
Abstract
PURPOSE High-grade gliomas in infants and very young children (less than 3 to 5 years old) pose significant challenges due to the limited scientific literature available and high risks associated with treatments. This study aims to investigate their characteristics, treatment, and outcomes. METHODS A cohort study was conducted at Children's Cancer Hospital, Egypt. Cases included children aged < 5 years old with confirmed CNS high-grade glioma. Baseline clinical and radiological characteristics, besides potential prognostic factors were assessed. RESULTS In total, 76 cases were identified, 7 of them were < 1 year old. Gross- or near-total resection (GTR/NTR) was achieved in 32.9% of all cases. Of the tested cases, H3K27M-alteration was present in 5 subjects only. The 3-year OS and EFS for all cases were 26.9% and 15.4%, respectively. Extent of resection was the most important prognostic factor, as those achieving GTR/NTR experienced more than double the survival compared to those who do not (p = 0.05). Age had a "bimodal" effect on EFS, with those aged 1 to 3 years old faring better than younger and older age groups. Subjects with midline tumors had worse survival compared to non-midline tumors (1-year EFS = 18.5% vs 35%, respectively, p = 0.02). CONCLUSION This study in a large cohort of HGG in infants and very young children offers insights into the characteristics and treatment challenges. Extent of resection, age group, and tumor localization are important prognostic factors. Further research with larger sample size is warranted to refine treatment approaches and improve outcomes.
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Affiliation(s)
- Omar Arafah
- Department of Pediatric Oncology, National Cancer Institute, Cairo University, Giza, Egypt
| | - Eslam Maher
- Clinical Research Unit, Children's Cancer Hospital, Cairo, Egypt
| | - Amal Mosaab
- Basic Research Unit, Children's Cancer Hospital, Cairo, Egypt
| | - Eman Naguib
- Pathology Department, Children's Cancer Hospital, Cairo, Egypt
- Department of Pathology, National Cancer Institute, Cairo University, Giza, Egypt
| | - Amal Refaat
- Department of Radiodiagnosis, National Cancer Institute, Cairo University, Giza, Egypt
- Department of Radiodiagnosis, Children's Cancer Hospital, Cairo, Egypt
| | - Soha Ahmed
- Clinical Oncology Department, Suez University, Suez, Egypt
| | - Hala Taha
- Pathology Department, Children's Cancer Hospital, Cairo, Egypt
- Department of Pathology, National Cancer Institute, Cairo University, Giza, Egypt
| | - Mohamed El-Beltagy
- Department of Neurosurgery, Children's Cancer Hospital, Cairo, Egypt
- Department of Neurosurgery, Kasr Al-Ainy School of Medicine, Cairo University, Cairo, Egypt
| | - Moatasem El-Ayadi
- Department of Pediatric Oncology, National Cancer Institute, Cairo University, Giza, Egypt.
- Department of Pediatric Oncology, Children's Cancer Hospital, Cairo, Egypt.
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Zuckermann M, He C, Andrews J, Bagchi A, Sloan-Henry R, Bianski B, Xie J, Wang Y, Twarog N, Onar-Thomas A, Ernst KJ, Yang L, Li Y, Zhu X, Ocasio JK, Budd KM, Dalton J, Li X, Chepyala D, Zhang J, Xu K, Hover L, Roach JT, Chan KCH, Hofmann N, McKinnon PJ, Pfister SM, Shelat AA, Rankovic Z, Freeman BB, Chiang J, Jones DTW, Tinkle CL, Baker SJ. Capmatinib is an effective treatment for MET-fusion driven pediatric high-grade glioma and synergizes with radiotherapy. Mol Cancer 2024; 23:123. [PMID: 38849845 PMCID: PMC11157767 DOI: 10.1186/s12943-024-02027-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2023] [Accepted: 05/21/2024] [Indexed: 06/09/2024] Open
Abstract
BACKGROUND Pediatric-type diffuse high-grade glioma (pHGG) is the most frequent malignant brain tumor in children and can be subclassified into multiple entities. Fusion genes activating the MET receptor tyrosine kinase often occur in infant-type hemispheric glioma (IHG) but also in other pHGG and are associated with devastating morbidity and mortality. METHODS To identify new treatment options, we established and characterized two novel orthotopic mouse models harboring distinct MET fusions. These included an immunocompetent, murine allograft model and patient-derived orthotopic xenografts (PDOX) from a MET-fusion IHG patient who failed conventional therapy and targeted therapy with cabozantinib. With these models, we analyzed the efficacy and pharmacokinetic properties of three MET inhibitors, capmatinib, crizotinib and cabozantinib, alone or combined with radiotherapy. RESULTS Capmatinib showed superior brain pharmacokinetic properties and greater in vitro and in vivo efficacy than cabozantinib or crizotinib in both models. The PDOX models recapitulated the poor efficacy of cabozantinib experienced by the patient. In contrast, capmatinib extended survival and induced long-term progression-free survival when combined with radiotherapy in two complementary mouse models. Capmatinib treatment increased radiation-induced DNA double-strand breaks and delayed their repair. CONCLUSIONS We comprehensively investigated the combination of MET inhibition and radiotherapy as a novel treatment option for MET-driven pHGG. Our seminal preclinical data package includes pharmacokinetic characterization, recapitulation of clinical outcomes, coinciding results from multiple complementing in vivo studies, and insights into molecular mechanism underlying increased efficacy. Taken together, we demonstrate the groundbreaking efficacy of capmatinib and radiation as a highly promising concept for future clinical trials.
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Affiliation(s)
- Marc Zuckermann
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, Germany.
- Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany.
| | - Chen He
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jared Andrews
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Aditi Bagchi
- Department of Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Roketa Sloan-Henry
- Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Brandon Bianski
- Department of Radiation Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jia Xie
- Department of Radiation Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Yingzhe Wang
- Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Nathaniel Twarog
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Arzu Onar-Thomas
- Department of Biostatistics, Departments of BiostatisticsSt. Jude Children's Research Hospital, Memphis, 262 Danny Thomas Place, TN, 38105, USA
| | - Kati J Ernst
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Lei Yang
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Yong Li
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Xiaoyan Zhu
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jennifer K Ocasio
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Kaitlin M Budd
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
- St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - James Dalton
- Department of Pathology, Departments of PathologySt. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Xiaoyu Li
- Department of Pathology, Departments of PathologySt. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Divyabharathi Chepyala
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Junyuan Zhang
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Ke Xu
- Center for Applied Bioinformatics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Laura Hover
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jordan T Roach
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
- St. Jude Graduate School of Biomedical Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Kenneth Chun-Ho Chan
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
| | - Nina Hofmann
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Peter J McKinnon
- Center for Pediatric Neurological Disease Research, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Stefan M Pfister
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Im Neuenheimer Feld 280, Heidelberg, Germany
- Department of Pediatric Oncology, Hematology and Immunology, Heidelberg University Hospital, Im Neuenheimer Feld 400, 69120, Heidelberg, Germany
| | - Anang A Shelat
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Zoran Rankovic
- Department of Chemical Biology and Therapeutics, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Burgess B Freeman
- Preclinical Pharmacokinetics Shared Resource, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Jason Chiang
- Department of Pathology, Departments of PathologySt. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - David T W Jones
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, Heidelberg, Germany
| | - Christopher L Tinkle
- Department of Radiation Oncology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA
| | - Suzanne J Baker
- Department of Developmental Neurobiology, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
- Center Of Excellence in Neuro-Oncology Sciences, St. Jude Children's Research Hospital, 262 Danny Thomas Place, Memphis, TN, 38105, USA.
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3
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Kumaria A, Kirkman MA, Howarth SP, Macarthur DC. Beating a skullduggerous infantile hemispheric high-grade glioma. Br J Neurosurg 2024; 38:544-545. [PMID: 33769175 DOI: 10.1080/02688697.2021.1905774] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/09/2021] [Accepted: 03/16/2021] [Indexed: 10/21/2022]
Abstract
A case of infantile hemispheric high grade glioma in a five-month-old boy is presented. Striking images of a 'beaten copper pot' skull were concerning at first, but with a successful surgical and oncological plan he is well three years later, displaying only minor signs of developmental delay.
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Affiliation(s)
- Ashwin Kumaria
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
| | | | - Simon P Howarth
- Department of Neurosurgery, Queen's Medical Centre, Nottingham, UK
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4
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Starling MTM, Pereira AAL, Arruda GV, Paiva WS, Neville IS, Restin FCF, Gouveia AG, de Sousa CFPM, Maldaun MVC, Pahl FH, Hanna SA, de Moraes FY, Marta GN. Brazilian pediatric patients with gliomas: treatment characteristics and survival outcomes. Rep Pract Oncol Radiother 2024; 29:90-96. [PMID: 39165603 PMCID: PMC11333073 DOI: 10.5603/rpor.99356] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2023] [Accepted: 01/23/2024] [Indexed: 08/22/2024] Open
Abstract
Background The current study aimed to determine the overall survival (OS) rates of patients diagnosed with pediatric gliomas in Brazil, accounting for the influence of age, treatment modalities, and tumor site, using a population-based national database. Materials and methods Patients diagnosed with pediatric gliomas of central nervous system (CNS) from 1999-2020 were identified from The Fundação Oncocentro de São Paulo public database. The Kaplan-Meier and the log-rank test were used for survival analysis. Results A total of 1296 patients were included. The most common histologic tumor types were glioblastomas (38.27%; n = 496), pilocytic astrocytoma (32.87%; n = 426), and astrocytoma grade II (20.76%; n = 269). A total of 379 (29.24%) had brainstem tumors. The mean follow-up was 135 months [95% confidence interval (CI) 128-142\. The 1-year, 3-year 5-year OS for pilocytic astrocytoma were 93.72%, 89.98%, and 88.97%; for grade II gliomas, 80.36%, 71.89%, and 68.60%; for grade III gliomas, 53.72%; 31.87%, and 28.33%; and for glioblastoma, 52.90%, 28.76%, 25.20%, respectively. Brainstem tumors had the worse OS compared to no brainstem tumors (p = 0.001). For high-grade glioma (grade III/IV), excluding brainstem tumors (n = 570), young patients had greater median OS (0 to 3 years:22 months; 4 to 18 years:13 months; p = 0.005). Regarding the treatment modalities, combined treatments were associated with higher median survival compared to less intensive therapy (surgery: 11 months; surgery and chemotherapy: 16 months; surgery, radiotherapy, and chemotherapy: 20 months; p = 0.005). Conclusion In our cohort, low-grade gliomas had favorable prognoses and outcomes. Patients diagnosed with glioblastomas and brainstem gliomas had the worst OS. For high-grade gliomas, undergoing treatment de-intensification in the Brazilian pediatric population is associated with worse survival.
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Affiliation(s)
| | | | - Gustavo Viani Arruda
- Ribeirão Preto Medical School, Department of Medical Imaging, Hematology and Oncology of University of São Paulo (FMRP-USP), Ribeirão Preto, SP, Brazil
- Latin America Cooperative Oncology Group (LACOG), Porto Alegre, Brazil
| | - Wellingson Silva Paiva
- Division of Neurosurgery Department of Neurology Faculdade de Medicina da Universidade de São Paulo São Paulo, Brazil
| | - Iuri Santana Neville
- Division of Neurosurgery Department of Neurology Faculdade de Medicina da Universidade de São Paulo São Paulo, Brazil
- Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
| | | | - André Guimarães Gouveia
- Juravinski Cancer Centre, Department of Oncology, Division of Radiation Oncology, Hamilton, ON, Canada
- Latin America Cooperative Oncology Group (LACOG), Porto Alegre, Brazil
| | | | | | | | | | - Fabio Ynoe de Moraes
- Department of Oncology, Queen's University, Kingston, ON, Canada
- Latin America Cooperative Oncology Group (LACOG), Porto Alegre, Brazil
| | - Gustavo Nader Marta
- Department of Radiation Oncology, Hospital Sírio-Libanês, São Paulo, Brazil
- Latin America Cooperative Oncology Group (LACOG), Porto Alegre, Brazil
- Postgraduation program of Departamento de Radiologia e Oncologia, Faculdade de Medicina FMUSP, Universidade de Sao Paulo, Sao Paulo, Brazil
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5
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Chiang J, Bagchi A, Li X, Dhanda SK, Huang J, Pinto SN, Sioson E, Dalton J, Tatevossian RG, Jia S, Partap S, Fisher PG, Bowers DC, Hassall TEG, Lu C, Zaldivar-Peraza A, Wright KD, Broniscer A, Qaddoumi I, Upadhyaya SA, Vinitsky A, Sabin ND, Orr BA, Klimo P, Boop FA, Ashford JM, Conklin HM, Onar-Thomas A, Zhou X, Ellison DW, Gajjar A, Robinson GW. High-grade glioma in infants and young children is histologically, molecularly, and clinically diverse: Results from the SJYC07 trial and institutional experience. Neuro Oncol 2024; 26:178-190. [PMID: 37503880 PMCID: PMC10768990 DOI: 10.1093/neuonc/noad130] [Citation(s) in RCA: 5] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2023] [Indexed: 07/29/2023] Open
Abstract
BACKGROUND High-grade gliomas (HGG) in young children pose a challenge due to favorable but unpredictable outcomes. While retrospective studies broadened our understanding of tumor biology, prospective data is lacking. METHODS A cohort of children with histologically diagnosed HGG from the SJYC07 trial was augmented with nonprotocol patients with HGG treated at St. Jude Children's Research Hospital from November 2007 to December 2020. DNA methylome profiling and whole genome, whole exome, and RNA sequencing were performed. These data were integrated with histopathology to yield an integrated diagnosis. Clinical characteristics and preoperative imaging were analyzed. RESULTS Fifty-six children (0.0-4.4 years) were identified. Integrated analysis split the cohort into four categories: infant-type hemispheric glioma (IHG), HGG, low-grade glioma (LGG), and other-central nervous system (CNS) tumors. IHG was the most prevalent (n = 22), occurred in the youngest patients (median age = 0.4 years), and commonly harbored receptor tyrosine kinase gene fusions (7 ALK, 2 ROS1, 3 NTRK1/2/3, 4 MET). The 5-year event-free (EFS) and overall survival (OS) for IHG was 53.13% (95%CI: 35.52-79.47) and 90.91% (95%CI: 79.66-100.00) vs. 0.0% and 16.67% (95%CI: 2.78-99.74%) for HGG (p = 0.0043, p = 0.00013). EFS and OS were not different between IHG and LGG (p = 0.95, p = 0.43). Imaging review showed IHGs are associated with circumscribed margins (p = 0.0047), hemispheric location (p = 0.0010), and intratumoral hemorrhage (p = 0.0149). CONCLUSIONS HGG in young children is heterogeneous and best defined by integrating histopathological and molecular features. Patients with IHG have relatively good outcomes, yet they endure significant deficits, making them good candidates for therapy de-escalation and trials of molecular targeted therapy.
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Affiliation(s)
- Jason Chiang
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Aditi Bagchi
- Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Xiaoyu Li
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Sandeep K Dhanda
- Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Jie Huang
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Soniya N Pinto
- Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Edgar Sioson
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - James Dalton
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Ruth G Tatevossian
- Cancer Biomarkers Laboratory, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Sujuan Jia
- Cancer Biomarkers Laboratory, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Sonia Partap
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Paul G Fisher
- Department of Neurology and Neurological Sciences, Stanford University, Stanford, CA, USA
| | - Daniel C Bowers
- Division of Pediatric Hematology-Oncology, University of Texas Southwestern Medical School, Dallas, TX, USA
| | | | - Congyu Lu
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Airen Zaldivar-Peraza
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Karen D Wright
- Dana Farber/Boston Children’s Cancer and Blood Disorders Center, Boston, MA, USA
| | - Alberto Broniscer
- Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Ibrahim Qaddoumi
- Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Santhosh A Upadhyaya
- Department of Pediatrics, Michigan Medicine, University of Michigan, Ann Arbor, MI, USA
| | - Anna Vinitsky
- Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Noah D Sabin
- Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Brent A Orr
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Paul Klimo
- Department of Surgery, St Jude Children’s Research Hospital, Memphis, TN, USA
- Department of Neurosurgery, University of Tennessee Health and Science Center, Memphis, TN, USA
- Le Bonheur Neuroscience Institute, Le Bonheur Children’s Hospital, Memphis, TN, USA
| | - Frederick A Boop
- Department of Surgery, St Jude Children’s Research Hospital, Memphis, TN, USA
- Department of Neurosurgery, University of Tennessee Health and Science Center, Memphis, TN, USA
- Le Bonheur Neuroscience Institute, Le Bonheur Children’s Hospital, Memphis, TN, USA
| | - Jason M Ashford
- Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Heather M Conklin
- Department of Psychology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Arzu Onar-Thomas
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Xin Zhou
- Department of Computational Biology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - David W Ellison
- Department of Pathology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Amar Gajjar
- Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
| | - Giles W Robinson
- Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, TN, USA
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6
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Semyachkina-Glushkovskaya O, Sokolovski S, Fedosov I, Shirokov A, Navolokin N, Bucharskaya A, Blokhina I, Terskov A, Dubrovski A, Telnova V, Tzven A, Tzoy M, Evsukova A, Zhlatogosrkaya D, Adushkina V, Dmitrenko A, Manzhaeva M, Krupnova V, Noghero A, Bragin D, Bragina O, Borisova E, Kurths J, Rafailov E. Transcranial Photosensitizer-Free Laser Treatment of Glioblastoma in Rat Brain. Int J Mol Sci 2023; 24:13696. [PMID: 37762000 PMCID: PMC10530910 DOI: 10.3390/ijms241813696] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2023] [Revised: 08/29/2023] [Accepted: 09/02/2023] [Indexed: 09/29/2023] Open
Abstract
Over sixty years, laser technologies have undergone a technological revolution and become one of the main tools in biomedicine, particularly in neuroscience, neurodegenerative diseases and brain tumors. Glioblastoma is the most lethal form of brain cancer, with very limited treatment options and a poor prognosis. In this study on rats, we demonstrate that glioblastoma (GBM) growth can be suppressed by photosensitizer-free laser treatment (PS-free-LT) using a quantum-dot-based 1267 nm laser diode. This wavelength, highly absorbed by oxygen, is capable of turning triplet oxygen to singlet form. Applying 1267 nm laser irradiation for a 4 week course with a total dose of 12.7 kJ/cm2 firmly suppresses GBM growth and increases survival rate from 34% to 64%, presumably via LT-activated apoptosis, inhibition of the proliferation of tumor cells, a reduction in intracranial pressure and stimulation of the lymphatic drainage and clearing functions. PS-free-LT is a promising breakthrough technology in non- or minimally invasive therapy for superficial GBMs in infants as well as in adult patients with high photosensitivity or an allergic reaction to PSs.
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Affiliation(s)
- Oxana Semyachkina-Glushkovskaya
- Physics Department, Humboldt University, Newtonstrasse 15, 12489 Berlin, Germany;
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Sergey Sokolovski
- Optoelectronics and Biomedical Photonics Group, AIPT, Aston University, Birmingham B4 7ET, UK;
| | - Ivan Fedosov
- Physics Department, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (I.F.); (A.D.); (M.T.)
| | - Alexander Shirokov
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
- Institute of Biochemistry and Physiology of Plants and Microorganisms, Russian Academy of Sciences, Prospekt Entuziastov 13, 410049 Saratov, Russia
| | - Nikita Navolokin
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
- Department of Pathological Anatomy, Saratov Medical State University, Bolshaya Kazachaya Str. 112, 410012 Saratov, Russia;
| | - Alla Bucharskaya
- Department of Pathological Anatomy, Saratov Medical State University, Bolshaya Kazachaya Str. 112, 410012 Saratov, Russia;
| | - Inna Blokhina
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Andrey Terskov
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Alexander Dubrovski
- Physics Department, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (I.F.); (A.D.); (M.T.)
| | - Valeria Telnova
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Anna Tzven
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Maria Tzoy
- Physics Department, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (I.F.); (A.D.); (M.T.)
| | - Arina Evsukova
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Daria Zhlatogosrkaya
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Viktoria Adushkina
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Alexander Dmitrenko
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Maria Manzhaeva
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Valeria Krupnova
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
| | - Alessio Noghero
- Lovelace Biomedical Research Institute, Albuquerque, NM 87108, USA; (A.N.); (D.B.); (O.B.)
| | - Denis Bragin
- Lovelace Biomedical Research Institute, Albuquerque, NM 87108, USA; (A.N.); (D.B.); (O.B.)
- Department of Neurology, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
| | - Olga Bragina
- Lovelace Biomedical Research Institute, Albuquerque, NM 87108, USA; (A.N.); (D.B.); (O.B.)
- Department of Neurology, School of Medicine, University of New Mexico, Albuquerque, NM 87131, USA
| | - Ekaterina Borisova
- Institute of Electronics, Bulgarian Academy of Sciences, Tsarigradsko Chaussee Blvd. 72, 1784 Sofia, Bulgaria;
| | - Jürgen Kurths
- Physics Department, Humboldt University, Newtonstrasse 15, 12489 Berlin, Germany;
- Department of Biology, Saratov State University, Astrakhanskaya Str. 83, 410012 Saratov, Russia; (A.S.); (N.N.); (I.B.); (A.T.); (V.T.); (A.T.); (A.E.); (D.Z.); (V.A.); (A.D.); (M.M.); (V.K.)
- Potsdam Institute for Climate Impact Research, Telegrafenberg A31, 14473 Potsdam, Germany
- Centre for Analysis of Complex Systems, Sechenov First Moscow State Medical University Moscow, 119991 Moscow, Russia
| | - Edik Rafailov
- Optoelectronics and Biomedical Photonics Group, AIPT, Aston University, Birmingham B4 7ET, UK;
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7
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Matsui JK, Allen PK, Perlow HK, Johnson JM, Paulino AC, McAleer MF, Fouladi M, Grosshans DR, Ghia AJ, Li J, Zaky WT, Chintagumpala MM, Palmer JD, McGovern SL. Prognostic factors for pediatric, adolescent, and young adult patients with non-DIPG grade 4 gliomas: a contemporary pooled institutional experience. J Neurooncol 2023; 163:717-726. [PMID: 37440097 PMCID: PMC11938388 DOI: 10.1007/s11060-023-04386-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Accepted: 06/28/2023] [Indexed: 07/14/2023]
Abstract
PURPOSE WHO grade 4 gliomas are rare in the pediatric and adolescent and young adult (AYA) population. We evaluated prognostic factors and outcomes in the pediatric versus AYA population. METHODS This retrospective pooled study included patients less than 30 years old (yo) with grade 4 gliomas treated with modern surgery and radiotherapy. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analysis. RESULTS Ninety-seven patients met criteria with median age 23.9 yo at diagnosis. Seventy-seven patients were ≥ 15 yo (79%) and 20 patients were < 15 yo (21%). Most had biopsy-proven glioblastoma (91%); the remainder had H3 K27M-altered diffuse midline glioma (DMG; 9%). All patients received surgery and radiotherapy. Median PFS and OS were 20.9 months and 79.4 months, respectively. Gross total resection (GTR) was associated with better PFS in multivariate analysis [HR 2.00 (1.01-3.62), p = 0.023]. Age ≥ 15 yo was associated with improved OS [HR 0.36 (0.16-0.81), p = 0.014] while female gender [HR 2.12 (1.08-4.16), p = 0.03] and DMG histology [HR 2.79 (1.11-7.02), p = 0.029] were associated with worse OS. Only 7% of patients experienced grade 2 toxicity. 62% of patients experienced tumor progression (28% local, 34% distant). Analysis of salvage treatment found that second surgery and systemic therapy significantly improved survival. CONCLUSION Age is a significant prognostic factor in WHO grade 4 glioma, which may reflect age-related molecular alterations in the tumor. DMG was associated with worse OS than glioblastoma. Reoperation and systemic therapy significantly increased survival after disease progression. Prospective studies in this population are warranted.
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Affiliation(s)
- Jennifer K Matsui
- The Ohio State University College of Medicine, Columbus, OH, 43201, USA
- Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1152, Houston, TX, 77030, USA
| | - Pamela K Allen
- Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1152, Houston, TX, 77030, USA
| | - Haley K Perlow
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43201, USA
| | - Jason M Johnson
- Department of Neuroradiology, MD Anderson Cancer Center, Houston, TX, 77030, USA
| | - Arnold C Paulino
- Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1152, Houston, TX, 77030, USA
| | - Mary Frances McAleer
- Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1152, Houston, TX, 77030, USA
| | - Maryam Fouladi
- Department of Pediatrics, Nationwide Children's Hospital, Columbus, OH, 43205, USA
| | - David R Grosshans
- Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1152, Houston, TX, 77030, USA
| | - Amol J Ghia
- Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1152, Houston, TX, 77030, USA
| | - Jing Li
- Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1152, Houston, TX, 77030, USA
| | - Wafik T Zaky
- Department of Pediatrics, MD Anderson Cancer Center, Houston, TX, 77030, USA
| | | | - Joshua D Palmer
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, 43201, USA
| | - Susan L McGovern
- Department of Radiation Oncology, MD Anderson Cancer Center, 1515 Holcombe Blvd, Box 1152, Houston, TX, 77030, USA.
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8
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Perwein T, Giese B, Nussbaumer G, von Bueren AO, van Buiren M, Benesch M, Kramm CM. How I treat recurrent pediatric high-grade glioma (pHGG): a Europe-wide survey study. J Neurooncol 2023; 161:525-538. [PMID: 36720762 PMCID: PMC9992031 DOI: 10.1007/s11060-023-04241-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2022] [Accepted: 01/05/2023] [Indexed: 02/02/2023]
Abstract
PURPOSE As there is no standard of care treatment for recurrent/progressing pediatric high-grade gliomas (pHGG), we aimed to gain an overview of different treatment strategies. METHODS In a web-based questionnaire, members of the SIOPE-BTG and the GPOH were surveyed on therapeutic options in four case scenarios (children/adolescents with recurrent/progressing HGG). RESULTS 139 clinicians with experience in pediatric neuro-oncology from 22 European countries participated in the survey. Most respondents preferred further oncological treatment in three out of four cases and chose palliative care in one case with marked symptoms. Depending on the case, 8-92% would initiate a re-resection (preferably hemispheric pHGG), combined with molecular diagnostics. Throughout all case scenarios, 55-77% recommended (re-)irradiation, preferably local radiotherapy > 20 Gy. Most respondents would participate in clinical trials and use targeted therapy (79-99%), depending on molecular genetic findings (BRAF alterations: BRAF/MEK inhibitor, 64-88%; EGFR overexpression: anti-EGFR treatment, 46%; CDKN2A deletion: CDK inhibitor, 18%; SMARCB1 deletion: EZH2 inhibitor, 12%). 31-72% would administer chemotherapy (CCNU, 17%; PCV, 8%; temozolomide, 19%; oral etoposide/trofosfamide, 8%), and 20-69% proposed immunotherapy (checkpoint inhibitors, 30%; tumor vaccines, 16%). Depending on the individual case, respondents would also include bevacizumab (6-18%), HDAC inhibitors (4-15%), tumor-treating fields (1-26%), and intraventricular chemotherapy (4-24%). CONCLUSION In each case, experts would combine conventional multimodal treatment concepts, including re-irradiation, with targeted therapy based on molecular genetic findings. International cooperative trials combining a (chemo-)therapy backbone with targeted therapy approaches for defined subgroups may help to gain valid clinical data and improve treatment in pediatric patients with recurrent/progressing HGG.
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Affiliation(s)
- Thomas Perwein
- Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 34/2, 8036, Graz, Austria.
| | - Barbara Giese
- Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 34/2, 8036, Graz, Austria
| | - Gunther Nussbaumer
- Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 34/2, 8036, Graz, Austria
| | - André O von Bueren
- Department of Pediatrics, Obstetrics and Gynecology, Division of Pediatric Hematology and Oncology, University Hospital of Geneva, Geneva, Switzerland
- Cansearch Research Platform for Pediatric Oncology and Hematology, Faculty of Medicine, Department of Pediatrics, Gynecology and Obstetrics, University of Geneva, Geneva, Switzerland
| | - Miriam van Buiren
- Department of Pediatric Hematology and Oncology, Center for Pediatrics, Medical Center, University of Freiburg, Freiburg, Germany
| | - Martin Benesch
- Division of Pediatric Hemato-Oncology, Department of Pediatrics and Adolescent Medicine, Medical University of Graz, Auenbruggerplatz 34/2, 8036, Graz, Austria
| | - Christof Maria Kramm
- Division of Pediatric Hematology and Oncology, University Medical Center Göttingen, Göttingen, Germany
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Hatoum R, Chen JS, Lavergne P, Shlobin NA, Wang A, Elkaim LM, Dodin P, Couturier CP, Ibrahim GM, Fallah A, Venne D, Perreault S, Wang AC, Jabado N, Dudley RWR, Weil AG. Extent of Tumor Resection and Survival in Pediatric Patients With High-Grade Gliomas: A Systematic Review and Meta-analysis. JAMA Netw Open 2022; 5:e2226551. [PMID: 35972743 PMCID: PMC9382445 DOI: 10.1001/jamanetworkopen.2022.26551] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/01/2022] Open
Abstract
IMPORTANCE Pediatric patients with high-grade gliomas have a poor prognosis. The association among the extent of resection, tumor location, and survival in these patients remains unclear. OBJECTIVE To ascertain whether gross total resection (GTR) in hemispheric, midline, or infratentorial pediatric high-grade gliomas (pHGGs) is independently associated with survival differences compared with subtotal resection (STR) and biopsy at 1 year and 2 years after tumor resection. DATA SOURCES PubMed, EBMR, Embase, and MEDLINE were systematically reviewed from inception to June 3, 2022, using the keywords high-grade glioma, pediatric, and surgery. No period or language restrictions were applied. STUDY SELECTION Randomized clinical trials and cohort studies of pHGGs that stratified patients by extent of resection and reported postoperative survival were included for study-level and individual patient data meta-analyses. DATA EXTRACTION AND SYNTHESIS Study characteristics and mortality rates were extracted from each article. Relative risk ratios (RRs) were pooled using random-effects models. Individual patient data were evaluated using multivariate mixed-effects Cox proportional hazards regression modeling. The PRISMA reporting guideline was followed, and the study was registered a priori. MAIN OUTCOMES AND MEASURES Hazard ratios (HRs) and RRs were extracted to indicate associations among extent of resection, 1-year and 2-year postoperative mortality, and overall survival. RESULTS A total of 37 studies with 1387 unique patients with pHGGs were included. In study-level meta-analysis, GTR had a lower mortality risk than STR at 1 year (RR, 0.69; 95% CI, 0.56-0.83; P < .001) and 2 years (RR, 0.74; 95% CI, 0.67-0.83; P < .001) after tumor resection. Subtotal resection was not associated with differential survival compared with biopsy at 1 year (RR, 0.82; 95% CI, 0.66-1.01; P = .07) but had decreased mortality risk at 2 years (RR, 0.89; 95% CI, 0.82-0.97; P = .01). The individual patient data meta-analysis of 27 articles included 427 patients (mean [SD] age at diagnosis, 9.3 [5.9] years), most of whom were boys (169 of 317 [53.3%]), had grade IV tumors (246 of 427 [57.7%]), and/or had tumors that were localized to either the cerebral hemispheres (133 of 349 [38.1%]) or midline structures (132 of 349 [37.8%]). In the multivariate Cox proportional hazards regression model, STR (HR, 1.91; 95% CI, 1.34-2.74; P < .001) and biopsy (HR, 2.10; 95% CI, 1.43-3.07; P < .001) had shortened overall survival compared with GTR but no survival differences between them (HR, 0.91; 95% CI, 0.67-1.24; P = .56). Gross total resection was associated with prolonged survival compared with STR for hemispheric (HR, 0.29; 95% CI, 0.15-0.54; P < .001) and infratentorial (HR, 0.44; 95% CI, 0.24-0.83; P = .01) tumors but not midline tumors (HR, 0.63; 95% CI, 0.34-1.19; P = .16). CONCLUSIONS AND RELEVANCE Results of this study show that, among patients with pHGG, GTR is independently associated with better overall survival compared with STR and biopsy, especially among patients with hemispheric and infratentorial tumors, and support the pursuit of maximal safe resection in the treatment of pHGGs.
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Affiliation(s)
- Rami Hatoum
- University of Montréal School of Medicine, Montréal, Quebec, Canada
| | - Jia-Shu Chen
- The Warren Alpert Medical School of Brown University, Providence, Rhode Island
| | - Pascal Lavergne
- Department of Neurological Surgery, University of Washington, Seattle
| | - Nathan A. Shlobin
- Department of Neurological Surgery, Northwestern University Feinberg School of Medicine, Chicago, Illinois
| | - Andrew Wang
- Department of Neurosurgery, David Geffen School of Medicine at UCLA (University of California, Los Angeles)
- College of Medicine, Charles R. Drew University of Medicine and Science, Los Angeles, California
| | - Lior M. Elkaim
- Division of Neurology and Neurosurgery, McGill University, McGill University Health Center, Montreal, Quebec, Canada
| | - Philippe Dodin
- Medical Library, Centre Hospitalier Universitaire (CHU) Sainte-Justine Children’s, Montréal, Quebec, Canada
| | - Charles P. Couturier
- Department of Neurology and Neurosurgery, Montréal Neurological Institute–Hospital, Montréal, Quebec, Canada
| | - George M. Ibrahim
- Division of Neurosurgery, The Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada
| | - Aria Fallah
- Department of Neurosurgery, David Geffen School of Medicine at UCLA (University of California, Los Angeles)
- Department of Pediatrics, David Geffen School of Medicine at UCLA
| | - Dominic Venne
- Division of Neurosurgery, Ste Justine Hospital, University of Montréal, Montréal, Quebec, Canada
| | | | - Anthony C. Wang
- Department of Neurosurgery, David Geffen School of Medicine at UCLA (University of California, Los Angeles)
- Department of Pediatrics, David Geffen School of Medicine at UCLA
| | - Nada Jabado
- Department of Human Genetics, McGill University, Montréal, Quebec, Canada
- Department of Pediatrics, McGill University and McGill University Health Centre Research Institute, Montréal, Quebec, Canada
| | - Roy W. R. Dudley
- Neurosurgery Service, Department of Surgery, McGill University and McGill University Health Centre Research Institute, Montréal, Quebec, Canada
| | - Alexander G. Weil
- Division of Neurosurgery, Ste Justine Hospital, University of Montréal, Montréal, Quebec, Canada
- Neurosurgery Service, Department of Surgery, University of Montreal Hospital Center, Montréal, Quebec, Canada
- Sainte-Justine University Hospital Research Center, Montréal, Quebec, Canada
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10
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Wyss J, Frank NA, Soleman J, Scheinemann K. Novel Pharmacological Treatment Options in Pediatric Glioblastoma-A Systematic Review. Cancers (Basel) 2022; 14:2814. [PMID: 35681794 PMCID: PMC9179254 DOI: 10.3390/cancers14112814] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/12/2022] [Revised: 05/30/2022] [Accepted: 05/31/2022] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND Pediatric glioblastoma (GBM) is an aggressive central nervous system tumor in children that has dismal prognosis. Standard of care is surgery with subsequent irradiation and temozolomide. We aimed to outline currently available data on novel pharmacological treatments for pediatric GBM. METHODS We conducted a systematic literature search in PubMed and Embase, including reports published in English from 2010 to 2021. We included randomized trials, cohort studies and case series. Phase I trials were not analyzed. We followed PRISMA guidelines, assessed the quality of the eligible reports using the Newcastle-Ottawa scale (NOS) and the RoB-2 tool and registered the protocol on PROSPERO. RESULTS We included 6 out of 1122 screened reports. All six selected reports were prospective, multicenter phase II trials (five single-arm and one randomized controlled trial). None of the investigated novel treatment modalities showed any benefit regarding overall or progression free survival. CONCLUSIONS To date, the role of pharmacological approaches regarding pediatric GBM remains unclear, since no novel treatment approach could provide a significant impact on overall or progression free survival. Further research should aim to combine different treatment strategies in large international multicenter trials with central comprehensive diagnostics regarding subgrouping. These novel treatment approaches should include targeted and immunotherapeutic treatments, potentially leading to a more successful outcome.
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Affiliation(s)
- Johanna Wyss
- Division of Oncology-Hematology, Department of Pediatrics, Kantonsspital Aarau, 5001 Aarau, Switzerland;
- Division of Pediatric Oncology-Hematology, University Children’s Hospital of Basel, 4056 Basel, Switzerland
| | - Nicole Alexandra Frank
- Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland; (N.A.F.); (J.S.)
| | - Jehuda Soleman
- Department of Neurosurgery, University Hospital of Basel, 4031 Basel, Switzerland; (N.A.F.); (J.S.)
- Department of Pediatric Neurosurgery, University Children’s Hospital of Basel, 4056 Basel, Switzerland
- Faculty of Medicine, University of Basel, 4056 Basel, Switzerland
| | - Katrin Scheinemann
- Division of Oncology-Hematology, Department of Pediatrics, Kantonsspital Aarau, 5001 Aarau, Switzerland;
- Department of Health Sciences and Medicine, University of Lucerne, 6002 Lucerne, Switzerland
- Department of Pediatrics, McMaster University Hamilton, Hamilton, ON L8S 4K1, Canada
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11
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The Intricate Epigenetic and Transcriptional Alterations in Pediatric High-Grade Gliomas: Targeting the Crosstalk as the Oncogenic Achilles’ Heel. Biomedicines 2022; 10:biomedicines10061311. [PMID: 35740334 PMCID: PMC9219798 DOI: 10.3390/biomedicines10061311] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2022] [Revised: 05/27/2022] [Accepted: 05/28/2022] [Indexed: 02/01/2023] Open
Abstract
Pediatric high-grade gliomas (pHGGs) are a deadly and heterogenous subgroup of gliomas for which the development of innovative treatments is urgent. Advances in high-throughput molecular techniques have shed light on key epigenetic components of these diseases, such as K27M and G34R/V mutations on histone 3. However, modification of DNA compaction is not sufficient by itself to drive those tumors. Here, we review molecular specificities of pHGGs subcategories in the context of epigenomic rewiring caused by H3 mutations and the subsequent oncogenic interplay with transcriptional signaling pathways co-opted from developmental programs that ultimately leads to gliomagenesis. Understanding how transcriptional and epigenetic alterations synergize in each cellular context in these tumors could allow the identification of new Achilles’ heels, thereby highlighting new levers to improve their therapeutic management.
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12
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Di Ruscio V, Carai A, Del Baldo G, Vinci M, Cacchione A, Miele E, Rossi S, Antonelli M, Barresi S, Caulo M, Colafati GS, Mastronuzzi A. Molecular Landscape in Infant High-Grade Gliomas: A Single Center Experience. Diagnostics (Basel) 2022; 12:diagnostics12020372. [PMID: 35204463 PMCID: PMC8871476 DOI: 10.3390/diagnostics12020372] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2021] [Revised: 01/24/2022] [Accepted: 01/27/2022] [Indexed: 02/06/2023] Open
Abstract
High-grade gliomas (HGG) represent about 15% of all pediatric brain tumors, with a dismal prognosis and survival rates ranging from 15 to 35%. Approximately 10–12% of pediatric HGGs (pHGG) occur in children younger than five years of age at diagnosis, specifically infants (iHGG), with an unexpected overall survival rate (OS) in 60–70% of cases. In the literature, iHGGs include a large variety of heterogeneous lesions with different molecular profiles that likely explain their different outcomes. We report our single-institution experience of iHGG including 11 children under five years of age with newly diagnosed HGG between 2011 and 2021. All patients received surgery and adjuvant chemotherapy; only two patients received radiotherapy because their age at diagnosis was more than four years-old. Molecular investigations, including next generation sequencing (NGS) and DNA methylation, detected three NTRK-fusions, one ROS1-fusions, one MN1-rearrangement, and two PATZ1-fusions. According to the molecular results, when chemotherapy failed to control the disease, two patients benefited from target therapy with a NTRK-Inhibitor larotrectinib, achieving a complete remission and a very good partial response, respectively, and no severe side-effects. In conclusion, molecular investigations play a fundamental role in the diagnostic work-up and also in the therapeutic decision. Their routine use in clinical practice could help to replace highly toxic chemotherapy regimens with a target therapy that has moderate adverse effects, even in long-term follow-up.
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Affiliation(s)
- Valentina Di Ruscio
- Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), 00165 Rome, Italy; (V.D.R.); (G.D.B.); (M.V.); (A.C.); (E.M.); (A.M.)
| | - Andrea Carai
- Neurosurgery Unit, Department of Neurosciences, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy
- Correspondence:
| | - Giada Del Baldo
- Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), 00165 Rome, Italy; (V.D.R.); (G.D.B.); (M.V.); (A.C.); (E.M.); (A.M.)
| | - Maria Vinci
- Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), 00165 Rome, Italy; (V.D.R.); (G.D.B.); (M.V.); (A.C.); (E.M.); (A.M.)
| | - Antonella Cacchione
- Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), 00165 Rome, Italy; (V.D.R.); (G.D.B.); (M.V.); (A.C.); (E.M.); (A.M.)
| | - Evelina Miele
- Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), 00165 Rome, Italy; (V.D.R.); (G.D.B.); (M.V.); (A.C.); (E.M.); (A.M.)
| | - Sabrina Rossi
- Department of Pathology, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (S.R.); (S.B.)
| | - Manila Antonelli
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, University Sapienza of Rome, 00185 Rome, Italy;
| | - Sabina Barresi
- Department of Pathology, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy; (S.R.); (S.B.)
| | - Massimo Caulo
- Department of Neuroscience, Imaging and Clinical Sciences, G. D’Annunzio University of Chieti, 66100 Chieti, Italy;
| | - Giovanna Stefania Colafati
- Department of Diagnostic Imaging Oncological Neuroradiology Unit, Bambino Gesù Children’s Hospital, IRCCS, 00165 Rome, Italy;
| | - Angela Mastronuzzi
- Department of Onco-Hematology, Cell and Gene Therapy, Bambino Gesù Children’s Hospital, Scientific Institute for Reasearch, Hospitalization and Healthcare (IRCCS), 00165 Rome, Italy; (V.D.R.); (G.D.B.); (M.V.); (A.C.); (E.M.); (A.M.)
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13
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Hehir-Kwa JY, Koudijs MJ, Verwiel ETP, Kester LA, van Tuil M, Strengman E, Buijs A, Kranendonk MEG, Hiemcke-Jiwa LS, de Haas V, van de Geer E, de Leng W, van der Lugt J, Lijnzaad P, Holstege FCP, Kemmeren P, Tops BBJ. Improved Gene Fusion Detection in Childhood Cancer Diagnostics Using RNA Sequencing. JCO Precis Oncol 2022; 6:e2000504. [PMID: 35085008 PMCID: PMC8830514 DOI: 10.1200/po.20.00504] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2020] [Revised: 08/27/2021] [Accepted: 12/03/2021] [Indexed: 12/16/2022] Open
Abstract
PURPOSE Gene fusions play a significant role in cancer etiology, making their detection crucial for accurate diagnosis, prognosis, and determining therapeutic targets. Current diagnostic methods largely focus on either targeted or low-resolution genome-wide techniques, which may be unable to capture rare events or both fusion partners. We investigate if RNA sequencing can overcome current limitations with traditional diagnostic techniques to identify gene fusion events. METHODS We first performed RNA sequencing on a validation cohort of 24 samples with a known gene fusion event, after which a prospective pan-pediatric cancer cohort (n = 244) was tested by RNA sequencing in parallel to existing diagnostic procedures. This cohort included hematologic malignancies, tumors of the CNS, solid tumors, and suspected neoplastic samples. All samples were processed in the routine diagnostic workflow and analyzed for gene fusions using standard-of-care methods and RNA sequencing. RESULTS We identified a clinically relevant gene fusion in 83 of 244 cases in the prospective cohort. Sixty fusions were detected by both routine diagnostic techniques and RNA sequencing, and one fusion was detected only in routine diagnostics, but an additional 24 fusions were detected solely by RNA sequencing. RNA sequencing, therefore, increased the diagnostic yield by 38%-39%. In addition, RNA sequencing identified both gene partners involved in the gene fusion, in contrast to most routine techniques. For two patients, the newly identified fusion by RNA sequencing resulted in treatment with targeted agents. CONCLUSION We show that RNA sequencing is sufficiently robust for gene fusion detection in routine diagnostics of childhood cancers and can make a difference in treatment decisions.
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Affiliation(s)
| | - Marco J. Koudijs
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
- Department of Laboratories, Pharmacy and Biomedical Genetics, Section of Genome Diagnostics, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | - Lennart A. Kester
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Marc van Tuil
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Eric Strengman
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Arjan Buijs
- Department of Laboratories, Pharmacy and Biomedical Genetics, Section of Genome Diagnostics, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | | | - Valerie de Haas
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Ellen van de Geer
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | - Wendy de Leng
- Department of Laboratories, Pharmacy and Biomedical Genetics, Section Pathology, University Medical Center Utrecht, Utrecht, the Netherlands
| | | | - Philip Lijnzaad
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
| | | | - Patrick Kemmeren
- Princess Máxima Center for Pediatric Oncology, Utrecht, the Netherlands
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14
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Gonçalves FG, Viaene AN, Vossough A. Advanced Magnetic Resonance Imaging in Pediatric Glioblastomas. Front Neurol 2021; 12:733323. [PMID: 34858308 PMCID: PMC8631300 DOI: 10.3389/fneur.2021.733323] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Accepted: 10/12/2021] [Indexed: 12/26/2022] Open
Abstract
The shortly upcoming 5th edition of the World Health Organization Classification of Tumors of the Central Nervous System is bringing extensive changes in the terminology of diffuse high-grade gliomas (DHGGs). Previously "glioblastoma," as a descriptive entity, could have been applied to classify some tumors from the family of pediatric or adult DHGGs. However, now the term "glioblastoma" has been divested and is no longer applied to tumors in the family of pediatric types of DHGGs. As an entity, glioblastoma remains, however, in the family of adult types of diffuse gliomas under the insignia of "glioblastoma, IDH-wildtype." Of note, glioblastomas still can be detected in children when glioblastoma, IDH-wildtype is found in this population, despite being much more common in adults. Despite the separation from the family of pediatric types of DHGGs, what was previously labeled as "pediatric glioblastomas" still remains with novel labels and as new entities. As a result of advances in molecular biology, most of the previously called "pediatric glioblastomas" are now classified in one of the four family members of pediatric types of DHGGs. In this review, the term glioblastoma is still apocryphally employed mainly due to its historical relevance and the paucity of recent literature dealing with the recently described new entities. Therefore, "glioblastoma" is used here as an umbrella term in the attempt to encompass multiple entities such as astrocytoma, IDH-mutant (grade 4); glioblastoma, IDH-wildtype; diffuse hemispheric glioma, H3 G34-mutant; diffuse pediatric-type high-grade glioma, H3-wildtype and IDH-wildtype; and high grade infant-type hemispheric glioma. Glioblastomas are highly aggressive neoplasms. They may arise anywhere in the developing central nervous system, including the spinal cord. Signs and symptoms are non-specific, typically of short duration, and usually derived from increased intracranial pressure or seizure. Localized symptoms may also occur. The standard of care of "pediatric glioblastomas" is not well-established, typically composed of surgery with maximal safe tumor resection. Subsequent chemoradiation is recommended if the patient is older than 3 years. If younger than 3 years, surgery is followed by chemotherapy. In general, "pediatric glioblastomas" also have a poor prognosis despite surgery and adjuvant therapy. Magnetic resonance imaging (MRI) is the imaging modality of choice for the evaluation of glioblastomas. In addition to the typical conventional MRI features, i.e., highly heterogeneous invasive masses with indistinct borders, mass effect on surrounding structures, and a variable degree of enhancement, the lesions may show restricted diffusion in the solid components, hemorrhage, and increased perfusion, reflecting increased vascularity and angiogenesis. In addition, magnetic resonance spectroscopy has proven helpful in pre- and postsurgical evaluation. Lastly, we will refer to new MRI techniques, which have already been applied in evaluating adult glioblastomas, with promising results, yet not widely utilized in children.
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Affiliation(s)
- Fabrício Guimarães Gonçalves
- Division of Neuroradiology, Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, United States
| | - Angela N Viaene
- Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
| | - Arastoo Vossough
- Division of Neuroradiology, Department of Radiology, Children's Hospital of Philadelphia, Philadelphia, PA, United States.,Department of Radiology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
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15
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Pearce J, Khabra K, Nanji H, Stone J, Powell K, Martin D, Zebian B, Hettige S, Reisz Z, Bodi I, Al-Sarraj S, Bridges LR, Clarke M, Jones C, Mandeville HC, Vaidya S, Marshall LV, Carceller F. High grade gliomas in young children: The South Thames Neuro-Oncology unit experience and recent advances in molecular biology and targeted therapies. Pediatr Hematol Oncol 2021; 38:707-721. [PMID: 33900873 DOI: 10.1080/08880018.2021.1907493] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2020] [Revised: 03/12/2021] [Accepted: 03/16/2021] [Indexed: 02/04/2023]
Abstract
High grade gliomas (HGG) have a dismal prognosis with survival rates of 15-35%. Approximately 10-12% of pediatric HGG occur in young children and their molecular biology and clinical outcomes differ from those arising at older ages. We report on four children aged <5 years newly diagnosed with non-brainstem HGG between 2011 and 2018 who were treated with surgery and BBSFOP chemotherapy. Two died of tumor progression. The other two are still alive without radiotherapy at 3.8 and 3.9 years from diagnosis: one of whom remains disease-free off treatment; and the other one, whose tumor harbored a KCTD16:NTRK2 fusion, went on to receive larotrectinib. Additionally we review the general management, outcomes and latest updates in molecular biology and targeted therapies for young children with HGG. Infant gliomas can be stratified in molecular subgroups with clinically actionable oncogenic drivers. Chemotherapy-based strategies can avoid or delay the need for radiotherapy in young children with HGG. Harnessing the potential of NTRK, ALK, ROS1 and MET inhibitors offers the opportunity to optimize the therapeutic armamentarium to improve current outcomes for these children.
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Affiliation(s)
- Janice Pearce
- Children & Young People's Unit, Pediatric & Adolescent Neuro-Oncology, The Royal Marsden NHS Foundation Trust, London, UK
| | - Komel Khabra
- Statistics Department, The Royal Marsden NHS Foundation Trust, London, UK
| | - Henry Nanji
- Statistics Department, The Royal Marsden NHS Foundation Trust, London, UK
| | - Joanna Stone
- Children & Young People's Unit, Pediatric & Adolescent Neuro-Oncology, The Royal Marsden NHS Foundation Trust, London, UK
| | - Karen Powell
- Children & Young People's Unit, Pediatric & Adolescent Neuro-Oncology, The Royal Marsden NHS Foundation Trust, London, UK
| | - Danielle Martin
- Children & Young People's Unit, Pediatric & Adolescent Neuro-Oncology, The Royal Marsden NHS Foundation Trust, London, UK
| | - Bassel Zebian
- Neurosurgery Department, King's College Hospital NHS Foundation Trust, London, UK
| | - Samantha Hettige
- Neurosurgery Department, St George's Hospital NHS Foundation Trust, London, UK
| | - Zita Reisz
- Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK
| | - Istvan Bodi
- Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK
| | - Safa Al-Sarraj
- Department of Clinical Neuropathology, King's College Hospital NHS Foundation Trust, London, UK
| | - Leslie R Bridges
- Department of Cellular Pathology, St George's Hospital NHS Foundation Trust, London, UK
| | - Matthew Clarke
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Chris Jones
- Division of Molecular Pathology, The Institute of Cancer Research, London, UK
| | - Henry C Mandeville
- Department of Radiation Oncology, The Royal Marsden NHS Foundation Trust, London, UK
- Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Sucheta Vaidya
- Children & Young People's Unit, Pediatric & Adolescent Neuro-Oncology, The Royal Marsden NHS Foundation Trust, London, UK
- Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Lynley V Marshall
- Children & Young People's Unit, Pediatric & Adolescent Neuro-Oncology, The Royal Marsden NHS Foundation Trust, London, UK
- Division of Clinical Studies, The Institute of Cancer Research, London, UK
| | - Fernando Carceller
- Children & Young People's Unit, Pediatric & Adolescent Neuro-Oncology, The Royal Marsden NHS Foundation Trust, London, UK
- Division of Clinical Studies, The Institute of Cancer Research, London, UK
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16
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Barritault M, Poncet D, Meyronet D, Vasiljevic A, Lopez J, Descotes F, Mottolese C, Basle A, Benoit-Janin M, Pissaloux D, Karanian M, Bringuier PP, Leblond P. NTRK2 gene fusion and resistance mutation: Seventeen-year course of a paediatric glioma. Pediatr Blood Cancer 2021; 68:e29114. [PMID: 34003575 DOI: 10.1002/pbc.29114] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2021] [Revised: 04/29/2021] [Accepted: 05/01/2021] [Indexed: 11/10/2022]
Affiliation(s)
- Marc Barritault
- Département de Biopathologie Moléculaire, Service de Cytologie et d'Anatomie Pathologique, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.,INSERM U1052, CNRS UMR 5286, Cancer Cell Plasticity department, Transcriptome Diversity in Stem Cells laboratory, Centre de recherche en Cancérologie de Lyon, Lyon, France
| | - Delphine Poncet
- Département de Biopathologie Moléculaire, Service de Cytologie et d'Anatomie Pathologique, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.,CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - David Meyronet
- Département de Biopathologie Moléculaire, Service de Cytologie et d'Anatomie Pathologique, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.,INSERM U1052, CNRS UMR 5286, Cancer Cell Plasticity department, Transcriptome Diversity in Stem Cells laboratory, Centre de recherche en Cancérologie de Lyon, Lyon, France.,CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Alexandre Vasiljevic
- Département de Biopathologie Moléculaire, Service de Cytologie et d'Anatomie Pathologique, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.,CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France
| | - Jonathan Lopez
- CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.,Service de Biochimie Biologie Moléculaire, Centre de biologie et pathologie Sud, Hospices Civils de Lyon (HCL), Pierre-Bénite, France
| | - Françoise Descotes
- CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.,Service de Biochimie Biologie Moléculaire, Centre de biologie et pathologie Sud, Hospices Civils de Lyon (HCL), Pierre-Bénite, France
| | - Carmine Mottolese
- Service de Neurochirurgie Lyon, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France
| | | | - Mélanie Benoit-Janin
- Département de Biopathologie Moléculaire, Service de Cytologie et d'Anatomie Pathologique, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France
| | - Daniel Pissaloux
- CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.,Département de Biopathologie, Centre Léon Bérard, Lyon, France
| | - Marie Karanian
- CNRS UMR 5286, INSERM U1052, Cancer Research Centre of Lyon, Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France.,Département de Biopathologie, Centre Léon Bérard, Lyon, France
| | - Pierre-Paul Bringuier
- Département de Biopathologie Moléculaire, Service de Cytologie et d'Anatomie Pathologique, Groupement Hospitalier Est, Hospices Civils de Lyon, Lyon, France.,INSERM U1052, CNRS UMR 5286, Cancer Cell Plasticity department, Transcriptome Diversity in Stem Cells laboratory, Centre de recherche en Cancérologie de Lyon, Lyon, France
| | - Pierre Leblond
- Service d'Oncologie, Institut d'Hématologie et d'Oncologie Pédiatrique, Lyon, France
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17
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Sager O, Dincoglan F, Demiral S, Uysal B, Gamsiz H, Colak O, Ozcan F, Gundem E, Elcim Y, Dirican B, Beyzadeoglu M. Concise review of stereotactic irradiation for pediatric glial neoplasms: Current concepts and future directions. World J Methodol 2021; 11:61-74. [PMID: 34026579 PMCID: PMC8127424 DOI: 10.5662/wjm.v11.i3.61] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Revised: 04/07/2021] [Accepted: 04/14/2021] [Indexed: 02/06/2023] Open
Abstract
Brain tumors, which are among the most common solid tumors in childhood, remain a leading cause of cancer-related mortality in pediatric population. Gliomas, which may be broadly categorized as low grade glioma and high grade glioma, account for the majority of brain tumors in children. Expectant management, surgery, radiation therapy (RT), chemotherapy, targeted therapy or combinations of these modalities may be used for management of pediatric gliomas. Several patient, tumor and treatment-related characteristics including age, lesion size, grade, location, phenotypic and genotypic features, symptomatology, predicted outcomes and toxicity profile of available therapeutic options should be considered in decision making for optimal treatment. Management of pediatric gliomas poses a formidable challenge to the physicians due to concerns about treatment induced toxicity. Adverse effects of therapy may include neurological deficits, hemiparesis, dysphagia, ataxia, spasticity, endocrine sequelae, neurocognitive and communication impairment, deterioration in quality of life, adverse socioeconomic consequences, and secondary cancers. Nevertheless, improved understanding of molecular pathology and technological advancements may pave the way for progress in management of pediatric glial neoplasms. Multidisciplinary management with close collaboration of disciplines including pediatric oncology, surgery, and radiation oncology is warranted to achieve optimal therapeutic outcomes. In the context of RT, stereotactic irradiation is a viable treatment modality for several central nervous system disorders and brain tumors. Considering the importance of minimizing adverse effects of irradiation, radiosurgery has attracted great attention for clinical applications in both adults and children. Radiosurgical applications offer great potential for improving the toxicity profile of radiation delivery by focused and precise targeting of well-defined tumors under stereotactic immobilization and image guidance. Herein, we provide a concise review of stereotactic irradiation for pediatric glial neoplasms in light of the literature.
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Affiliation(s)
- Omer Sager
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Ferrat Dincoglan
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Selcuk Demiral
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Bora Uysal
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Hakan Gamsiz
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Onurhan Colak
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Fatih Ozcan
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Esin Gundem
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Yelda Elcim
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Bahar Dirican
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
| | - Murat Beyzadeoglu
- Department of Radiation Oncology, Gulhane Medical Faculty, University of Health Sciences, Ankara 06018, Turkey
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18
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Feasibility of Proton Beam Therapy for Infants with Brain Tumours: Experiences from the Prospective KiProReg Registry Study. Clin Oncol (R Coll Radiol) 2021; 33:e295-e304. [PMID: 33820696 DOI: 10.1016/j.clon.2021.03.006] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/16/2021] [Accepted: 03/09/2021] [Indexed: 11/22/2022]
Abstract
AIMS Proton beam therapy (PBT) has increasingly been applied for the treatment of young children when radiotherapy is needed. The treatment requires intensive multimodality care and is logistically demanding. In this analysis, we evaluated our experiences in treating infants with tumours of the central nervous system with PBT. MATERIALS AND METHODS Children younger than 2 years of age treated with PBT for central nervous system tumours enrolled in the prospective registry study KiProReg were retrospectively analysed. Information on patient characteristics, treatment, toxicities and outcome were evaluated. Adverse events were classified according to the National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE V4.0) before, during and after PBT. RESULTS Between September 2013 and June 2018, 51 infants were eligible. The median age was 19 months (range 11-23 months) at the time of PBT. Tumour entities were ependymoma (51.0%), atypical teratoid rhabdoid tumour (39.0%), high-grade glioma (6.0%), pineoblastoma (2.0%) and medulloblastoma (2.0%). The prescribed median total dose was 54.0 Gy (range 45.0-59.4 Gy). Most received local radiotherapy. In four patients, craniospinal irradiation followed by a boost to the local tumour bed was applied. The median follow-up time was 42.0 months (range 7.3-86.2 months). The estimated 3-year local control, progression-free survival and overall survival rates for all patients were 62.7, 47.1 and 76.5%, respectively. During radiotherapy, 24 events of higher-grade (CTCAE ≥ °III) toxicities were reported. Interruption of radiotherapy for more than 2 days was due to infection (n = 3) or shunt complication (n = 2). Unexpected hospitalisation during radiotherapy affected 12 patients. Late adverse events attributable to radiotherapy included endocrinopathy (CTCAE °II; 7.8%), new onset of hearing loss (CTCAE °III; 5.8%) and visual impairment (CTCAE °IV; 1.9%). Transient radiation-induced imaging changes occurred in five patients (9.8%). CONCLUSIONS Our study indicates that PBT is feasible for very young children with central nervous system tumours, at least in the short term. However, it requires challenging interdisciplinary medical care and high logistical effort. For evaluation of late effects, longer follow-up and evaluation of neurocognitive outcome are desirable. More data have to be gathered to further define the role of radiotherapy in infants over time.
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19
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Mayr L, Guntner AS, Madlener S, Schmook MT, Peyrl A, Azizi AA, Dieckmann K, Reisinger D, Stepien NM, Schramm K, Laemmerer A, Jones DTW, Ecker J, Sahm F, Milde T, Pajtler KW, Blattner-Johnson M, Strbac M, Dorfer C, Czech T, Kirchhofer D, Gabler L, Berger W, Haberler C, Müllauer L, Buchberger W, Slavc I, Lötsch-Gojo D, Gojo J. Cerebrospinal Fluid Penetration and Combination Therapy of Entrectinib for Disseminated ROS1/NTRK-Fusion Positive Pediatric High-Grade Glioma. J Pers Med 2020; 10:E290. [PMID: 33353026 PMCID: PMC7766483 DOI: 10.3390/jpm10040290] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 12/15/2020] [Accepted: 12/16/2020] [Indexed: 12/20/2022] Open
Abstract
Targeting oncogenic fusion-genes in pediatric high-grade gliomas (pHGG) with entrectinib has emerged as a highly promising therapeutic approach. Despite ongoing clinical studies, to date, no reports on the treatment of cerebrospinal fluid (CSF) disseminated fusion-positive pHGG exist. Moreover, clinically important information of combination with other treatment modalities such as intrathecal therapy, radiotherapy and other targeted agents is missing. We report on our clinical experience of entrectinib therapy in two CSF disseminated ROS1/NTRK-fusion-positive pHGG cases. Combination of entrectinib with radiotherapy or intrathecal chemotherapy appears to be safe and has the potential to act synergistically with entrectinib treatment. In addition, we demonstrate CSF penetrance of entrectinib for the first time in patient samples suggesting target engagement even upon CSF dissemination. Moreover, in vitro analyses of two novel cell models derived from one case with NTRK-fusion revealed that combination therapy with either a MEK (trametinib) or a CDK4/6 (abemaciclib) inhibitor synergistically enhances entrectinib anticancer effects. In summary, our comprehensive study, including clinical experience, CSF penetrance and in vitro data on entrectinib therapy of NTRK/ROS1-fusion-positive pHGG, provides essential clinical and preclinical insights into the multimodal treatment of these highly aggressive tumors. Our data suggest that combined inhibition of NTRK/ROS1 and other therapeutic vulnerabilities enhances the antitumor effect, which should be followed-up in further preclinical and clinical studies.
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Affiliation(s)
- Lisa Mayr
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (W.B.)
- Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, 1090 Vienna, Austria
| | - Armin S. Guntner
- Institute of Analytical Chemistry, Johannes Kepler University, 4020 Linz, Austria; (A.S.G.); (W.B.)
| | - Sibylle Madlener
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
- Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, 1090 Vienna, Austria
| | - Maria T. Schmook
- Division of Neuroradiology and Musculoskeletal Radiology, Department of Biomedical Imaging and Image-Guided Therapy, Medical University of Vienna, 1090 Vienna, Austria;
| | - Andreas Peyrl
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
| | - Amedeo A. Azizi
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
| | - Karin Dieckmann
- Department of Radiotherapy, Medical University of Vienna, 1090 Vienna, Austria;
| | - Dominik Reisinger
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
| | - Natalia M. Stepien
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
| | - Kathrin Schramm
- Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; (K.S.); (D.T.W.J.); (T.M.); (K.W.P.); (M.B.-J.)
- Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Anna Laemmerer
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (W.B.)
- Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, 1090 Vienna, Austria
| | - David T. W. Jones
- Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; (K.S.); (D.T.W.J.); (T.M.); (K.W.P.); (M.B.-J.)
- Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Jonas Ecker
- Clinical Cooperation Unit Pediatric Oncology, Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany;
| | - Felix Sahm
- Department of Neuropathology, Institute of Pathology, University Hospital Heidelberg, 69120 Heidelberg, Germany;
- Clinical Cooperation Unit Neuropathology, German Consortium for Translational Cancer Research (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Till Milde
- Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; (K.S.); (D.T.W.J.); (T.M.); (K.W.P.); (M.B.-J.)
- Clinical Cooperation Unit Pediatric Oncology, Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany;
| | - Kristian W. Pajtler
- Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; (K.S.); (D.T.W.J.); (T.M.); (K.W.P.); (M.B.-J.)
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, and Immunology, University Hospital Heidelberg, 69120 Heidelberg, Germany
| | - Mirjam Blattner-Johnson
- Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; (K.S.); (D.T.W.J.); (T.M.); (K.W.P.); (M.B.-J.)
- Pediatric Glioma Research Group, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
| | - Miroslav Strbac
- Department of Laboratory Medicine and Pathology, Tree Top Hospital, Hulhumale 23000, Maldives;
| | - Christian Dorfer
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (C.D.); (T.C.)
| | - Thomas Czech
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (C.D.); (T.C.)
| | - Dominik Kirchhofer
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (W.B.)
- Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, 1090 Vienna, Austria
| | - Lisa Gabler
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (W.B.)
- Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, 1090 Vienna, Austria
| | - Walter Berger
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (W.B.)
- Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, 1090 Vienna, Austria
| | - Christine Haberler
- Division of Neuropathology and Neurochemistry, Department of Neurology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Leonhard Müllauer
- Department of Pathology, Medical University of Vienna, 1090 Vienna, Austria;
| | - Wolfgang Buchberger
- Institute of Analytical Chemistry, Johannes Kepler University, 4020 Linz, Austria; (A.S.G.); (W.B.)
| | - Irene Slavc
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
| | - Daniela Lötsch-Gojo
- Department of Medicine I, Institute of Cancer Research, Medical University of Vienna, 1090 Vienna, Austria; (L.G.); (W.B.)
- Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, 1090 Vienna, Austria
- Department of Neurosurgery, Medical University of Vienna, 1090 Vienna, Austria; (C.D.); (T.C.)
| | - Johannes Gojo
- Department of Pediatrics and Adolescent Medicine and Comprehensive Center for Pediatrics, Medical University of Vienna, 1090 Vienna, Austria; (L.M.); (S.M.); (A.P.); (A.A.A.); (D.R.); (N.M.S.); (A.L.); (D.K.); (I.S.)
- Comprehensive Cancer Center-Central Nervous System Tumors Unit, Medical University of Vienna, 1090 Vienna, Austria
- Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; (K.S.); (D.T.W.J.); (T.M.); (K.W.P.); (M.B.-J.)
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
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Coleman C, Stoller S, Grotzer M, Stucklin AG, Nazarian J, Mueller S. Pediatric hemispheric high-grade glioma: targeting the future. Cancer Metastasis Rev 2020; 39:245-260. [PMID: 31989507 DOI: 10.1007/s10555-020-09850-5] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Pediatric high-grade gliomas (pHGGs) are a group of tumors affecting approximately 0.85 children per 100,000 annually. The general outcome for these tumors is poor with 5-year survival rates of less than 20%. It is now recognized that these tumors represent a heterogeneous group of tumors rather than one entity. Large-scale genomic analyses have led to a greater understanding of the molecular drivers of different subtypes of these tumors and have also aided in the development of subtype-specific therapies. For example, for pHGG with NTRK fusions, promising new targeted therapies are actively being explored. Herein, we review the clinico-pathologic and molecular classification of these tumors, historical treatments, current management strategies, and therapies currently under investigation.
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Affiliation(s)
- Christina Coleman
- Division of Pediatric Hematology/Oncology, Department of Pediatrics, UCSF Benioff Children's Hospital, Oakland, 747 52nd Street, Oakland, CA, 94609, USA
| | - Schuyler Stoller
- Department of Neurology, University of California, San Francisco, 625 Nelson Rising Lane, Box 0663, San Francisco, CA, 94158, USA
| | - Michael Grotzer
- Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Ana Guerreiro Stucklin
- Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Javad Nazarian
- Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Sabine Mueller
- Department of Neurology, University of California, San Francisco, 625 Nelson Rising Lane, Box 0663, San Francisco, CA, 94158, USA.
- Department of Oncology and Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland.
- Division of Hematology/Oncology, Department of Pediatrics, University of California, San Francisco, 550 16th Street, 4th Floor, San Francisco, CA, 94158, USA.
- Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Avenue, M779, San Francisco, CA, USA.
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21
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Clarke M, Mackay A, Ismer B, Pickles JC, Tatevossian RG, Newman S, Bale TA, Stoler I, Izquierdo E, Temelso S, Carvalho DM, Molinari V, Burford A, Howell L, Virasami A, Fairchild AR, Avery A, Chalker J, Kristiansen M, Haupfear K, Dalton JD, Orisme W, Wen J, Hubank M, Kurian KM, Rowe C, Maybury M, Crosier S, Knipstein J, Schüller U, Kordes U, Kram DE, Snuderl M, Bridges L, Martin AJ, Doey LJ, Al-Sarraj S, Chandler C, Zebian B, Cairns C, Natrajan R, Boult JKR, Robinson SP, Sill M, Dunkel IJ, Gilheeney SW, Rosenblum MK, Hughes D, Proszek PZ, Macdonald TJ, Preusser M, Haberler C, Slavc I, Packer R, Ng HK, Caspi S, Popović M, Faganel Kotnik B, Wood MD, Baird L, Davare MA, Solomon DA, Olsen TK, Brandal P, Farrell M, Cryan JB, Capra M, Karremann M, Schittenhelm J, Schuhmann MU, Ebinger M, Dinjens WNM, Kerl K, Hettmer S, Pietsch T, Andreiuolo F, Driever PH, Korshunov A, Hiddingh L, Worst BC, Sturm D, Zuckermann M, Witt O, Bloom T, Mitchell C, Miele E, Colafati GS, Diomedi-Camassei F, Bailey S, Moore AS, Hassall TEG, Lowis SP, Tsoli M, Cowley MJ, Ziegler DS, Karajannis MA, Aquilina K, Hargrave DR, Carceller F, Marshall LV, et alClarke M, Mackay A, Ismer B, Pickles JC, Tatevossian RG, Newman S, Bale TA, Stoler I, Izquierdo E, Temelso S, Carvalho DM, Molinari V, Burford A, Howell L, Virasami A, Fairchild AR, Avery A, Chalker J, Kristiansen M, Haupfear K, Dalton JD, Orisme W, Wen J, Hubank M, Kurian KM, Rowe C, Maybury M, Crosier S, Knipstein J, Schüller U, Kordes U, Kram DE, Snuderl M, Bridges L, Martin AJ, Doey LJ, Al-Sarraj S, Chandler C, Zebian B, Cairns C, Natrajan R, Boult JKR, Robinson SP, Sill M, Dunkel IJ, Gilheeney SW, Rosenblum MK, Hughes D, Proszek PZ, Macdonald TJ, Preusser M, Haberler C, Slavc I, Packer R, Ng HK, Caspi S, Popović M, Faganel Kotnik B, Wood MD, Baird L, Davare MA, Solomon DA, Olsen TK, Brandal P, Farrell M, Cryan JB, Capra M, Karremann M, Schittenhelm J, Schuhmann MU, Ebinger M, Dinjens WNM, Kerl K, Hettmer S, Pietsch T, Andreiuolo F, Driever PH, Korshunov A, Hiddingh L, Worst BC, Sturm D, Zuckermann M, Witt O, Bloom T, Mitchell C, Miele E, Colafati GS, Diomedi-Camassei F, Bailey S, Moore AS, Hassall TEG, Lowis SP, Tsoli M, Cowley MJ, Ziegler DS, Karajannis MA, Aquilina K, Hargrave DR, Carceller F, Marshall LV, von Deimling A, Kramm CM, Pfister SM, Sahm F, Baker SJ, Mastronuzzi A, Carai A, Vinci M, Capper D, Popov S, Ellison DW, Jacques TS, Jones DTW, Jones C. Infant High-Grade Gliomas Comprise Multiple Subgroups Characterized by Novel Targetable Gene Fusions and Favorable Outcomes. Cancer Discov 2020; 10:942-963. [PMID: 32238360 PMCID: PMC8313225 DOI: 10.1158/2159-8290.cd-19-1030] [Show More Authors] [Citation(s) in RCA: 170] [Impact Index Per Article: 34.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2019] [Revised: 03/03/2020] [Accepted: 03/20/2020] [Indexed: 11/16/2022]
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 commentary by Szulzewsky and Cimino, p. 904.This article is highlighted in the In This Issue feature, p. 890.
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Affiliation(s)
- Matthew Clarke
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Alan Mackay
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Britta Ismer
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Faculty of Biosciences, Heidelberg University, Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
| | - Jessica C Pickles
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Ruth G Tatevossian
- Department of Neuropathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Scott Newman
- Department of Computational Biology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Tejus A Bale
- Department of Neuropathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Iris Stoler
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany
| | - Elisa Izquierdo
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Sara Temelso
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Diana M Carvalho
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Valeria Molinari
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Anna Burford
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Louise Howell
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
| | - Alex Virasami
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Amy R Fairchild
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Aimee Avery
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Jane Chalker
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Mark Kristiansen
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom
| | - Kelly Haupfear
- Department of Neuropathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - James D Dalton
- Department of Neuropathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Wilda Orisme
- Department of Neuropathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Ji Wen
- Department of Neuropathology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Michael Hubank
- Molecular Diagnostics, Royal Marsden Hospital NHS Trust, Sutton, United Kingdom
| | - Kathreena M Kurian
- Brain Tumour Research Centre, University of Bristol, Bristol, United Kingdom
| | - Catherine Rowe
- Brain Tumour Research Centre, University of Bristol, Bristol, United Kingdom
| | - Mellissa Maybury
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Australia
- Oncology Service, Queensland Children's Hospital, Brisbane, Australia
- Child Health Research Centre, The University of Queensland, South Brisbane, Australia
| | - Stephen Crosier
- Newcastle Hospitals NHS Foundation Trust, Newcastle, United Kingdom
| | - Jeffrey Knipstein
- Division of Pediatric Hematology/Oncology/BMT, Medical College of Wisconsin, Milwaukee, Wisconsin
| | - Ulrich Schüller
- Department of Neuropathology, University Hospital Hamburg-Eppendorf, and Research Institute Children's Cancer Center, Hamburg, Germany
- Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - Uwe Kordes
- Pediatric Hematology and Oncology, University Hospital Hamburg-Eppendorf, Hamburg, Germany
| | - David E Kram
- Section of Pediatric Hematology-Oncology, Wake Forest School of Medicine, Winston-Salem, North Carolina
| | - Matija Snuderl
- Department of Neuropathology, NYU Langone Health, New York, New York
| | - Leslie Bridges
- Department of Neuropathology, St George's Hospital NHS Trust, London, United Kingdom
| | - Andrew J Martin
- Department of Neurosurgery, St George's Hospital NHS Trust, London, United Kingdom
| | - Lawrence J Doey
- Department of Clinical Neuropathology, Kings College Hospital NHS Trust, London, United Kingdom
| | - Safa Al-Sarraj
- Department of Clinical Neuropathology, Kings College Hospital NHS Trust, London, United Kingdom
| | - Christopher Chandler
- Department of Neurosurgery, Kings College Hospital NHS Trust, London, United Kingdom
| | - Bassel Zebian
- Department of Neurosurgery, Kings College Hospital NHS Trust, London, United Kingdom
| | - Claire Cairns
- Department of Neurosurgery, Kings College Hospital NHS Trust, London, United Kingdom
| | - Rachael Natrajan
- The Breast Cancer Now Toby Robins Research Centre, The Institute of Cancer Research, London, United Kingdom
| | - Jessica K R Boult
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom
| | - Simon P Robinson
- Division of Radiotherapy and Imaging, The Institute of Cancer Research, London, United Kingdom
| | - Martin Sill
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ira J Dunkel
- Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Stephen W Gilheeney
- Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Marc K Rosenblum
- Department of Neuropathology, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Debbie Hughes
- Molecular Diagnostics, Royal Marsden Hospital NHS Trust, Sutton, United Kingdom
| | - Paula Z Proszek
- Molecular Diagnostics, Royal Marsden Hospital NHS Trust, Sutton, United Kingdom
| | - Tobey J Macdonald
- Aflac Cancer and Blood Disorders Center, Department of Pediatrics, Emory University School of Medicine, Atlanta, Georgia
| | - Matthias Preusser
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Christine Haberler
- Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
- Institute of Neurology, Medical University of Vienna, Vienna, Austria
| | - Irene Slavc
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
| | - Roger Packer
- Center for Neuroscience and Behavioural Medicine, Children's National Medical Center, Washington, DC
| | - Ho-Keung Ng
- Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, China
| | - Shani Caspi
- Cancer Research Center, Sheba Medical Center, Tel Aviv, Israel
| | - Mara Popović
- Faculty of Medicine, University of Ljubljana, Ljubljana, Slovenia
| | - Barbara Faganel Kotnik
- Department of Hematology and Oncology, University Children's Hospital, Ljubljana, Slovenia
| | - Matthew D Wood
- Department of Pathology, Oregon Health & Science University, Portland, Oregon
| | - Lissa Baird
- Department of Neurosurgery, Oregon Health & Science University, Portland, Oregon
| | - Monika Ashok Davare
- Department of Pediatrics, Oregon Health & Science University, Portland, Oregon
| | - David A Solomon
- Department of Pathology, University of California, San Francisco, California
- Clinical Cancer Genomics Laboratory, University of California, San Francisco, California
| | - Thale Kristin Olsen
- Department of Women's and Children's Health, Karolinska Institute, Stockholm, Sweden
| | - Petter Brandal
- Department of Oncology, Oslo University Hospital, Oslo, Norway
| | - Michael Farrell
- Department of Histopathology, Beaumont Hospital, Dublin, Ireland
| | - Jane B Cryan
- Department of Histopathology, Beaumont Hospital, Dublin, Ireland
| | - Michael Capra
- Paediatric Oncology, Our Lady's Children's Hospital, Dublin, Ireland
| | - Michael Karremann
- Department of Pediatrics, University Medical Center Mannheim, Medical Faculty Mannheim, Heidelberg University, Mannheim, Germany
| | - Jens Schittenhelm
- Institute of Pathology and Neuropathology, University Hospital Tübingen, Germany
| | | | - Martin Ebinger
- Department of Pediatric Hematology and Oncology, University Hospital Tübingen, Germany
| | - Winand N M Dinjens
- Department of Pathology, Erasmus Medical Center, Rotterdam, the Netherlands
| | - Kornelius Kerl
- Department of Pediatric Hematology and Oncology, University Hospital Muenster, Germany
| | - Simone Hettmer
- Department of Pediatric Hematology and Oncology, University Hospital Freiburg, Germany
| | - Torsten Pietsch
- Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
| | - Felipe Andreiuolo
- Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn Medical Center, Bonn, Germany
| | - Pablo Hernáiz Driever
- Department of Paediatric Haematology/Oncology Charité Universitätsmedizin, Berlin, Germany
| | - Andrey Korshunov
- Department of Neuropathology, University Hospital Heidelberg, Germany
| | - Lotte Hiddingh
- German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Barbara C Worst
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Dominik Sturm
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Marc Zuckermann
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
| | - Olaf Witt
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Tabitha Bloom
- BRAIN UK, University of Southampton, Southampton, United Kingdom
| | - Clare Mitchell
- BRAIN UK, University of Southampton, Southampton, United Kingdom
| | - Evelina Miele
- Department of Onco-haematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Giovanna Stefania Colafati
- Oncological Neuroradiology Unit, Department of Diagnostic Imaging, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | | | - Simon Bailey
- Newcastle Hospitals NHS Foundation Trust, Newcastle, United Kingdom
| | - Andrew S Moore
- The University of Queensland Diamantina Institute, The University of Queensland, Woolloongabba, Australia
- Oncology Service, Queensland Children's Hospital, Brisbane, Australia
- Child Health Research Centre, The University of Queensland, South Brisbane, Australia
| | - Timothy E G Hassall
- Oncology Service, Queensland Children's Hospital, Brisbane, Australia
- Institute for Molecular Bioscience, The University of Queensland, St Lucia, Australia
- School of Biomedical Sciences, Faculty of Health, Queensland University of Technology, Brisbane, Australia
| | - Stephen P Lowis
- Brain Tumour Research Centre, University of Bristol, Bristol, United Kingdom
| | - Maria Tsoli
- Children's Cancer Institute, University of New South Wales, Sydney, Australia
- Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia
| | - Mark J Cowley
- Children's Cancer Institute, University of New South Wales, Sydney, Australia
- Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia
| | - David S Ziegler
- Children's Cancer Institute, University of New South Wales, Sydney, Australia
- Kids Cancer Centre, Sydney Children's Hospital, Randwick, Australia
| | - Matthias A Karajannis
- Department of Pediatrics, Memorial Sloan-Kettering Cancer Center, New York, New York
| | - Kristian Aquilina
- Department of Neurosurgery, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Darren R Hargrave
- Department of Paediatric Oncology, Great Ormond Street Hospital NHS Foundation Trust, London, United Kingdom
| | - Fernando Carceller
- Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
- Children & Young People's Unit, Royal Marsden Hospital NHS Trust, Sutton, United Kingdom
| | - Lynley V Marshall
- Division of Clinical Studies, The Institute of Cancer Research, London, United Kingdom
- Children & Young People's Unit, Royal Marsden Hospital NHS Trust, Sutton, United Kingdom
| | - Andreas von Deimling
- Department of Neuropathology, University Hospital Heidelberg, Germany
- Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Christof M Kramm
- Division of Pediatric Hematology and Oncology, University Medical Centre Göttingen, Germany
| | - Stefan M Pfister
- German Cancer Research Center (DKFZ), Heidelberg, Germany
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany
| | - Felix Sahm
- Department of Paediatric Haematology/Oncology Charité Universitätsmedizin, Berlin, Germany
- Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Suzanne J Baker
- Department of Neurobiology, St. Jude Children's Research Hospital, Memphis, Tennessee
| | - Angela Mastronuzzi
- Neuro-oncology Unit, Department of Onco-haematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Andrea Carai
- Oncological Neurosurgery Unit, Department of Neuroscience and Neurorehabilitation, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - Maria Vinci
- Department of Onco-haematology, Cell and Gene Therapy, Bambino Gesù Children's Hospital-IRCCS, Rome, Italy
| | - David Capper
- Charité Universitätsmedizin Berlin, corporate member of Freie Universität Berlin, Humboldt-Universität zu Berlin, and Berlin Institute of Health, Department of Neuropathology, Berlin, Germany
- German Cancer Consortium (DKTK), Partner Site Berlin, German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Sergey Popov
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom
- Department of Pathology, University of Wales Hospital NHS Trust, Cardiff, United Kingdom
| | - David W Ellison
- Department of Neuropathology, St. Jude Children's Research Hospital, Memphis, Tennessee.
| | - Thomas S Jacques
- UCL Great Ormond Street Institute of Child Health, London, United Kingdom.
| | - David T W Jones
- German Cancer Research Center (DKFZ), Heidelberg, Germany.
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
| | - Chris Jones
- Division of Molecular Pathology, Institute of Cancer Research, London, United Kingdom.
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22
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Bravo P, Bertin L, Pinon A, Tortolano L, Fleury T, Raimbault S, Chachaty E, Annereau M, Lemare F. Development and stability of an oral suspension of procarbazine in pediatrics. J Drug Deliv Sci Technol 2019. [DOI: 10.1016/j.jddst.2018.11.002] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
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23
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Azizi AA, Paur S, Kaider A, Dieckmann K, Peyrl A, Chocholous M, Czech T, Slavc I. Does the interval from tumour surgery to radiotherapy influence survival in paediatric high grade glioma? Strahlenther Onkol 2018; 194:552-559. [PMID: 29349602 PMCID: PMC5959993 DOI: 10.1007/s00066-018-1260-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/15/2017] [Accepted: 01/05/2018] [Indexed: 12/01/2022]
Abstract
PURPOSE Paediatric high grade glioma (pHGG) are rare. Following maximum safe resection, children >3 years with HGG receive radiotherapy as standard of care. Whether the interval from tumour surgery to radiotherapy (ISRT) influences survival is disputed in adults with glioblastoma, data for children are lacking. This retrospective single-centre analysis investigates a possible impact of ISRT on survival in paediatric patients with HGG. METHODS Survival was analysed in patients aged 3-19 years with non-pontine HGG. RESULTS Thirty-eight patients were included (female:male 19:19) with a median age of 11.0 years (3.4-17.7). Seventeen patients had grade 3 and 21 grade 4 glioma. Gross total resection was achieved in 26.3%, partial resection in 36.8% and 36.8% underwent biopsy only. All patients received concomitant and adjuvant chemotherapy. Fifty percent (n = 19) started irradiation ≤17 days (median interval 12 days [range 5-17]), 50% thereafter (median 28 days [range 19-78]). More patients with grade 4 tumours were irradiated shortly after surgery. ISRT (as a continuous variable and dichotomised into two groups by the median ISRT of 18 days) did not significantly influence overall survival (OS) or progression-free survival (PFS). Higher extent of resection (EOR), lower tumour grade as well as chemotherapy with temozolomide had a significant positive impact on OS and PFS in univariate analysis and (except for the effect of temozolomide on PFS) also in multivariable analysis. CONCLUSIONS ISRT did not influence survival in pHGG. In view of upcoming targeted treatment options in pHGG the present data suggest that it is safe to perform molecular analyses within a 4-week timeframe before radiotherapy.
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Affiliation(s)
- Amedeo A Azizi
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria.
| | - Simon Paur
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Alexandra Kaider
- Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | - Karin Dieckmann
- Department of Radiation Oncology, Medical University of Vienna, Vienna, Austria
| | - Andreas Peyrl
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Monika Chocholous
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
| | - Thomas Czech
- Department of Neurosurgery, Medical University of Vienna, Vienna, Austria
| | - Irene Slavc
- Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Spitalgasse 23, 1090, Vienna, Austria
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Liu M, Thakkar JP, Garcia CR, Dolecek TA, Wagner LM, Dressler EVM, Villano JL. National cancer database analysis of outcomes in pediatric glioblastoma. Cancer Med 2018. [PMID: 29532996 PMCID: PMC5911617 DOI: 10.1002/cam4.1404] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Glioblastoma in children is an aggressive disease with no defined standard therapy. We evaluated hospital‐based demographic and survival patterns obtained through the National Cancer Database to better characterize children with glioblastoma. Our study identified 1173 patients from 0 to 19 years of age between 1998 and 2011. Comparisons were made among demographics, clinical characteristics, treatment, and survival variables. Fifty‐four percent of patients were over 10 years of age. Approximately 80% of patients underwent either partial or complete resection. Adjuvant therapy was used variably, and its use increased with patient age. Forty‐eight percent of patients received the combination of surgery, radiation, and chemotherapy, and 4% did not receive any treatment. As expected, patients ≤5 years of age had better 5‐year survival than those ages 6–10 (P = 0.01) or 11–19 years (P = 0.0077). Other factors associated with poor survival included black race and central tumor location. Better outcomes were associated with treatment that included surgery, radiotherapy, and chemotherapy compared to any other treatment combinations. Radiotherapy had no impact on survival in the 0 to 10‐year‐old age group, but was associated with improved survival for patients 11–19 years. We report an extensive demographic and survival analysis of pediatric glioblastoma. The observed differences likely reflect variances in tumor biology and likelihood of treatment receipt. Improved survival was associated with the use of surgery, radiotherapy, and chemotherapy. Radiation therapy was not associated with survival in patients younger than 10 years of age.
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Affiliation(s)
- Meng Liu
- Division of Cancer Biostatistics, University of Kentucky, Lexington, Kentucky.,Markey Cancer Center, University of Kentucky, Lexington, Kentucky
| | - Jigisha P Thakkar
- Department of Neurology, University of Kentucky, Lexington, Kentucky
| | | | - Therese A Dolecek
- Division of Epidemiology and Biostatistics and Institute for Health Research and Policy, School of Public Health, University of Illinois at Chicago, Chicago, Illinois
| | - Lars M Wagner
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky.,Department of Pediatric Hematology and Oncology, University of Kentucky, Lexington, Kentucky.,Department of Medicine, University of Kentucky, Lexington, Kentucky
| | - Emily Van Meter Dressler
- Department of Biostatistical Sciences, School of Medicine, Wake Forest Baptist Health, Winston Salem, North Carolina
| | - John L Villano
- Markey Cancer Center, University of Kentucky, Lexington, Kentucky.,Department of Neurology, University of Kentucky, Lexington, Kentucky.,Department of Medicine, University of Kentucky, Lexington, Kentucky.,Department of Neurosurgery, University of Kentucky, Lexington, Kentucky
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Bavle A, Chintagumpala M. Pediatric high-grade glioma: a review of biology, prognosis, and treatment. ACTA ACUST UNITED AC 2018. [DOI: 10.1007/s13566-018-0344-9] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/18/2023]
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26
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Diffuse intrinsic pontine gliomas (DIPG) at recurrence: is there a window to test new therapies in some patients? J Neurooncol 2017; 137:111-118. [PMID: 29198053 DOI: 10.1007/s11060-017-2702-7] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2017] [Accepted: 11/24/2017] [Indexed: 02/08/2023]
Abstract
Children with diffuse intrinsic pontine glioma (DIPG) need new and more efficient treatments. They can be developed at relapse or at diagnosis, but therefore they must be combined with radiotherapy. Survival of children after recurrence and its predictors were studied to inform the possibility to design early phase clinical trials for DIPG at this stage. Among 142 DIPG patients treated between 1998 and 2014, 114 had biopsy-proven DIPG with histone H3 status available for 83. We defined as long survivors' patients who survived more than 3 months after relapse which corresponds to the minimal life expectancy requested for phase I/II trials. Factors influencing post-relapse survival were accordingly compared between short and long-term survivors after relapse. Fifty-seven percent of patients were considered long survivors and 70% of them had a Lansky Play Scale (LPS) above 50% at relapse. Patients who became steroids-independent after initial treatment for at least 2 months had better survival after relapse (3.7 versus 2.6 months, p = 0.001). LPS above 50% at relapse was correlated with better survival after relapse (3.8 versus 1.8 months, p < 0.001). Patients with H3.1 mutation survived longer after relapse (4.9 versus 2.7 months, p = 0.007). Patients who received a second radiotherapy at the time of relapse had an improved survival (7.5 versus 4 months, p = 0.001). In the two-way ANOVA analysis, steroid-independence and LPS predicted survival best and the type of histone H3 (H3.1 or H3.3) mutated did not improve prediction. Survival of many DIPG patients after relapse over 3 months would make possible to propose specific trials for this condition. Steroid-independence, H3 mutation status and LPS should be considered to predict eligibility.
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27
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Lam S, Lin Y, Zinn P, Su J, Pan IW. Patient and treatment factors associated with survival among pediatric glioblastoma patients: A Surveillance, Epidemiology, and End Results study. J Clin Neurosci 2017; 47:285-293. [PMID: 29102237 DOI: 10.1016/j.jocn.2017.10.041] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2017] [Accepted: 10/10/2017] [Indexed: 10/18/2022]
Abstract
Glioblastoma (GBM) is a rare malignancy in children. The United States Surveillance, Epidemiology, and End Results (SEER) database allows large-scale analyses of clinical characteristics and prognostic features. We used it to study patients aged <20 years with histologically confirmed GBM (2000-2010) and examined the relationship between patient demographics, tumor characteristics, patterns of treatment, and outcomes. The primary outcome was disease-specific survival. 302 subjects were identified, with median age 11 years. Median follow-up was 32 months (95% CI 27-39). 34.4% had gross total resection (GTR). 61% underwent radiation after surgery (17% of subjects <3 years, 67% of those aged 4-19 years). Median survival and 2-year survival rates were 20 months and 46.9%, respectively. In multivariate analyses, age, tumor location, extent of resection, and year of diagnosis were significantly associated with the primary outcome. Compared to those aged 0-4 years, subjects aged 5-9 years and 10-14 years had higher risk of mortality. Infratentorial tumor location (HR 2.0, 95% CI 1.2-3.3, p = 0.007) and subtotal resection (HR 2.04, 95% CI 1.4-3.0, p < 0.001) were associated with increased mortality. Later year of diagnosis was significantly associated with decreased risk of death (HR 0.93, 95% CI 0.9-0.99, p = 0.031). There was no association between sex, race, region, or tumor size and the primary outcome. Repeat analyses examining all-cause mortality identified the same risk factors as for CNS cancer-specific mortality. Younger age, supratentorial location, GTR, and later year of diagnosis were associated with improved survival.
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Affiliation(s)
- Sandi Lam
- Baylor College of Medicine, Department of Neurosurgery, Houston, TX, USA; Texas Children's Hospital, Division of Pediatric Neurosurgery, Houston, TX, USA.
| | - Yimo Lin
- Baylor College of Medicine, Department of Neurosurgery, Houston, TX, USA; Texas Children's Hospital, Division of Pediatric Neurosurgery, Houston, TX, USA
| | - Pascal Zinn
- Baylor College of Medicine, Department of Neurosurgery, Houston, TX, USA; Texas Children's Hospital, Division of Pediatric Neurosurgery, Houston, TX, USA
| | - Jack Su
- Baylor College of Medicine, Department of Pediatrics, Houston, TX, USA; Texas Children's Hospital, Division of Pediatric Hematology/Oncology, Houston, TX, USA
| | - I-Wen Pan
- Baylor College of Medicine, Department of Neurosurgery, Houston, TX, USA; Texas Children's Hospital, Division of Pediatric Neurosurgery, Houston, TX, USA
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28
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High-grade glioma in very young children: a rare and particular patient population. Oncotarget 2017; 8:64564-64578. [PMID: 28969094 PMCID: PMC5610026 DOI: 10.18632/oncotarget.18478] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2017] [Accepted: 05/17/2017] [Indexed: 01/05/2023] Open
Abstract
In the past years, pediatric high-grade gliomas (HGG) have been the focus of several research articles and reviews, given the recent discoveries on the genetic and molecular levels pointing out a clinico-biological uniqueness of the pediatric population compared to their adult counterparts with HGG. On the other hand, there are only scarce data about HGG in very young children (below 3 years of age at diagnosis) due to their relatively low incidence. However, the few available data suggest further distinction of this very rare subgroup from older children and adults at several levels including their molecular and biological characteristics, their treatment management, as well as their outcome. This review summarizes and discusses the current available knowledge on the epidemiological, neuropathological, genetic and molecular data of this subpopulation. We discuss these findings and differences compared to older patients suffering from the same histologic disease. In addition, we highlight the particular clinical and neuro-radiological findings in this specific subgroup of patients as well as their current management approaches and treatment outcomes.
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29
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Risk assessment in paediatric glioma—Time to move on from the binary classification. Crit Rev Oncol Hematol 2017; 111:52-59. [DOI: 10.1016/j.critrevonc.2017.01.012] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2016] [Revised: 11/28/2016] [Accepted: 01/18/2017] [Indexed: 11/24/2022] Open
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30
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Espinoza JC, Haley K, Patel N, Dhall G, Gardner S, Allen J, Torkildson J, Cornelius A, Rassekh R, Bedros A, Etzl M, Garvin J, Pradhan K, Corbett R, Sullivan M, McGowage G, Stein D, Jasty R, Sands SA, Ji L, Sposto R, Finlay JL. Outcome of young children with high-grade glioma treated with irradiation-avoiding intensive chemotherapy regimens: Final report of the Head Start II and III trials. Pediatr Blood Cancer 2016; 63:1806-13. [PMID: 27332770 PMCID: PMC5598351 DOI: 10.1002/pbc.26118] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/30/2015] [Revised: 05/03/2016] [Accepted: 05/21/2016] [Indexed: 11/08/2022]
Abstract
PURPOSE To report the final analysis of survival outcomes for children with newly diagnosed high-grade glioma (HGG) treated on the "Head Start" (HS) II and III protocols with chemotherapy and intent to avoid irradiation in children <6 years old. PATIENTS AND METHODS Between 1997 and 2009, 32 eligible children were enrolled in HS II and III with anaplastic astrocytoma (AA, n = 19), glioblastoma multiforme (GBM, n = 11), or other HGG (n = 2). Central pathology review was completed on 78% of patients. Patients with predominantly brainstem tumors were excluded. Patients were to be treated with single induction chemotherapy regimen C, comprising four cycles of vincristine, carboplatin, and temozolomide. Following induction, patients underwent marrow-ablative chemotherapy and autologous hematopoietic cell rescue. Irradiation was used for patients with residual tumor after consolidation or >6 years old or at the time of tumor progression. RESULTS The 5-year event-free survival (EFS) and overall survival (OS) for all HGG patients were 25 ± 8% and 36 ± 9%, respectively. The EFS at 5 years for patients with AA and GBM were 24 ± 11% and 30 ± 16%, respectively (P = 0.65). The OS at 5 years for patients with AA and GBM was 34 ± 12% and 35 ± 16%, respectively (P = 0.83). Children <36 months old experienced improved 5-year EFS and OS of 44 ± 17% and 63 ± 17%, compared with children 36-71 months old (31 ± 13% and 38 ± 14%) and children >72 months old (0% and 13 ± 12%). CONCLUSIONS Irradiation-avoiding treatment strategies should be evaluated further in young children with HGG given similar survival rates to older children receiving standard irradiation-containing therapies.
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Affiliation(s)
| | - Kelley Haley
- Children's Hospital Los Angeles, Los Angeles, California
| | - Neha Patel
- Department of pediatrics, University of Wisconsin, Madison, Wisconsin
| | - Girish Dhall
- Children's Hospital Los Angeles, Los Angeles, California
| | - Sharon Gardner
- Department of pediatrics, New York University Medical Center, New York, New York
| | - Jeffrey Allen
- Department of pediatrics, New York University Medical Center, New York, New York
| | | | | | - Rod Rassekh
- British Columbia Children's Hospital, Vancouver, British Columbia, Canada
| | - Antranik Bedros
- Department of pediatrics, Loma Linda University Medical Center, Loma Linda, California
| | - Morris Etzl
- Phoenix Children's Hospital, Phoenix, Arizona
| | - James Garvin
- Columbia Children's Hospital, New York, New York
| | | | - Robin Corbett
- Department of pediatrics, University of Otago, Christchurch, New Zealand
| | - Michael Sullivan
- Department of pediatrics, University of Otago, Christchurch, New Zealand
| | | | | | | | - Stephen A. Sands
- Department of pediatrics, Columbia University Medical Center, New York, New York
| | - Lingyun Ji
- USC Norris Comprehensive Cancer Center, Los Angeles, California
| | - Richard Sposto
- Children's Hospital Los Angeles, Los Angeles, California
| | - Jonathan L. Finlay
- Department of pediatrics, Division of Hematology, Oncology and BMT, Nationwide Children's Hospital, The Ohio State University, Columbus, Ohio
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31
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Lee MJ. Overview of CNS Gliomas in Childhood. CLINICAL PEDIATRIC HEMATOLOGY-ONCOLOGY 2016. [DOI: 10.15264/cpho.2016.23.1.8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022] Open
Affiliation(s)
- Mee Jeong Lee
- Department of Pediatrics, Dankook University College of Medicine, Cheonan, Korea
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32
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McCrea HJ, Bander ED, Venn RA, Reiner AS, Iorgulescu JB, Puchi LA, Schaefer PM, Cederquist G, Greenfield JP. Sex, Age, Anatomic Location, and Extent of Resection Influence Outcomes in Children With High-grade Glioma. Neurosurgery 2016; 77:443-52; discussion 452-3. [PMID: 26083157 DOI: 10.1227/neu.0000000000000845] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Survival duration and prognostic factors in adult high-grade glioma have been comprehensively analyzed, but less is known about factors contributing to overall survival (OS) and progression-free survival (PFS) in pediatric patients. OBJECTIVE To identify these factors in the pediatric population. METHODS We retrospectively reviewed institutional databases evaluating all patients ≤21 years with high-grade glioma treated between 1988 and 2010. Kaplan-Meier curves and log-rank statistics were used to compare groups univariately. Multivariate analyses were completed using Cox proportional hazards regression models. RESULTS Ninety-seven patients were identified with a median age of 11 years. Median OS was 1.7 years, and median PFS was 272 days. Location was significant for OS (P < .001). Patients with gross total resection (GTR) had a median OS of 3.4 years vs 1.6 years for subtotal resection and 1.3 years for biopsy patients (P < .001). Female patients had improved OS (P = .01). Female patients with GTR had a mean OS of 8.1 years vs 2.4 years for male patients with GTR and 1.4 years for all other female patients and male patients (P = .001). PFS favored patients ≤3 and ≥13 years and females (P = .003 and .001). CONCLUSION OS was significantly correlated with the location of the tumor and the extent of resection. GTR significantly improved overall survival for both glioblastoma multiforme and anaplastic astrocytoma patients, and female patients showed a much larger survival benefit from GTR than male patients.
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Affiliation(s)
- Heather J McCrea
- *Department of Neurological Surgery, Weill Cornell Medical College, New York Presbyterian Hospital, New York, New York; ‡Department of Neurosurgery, Memorial Sloan Kettering Cancer Center, New York, New York; §Department of Epidemiology & Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York; ¶Children's Brain Tumor Project, New York, New York
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Stival A, Lucchesi M, Farina S, Buccoliero AM, Castiglione F, Genitori L, de Martino M, Sardi I. An infant with hyperalertness, hyperkinesis, and failure to thrive: a rare diencephalic syndrome due to hypothalamic anaplastic astrocytoma. BMC Cancer 2015; 15:616. [PMID: 26337554 PMCID: PMC4559913 DOI: 10.1186/s12885-015-1626-x] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2014] [Accepted: 06/14/2015] [Indexed: 01/12/2023] Open
Abstract
BACKGROUND Diencephalic Syndrome is a rare clinical condition of failure to thrive despite a normal caloric intake, hyperalertness, hyperkinesis, and euphoria usually associated with low-grade hypothalamic astrocytomas. CASE PRESENTATION We reported an unusual case of diencephalic cachexia due to hypothalamic anaplastic astrocytoma (WHO-grade III). Baseline endocrine function evaluation was performed in this patient before surgery. After histological diagnosis, he enrolled to a chemotherapy program with sequential high-dose chemotherapy followed by hematopoietic stem cell rescue. The last MRI evaluation showed a good response. The patient is still alive with good visual function 21 months after starting chemotherapy. CONCLUSIONS Diencephalic cachexia can rarely be due to high-grade hypothalamic astrocytoma. We suggest that a nutritional support with chemotherapy given to high doses without radiotherapy could be an effective strategy for treatment of a poor-prognosis disease.
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Affiliation(s)
- Alessia Stival
- Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital and Department of Health Sciences, University of Florence, Florence, Italy.
| | - Maurizio Lucchesi
- Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital and Department of Health Sciences, University of Florence, Florence, Italy.
| | - Silvia Farina
- Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital and Department of Health Sciences, University of Florence, Florence, Italy.
| | | | | | - Lorenzo Genitori
- Neurosurgery Unit, Department of Neurosciences, Anna Meyer Children's University Hospital, Florence, Italy.
| | - Maurizio de Martino
- Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital and Department of Health Sciences, University of Florence, Florence, Italy.
| | - Iacopo Sardi
- Neuro-oncology Unit, Department of Paediatric Medicine, Anna Meyer Children's University Hospital and Department of Health Sciences, University of Florence, Florence, Italy.
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Adamski J, Tabori U, Bouffet E. Advances in the Management of Paediatric High-Grade Glioma. Curr Oncol Rep 2014; 16:414. [DOI: 10.1007/s11912-014-0414-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
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Vanan MI, Eisenstat DD. Management of high-grade gliomas in the pediatric patient: Past, present, and future. Neurooncol Pract 2014; 1:145-157. [PMID: 26034626 DOI: 10.1093/nop/npu022] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2014] [Indexed: 11/12/2022] Open
Abstract
High-grade gliomas (HGGs) constitute ∼15% of all primary brain tumors in children and adolescents. Routine histopathological diagnosis is based on tissue obtained from biopsy or, preferably, from the resected tumor itself. The majority of pediatric HGGs are clinically and biologically distinct from histologically similar adult malignant gliomas; these differences may explain the disparate responses to therapy and clinical outcomes when comparing children and adults with HGG. The recently proposed integrated genomic classification identifies 6 distinct biological subgroups of glioblastoma (GBM) throughout the age spectrum. Driver mutations in genes affecting histone H3.3 (K27M and G34R/V) coupled with mutations involving specific proteins (TP53, ATRX, DAXX, SETD2, ACVR1, FGFR1, NTRK) induce defects in chromatin remodeling and may play a central role in the genesis of many pediatric HGGs. Current clinical practice in pediatric HGGs includes surgical resection followed by radiation therapy (in children aged > 3 years) with concurrent and adjuvant chemotherapy with temozolomide. However, these multimodality treatment strategies have had a minimal impact on improving survival. Ongoing clinical trials are investigating new molecular targets, chemoradiation sensitization strategies, and immunotherapy. Future clinical trials of pediatric HGG will incorporate the distinction between GBM molecular subgroups and stratify patients using group-specific biomarkers.
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Affiliation(s)
- Magimairajan Issai Vanan
- Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, Departments of Pediatrics & Child Health and Biochemistry & Medical Genetics , University of Manitoba , Winnipeg, Manitoba , Canada (M.I.V.); Division of Hematology/Oncology and Palliative Care, Stollery Children's Hospital, Departments of Pediatrics, Medical Genetics and Oncology , University of Alberta , Edmonton, Alberta , Canada (D.D.E.)
| | - David D Eisenstat
- Section of Pediatric Hematology/Oncology/BMT, CancerCare Manitoba, Departments of Pediatrics & Child Health and Biochemistry & Medical Genetics , University of Manitoba , Winnipeg, Manitoba , Canada (M.I.V.); Division of Hematology/Oncology and Palliative Care, Stollery Children's Hospital, Departments of Pediatrics, Medical Genetics and Oncology , University of Alberta , Edmonton, Alberta , Canada (D.D.E.)
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Wu L, Li X, Janagam DR, Lowe TL. Overcoming the blood-brain barrier in chemotherapy treatment of pediatric brain tumors. Pharm Res 2013; 31:531-40. [PMID: 23996470 DOI: 10.1007/s11095-013-1196-z] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/23/2013] [Accepted: 08/21/2013] [Indexed: 12/19/2022]
Abstract
Pediatric brain tumors are most common cancers in childhood and among the leading causes of death in children. Chemotherapy has been used as adjuvant (i.e. after) or neoadjuvant (i.e. before) therapy to surgery and radiotherapy for the management of pediatric brain tumors for more than four decades and gained more attention in the recent two decades. Although chemotherapy has demonstrated its effectiveness in the management of some pediatric brain tumors, failure or inactiveness of chemotherapy is commonly met in the clinics and clinical trials. Some of these failures might be attributed to the blood-brain barrier (BBB), limiting the penetration of systemically administered chemotherapeutics into pediatric brain tumors. Therefore, various strategies have been developed and used to address this issue. Herein, we review different methods reported in the literature to circumvent the BBB for enhancing the present of chemotherapeutics in the brain to treat pediatric brain tumors.
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Affiliation(s)
- Linfeng Wu
- Department of Pharmaceutical Sciences, University of Tennessee Health Science Center, Memphis, Tennessee, 38163, USA
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37
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Puget S, Boddaert N, Veillard AS, Garnett M, Miquel C, Andreiuolo F, Sainte-Rose C, Roujeau T, DiRocco F, Bourgeois M, Zerah M, Doz F, Grill J, Varlet P. Neuropathological and neuroradiological spectrum of pediatric malignant gliomas: correlation with outcome. Neurosurgery 2013; 69:215-24. [PMID: 21368704 DOI: 10.1227/neu.0b013e3182134340] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
Abstract
BACKGROUND The diagnostic accuracy and reproducibility for glioma histological diagnosis are suboptimal. OBJECTIVE To characterize radiological and histological features in pediatric malignant gliomas and to determine whether they had an impact on survival. METHODS We retrospectively reviewed a series of 96 pediatric malignant gliomas. All histological samples were blindly and independently reviewed and classified according to World Health Organization 2007 and Sainte-Anne classifications. Radiological features were reviewed independently. Statistical analyses were performed to investigate the relationship between clinical, radiological, and histological features and survival. RESULTS Cohort median age was 7.8 years; median follow-up was 4.8 years. Tumors involved cerebral hemispheres or basal ganglia in 82% of cases and brainstem in the remaining 18%. After histopathological review, low-grade gliomas and nonglial tumors were excluded (n = 27). The World Health Organization classification was not able to demonstrate differences between groups and patients survival. The Sainte-Anne classification identified a 3-year survival rate difference between the histological subgroups (oligodendroglioma A, oligodendroglioma B, malignant glioneuronal tumors, and glioblastomas; P = .02). The malignant glioneuronal tumor was the only glioma subtype with specific radiological features. Tumor location was significantly associated with 3-year survival rate (P = .005). Meningeal attachment was the only radiological criteria associated with longer survival (P = .02). CONCLUSION The Sainte-Anne classification was better able to distinguish pediatric malignant gliomas in terms of survival compared with the World Health Organization classification. In this series, neither of these 2 histological classifications provided a prognostic stratification of the patients.
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Affiliation(s)
- Stéphanie Puget
- Department of Neurosurgery, Hôpital Necker Enfants Malades, Université Paris Descartes, Paris, France.
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Gajjar A, Packer RJ, Foreman N, Cohen K, Haas-Kogan D, Merchant TE. Children's Oncology Group's 2013 blueprint for research: central nervous system tumors. Pediatr Blood Cancer 2013; 60:1022-6. [PMID: 23255213 PMCID: PMC4184243 DOI: 10.1002/pbc.24427] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2012] [Accepted: 11/09/2012] [Indexed: 12/29/2022]
Abstract
In the US, approximately 2,500 children are diagnosed annually with brain tumors. Their survival ranges from >90% to <10%. For children with medulloblastoma, the most common malignant brain tumor, 5-year survival ranges from >80% (standard-risk) to 60% (high-risk). For those with high-grade gliomas (HGGs) including diffuse intrinsic pontine gliomas, 5-year survival remains <10%. Sixty-five percent patients with ependymoma are cured after surgery and radiation therapy depending on the degree of resection and histopathology of the tumor. Phase II trials for brain tumors will investigate agents that act on cMET, PDGFRA, or EZH2 in HGG, DIPG, or medulloblastoma, respectively. Phase III trials will explore risk-based therapy stratification guided by molecular and clinical traits of children with medulloblastoma or ependymoma.
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Affiliation(s)
- Amar Gajjar
- Department of Oncology, St. Jude Children's Research Hospital, Memphis, TN 38105, USA.
| | - Roger J. Packer
- Brain Tumor Institute, Children's National, Washington, District of Columbia
| | - N.K. Foreman
- Department of Pediatrics, University of Colorado, Denver
| | - Kenneth Cohen
- Oncology and Pediatrics, The Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins, Baltimore, Maryland
| | - Daphne Haas-Kogan
- Department of Radiation Oncology, Helen Diller Comprehensive Cancer Center, San Francisco, California
| | - Thomas E. Merchant
- Department of Radiological Sciences, St. Jude Children's Research Hospital, Memphis, Tennessee
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Abstract
OPINION STATEMENT Gliomas are the most common brain tumor in children and represent nearly 50 % of all pediatric central nervous system (CNS) tumors. They are a heterogeneous group of diseases, ranging from highly malignant and frequently fatal to histologically benign and curable by surgery alone. A uniform treatment approach to these tumors is not practical, due to their histological and biological heterogeneity. Low-grade gliomas (LGGs) are best treated with maximally safe surgical resection, generally achievable for hemispheric or cerebellar locations. Patients with deep midline, optic pathway/hypothalamic, and brain stem locations should undergo subtotal resection or biopsy only. If a complete resection is not feasible, subtotal resection followed by adjuvant chemotherapy or radiotherapy is the standard approach; however, observation alone with serial neuroimaging is used in some asymptomatic, surgically inaccessible lesions. Chemotherapy is used first-line in cases of residual or progressive disease, to avoid or delay radiation therapy and its associated side effects. Regimens demonstrating objective responses and increased progression free survival (PFS) include carboplatin and vincristine (CV), thioguanine/procarbazine/CCNU/vincristine (TPCV), or weekly vinblastine. High-grade gliomas (HGGs) are less common in children than in adults, though are similar in their aggressive clinical behavior, resistance to therapy, and dismal outcomes. There is not a single "standard of care" therapy for non-metastatic HGGs, but generally accepted is an aggressive attempt at a complete surgical resection, followed by multimodality therapy with focal radiation and chemotherapy. The use of temozolomide (TMZ) during and following radiotherapy is common, though it appeared not to improve the outcome in a cooperative group clinical trial when compared to an historical control cohort. The angiogenesis inhibitor bevacizumab, used alone or in combination with irinotecan, is also commonly used as maintenance therapy after radiation. Current trials are prospectively comparing TMZ to newer agents (vorinostat, bevacizumab) in a randomized phase II trial. Brainstem gliomas are a unique category of childhood gliomas. Approximately 80 % of childhood brainstem gliomas arise within the pons as diffuse intrinsic pontine gliomas (DIPG). When biopsied, these are usually HGGs and carry a dismal prognosis. Standard therapy is focal radiation (54-58 Gy), preferably on a clinical trial testing concurrent chemotherapy or biologic agent. No standard chemotherapy agent has impacted survival. The remaining 20 % of brainstem gliomas are low-grade, arise in the midbrain, dorsal medulla, or cervicomedullary junction, and are indolent in nature with a much better prognosis. Improvement in the outcome of all childhood gliomas will require increased knowledge of the underlying biology of these tumors, in order to treat with more biologically based and precise therapies.
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Affiliation(s)
- Jane E Minturn
- Division of Oncology and Center for Childhood Cancer Research, Children's Hospital of Philadelphia, 3501 Civic Center Boulevard, CTRB 4028, Philadelphia, PA, 19104, USA
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Abstract
Central nervous system tumors are the most frequent malignant tumor in children and the main cause of death in this age group after traffic accidents. The current estimates are that one adult in 2500 is a survivor of a brain tumor that occurred during childhood. These tumors are particularly heterogeneous in terms of histology/biology, treatment, and outcome. They share, however, a high risk of neurological and cognitive morbidity due to the disease itself and the treatment modalities (radiotherapy, surgery, and chemotherapy). Diagnosis is frequently delayed because symptoms are usually nonspecific at the beginning of the evolution. Posterior fossa is the most frequent site and the tumors present most frequently with signs of intracranial hypertension. Supratentorial tumors are more frequent in infants and in adolescents; seizures are not uncommon, especially for benign tumors. When adjuvant treatment is needed, radiotherapy is usually the mainstay apart from some histologies where chemotherapy may be sufficient: low-grade gliomas, desmoplastic medulloblastomas, malignant glial tumors in infants. Multidisciplinary care is best performed in tertiary care centers and should include early rehabilitation programs soon after surgery.
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Affiliation(s)
- Grill Jacques
- Brain Tumor Program, Department of Pediatric and Adolescent Oncology, Gustave Roussy Cancer Institute, Villejuif, France.
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Fangusaro J. Pediatric high grade glioma: a review and update on tumor clinical characteristics and biology. Front Oncol 2012; 2:105. [PMID: 22937526 PMCID: PMC3426754 DOI: 10.3389/fonc.2012.00105] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2012] [Accepted: 08/10/2012] [Indexed: 12/16/2022] Open
Abstract
High grade gliomas (HGG) are one of the most common central nervous system (CNS) tumors encountered in adults, but they only represent approximately 8–12% of all pediatric CNS tumors. Historically, pediatric HGG were thought to be similar to adult HGG since they appear histologically identical; however, molecular, genetic, and biologic data reveal that they are distinct. Similar to adults, pediatric HGG are very aggressive and malignant lesions with few patients achieving long-term survival despite a variety of therapies. Initial treatment strategies typically consist of a gross total resection (GTR) when feasible followed by focal radiotherapy combined with chemotherapy. Over the last few decades, a wealth of data has emerged from basic science and pre-clinical animal models helping to better define the common biologic, genetic, and molecular make-up of these tumors. These data have not only provided a better understanding of tumor biology, but they have also provided new areas of research targeting molecular and genetic pathways with the potential for novel treatment strategies and improved patient outcomes. Here we provide a review of pediatric non-brainstem HGG, including epidemiology, presentation, histology, imaging characteristics, treatments, survival outcomes, and an overview of both basic and translational research. An understanding of all relevant pre-clinical tumor models, including their strengths and pitfalls is essential in realizing improved patient outcomes in this population.
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Affiliation(s)
- Jason Fangusaro
- Pediatric Neuro-Oncology, The Ann & Robert H. Lurie Children's Hospital of Chicago, Feinberg School of Medicine, Northwestern University Chicago, IL, USA
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Gomi K, Tanaka M, Yoshida M, Ito S, Sonoda M, Iwasaki F, Niwa T, Aida N, Kigasawa H, Tanaka Y. Primary cerebellar histiocytic sarcoma in a 17-month-old girl. J Neurosurg Pediatr 2012; 10:126-9. [PMID: 22747089 DOI: 10.3171/2012.5.peds11270] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
The authors report on a case of histiocytic sarcoma (HS) in a pediatric patient presenting with a solitary tumor in the cerebellum, with the aim of providing insight into primary HS in the CNS, which is especially rare. A 17-month-old Japanese girl presented with a 2-week history of progressive gait disturbance. Brain MRI revealed a 4.7 × 4.3 × 4.3-cm well-demarcated solitary mass in the right hemisphere of the cerebellum, initially suggestive of medulloblastoma, ependymoma, or anaplastic astrocytoma. On intraoperative inspection the cerebellar tumor showed intensive dural attachment and was subtotally removed. Histological and immunohistochemical findings were consistent with HS. The patient subsequently received chemotherapy, and her preoperative neurological symptoms improved. Primary HS in the CNS usually demonstrates an aggressive clinical course and is currently considered to have a poor prognosis. The possibility of this rare tumor should be included in the differential diagnosis of localized cerebellar tumors in the pediatric age group.
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Affiliation(s)
- Kiyoshi Gomi
- Division of Pathology, Kanagawa Children's Medical Center, Yokohama, Japan.
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Jones C, Perryman L, Hargrave D. Paediatric and adult malignant glioma: close relatives or distant cousins? Nat Rev Clin Oncol 2012; 9:400-13. [PMID: 22641364 DOI: 10.1038/nrclinonc.2012.87] [Citation(s) in RCA: 155] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Gliomas in children differ from their adult counterparts by their distribution of histological grade, site of presentation and rate of malignant transformation. Although rare in the paediatric population, patients with high-grade gliomas have, for the most part, a comparably dismal clinical outcome to older patients with morphologically similar lesions. Molecular profiling data have begun to reveal the major genetic alterations underpinning these malignant tumours in children. Indeed, the accumulation of large datasets on adult high-grade glioma has revealed key biological differences between the adult and paediatric disease. Furthermore, subclassifications within the childhood age group can be made depending on age at diagnosis and tumour site. However, challenges remain on how to reconcile clinical data from adult patients to tailor novel treatment strategies specifically for paediatric patients.
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Affiliation(s)
- Chris Jones
- Divisions of Molecular Pathology and Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton SM2 5NG, UK
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Rivero-Garvía M, Márquez-Rivas J, Rueda-Torres AB, Pascual-Argente D, Ramírez G. Treatment of glioblastoma multiforme with high doses of carmustine intracavitary, in an infant. Childs Nerv Syst 2012; 28:747-50. [PMID: 22205534 DOI: 10.1007/s00381-011-1665-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/01/2011] [Accepted: 12/14/2011] [Indexed: 11/26/2022]
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Blakeley J, Grossman SA. Chemotherapy with cytotoxic and cytostatic agents in brain cancer. HANDBOOK OF CLINICAL NEUROLOGY 2012; 104:229-54. [PMID: 22230447 DOI: 10.1016/b978-0-444-52138-5.00017-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
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Dufour C, Beaugrand A, Le Deley MC, Bourdeaut F, André N, Leblond P, Bertozzi AI, Frappaz D, Rialland X, Fouyssac F, Edan C, Grill J, Quidot M, Varlet P. Clinicopathologic prognostic factors in childhood atypical teratoid and rhabdoid tumor of the central nervous system: a multicenter study. Cancer 2011; 118:3812-21. [PMID: 22180295 DOI: 10.1002/cncr.26684] [Citation(s) in RCA: 84] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2011] [Revised: 10/04/2011] [Accepted: 10/18/2011] [Indexed: 12/21/2022]
Abstract
BACKGROUND The objective of this study was to describe the clinical and pathologic features and to identify prognostic factors in patients with atypical teratoid/rhabdoid tumors (AT/RT) of the central nervous system (CNS). METHODS Patients aged <18 years with newly diagnosed CNS AT/RT who were treated in France between 1998 and 2008 were retrospectively identified. The study included all patients who had a diagnosis of AT/RT confirmed by pathologic review, including immunostaining for INI 1, tumor protein 53 (p53), β-catenin, claudin-6, and Ki-67 and analysis for SMARCB1/hSNF5/INI1 mutation. RESULTS Fifty-eight patients with confirmed AT/RT were eligible for the current analysis. The median age at diagnosis was 1.4 years (range, 14 days to 8.5 years). The site of the primary tumor was supratentorial in 26 patients, infratentorial in 28 patients and spinal in 4 patients. Loss of INI1 nuclear expression was observed in 49 of 50 evaluable tumors. Positive claudin-6 was observed in 37 of 42 assessed tumors and, in 12 of those tumors, the staining was strong and diffuse. Positive nuclear immunoreactivity for β-catenin was observed in 24 of 44 tumors, and P53 was overexpressed in 31 of 44 tumors. Primary adjuvant therapy included chemotherapy in 47 patients and radiotherapy in 16 patients. The median follow-up was 58 months (range, 9-125 months), and the median survival was 9 months. Multivariate analysis identified age <2 years (P = .01), metastasis at diagnosis (P = .03), and strong immunopositivity for claudin-6 (P = .03) as prognostic factors for the risk of death. CONCLUSIONS AT/RT tumors in children carry a dismal prognosis. Age <2 years, metastasis at diagnosis, and strong claudin-6 positivity appeared to be independent prognostic factors for outcome.
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Affiliation(s)
- Christelle Dufour
- Department of Pediatric and Adolescent Oncology, Gustave Roussy Institute, 114 rue Edouard Vaillant,Villejuif, France.
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Armand JP, Ribrag V, Harrousseau JL, Abrey L. Reappraisal of the use of procarbazine in the treatment of lymphomas and brain tumors. Ther Clin Risk Manag 2011; 3:213-24. [PMID: 18360630 PMCID: PMC1936303 DOI: 10.2147/tcrm.2007.3.2.213] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/23/2022] Open
Abstract
Procarbazine HCl is a 'nonclassical' oral alkylating anticancer agent that was first synthesized in the late 1950s. It has been used in the treatment of many cancers, but its main use is in the treatment of Hodgkin's lymphoma and brain tumors and, to a lesser extent, Non-Hodgkin's lymphoma and primary central nervous system lymphoma. Procarbazine is a prodrug that undergoes metabolic transformation into active intermediates that are thought to inhibit DNA, RNA, and protein synthesis. Early use of procarbazine in combination with mechlorethamine, vincristine, and prednisone (MOPP) was effective in the treatment of advanced Hodgkin's lymphoma, but late toxic effects such as secondary cancer and infertility led to its replacement by other regimens. However, its recent reintroduction in the dose-intensified BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone) regimen has yielded very promising findings. Procarbazine alone, or more commonly combined in the PCV (procarbazine, lomustine [CCNU], and vincristine) regimen, is also effective in treating gliomas comprising astrocytomas, glioblastomas, and oligodendrogliomas. The most common side effects of procarbazine are gastrointestinal disturbances, myelosuppression, and central nervous system effects. In conclusion, the use of procarbazine in combination with other drugs means that it remains a major anticancer drug in the management of Hodgkin's lymphoma and gliomas.
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Affiliation(s)
| | - Vincent Ribrag
- Institut Gustave-RoussyDesmolins, Villejuif Cedex, France
| | | | - Lauren Abrey
- Memorial Sloan-Kettering Cancer CenterNew York, New York, USA
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Barrow J, Adamowicz-Brice M, Cartmill M, MacArthur D, Lowe J, Robson K, Brundler MA, Walker DA, Coyle B, Grundy R. Homozygous loss of ADAM3A revealed by genome-wide analysis of pediatric high-grade glioma and diffuse intrinsic pontine gliomas. Neuro Oncol 2010; 13:212-22. [PMID: 21138945 DOI: 10.1093/neuonc/noq158] [Citation(s) in RCA: 96] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Overall, pediatric high-grade glioma (pHGG) has a poor prognosis, in part due to the lack of understanding of the underlying biology. High-resolution 244 K oligo array comparative genomic hybridization (CGH) was used to analyze DNA from 38 formalin-fixed paraffin-embedded predominantly pretreatment pHGG samples, including 13 diffuse intrinsic pontine gliomas (DIPGs). The patterns of gains and losses were distinct from those seen in HGG arising in adults. In particular, we found 1q gain in up to 27% of our cohort compared with 9% reported in adults. A total of 13% had a balanced genetic profile with no large-scale copy number alterations. Homozygous loss at 8p12 was seen in 6 of 38 (16%) cases of pHGG. This novel deletion, which includes the ADAM3A gene, was confirmed by quantitative real-time PCR (qPCR). Loss of CDKN2A/CDKN2B in 4 of 38 (10%) samples by oligo array CGH was confirmed by fluorescent in situ hybridization on tissue microarrays and was restricted to supratentorial tumors. Only ∼50% of supratentorial tumors were positive for CDKN2B expression by immunohistochemistry (IHC), while ∼75% of infratentorial tumors were positive for CDKN2B expression (P = 0.03). Amplification of the 4q11-13 region was detected in 8% of cases and included PDGFRA and KIT, and subsequent qPCR analysis was consistent with the amplification of PDGFRA. MYCN amplification was seen in 5% of samples being significantly associated with anaplastic astrocytomas (P= 0.03). Overall, DIPG shared similar spectrum of changes to supratentorial HGG with some notable differences, including high-frequency loss of 17p and 14q and lack of CDKN2A/CDKN2B deletion. Informative genetic data providing insight into the underlying biology and potential therapeutic possibilities can be generated from archival tissue and typically small biopsies from DIPG. Our findings highlight the importance of obtaining pretreatment samples.
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Affiliation(s)
- Jennifer Barrow
- Children's Brain Tumour Research Centre, School of Clinical Sciences, Queen's Medical Centre, University of Nottingham, Nottingham NG7 2UH
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Sharma S, Free A, Mei Y, Peiper SC, Wang Z, Cowell JK. Distinct molecular signatures in pediatric infratentorial glioblastomas defined by aCGH. Exp Mol Pathol 2010; 89:169-74. [PMID: 20621092 DOI: 10.1016/j.yexmp.2010.06.009] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2010] [Accepted: 06/29/2010] [Indexed: 01/16/2023]
Abstract
Glioblastomas (GBM) are rare in children, but reportedly have more varied outcome which suggests differences in tumor etiology compared to typical GBM of adults. To investigate this we performed high resolution array comparative genomic hybridization (aCGH) analysis on three pediatric infratentorial GBM, ages 3.5, 7 and 14 years. Two of these tumors occurred in the brainstem and one in the spinal cord. While histologically typical, one brainstem tumor showed mainly pleomorphic astrocytic cells, whereas the other brainstem and spinal tumors showed a GFAP positive small cell component. Whole chromosomal gains (#1 and #2) and loss (#20) were seen only in the pleomorphic brainstem GBM, which also showed a high level of segmental genomic copy number changes. Segmental loss involving chromosome 8 was seen in all three tumors (Chr8;133039446-136869494, Chr8;pter-3581577, and Chr8;pter-30480019 respectively), whereas loss involving chromosome 16 was seen in only 2 cases with small cell components (Chr16;31827239-qter and Chr16;pter-29754532). Segmental gain of chromosome 7 was shared only between the 2 brainstem cases (Chr7;17187166-qter and Chr7;69824947-qter). Chromosome 17 showed segmental gain of 17q in the backdrop of loss of 17p only in case 1. Segmental gain of chromosome 1q was seen only in case 2. The spinal GBM showed a relatively stable karyotype with a unique loss of Chr19;32848902-qter. None of the frequent losses, gains and amplifications known to occur in adult GBM were identified, suggesting that pediatric infratentorial glioblastomas show a molecular karyotype that was more characteristic of pediatric embryonal tumors than adult GBM.
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Affiliation(s)
- S Sharma
- Department of Pathology, Medical College of Georgia, Augusta, GA, USA
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Grundy RG, Wilne SH, Robinson KJ, Ironside JW, Cox T, Chong WK, Michalski A, Campbell RHA, Bailey CC, Thorp N, Pizer B, Punt J, Walker DA, Ellison DW, Machin D. Primary postoperative chemotherapy without radiotherapy for treatment of brain tumours other than ependymoma in children under 3 years: results of the first UKCCSG/SIOP CNS 9204 trial. Eur J Cancer 2010; 46:120-33. [PMID: 19818598 DOI: 10.1016/j.ejca.2009.09.013] [Citation(s) in RCA: 74] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2009] [Revised: 09/07/2009] [Accepted: 09/10/2009] [Indexed: 11/28/2022]
Abstract
BACKGROUND Radiotherapy is an effective adjuvant treatment for brain tumours arising in very young children, but it has the potential to damage the child's developing nervous system at a crucial time - with a resultant reduction in IQ leading to cognitive impairment, associated endocrinopathy and risk of second malignancy. We aimed to assess the role of a primary chemotherapy strategy in avoiding or delaying radiotherapy in children younger than 3 years with malignant brain tumours other than ependymoma, the results of which have already been published. METHODS Ninety-seven children were enrolled between March 1993 and July 2003 and, following diagnostic review, comprised: medulloblastoma (n=31), astrocytoma (26), choroid plexus carcinoma [CPC] (15), CNS PNET (11), atypical teratoid/rhabdoid tumours [AT/RT] (6) and ineligible (6). Following maximal surgical resection, chemotherapy was delivered every 14 d for 1 year or until disease progression. Radiotherapy was withheld in the absence of progression. FINDINGS Over all diagnostic groups the cumulative progression rate was 80.9% at 5 years while the corresponding need-for-radiotherapy rate for progression was 54.6%, but both rates varied by tumour type. There was no clear relationship between chemotherapy dose intensity and outcome. Patients with medulloblastoma presented as a high-risk group, 83.9% having residual disease and/or metastases at diagnosis. For these patients, outcome was related to histology. The 5-year OS for desmoplastic/nodular medulloblastoma was 52.9% (95% confidence interval (CI): 27.6-73.0) and for classic medulloblastoma 33.3% (CI: 4.6-67.6); the 5-year EFS were 35.3% (CI: 14.5-57.0) and 33.3% (CI: 4.6-67.6), respectively. All children with large cell or anaplastic variants of medulloblastoma died within 2 years of diagnosis. The 5-year EFS for non-brainstem high-grade gliomas [HGGs] was 13.0% (CI: 2.2-33.4) and the OS was 30.9% (CI: 11.5-52.8). For CPC the 5-year OS was 26.67% (CI: 8.3-49.6) without RT. This treatment strategy was less effective for AT/RT with 3-year OS of 16.7% (CI: 0.8-51.7) and CNS PNET with 1-year OS of 9.1% (CI: 0.5-33.3). INTERPRETATION The outcome for very young children with brain tumours is dictated by degree of surgical resection and histological tumour type and underlying biology as an indicator of treatment sensitivity. Overall, the median age at radiotherapy was 3 years and radiotherapy was avoided in 45% of patients. Desmoplastic/nodular sub-type of medulloblastoma has a better prognosis than classic histology, despite traditional adverse clinical features of metastatic disease and incomplete surgical resection. A subgroup with HGG and CPC are long-term survivors without RT. This study highlights the differing therapeutic challenges presented by the malignant brain tumours of early childhood, the importance of surgical approaches and the need to explore individualised brain sparing approaches to the range of malignant brain tumours that present in early childhood.
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Affiliation(s)
- R G Grundy
- Children's Brain Tumour Research Centre, University of Nottingham, Queen's Medical Centre, Nottingham, UK.
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