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Hajikarimloo B, Tos SM, Kooshki A, Alvani MS, Hasanzade A, Zare AH, Zare AH, Tavanaei R, Akhlaghpasand M, Najari D, Habibi MA. The efficacy and safety of Bevacizumab-based treatments in Optic Pathway Glioma among pediatric population: a systematic review and meta-analysis. Neurosurg Rev 2025; 48:77. [PMID: 39849189 DOI: 10.1007/s10143-025-03227-4] [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: 09/03/2024] [Revised: 01/02/2025] [Accepted: 01/14/2025] [Indexed: 01/25/2025]
Abstract
The optimal therapeutic intervention for pediatrics with optic pathway glioma (OPG) remained controversial in the literature. Recently, due to substantial adverse events (AEs) of chemotherapy and its impact on children's lives, the efficacy of other options has been investigated. Bevacizumab (BVZ) is an anti-vascular endothelial growth factor (VEGF) agent that alters the lesion microenvironment. In this systematic review and meta-analysis, we aimed to evaluate the efficacy of BVZ-based treatment (BBT) in pediatrics with OPG. The electronic databases of PubMed/Medline, Scopus, Embase, and Web of Science were searched from inception to 15 October 2024. The R program performed the meta-analyses, sensitivity analysis, publication bias, and meta-regression. A total of ten studies with 185 patients were included. Our meta-analysis revealed a pooled local control rate of 80% (95% CI: 60-91%), radiological response rate of 18% (95% CI: 6-41%), stable disease rate of 57% (95% CI: 39-73%), and progression rate of 20% (95% CI: 9-40%). Our results demonstrated a pooled visual acuity (VA) improvement rate of 31% (95% CI: 24-39%), a stable rate of 60% (95% CI: 52- 67%), and a worsening rate of 15% (95% CI: 6 - 30%). Our meta-analysis revealed a pooled VF improvement rate of 40% (95% CI: 20- 64%) and a worsening rate of 18% (95% CI: 10 - 30%). BBT is associated with favorable outcomes and a low occurrence rate of severe AE and could be considered a promising therapeutic option in children with OPG.
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Affiliation(s)
- Bardia Hajikarimloo
- Department of Neurological Surgery, University of Virginia, Charlottesville, VA, USA.
| | - Salem M Tos
- Department of Neurological Surgery, University of Virginia, Charlottesville, VA, USA
| | - Alireza Kooshki
- Student Research Committee, Birjand University of Medical Sciences, Birjand, Iran
| | - Mohammadamin Sabbagh Alvani
- Department of Neurological Surgery, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Arman Hasanzade
- Department of Neurological Surgery, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Amir Hossein Zare
- Department of Neurological Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Amir Hessam Zare
- Department of Neurological Surgery, Tehran University of Medical Sciences, Tehran, Iran
| | - Roozbeh Tavanaei
- Department of Neurological Surgery, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammadhosein Akhlaghpasand
- Department of Neurological Surgery, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Dorsa Najari
- Department of Neurological Surgery, Shohada Tajrish Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Mohammad Amin Habibi
- Department of Neurosurgery, Shariati Hospital, Tehran University of Medical Sciences, Tehran, Iran.
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Mohamed AA, Alshaibi R, Faragalla S, Mohamed Y, Lucke-Wold B. Updates on management of gliomas in the molecular age. World J Clin Oncol 2024; 15:178-194. [PMID: 38455131 PMCID: PMC10915945 DOI: 10.5306/wjco.v15.i2.178] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2023] [Revised: 01/06/2024] [Accepted: 01/25/2024] [Indexed: 02/20/2024] Open
Abstract
Gliomas are primary brain tumors derived from glial cells of the central nervous system, afflicting both adults and children with distinct characteristics and therapeutic challenges. Recent developments have ushered in novel clinical and molecular prognostic factors, reshaping treatment paradigms based on classification and grading, determined by histological attributes and cellular lineage. This review article delves into the diverse treatment modalities tailored to the specific grades and molecular classifications of gliomas that are currently being discussed and used clinically in the year 2023. For adults, the therapeutic triad typically consists of surgical resection, chemotherapy, and radiotherapy. In contrast, pediatric gliomas, due to their diversity, require a more tailored approach. Although complete tumor excision can be curative based on the location and grade of the glioma, certain non-resectable cases demand a chemotherapy approach usually involving, vincristine and carboplatin. Additionally, if surgery or chemotherapy strategies are unsuccessful, Vinblastine can be used. Despite recent advancements in treatment methodologies, there remains a need of exploration in the literature, particularly concerning the efficacy of treatment regimens for isocitrate dehydrogenase type mutant astrocytomas and fine-tuned therapeutic approaches tailored for pediatric cohorts. This review article explores into the therapeutic modalities employed for both adult and pediatric gliomas in the context of their molecular classification.
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Affiliation(s)
- Ali Ahmed Mohamed
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, United States
| | - Rakan Alshaibi
- Herbert Wertheim College of Medicine, Florida International University, Miami, FL 33199, United States
| | - Steven Faragalla
- Charles E. Schmidt College of Medicine, Florida Atlantic University, Boca Raton, FL 33431, United States
| | - Youssef Mohamed
- College of Osteopathic Medicine, Kansas City University, Joplin, MO 64804, United States
| | - Brandon Lucke-Wold
- Department of Neurosurgery, University of Florida, Gainesville, FL 32611, United States
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Johns DA, Williams RJ, Smith CM, Nadaminti PP, Samarasinghe RM. Novel insights on genetics and epigenetics as clinical targets for paediatric astrocytoma. Clin Transl Med 2024; 14:e1560. [PMID: 38299304 PMCID: PMC10831580 DOI: 10.1002/ctm2.1560] [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: 07/02/2023] [Revised: 01/07/2024] [Accepted: 01/12/2024] [Indexed: 02/02/2024] Open
Abstract
Paediatric and adult astrocytomas are notably different, where clinical treatments used for adults are not as effective on children with the same form of cancer and these treatments lead to adverse long-term health concerns. Integrative omics-based studies have shown the pathology and fundamental molecular characteristics differ significantly and cannot be extrapolated from the more widely studied adult disease. Recent clinical advances in our understanding of paediatric astrocytomas, with the aid of next-generation sequencing and epigenome-wide profiling, have led to the identification of key canonical mutations that vary based on the tumour location and age of onset. These driver mutations, in particular the identification of the recurrent histone H3 mutations in high-grade tumours, have confirmed the important role epigenetic dysregulations play in cancer progression. This review summarises the current updates of the classification, epidemiology, pathogenesis and clinical management of paediatric astrocytoma based on their grades and the ongoing clinical trials. It also provides novel insights on genetic and epigenetic alterations as diagnostic biomarkers, highlighting the potential of targeting these pathways as therapeutics for this devastating childhood cancer.
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Affiliation(s)
- Dona A. Johns
- School of Medicine, Deakin UniversityGeelongVictoriaAustralia
| | - Richard J. Williams
- School of Medicine, Deakin UniversityGeelongVictoriaAustralia
- Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin UniversityGeelongVictoriaAustralia
- The Graeme Clark Institute, The University of MelbourneMelbourneVICAustralia
| | - Craig M. Smith
- School of Medicine, Deakin UniversityGeelongVictoriaAustralia
- Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin UniversityGeelongVictoriaAustralia
| | - Pavani P. Nadaminti
- School of Agriculture, Food and Ecosystem Sciences, Faculty of Science, The University of Melbourne, ParkvilleMelbourneVictoriaAustralia
| | - Rasika M. Samarasinghe
- School of Medicine, Deakin UniversityGeelongVictoriaAustralia
- Institute for Mental and Physical Health and Clinical Translation, School of Medicine, Deakin UniversityGeelongVictoriaAustralia
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Malik JR, Podany AT, Khan P, Shaffer CL, Siddiqui JA, Baranowska‐Kortylewicz J, Le J, Fletcher CV, Ether SA, Avedissian SN. Chemotherapy in pediatric brain tumor and the challenge of the blood-brain barrier. Cancer Med 2023; 12:21075-21096. [PMID: 37997517 PMCID: PMC10726873 DOI: 10.1002/cam4.6647] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 09/18/2023] [Accepted: 10/12/2023] [Indexed: 11/25/2023] Open
Abstract
BACKGROUND Pediatric brain tumors (PBT) stand as the leading cause of cancer-related deaths in children. Chemoradiation protocols have improved survival rates, even for non-resectable tumors. Nonetheless, radiation therapy carries the risk of numerous adverse effects that can have long-lasting, detrimental effects on the quality of life for survivors. The pursuit of chemotherapeutics that could obviate the need for radiotherapy remains ongoing. Several anti-tumor agents, including sunitinib, valproic acid, carboplatin, and panobinostat, have shown effectiveness in various malignancies but have not proven effective in treating PBT. The presence of the blood-brain barrier (BBB) plays a pivotal role in maintaining suboptimal concentrations of anti-cancer drugs in the central nervous system (CNS). Ongoing research aims to modulate the integrity of the BBB to attain clinically effective drug concentrations in the CNS. However, current findings on the interaction of exogenous chemical agents with the BBB remain limited and do not provide a comprehensive explanation for the ineffectiveness of established anti-cancer drugs in PBT. METHODS We conducted our search for chemotherapeutic agents associated with the blood-brain barrier (BBB) using the following keywords: Chemotherapy in Cancer, Chemotherapy in Brain Cancer, Chemotherapy in PBT, BBB Inhibition of Drugs into CNS, Suboptimal Concentration of CNS Drugs, PBT Drugs and BBB, and Potential PBT Drugs. We reviewed each relevant article before compiling the information in our manuscript. For the generation of figures, we utilized BioRender software. FOCUS We focused our article search on chemical agents for PBT and subsequently investigated the role of the BBB in this context. Our search criteria included clinical trials, both randomized and non-randomized studies, preclinical research, review articles, and research papers. FINDING Our research suggests that, despite the availability of potent chemotherapeutic agents for several types of cancer, the effectiveness of these chemical agents in treating PBT has not been comprehensively explored. Additionally, there is a scarcity of studies examining the role of the BBB in the suboptimal outcomes of PBT treatment, despite the effectiveness of these drugs for other types of tumors.
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Affiliation(s)
- Johid Reza Malik
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Anthony T. Podany
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
- Pediatric Clinical Pharmacology ProgramChild Health Research Institute, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Parvez Khan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | - Christopher L. Shaffer
- Pediatric Clinical Pharmacology ProgramChild Health Research Institute, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Jawed A. Siddiqui
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNebraskaUSA
| | | | - Jennifer Le
- University of California San Diego Skaggs School of Pharmacy and Pharmaceutical SciencesSan DiegoCaliforniaUSA
| | - Courtney V. Fletcher
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Sadia Afruz Ether
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
| | - Sean N. Avedissian
- Antiviral Pharmacology LaboratoryCollege of Pharmacy, University of Nebraska Medical CenterOmahaNebraskaUSA
- Pediatric Clinical Pharmacology ProgramChild Health Research Institute, University of Nebraska Medical CenterOmahaNebraskaUSA
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Tosi U, Souweidane M. Fifty years of DIPG: looking at the future with hope. Childs Nerv Syst 2023; 39:2675-2686. [PMID: 37382660 DOI: 10.1007/s00381-023-06037-5] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/02/2023] [Accepted: 06/17/2023] [Indexed: 06/30/2023]
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a primary brainstem tumor of childhood that carries a dismal prognosis, with median survival of less than 1 year. Because of the brain stem location and pattern of growth within the pons, Dr. Harvey Cushing, the father of modern neurosurgery, urged surgical abandonment. Such a dismal prognosis remained unchanged for decades, coupled with a lack of understanding of tumor biology and an unchanging therapeutic panorama. Beyond palliative external beam radiation therapy, no therapeutic approach has been widely accepted. In the last one to two decades, however, increased tissue availability, an improving understanding of biology, genetics, and epigenetics have led to the development of novel therapeutic targets. In parallel with this biological revolution, new methods intended to enhance drug delivery into the brain stem are contributing to a surge of exciting experimental therapeutic strategies.
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Affiliation(s)
- Umberto Tosi
- Department of Neurosurgery, Weill Cornell Medicine, 525 E 68th St Box 99, New York, NY, 10021, USA
| | - Mark Souweidane
- Department of Neurosurgery, Weill Cornell Medicine, 525 E 68th St Box 99, New York, NY, 10021, USA.
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Larrosa C, Mora J, Cheung NK. Global Impact of Monoclonal Antibodies (mAbs) in Children: A Focus on Anti-GD2. Cancers (Basel) 2023; 15:3729. [PMID: 37509390 PMCID: PMC10378537 DOI: 10.3390/cancers15143729] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2023] [Revised: 07/16/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Monoclonal antibodies (mAbs), as the name implies, are clonal antibodies that bind to the same antigen. mAbs are broadly used as diagnostic or therapeutic tools for neoplasms, autoimmune diseases, allergic conditions, and infections. Although most mAbs are approved for treating adult cancers, few are applicable to childhood malignancies, limited mostly to hematological cancers. As for solid tumors, only anti-disialoganglioside (GD2) mAbs are approved specifically for neuroblastoma. Inequities of drug access have continued, affecting most therapeutic mAbs globally. To understand these challenges, a deeper dive into the complex transition from basic research to the clinic, or between marketing and regulatory agencies, is timely. This review focuses on current mAbs approved or under investigation in pediatric cancer, with special attention on solid tumors and anti-GD2 mAbs, and the hurdles that limit their broad global access. Beyond understanding the mechanisms of drug resistance, the continual discovery of next generation drugs safer for children and easier to administer, the discovery of predictive biomarkers to avoid futility should ease the acceptance by patient, health care professionals and regulatory agencies, in order to expand clinical utility. With a better integration into the multimodal treatment for each disease, protocols that align with the regional clinical practice should also improve acceptance and cost-effectiveness. Communication and collaboration between academic institutions, pharmaceutical companies, and regulatory agencies should help to ensure accessible, affordable, and sustainable health care for all.
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Affiliation(s)
- Cristina Larrosa
- Pediatric Cancer Center Barcelona, 08950 Barcelona, Spain; (C.L.); (J.M.)
| | - Jaume Mora
- Pediatric Cancer Center Barcelona, 08950 Barcelona, Spain; (C.L.); (J.M.)
| | - Nai-Kong Cheung
- Memorial Sloan-Kettering Cancer Center, New York, NY 10065, USA
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Rechberger JS, Bouchal SM, Power EA, Nonnenbroich LF, Nesvick CL, Daniels DJ. Bench-to-bedside investigations of H3 K27-altered diffuse midline glioma: drug targets and potential pharmacotherapies. Expert Opin Ther Targets 2023; 27:1071-1086. [PMID: 37897190 PMCID: PMC11079776 DOI: 10.1080/14728222.2023.2277232] [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: 08/30/2023] [Accepted: 10/26/2023] [Indexed: 10/29/2023]
Abstract
INTRODUCTION H3 K27-altered diffuse midline glioma (DMG) is the most common malignant brainstem tumor in the pediatric population. Despite enormous preclinical and clinical efforts, the prognosis remains dismal, with fewer than 10% of patients surviving for two years after diagnosis. Fractionated radiation remains the only standard treatment options for DMG. Developing novel treatments and therapeutic delivery methods is critical to improving outcomes in this devastating disease. AREAS COVERED This review addresses recent advances in molecularly targeted pharmacotherapy and immunotherapy in DMG. The clinical presentation, diagnostic workup, unique pathological challenges, and current clinical trials are highlighted throughout. EXPERT OPINION Promising pharmacotherapies targeting various components of DMG pathology and the application of immunotherapies have the potential to improve patient outcomes. However, novel approaches are needed to truly revolutionize treatment for this tumor. First, combinational therapy should be employed, as DMG can develop resistance to single-agent approaches and many therapies are susceptible to rapid clearance from the brain. Second, drug-tumor residence time, i.e. the time for which a therapeutic is present at efficacious concentrations within the tumor, must be maximized to facilitate a durable treatment response. Engineering extended drug delivery methods with minimal off-tumor toxicity should be a focus of future studies.
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Affiliation(s)
- Julian S. Rechberger
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
| | - Samantha M. Bouchal
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
| | - Erica A. Power
- Loyola University Chicago Stritch School of Medicine, Maywood, IL, USA
| | - Leo F. Nonnenbroich
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
- Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Clinical Cooperation Unit Pediatric Oncology, German Cancer Research Center (DKFZ) and German Consortium for Translational Cancer Research (DKTK), Heidelberg, Germany
| | - Cody L. Nesvick
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
| | - David J. Daniels
- Department of Neurologic Surgery, Mayo Clinic, Rochester, MN, USA
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic Graduate School of Biomedical Sciences, Rochester, MN, USA
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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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Noureldine MHA, Shimony N, Jallo GI. Malignant Spinal Tumors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2023; 1405:565-581. [PMID: 37452954 DOI: 10.1007/978-3-031-23705-8_22] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 07/18/2023]
Abstract
Malignant spinal tumors constitute around 22% of all primary spinal tumors. The most common location of metastases to the spinal region is the extradural compartment. The molecular and genetic characterization of these tumors was the basis for the updated WHO classification of CNS tumors in 2016, where many CNS tumors are now diagnosed according to their genetic profile rather than relying solely on the histopathological appearance. Magnetic resonance imaging (MRI) is the current gold standard for the initial evaluation and subsequent follow-up on intradural spinal cord tumors, and the imaging sequences must include T2-weighted images (WI), short time inversion recovery (STIR), and pre- and post-contrast T1-WI in the axial, sagittal, and coronal planes. The clinical presentation is highly variable and depends on the tumor size, growth rate, type, infiltrative, necrotic and hemorrhagic potential as well as the exact location within the spinal compartment. Surgical intervention remains the mainstay of management of symptomatic and radiographically enlarging spinal tumors, where the goal is to achieve maximal safe resection. Tumor recurrences are managed with repeat surgical resection (preferred whenever possible and safe), radiotherapy, chemotherapy, or any combination of these therapies.
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Affiliation(s)
- Mohammad Hassan A Noureldine
- Department of Neurosurgery and Brain Repair, University of South Florida Morsani College of Medicine, Tampa, FL, USA
- Johns Hopkins University School of Medicine, Institute for Brain Protection Sciences, Johns Hopkins All Children's Hospital, Saint Petersburg, FL, USA
| | - Nir Shimony
- Johns Hopkins University School of Medicine, Institute for Brain Protection Sciences, Johns Hopkins All Children's Hospital, Saint Petersburg, FL, USA
- Geisinger Medical Center, Institute of Neuroscience, Geisinger Commonwealth School of Medicine, Danville, PA, USA
| | - George I Jallo
- Institute for Brain Protections Sciences, Johns Hopkins All Children's Hospital, Saint Petersburg, FL, USA.
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Aggarwal P, Luo W, Pehlivan KC, Hoang H, Rajappa P, Cripe TP, Cassady KA, Lee DA, Cairo MS. Pediatric versus adult high grade glioma: Immunotherapeutic and genomic considerations. Front Immunol 2022; 13:1038096. [PMID: 36483545 PMCID: PMC9722734 DOI: 10.3389/fimmu.2022.1038096] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2022] [Accepted: 11/07/2022] [Indexed: 11/23/2022] Open
Abstract
High grade gliomas are identified as malignant central nervous tumors that spread rapidly and have a universally poor prognosis. Historically high grade gliomas in the pediatric population have been treated similarly to adult high grade gliomas. For the first time, the most recent classification of central nervous system tumors by World Health Organization has divided adult from pediatric type diffuse high grade gliomas, underscoring the biologic differences between these tumors in different age groups. The objective of our review is to compare high grade gliomas in the adult versus pediatric patient populations, highlighting similarities and differences in epidemiology, etiology, pathogenesis and therapeutic approaches. High grade gliomas in adults versus children have varying clinical presentations, molecular biology background, and response to chemotherapy, as well as unique molecular targets. However, increasing evidence show that they both respond to recently developed immunotherapies. This review summarizes the distinctions and commonalities between the two in disease pathogenesis and response to therapeutic interventions with a focus on immunotherapy.
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Affiliation(s)
- Payal Aggarwal
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States
| | - Wen Luo
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States,Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, United States
| | | | - Hai Hoang
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States
| | - Prajwal Rajappa
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Timothy P. Cripe
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Kevin A. Cassady
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Dean A. Lee
- Center for Childhood Cancer Research, Abigail Wexner Research Institute at Nationwide Children’s Hospital, Columbus, OH, United States
| | - Mitchell S. Cairo
- Department of Pediatrics, New York Medical College, Valhalla, NY, United States,Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, NY, United States,Department of Medicine, New York Medical College, Valhalla, NY, United States,Department of Cell Biology and Anatomy, New York Medical College, Valhalla, NY, United States,*Correspondence: Mitchell S. Cairo,
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11
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Evans M, Gill R, Bull KS. Does a Bevacizumab-based regime have a role in the treatment of children with diffuse intrinsic pontine glioma? A systematic review. Neurooncol Adv 2022; 4:vdac100. [PMID: 35821674 PMCID: PMC9270727 DOI: 10.1093/noajnl/vdac100] [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] [Indexed: 11/23/2022] Open
Abstract
Background There are no effective treatments for diffuse intrinsic pontine glioma (DIPG); median survival is 11.2 months. Bevacizumab has the potential to improve quality of life (QOL) and survival in DIPG but has never been evaluated systematically. The aim of this review was to assess Bevacizumab’s role in the treatment of DIPG. Methods MEDLINE, EMBASE, Scopus, and Web of Science were searched for relevant studies using terms developed from alternatives for Bevacizumab and DIPG. One reviewer screened titles and abstracts, then two reviewers screened full texts. Data were extracted into tables and quality assessed using methodological index for non-randomized studies and JBI tools. Results Searching revealed 1001 papers; after deduplication 851 remained. After screening of titles and abstracts, then 28 full texts, 11 studies were included. Four studies reported a median overall survival longer than historical data, however, two found no significant impact of Bevacizumab. Five studies reported a radiological response in a proportion of participants and two reported no response. Three studies, evaluating clinical response, reported improvement in a proportion of patients. Three studies, evaluating QOL, reported stability or improvement. Four studies, evaluating steroid use, reported reductions in the proportion of patients receiving steroids. In radiation necrosis treatment, Bevacizumab led to clinical improvement in 6/12 patients in 2 studies and permitted a reduction in steroid use in most patients. Conclusions Insufficient evidence means the role of Bevacizumab in the treatment of DIPG is unclear. However, Bevacizumab may be beneficial to some patients. The review highlights the need for further research in this area.
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Affiliation(s)
- Mia Evans
- Faculty of medicine, University of Southampton , Southampton , UK
| | - Ria Gill
- Faculty of medicine, University of Southampton , Southampton , UK
| | - Kim S Bull
- Clinical and Experimental Sciences, University of Southampton , Southampton , UK
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12
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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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13
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Patel JP, Spiller SE, Barker ED. Drug penetration in pediatric brain tumors: Challenges and opportunities. Pediatr Blood Cancer 2021; 68:e28983. [PMID: 33719183 DOI: 10.1002/pbc.28983] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2020] [Revised: 02/11/2021] [Accepted: 02/12/2021] [Indexed: 12/23/2022]
Abstract
Larger clinical trial enrollments and a greater understanding of biological heterogeneity have led to improved survival rates for children diagnosed with brain tumors in the last 50 years. However, reducing long-term morbidities and improving survival rates of high-risk tumors remain major challenges. Chemotherapy can reduce tumor burden, but effective drug penetration at the tumor site is limited by barriers in the route of drug administration and within the tumor microenvironment. Bioavailability of drugs is impeded by the blood-brain barrier, plasma protein binding, and structural components by the tumor including the matrix and vasculature contributing to increased interstitial fluid pressure, hypoxia, and acidity. Designing drug delivery systems to circumvent these barriers could lead to improved drug penetration at the tumor site and reduce adverse systemic side effects. In this review, we expand on how systemic and local barriers limit drug penetration and present potential methods to enhance drug penetration in pediatric brain tumors.
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Affiliation(s)
- Jenny P Patel
- Department of Mechanical, Aerospace, and Biomedical Engineering, The University of Tennessee at Knoxville, Knoxville, Tennessee
| | - Susan E Spiller
- Pediatric Hematology/Oncology, East Tennessee Children's Hospital, Knoxville, Tennessee
| | - Elizabeth D Barker
- Department of Mechanical, Aerospace, and Biomedical Engineering, The University of Tennessee at Knoxville, Knoxville, Tennessee
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14
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Ollauri-Ibáñez C, Astigarraga I. Use of Antiangiogenic Therapies in Pediatric Solid Tumors. Cancers (Basel) 2021; 13:E253. [PMID: 33445470 PMCID: PMC7827326 DOI: 10.3390/cancers13020253] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/20/2020] [Revised: 01/08/2021] [Accepted: 01/08/2021] [Indexed: 12/23/2022] Open
Abstract
Cancer is an important cause of death in childhood. In recent years, scientists have made an important effort to achieve greater precision and more personalized treatments against cancer. But since only a few pediatric patients have identifiable therapeutic targets, other ways to stop the neoplastic cell proliferation and dissemination are needed. Therefore, the inhibition of general processes involved in the growth and behavior of tumors can be a relevant strategy for the development of new cancer therapies. In the case of solid tumors, one of these processes is angiogenesis, essential for tumor growth and generation of metastases. This review summarizes the results obtained with the use of antiangiogenic drugs in the main pediatric malignant solid tumors and also an overview of clinical trials currently underway. It should be noted that due to the rarity and heterogeneity of the different types of pediatric cancer, most studies on antiangiogenic drugs include only a small number of patients or isolated clinical cases, so they are not conclusive and further studies are needed.
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Affiliation(s)
- Claudia Ollauri-Ibáñez
- Pediatric Oncology Group, BioCruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain;
| | - Itziar Astigarraga
- Pediatric Oncology Group, BioCruces Bizkaia Health Research Institute, 48903 Barakaldo, Spain;
- Pediatrics Department, Hospital Universitario Cruces, 48903 Barakaldo, Spain
- Pediatrics Department, University of the Basque Country UPV/EHU, 48940 Leioa, Spain
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15
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Mudassar F, Shen H, O'Neill G, Hau E. Targeting tumor hypoxia and mitochondrial metabolism with anti-parasitic drugs to improve radiation response in high-grade gliomas. J Exp Clin Cancer Res 2020; 39:208. [PMID: 33028364 PMCID: PMC7542384 DOI: 10.1186/s13046-020-01724-6] [Citation(s) in RCA: 91] [Impact Index Per Article: 18.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2020] [Accepted: 09/30/2020] [Indexed: 02/06/2023] Open
Abstract
High-grade gliomas (HGGs), including glioblastoma and diffuse intrinsic pontine glioma, are amongst the most fatal brain tumors. These tumors are associated with a dismal prognosis with a median survival of less than 15 months. Radiotherapy has been the mainstay of treatment of HGGs for decades; however, pronounced radioresistance is the major obstacle towards the successful radiotherapy treatment. Herein, tumor hypoxia is identified as a significant contributor to the radioresistance of HGGs as oxygenation is critical for the effectiveness of radiotherapy. Hypoxia plays a fundamental role in the aggressive and resistant phenotype of all solid tumors, including HGGs, by upregulating hypoxia-inducible factors (HIFs) which stimulate vital enzymes responsible for cancer survival under hypoxic stress. Since current attempts to target tumor hypoxia focus on reducing oxygen demand of tumor cells by decreasing oxygen consumption rate (OCR), an attractive strategy to achieve this is by inhibiting mitochondrial oxidative phosphorylation, as it could decrease OCR, and increase oxygenation, and could therefore improve the radiation response in HGGs. This approach would also help in eradicating the radioresistant glioma stem cells (GSCs) as these predominantly rely on mitochondrial metabolism for survival. Here, we highlight the potential for repurposing anti-parasitic drugs to abolish tumor hypoxia and induce apoptosis of GSCs. Current literature provides compelling evidence that these drugs (atovaquone, ivermectin, proguanil, mefloquine, and quinacrine) could be effective against cancers by mechanisms including inhibition of mitochondrial metabolism and tumor hypoxia and inducing DNA damage. Therefore, combining these drugs with radiotherapy could potentially enhance the radiosensitivity of HGGs. The reported efficacy of these agents against glioblastomas and their ability to penetrate the blood-brain barrier provides further support towards promising results and clinical translation of these agents for HGGs treatment.
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Affiliation(s)
- Faiqa Mudassar
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, NSW, Westmead, Australia
| | - Han Shen
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, NSW, Westmead, Australia.
- Sydney Medical School, University of Sydney, NSW, Sydney, Australia.
| | - Geraldine O'Neill
- Children's Cancer Research Unit, The Children's Hospital at Westmead, NSW, Westmead, Australia
- Children's Hospital at Westmead Clinical School, Faculty of Medicine and Health, University of Sydney, NSW, Sydney, Australia
- School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, NSW, Sydney, Australia
| | - Eric Hau
- Translational Radiation Biology and Oncology Laboratory, Centre for Cancer Research, Westmead Institute for Medical Research, NSW, Westmead, Australia
- Sydney Medical School, University of Sydney, NSW, Sydney, Australia
- Department of Radiation Oncology, Crown Princess Mary Cancer Centre, Westmead Hospital, NSW, Westmead, Australia
- Blacktown Hematology and Cancer Centre, Blacktown Hospital, NSW, Blacktown, Australia
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16
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Miklja Z, Yadav VN, Cartaxo RT, Siada R, Thomas CC, Cummings JR, Mullan B, Stallard S, Paul A, Bruzek AK, Wierzbicki K, Yang T, Garcia T, Wolfe I, Leonard M, Robertson PL, Garton HJ, Wahl DR, Parmar H, Sarkaria JN, Kline C, Mueller S, Nicolaides T, Glasser C, Leary SE, Venneti S, Kumar-Sinha C, Chinnaiyan AM, Mody R, Pai MP, Phoenix TN, Marini BL, Koschmann C. Everolimus improves the efficacy of dasatinib in PDGFRα-driven glioma. J Clin Invest 2020; 130:5313-5325. [PMID: 32603316 PMCID: PMC7524471 DOI: 10.1172/jci133310] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Accepted: 06/24/2020] [Indexed: 12/26/2022] Open
Abstract
Pediatric and adult high-grade gliomas (HGGs) frequently harbor PDGFRA alterations. We hypothesized that cotreatment with everolimus may improve the efficacy of dasatinib in PDGFRα-driven glioma through combinatorial synergism and increased tumor accumulation of dasatinib. We performed dose-response, synergism, P-glycoprotein inhibition, and pharmacokinetic studies in in vitro and in vivo human and mouse models of HGG. Six patients with recurrent PDGFRα-driven glioma were treated with dasatinib and everolimus. We found that dasatinib effectively inhibited the proliferation of mouse and human primary HGG cells with a variety of PDGFRA alterations. Dasatinib exhibited synergy with everolimus in the treatment of HGG cells at low nanomolar concentrations of both agents, with a reduction in mTOR signaling that persisted after dasatinib treatment alone. Prolonged exposure to everolimus significantly improved the CNS retention of dasatinib and extended the survival of PPK tumor-bearing mice (mutant TP53, mutant PDGFRA, H3K27M). Six pediatric patients with glioma tolerated this combination without significant adverse events, and 4 patients with recurrent disease (n = 4) had a median overall survival of 8.5 months. Our results show that the efficacy of dasatinib treatment of PDGFRα-driven HGG was enhanced with everolimus and suggest a promising route for improving targeted therapy for this patient population.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | | - Hemant Parmar
- Department of Radiology, Michigan Medicine, Ann Arbor, Michigan, USA
| | - Jann N. Sarkaria
- Department of Oncology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA
| | - Cassie Kline
- Department of Pediatrics and
- Department of Neurology, UCSF, San Francisco, California, USA
| | - Sabine Mueller
- Department of Pediatrics and
- Department of Neurology, UCSF, San Francisco, California, USA
| | - Theodore Nicolaides
- Division of Pediatric Hematology/Oncology, NYU Langone Medical Center, New York, New York, USA
| | - Chana Glasser
- Division of Pediatric Hematology/Oncology, NYU Winthrop Hospital, Mineola, New York, USA
| | - Sarah E.S. Leary
- Seattle Children’s Hospital/University of Washington (UW), Seattle, Washington, USA
| | | | | | - Arul M. Chinnaiyan
- Department of Pathology
- Department of Urology
- Michigan Center for Translational Pathology
- Howard Hughes Medical Institute
- Rogel Cancer Center, and
| | | | - Manjunath P. Pai
- College of Pharmacy, Michigan Medicine, Ann Arbor, Michigan, USA
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17
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Convection Enhanced Delivery for Diffuse Intrinsic Pontine Glioma: Review of a Single Institution Experience. Pharmaceutics 2020; 12:pharmaceutics12070660. [PMID: 32674336 PMCID: PMC7407112 DOI: 10.3390/pharmaceutics12070660] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2020] [Revised: 07/11/2020] [Accepted: 07/13/2020] [Indexed: 01/24/2023] Open
Abstract
Diffuse intrinsic pontine gliomas (DIPGs) are a pontine subtype of diffuse midline gliomas (DMGs), primary central nervous system (CNS) tumors of childhood that carry a terrible prognosis. Because of the highly infiltrative growth pattern and the anatomical position, cytoreductive surgery is not an option. An initial response to radiation therapy is invariably followed by recurrence; mortality occurs approximately 11 months after diagnosis. The development of novel therapeutics with great preclinical promise has been hindered by the tightly regulated blood-brain barrier (BBB), which segregates the tumor comportment from the systemic circulation. One possible solution to this obstacle is the use of convection enhanced delivery (CED), a local delivery strategy that bypasses the BBB by direct infusion into the tumor through a small caliber cannula. We have recently shown CED to be safe in children with DIPG (NCT01502917). In this review, we discuss our experience with CED, its advantages, and technical advancements that are occurring in the field. We also highlight hurdles that will likely need to be overcome in demonstrating clinical benefit with this therapeutic strategy.
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18
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Xu Y, Li Q, Ma H, Sun T, Xiang R, Di F. Therapeutic effect and side effects of Bevacizumab combined with Irinotecan in the treatment of paediatric intracranial tumours: Meta-analysis and Systematic Review. J Clin Pharm Ther 2020; 45:1363-1371. [PMID: 32598559 PMCID: PMC7689821 DOI: 10.1111/jcpt.13228] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Revised: 06/12/2020] [Accepted: 06/13/2020] [Indexed: 12/19/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Bevacizumab (BVZ) is an angiogenesis inhibitor that often works well with chemotherapeutic drugs for the treatment of solid intracranial tumours in children. This meta-analysis discusses the efficacy and side effects of BVZ combined with irinotecan in the treatment of patients (younger than 21 years of age) with recurrent, progressive or refractory intracranial tumours. METHODS We searched for articles published before 31 October 2018 in PubMed, EMBASE, Cochrane library and Web of Science. We selected relevant literature on the combination of BVZ and irinotecan in the treatment of children with intracranial tumours. Objective response was evaluated by combining partial response (PR), complete response (CR), stable disease (SD) and progressive disease (PD), and survival time was evaluated by combining overall survival (OS) and progression-free survival (PFS); common side effects were also analysed. All data included were obtained from single-arm data, with no control groups. RESULTS AND DISCUSSION A total of 13 studies involving 272 patients were included. We found that out of 41% patients who showed an objective response following the BVZ therapy combined with irinotecan, 28% achieved a PR, 13% achieved a CR, 32% showed a SD, and 43% had a PD; PFS and OS were 6.47 and 11.9 months, respectively; gastrointestinal dysfunction, leukopenia and hypertension were the three most common adverse events, accounting for 36.7%, 33.6% and 22.1%, respectively, whereas musculoskeletal disorders had the lowest occurrence, accounting for 3.9%. WHAT IS NEW AND CONCLUSION BVZ combined with irinotecan-based chemotherapy had a better response and prolonged survival in the treatment of paediatric intracranial tumours than radiation therapy or chemotherapy. Gastrointestinal dysfunction, leukopenia and hypertension were the toxic side effects with the highest incidence.
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Affiliation(s)
- Yan Xu
- Department of NeurosurgeryBeijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Qiang Li
- Department of NeurosurgeryXinle City HospitalXinleHebeiChina
| | - Hai‐Yang Ma
- Department of NeurosurgeryBeijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Tao Sun
- Department of NeurosurgeryBeijing Tiantan HospitalCapital Medical UniversityBeijingChina
| | - Ruo‐Lan Xiang
- Department of Physiology and PathophysiologyPeking University School of Basic Medical SciencesBeijingChina
| | - Fei Di
- Department of NeurosurgeryBeijing Tiantan HospitalCapital Medical UniversityBeijingChina
- Department of NeurosurgeryZhangJiakou First HospitalZhangjiakouHebeiChina
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19
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Primary bulbo-medullary glioblastoma in a child: case report. Childs Nerv Syst 2019; 35:2417-2421. [PMID: 31667535 DOI: 10.1007/s00381-019-04396-6] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2019] [Accepted: 09/26/2019] [Indexed: 12/23/2022]
Abstract
Glioblastoma (GBM) of the spinal cord represents a rare entity in children and account for less than 1% of all central nervous system (CNS) cancers. Their biology, localization, and controversial treatment options have been discussed in a few pediatric cases. Here, we report a case of primary spinal cord glioblastoma in a 5-year-old girl having the particularity to be extended to the brainstem. This tumor has been revealed by torticollis and bilateral brachial paresis. The patient underwent subtotal resection; unfortunately, she died in reanimation 1 week later by severe pneumopathy. To the best of our knowledge, this is the first case in the literature reporting this particular localization in a child. Beyond their dismal prognosis, we discuss the rarity of the disease and describe the peculiar characteristics, management, and prognosis of this rare tumor in pediatric oncology. This case appears to be unusual for both the histological type and the extension to brain stern.
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20
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Howarth A, Madureira PA, Lockwood G, Storer LCD, Grundy R, Rahman R, Pilkington GJ, Hill R. Modulating autophagy as a therapeutic strategy for the treatment of paediatric high-grade glioma. Brain Pathol 2019; 29:707-725. [PMID: 31012506 PMCID: PMC8028648 DOI: 10.1111/bpa.12729] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2018] [Accepted: 04/17/2019] [Indexed: 12/18/2022] Open
Abstract
Paediatric high-grade gliomas (pHGG) represent a therapeutically challenging group of tumors. Despite decades of research, there has been minimal improvement in treatment and the clinical prognosis remains poor. Autophagy, a highly conserved process for recycling metabolic substrates is upregulated in pHGG, promoting tumor progression and evading cell death. There is significant crosstalk between autophagy and a plethora of critical cellular pathways, many of which are dysregulated in pHGG. The following article will discuss our current understanding of autophagy signaling in pHGG and the potential modulation of this network as a therapeutic target.
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Affiliation(s)
- Alison Howarth
- Brain Tumour Research Centre, Institute of Biomedical and Biomolecular Sciences, IBBSUniversity of PortsmouthPortsmouthUK
| | - Patricia A. Madureira
- Brain Tumour Research Centre, Institute of Biomedical and Biomolecular Sciences, IBBSUniversity of PortsmouthPortsmouthUK
- Centre for Biomedical Research (CBMR)University of AlgarveFaroPortugal
| | - George Lockwood
- Children’s Brain Tumour Research Centre, School of Medicine, Queen’s Medical CentreUniversity of NottinghamNottinghamUK
| | - Lisa C. D. Storer
- Children’s Brain Tumour Research Centre, School of Medicine, Queen’s Medical CentreUniversity of NottinghamNottinghamUK
| | - Richard Grundy
- Children’s Brain Tumour Research Centre, School of Medicine, Queen’s Medical CentreUniversity of NottinghamNottinghamUK
| | - Ruman Rahman
- Children’s Brain Tumour Research Centre, School of Medicine, Queen’s Medical CentreUniversity of NottinghamNottinghamUK
| | - Geoffrey J. Pilkington
- Brain Tumour Research Centre, Institute of Biomedical and Biomolecular Sciences, IBBSUniversity of PortsmouthPortsmouthUK
| | - Richard Hill
- Brain Tumour Research Centre, Institute of Biomedical and Biomolecular Sciences, IBBSUniversity of PortsmouthPortsmouthUK
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21
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Mackay A, Burford A, Molinari V, Jones DTW, Izquierdo E, Brouwer-Visser J, Giangaspero F, Haberler C, Pietsch T, Jacques TS, Figarella-Branger D, Rodriguez D, Morgan PS, Raman P, Waanders AJ, Resnick AC, Massimino M, Garrè ML, Smith H, Capper D, Pfister SM, Würdinger T, Tam R, Garcia J, Thakur MD, Vassal G, Grill J, Jaspan T, Varlet P, Jones C. Molecular, Pathological, Radiological, and Immune Profiling of Non-brainstem Pediatric High-Grade Glioma from the HERBY Phase II Randomized Trial. Cancer Cell 2018; 33:829-842.e5. [PMID: 29763623 PMCID: PMC5956280 DOI: 10.1016/j.ccell.2018.04.004] [Citation(s) in RCA: 151] [Impact Index Per Article: 21.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/12/2018] [Revised: 02/28/2018] [Accepted: 04/10/2018] [Indexed: 12/30/2022]
Abstract
The HERBY trial was a phase II open-label, randomized, multicenter trial evaluating bevacizumab (BEV) in addition to temozolomide/radiotherapy in patients with newly diagnosed non-brainstem high-grade glioma (HGG) between the ages of 3 and 18 years. We carried out comprehensive molecular analysis integrated with pathology, radiology, and immune profiling. In post-hoc subgroup analysis, hypermutator tumors (mismatch repair deficiency and somatic POLE/POLD1 mutations) and those biologically resembling pleomorphic xanthoastrocytoma ([PXA]-like, driven by BRAF_V600E or NF1 mutation) had significantly more CD8+ tumor-infiltrating lymphocytes, and longer survival with the addition of BEV. Histone H3 subgroups (hemispheric G34R/V and midline K27M) had a worse outcome and were immune cold. Future clinical trials will need to take into account the diversity represented by the term "HGG" in the pediatric population.
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Affiliation(s)
- Alan Mackay
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
| | - Anna Burford
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
| | - Valeria Molinari
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
| | - David T W Jones
- Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Elisa Izquierdo
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK
| | | | - Felice Giangaspero
- Department of Radiology, Oncology and Anatomic-Pathology Sciences, Sapienza University, Rome, Italy; IRCCS Neuromed, Pozzilli, Italy
| | - Christine Haberler
- Institute of Neurology, Medical University of Vienna, Vienna, Austria; Comprehensive Cancer Center, Medical University of Vienna, Vienna, Austria
| | - Torsten Pietsch
- DGNN Brain Tumor Reference Center, Institute of Neuropathology, University of Bonn Medical Center, Bonn, Germany
| | - Thomas S Jacques
- UCL Great Ormond Street Institute of Child Health, London, UK; Department of Histopathology, Great Ormond Street Hospital for Children, London, UK
| | | | | | | | - Pichai Raman
- The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Angela J Waanders
- The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Adam C Resnick
- The Center for Data Driven Discovery in Biomedicine (D(3)b), Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Neurosurgery, Children's Hospital of Philadelphia, Philadelphia, PA, USA; Division of Oncology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
| | - Maura Massimino
- Pediatric Oncology Unit, Fondazione IRCCS, Istituto Nazionale Tumori, Milan, Italy
| | | | - Helen Smith
- F. Hoffmann-La Roche Ltd, Basel, Switzerland
| | - David Capper
- Charité - Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin, Germany; Berlin Institute of Health, Institute of Neuropathology, Berlin, Germany; Department of Neuropathology, University Hospital Heidelberg and Clinical Cooperation Unit Neuropathology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Stefan M Pfister
- Hopp Children's Cancer Center at the NCT Heidelberg (KiTZ), Heidelberg, Germany; Division of Paediatric Neuro-oncology, German Cancer Consortium (DKTK), German Cancer Research Center (DKFZ), Heidelberg, Germany; Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Thomas Würdinger
- Department of Neurosurgery, Brain Tumor Center Amsterdam, VU Medical Center, Amsterdam, the Netherlands
| | | | | | | | - Gilles Vassal
- Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France
| | - Jacques Grill
- Pediatric and Adolescent Oncology and Unite Mixte de Recherche 8203 du Centre National de la Recherche Scientifique, Gustave Roussy, Paris-Saclay University, Villejuif, France
| | - Tim Jaspan
- Nottingham University Hospitals, Nottingham, UK
| | - Pascale Varlet
- Sainte-Anne Hospital, Paris-Descartes University, Paris, France
| | - Chris Jones
- Division of Molecular Pathology, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK; Division of Cancer Therapeutics, The Institute of Cancer Research, 15 Cotswold Road, Sutton, London, Surrey SM2 5NG, UK.
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22
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Mathew RK, Rutka JT. Diffuse Intrinsic Pontine Glioma : Clinical Features, Molecular Genetics, and Novel Targeted Therapeutics. J Korean Neurosurg Soc 2018; 61:343-351. [PMID: 29742880 PMCID: PMC5957322 DOI: 10.3340/jkns.2018.0008] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/06/2018] [Accepted: 01/21/2018] [Indexed: 12/18/2022] Open
Abstract
Diffuse intrinsic pontine glioma (DIPG) is a deadly paediatric brain cancer. Transient response to radiation, ineffective chemotherapeutic agents and aggressive biology result in rapid progression of symptoms and a dismal prognosis. Increased availability of tumour tissue has enabled the identification of histone gene aberrations, genetic driver mutations and methylation changes, which have resulted in molecular and phenotypic subgrouping. However, many of the underlying mechanisms of DIPG oncogenesis remain unexplained. It is hoped that more representative in vitro and preclinical models–using both xenografted material and genetically engineered mice–will enable the development of novel chemotherapeutic agents and strategies for targeted drug delivery. This review provides a clinical overview of DIPG, the barriers to progress in developing effective treatment, updates on drug development and preclinical models, and an introduction to new technologies aimed at enhancing drug delivery.
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Affiliation(s)
- Ryan K Mathew
- Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.,Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada.,Leeds Institute of Cancer and Pathology, University of Leeds, Leeds, UK.,Department of Neurosurgery, Leeds General Infirmary, Leeds, UK
| | - James T Rutka
- Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, Canada.,Division of Neurosurgery, Department of Surgery, University of Toronto, Toronto, Canada
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23
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Tullius BP, Athale U, van Ommen CH, Chan AKC, Palumbo JS, Balagtas JMS. The identification of at-risk patients and prevention of venous thromboembolism in pediatric cancer: guidance from the SSC of the ISTH. J Thromb Haemost 2018; 16:175-180. [PMID: 29178421 DOI: 10.1111/jth.13895] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2016] [Indexed: 01/19/2023]
Affiliation(s)
- B P Tullius
- Division of Pediatric Hematology/Oncology and BMT, Nationwide Children's Hospital, Columbus, OH, USA
| | - U Athale
- Pediatrics, McMaster University and Division of Paediatric Hematology/Oncology, McMaster Children's Hospital, Hamilton Health Sciences, Hamilton, ON, Canada
| | - C H van Ommen
- Department of Pediatric Hematology, Erasmus MC Sophia Children's Hospital, Rotterdam, the Netherlands
| | - A K C Chan
- Pediatrics, McMaster University and Division of Paediatric Hematology/Oncology, McMaster Children's Hospital, Hamilton Health Sciences, Hamilton, ON, Canada
| | - J S Palumbo
- Division of Pediatric Hematology, University of Cincinnati, Cincinnati, OH, USA
| | - J M S Balagtas
- Division of Pediatric Hematology/Oncology, Stanford University, Stanford, CA, USA
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24
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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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25
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Gauvain K, Ponisio MR, Barone A, Grimaldi M, Parent E, Leeds H, Goyal M, Rubin J, McConathy J. 18F-FDOPA PET/MRI for monitoring early response to bevacizumab in children with recurrent brain tumors. Neurooncol Pract 2017; 5:28-36. [PMID: 29692922 DOI: 10.1093/nop/npx008] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Background Noninvasively predicting early response to therapy in recurrent pediatric brain tumors provides a challenge. 3,4-dihydroxy-6-[18F]fluoro-L-phenylalanine (18F-FDOPA) PET/MRI has not been previously studied as a tool to evaluate early response to antiangiogenic therapy in children. The purpose of this study was to evaluate the safety and feasibility of using 18F-FDOPA PET/MRI to assess response to bevacizumab in children with relapsed brain tumors. Materials and Methods Six patients with recurrent gliomas (5 low-grade, 1 high-grade) planned to undergo treatment with bevacizumab were enrolled. 18F-FDOPA PET/MRI scans were obtained prior to and 4 weeks following the start of treatment, and these were compared with the clinical response determined at the 3-month MRI. The primary PET measure was metabolic tumor volume (MTV) at 10 to 15 min after 18F-FDOPA injection. For each tumor, the MTV was determined by manually defining initial tumor volumes of interest (VOI) and then applying a 1.5-fold threshold relative to the mean standardized uptake value (SUV) of a VOI in the frontal lobe contralateral to the tumor. Results 18F-FDOPA PET/MRI was well tolerated by all patients. All tumors were well visualized with 18F-FDOPA on the initial study, with peak tumor uptake occurring approximately 10 min after injection. Maximum and mean SUVs as well as tumor-to-brain ratios were not predictors of response at 3 months. Changes in MTVs after therapy ranged from 23% to 98% (n = 5). There is a trend towards the percent MTV change seen on the 4-week scan correlating with progression-free survival. Conclusion 18F-FDOPA PET/MRI was well tolerated in pediatric patients and merits further investigation as an early predictor of response to therapy.
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Affiliation(s)
- Karen Gauvain
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO
| | - Maria Rosana Ponisio
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO.,Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO
| | - Amy Barone
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO
| | - Michael Grimaldi
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO.,Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO
| | - Ephraim Parent
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO.,Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO
| | - Hayden Leeds
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO.,Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO
| | - Manu Goyal
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO.,Washington University School of Medicine, Mallinckrodt Institute of Radiology, St. Louis, MO
| | - Joshua Rubin
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO
| | - Jonathan McConathy
- Washington University School of Medicine, Pediatric Hematology/Oncology, St. Louis, MO.,University of Alabama at Birmingham, Department of Radiology, Birmingham, AL
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26
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Konar SK, Bir SC, Maiti TK, Nanda A. A systematic review of overall survival in pediatric primary glioblastoma multiforme of the spinal cord. J Neurosurg Pediatr 2017; 19:239-248. [PMID: 27813458 DOI: 10.3171/2016.8.peds1631] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/23/2022]
Abstract
OBJECTIVE The incidence of primary spinal cord glioblastoma multiforme (GBM) in the pediatric age group is very rare. Only a few case series and case reports have been published in the literature; therefore, overall survival (OS) outcome and the as-yet poorly defined management options are not discussed in detail. The authors performed a cumulative survival analysis of all reported cases of pediatric spinal cord GBM to identify the predictive factors related to final survival outcome. METHODS A comprehensive search for relevant articles was performed on PubMed's electronic database MEDLINE for the period from 1950 to 2015 using the search words "malignant spinal cord tumor" and "spinal glioblastoma multiforme." This study was limited to patients younger than 18 years of age. Survival rates for children with various tumor locations and treatments were collected from the published articles and analyzed. RESULTS After an extensive literature search, 29 articles met the study inclusion criteria. From the detailed information in these articles, the authors found 53 children eligible for the survival analysis. The majority (45%) of the children were more than 12 years old. Thirty-four percent of the cases were between 7 and 12 years of age, and 21% were younger than 7 years. In the Kaplan-Meier survival analysis, children younger than 7 years of age had better survival (13 months) than the children older than 7 years (7-12 years: 10 months, > 12 years: 9 months; p = 0.01, log-rank test). Fifty-five percent of the children were female and 45% were male. A cervical tumor location (32%) was the most common, followed by thoracic (28.3%). Cervicothoracic (18.9%) and conus (18.8%) tumor locations shared the same percentage of cases. Cervical tumors had a worse outcome than tumors in other locations (p = 0.003, log-rank test). The most common presenting symptom was limb weakness (53%), followed by sensory disturbances (25%). Median OS was 10 months. The addition of adjuvant therapy (radiotherapy [RT] and/or chemotherapy [CT]) after surgery significantly improved OS (p = 0.01, log-rank test). Children who underwent gross-total resection and RT had better outcomes than those who underwent subtotal resection and RT (p = 0.04, log-rank test). Cerebrospinal fluid spread, hydrocephalus, brain metastasis, and spinal metastasis were not correlated with OS in primary spinal GBM. CONCLUSIONS Adjuvant therapy after surgery had a beneficial effect on overall outcome of spinal GBM in the pediatric age group. Gross-total resection followed by RT produced a better outcome than subtotal resection with RT. Further large-scale prospective study is required to establish the genetic and molecular factors related to OS in primary GBM of the spinal cord in pediatric patients.
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Affiliation(s)
- Subhas K Konar
- Department of Neurosurgery, LSU Health Shreveport, Louisiana
| | - Shyamal C Bir
- Department of Neurosurgery, LSU Health Shreveport, Louisiana
| | - Tanmoy K Maiti
- Department of Neurosurgery, LSU Health Shreveport, Louisiana
| | - Anil Nanda
- Department of Neurosurgery, LSU Health Shreveport, Louisiana
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27
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Jansen MHA, Lagerweij T, Sewing ACP, Vugts DJ, van Vuurden DG, Molthoff CFM, Caretti V, Veringa SJE, Petersen N, Carcaboso AM, Noske DP, Vandertop WP, Wesseling P, van Dongen GAMS, Kaspers GJL, Hulleman E. Bevacizumab Targeting Diffuse Intrinsic Pontine Glioma: Results of 89Zr-Bevacizumab PET Imaging in Brain Tumor Models. Mol Cancer Ther 2016; 15:2166-74. [PMID: 27325687 DOI: 10.1158/1535-7163.mct-15-0558] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2015] [Accepted: 05/26/2016] [Indexed: 11/16/2022]
Abstract
The role of the VEGF inhibitor bevacizumab in the treatment of diffuse intrinsic pontine glioma (DIPG) is unclear. We aim to study the biodistribution and uptake of zirconium-89 ((89)Zr)-labeled bevacizumab in DIPG mouse models. Human E98-FM, U251-FM glioma cells, and HSJD-DIPG-007-FLUC primary DIPG cells were injected into the subcutis, pons, or striatum of nude mice. Tumor growth was monitored by bioluminescence imaging (BLI) and visualized by MRI. Seventy-two to 96 hours after (89)Zr-bevacizumab injections, mice were imaged by positron emission tomography (PET), and biodistribution was analyzed ex vivo High VEGF expression in human DIPG was confirmed in a publically available mRNA database, but no significant (89)Zr-bevacizumab uptake could be detected in xenografts located in the pons and striatum at an early or late stage of the disease. E98-FM, and to a lesser extent the U251-FM and HSJD-DIPG-007 subcutaneous tumors, showed high accumulation of (89)Zr-bevacizumab. VEGF expression could not be demonstrated in the intracranial tumors by in situ hybridization (ISH) but was clearly present in the perinecrotic regions of subcutaneous E98-FM tumors. The poor uptake of (89)Zr-bevacizumab in xenografts located in the brain suggests that VEGF targeting with bevacizumab has limited efficacy for diffuse infiltrative parts of glial brain tumors in mice. Translating these results to the clinic would imply that treatment with bevacizumab in patients with DIPG is only justified after targeting of VEGF has been demonstrated by (89)Zr-bevacizumab immuno-PET. We aim to confirm this observation in a clinical PET study with patients with DIPG. Mol Cancer Ther; 15(9); 2166-74. ©2016 AACR.
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Affiliation(s)
- Marc H A Jansen
- Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands
| | - Tonny Lagerweij
- Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. Department of Neurosurgery VU University Medical Center and Academic Medical Center, Amsterdam, the Netherlands
| | - A Charlotte P Sewing
- Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands
| | - Danielle J Vugts
- Department of Radiology & Nuclear Medicine VU University Medical Center, Amsterdam, the Netherlands
| | - Dannis G van Vuurden
- Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands
| | - Carla F M Molthoff
- Department of Radiology & Nuclear Medicine VU University Medical Center, Amsterdam, the Netherlands
| | - Viola Caretti
- Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. Departments of Neurology, Pediatrics and Neurosurgery, Stanford University School of Medicine, Stanford, California
| | - Susanna J E Veringa
- Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands
| | - Naomi Petersen
- Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands
| | - Angel M Carcaboso
- Preclinical Therapeutics and Drug Delivery Research Program, Department of Oncology, Hospital Sant Joan de Déu, Barcelona, Spain
| | - David P Noske
- Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. Department of Neurosurgery VU University Medical Center and Academic Medical Center, Amsterdam, the Netherlands
| | - W Peter Vandertop
- Department of Neurosurgery VU University Medical Center and Academic Medical Center, Amsterdam, the Netherlands
| | - Pieter Wesseling
- Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands. Department of Pathology VU University Medical Center. Amsterdam, the Netherlands. Department of Pathology, Radboud University Medical Center, Nijmegen, The Netherlands
| | - Guus A M S van Dongen
- Department of Radiology & Nuclear Medicine VU University Medical Center, Amsterdam, the Netherlands
| | - Gertjan J L Kaspers
- Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands
| | - Esther Hulleman
- Department of Pediatrics, Pediatric Hematology and Oncology, Cancer Center, Amsterdam, the Netherlands. Neuro-oncology Research Group Cancer Center, Amsterdam, the Netherlands.
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28
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Daudigeos-Dubus E, Le Dret L, Lanvers-Kaminsky C, Bawa O, Opolon P, Vievard A, Villa I, Pagès M, Bosq J, Vassal G, Zopf D, Geoerger B. Regorafenib: Antitumor Activity upon Mono and Combination Therapy in Preclinical Pediatric Malignancy Models. PLoS One 2015; 10:e0142612. [PMID: 26599335 PMCID: PMC4658168 DOI: 10.1371/journal.pone.0142612] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 10/05/2015] [Indexed: 12/14/2022] Open
Abstract
The multikinase inhibitor regorafenib (BAY 73-4506) exerts both anti-angiogenic and anti-tumorigenic activity in adult solid malignancies mainly advanced colorectal cancer and gastrointestinal stromal tumors. We intended to explore preclinically the potential of regorafenib against solid pediatric malignancies alone and in combination with anticancer agents to guide the pediatric development plan. In vitro effects on cell proliferation were screened against 33 solid tumor cell lines of the Innovative Therapies for Children with Cancer (ITCC) panel covering five pediatric solid malignancies. Regorafenib inhibited cell proliferation with a mean half maximal growth inhibition of 12.5 μmol/L (range 0.7 μmol/L to 28 μmol/L). In vivo, regorafenib was evaluated alone at 10 or 30 mg/kg/d or in combination with radiation, irinotecan or the mitogen-activated protein kinase kinase (MEK) inhibitor refametinib against various tumor types, including patient-derived brain tumor models with an amplified platelet-derived growth factor receptor A (PDGFRA) gene. Regorafenib alone significantly inhibited tumor growth in all xenografts derived from nervous system and connective tissue tumors. Enhanced effects were observed when regorafenib was combined with irradiation and irinotecan against PDGFRA amplified IGRG93 glioma and IGRM57 medulloblastoma respectively, resulting in 100% tumor regressions. Antitumor activity was associated with decreased tumor vascularization, inhibition of PDGFR signaling, and induction of apoptotic cell death. Our work demonstrates that regorafenib exhibits significant antitumor activity in a wide spectrum of preclinical pediatric models through inhibition of angiogenesis and induction of apoptosis. Furthermore, radio- and chemosensitizing effects were observed with DNA damaging agents in PDGFR amplified tumors.
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Affiliation(s)
- Estelle Daudigeos-Dubus
- Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France
- CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France
- Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France
| | - Ludivine Le Dret
- Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France
- CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France
- Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France
| | - Claudia Lanvers-Kaminsky
- University Children’s Hospital, Department of Pediatric Hematology and Oncology, Münster, Germany
| | - Olivia Bawa
- PFEP (Plateforme d’évaluation préclinique), Gustave Roussy, Villejuif, France
| | - Paule Opolon
- PFEP (Plateforme d’évaluation préclinique), Gustave Roussy, Villejuif, France
| | | | - Irène Villa
- Pathology Laboratory, Gustave Roussy, Villejuif, France
| | - Mélanie Pagès
- Department of Neuropathology, Sainte-Anne’s Hospital, Paris, France
- Paris Descartes University, Paris, France
| | - Jacques Bosq
- Pathology Laboratory, Gustave Roussy, Villejuif, France
| | - Gilles Vassal
- Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France
- CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France
- Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France
| | - Dieter Zopf
- Bayer Pharma Aktiengesellschaft, Berlin, Germany
| | - Birgit Geoerger
- Université Paris-Sud 11, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France
- CNRS, Vectorology and Anticancer Therapeutics, UMR 8203, Orsay, France
- Gustave Roussy, Vectorology and Anticancer Therapeutics, UMR 8203, Villejuif, France
- * E-mail:
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29
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Vanan MI, Eisenstat DD. DIPG in Children - What Can We Learn from the Past? Front Oncol 2015; 5:237. [PMID: 26557503 PMCID: PMC4617108 DOI: 10.3389/fonc.2015.00237] [Citation(s) in RCA: 135] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Accepted: 10/08/2015] [Indexed: 02/02/2023] Open
Abstract
Brainstem tumors represent 10–15% of pediatric central nervous system tumors and diffuse intrinsic pontine glioma (DIPG) is the most common brainstem tumor of childhood. DIPG is almost uniformly fatal and is the leading cause of brain tumor-related death in children. To date, radiation therapy (RT) is the only form of treatment that offers a transient benefit in DIPG. Chemotherapeutic strategies including multi-agent neoadjuvant chemotherapy, concurrent chemotherapy with RT, and adjuvant chemotherapy have not provided any survival advantage. To overcome the restrictive ability of the intact blood–brain barrier (BBB) in DIPG, several alternative drug delivery strategies have been proposed but have met with minimal success. Targeted therapies either alone or in combination with RT have also not improved survival. Five decades of unsuccessful therapies coupled with recent advances in the genetics and biology of DIPG have taught us several important lessons (1). DIPG is a heterogeneous group of tumors that are biologically distinct from other pediatric and adult high grade gliomas (HGG). Adapting chemotherapy and targeted therapies that are used in pediatric or adult HGG for the treatment of DIPG should be abandoned (2). Biopsy of DIPG is relatively safe and informative and should be considered in the context of multicenter clinical trials (3). DIPG probably represents a whole brain disease so regular neuraxis imaging is important at diagnosis and during therapy (4). BBB permeability is of major concern in DIPG and overcoming this barrier may ensure that drugs reach the tumor (5). Recent development of DIPG tumor models should help us accurately identify and validate therapeutic targets and small molecule inhibitors in the treatment of this deadly tumor.
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Affiliation(s)
- Magimairajan Issai Vanan
- Department of Pediatrics and Child Health, University of Manitoba , Winnipeg, MB , Canada ; Department of Biochemistry and Medical Genetics, University of Manitoba , Winnipeg, MB , Canada
| | - David D Eisenstat
- Department of Pediatrics, University of Alberta , Edmonton, AB , Canada ; Department of Medical Genetics, University of Alberta , Edmonton, AB , Canada ; Department of Oncology, University of Alberta , Edmonton, AB , Canada
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30
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Rizzo D, Ruggiero A, Martini M, Rizzo V, Maurizi P, Riccardi R. Molecular Biology in Pediatric High-Grade Glioma: Impact on Prognosis and Treatment. BIOMED RESEARCH INTERNATIONAL 2015; 2015:215135. [PMID: 26448930 PMCID: PMC4584033 DOI: 10.1155/2015/215135] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/26/2014] [Accepted: 11/04/2014] [Indexed: 12/17/2022]
Abstract
High-grade gliomas are the main cause of death in children with brain tumours. Despite recent advances in cancer therapy, their prognosis remains poor and the treatment is still challenging. To date, surgery followed by radiotherapy and temozolomide is the standard therapy. However, increasing knowledge of glioma biology is starting to impact drug development towards targeted therapies. The identification of agents directed against molecular targets aims at going beyond the traditional therapeutic approach in order to develop a personalized therapy and improve the outcome of pediatric high-grade gliomas. In this paper, we critically review the literature regarding the genetic abnormalities implicated in the pathogenesis of pediatric malignant gliomas and the current development of molecularly targeted therapies. In particular, we analyse the impact of molecular biology on the prognosis and treatment of pediatric high-grade glioma, comparing it to that of adult gliomas.
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Affiliation(s)
- Daniela Rizzo
- Department of Pediatric Oncology, A. Gemelli Hospital, Catholic University of Rome, Largo A Gemelli, 1, 00168 Rome, Italy
| | - Antonio Ruggiero
- Department of Pediatric Oncology, A. Gemelli Hospital, Catholic University of Rome, Largo A Gemelli, 1, 00168 Rome, Italy
| | - Maurizio Martini
- Anatomic Pathology, Catholic University, “A. Gemelli” Hospital, 00168 Rome, Italy
| | - Valentina Rizzo
- Department of Pediatric Oncology, A. Gemelli Hospital, Catholic University of Rome, Largo A Gemelli, 1, 00168 Rome, Italy
| | - Palma Maurizi
- Department of Pediatric Oncology, A. Gemelli Hospital, Catholic University of Rome, Largo A Gemelli, 1, 00168 Rome, Italy
| | - Riccardo Riccardi
- Department of Pediatric Oncology, A. Gemelli Hospital, Catholic University of Rome, Largo A Gemelli, 1, 00168 Rome, Italy
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31
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Gajjar A, Bowers DC, Karajannis MA, Leary S, Witt H, Gottardo NG. Pediatric Brain Tumors: Innovative Genomic Information Is Transforming the Diagnostic and Clinical Landscape. J Clin Oncol 2015; 33:2986-98. [PMID: 26304884 DOI: 10.1200/jco.2014.59.9217] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022] Open
Abstract
Pediatric neuro-oncology has undergone an exciting and dramatic transformation during the past 5 years. This article summarizes data from collaborative group and institutional trials that have advanced the science of pediatric brain tumors and survival of patients with these tumors. Advanced genomic analysis of the entire spectrum of pediatric brain tumors has heralded an era in which stakeholders in the pediatric neuro-oncology community are being challenged to reconsider their current research and diagnostic and treatment strategies. The incorporation of this new information into the next-generation treatment protocols will unleash new challenges. This review succinctly summarizes the key advances in our understanding of the common pediatric brain tumors (ie, medulloblastoma, low- and high-grade gliomas, diffuse intrinsic pontine glioma, and ependymoma) and some selected rare tumors (ie, atypical teratoid/rhabdoid tumor and CNS primitive neuroectodermal tumor). The potential impact of this new information on future clinical protocols also is discussed. Cutting-edge genomics technologies and the information gained from such studies are facilitating the identification of molecularly defined subgroups within patients with particular pediatric brain tumors. The number of evaluable patients in each subgroup is small, particularly in the subgroups of rare diseases. Therefore, international collaboration will be crucial to draw meaningful conclusions about novel approaches to treating pediatric brain tumors.
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Affiliation(s)
- Amar Gajjar
- Amar Gajjar, St Jude Children's Research Hospital, Memphis, TN; Daniel C. Bowers, University of Texas Southwestern Medical Center, Dallas, TX; Matthias A. Karajannis, New York University (NYU) Perlmutter Cancer Center and NYU Langone Medical Center, New York, NY; Sarah Leary, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, WA; Hendrik Witt, German Cancer Research Center and University of Heidelberg, Heidelberg, Germany; and Nicholas G. Gottardo, Princess Margaret Hospital for Children and The University of Western Australia, Perth, Western Australia, Australia.
| | - Daniel C Bowers
- Amar Gajjar, St Jude Children's Research Hospital, Memphis, TN; Daniel C. Bowers, University of Texas Southwestern Medical Center, Dallas, TX; Matthias A. Karajannis, New York University (NYU) Perlmutter Cancer Center and NYU Langone Medical Center, New York, NY; Sarah Leary, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, WA; Hendrik Witt, German Cancer Research Center and University of Heidelberg, Heidelberg, Germany; and Nicholas G. Gottardo, Princess Margaret Hospital for Children and The University of Western Australia, Perth, Western Australia, Australia
| | - Matthias A Karajannis
- Amar Gajjar, St Jude Children's Research Hospital, Memphis, TN; Daniel C. Bowers, University of Texas Southwestern Medical Center, Dallas, TX; Matthias A. Karajannis, New York University (NYU) Perlmutter Cancer Center and NYU Langone Medical Center, New York, NY; Sarah Leary, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, WA; Hendrik Witt, German Cancer Research Center and University of Heidelberg, Heidelberg, Germany; and Nicholas G. Gottardo, Princess Margaret Hospital for Children and The University of Western Australia, Perth, Western Australia, Australia
| | - Sarah Leary
- Amar Gajjar, St Jude Children's Research Hospital, Memphis, TN; Daniel C. Bowers, University of Texas Southwestern Medical Center, Dallas, TX; Matthias A. Karajannis, New York University (NYU) Perlmutter Cancer Center and NYU Langone Medical Center, New York, NY; Sarah Leary, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, WA; Hendrik Witt, German Cancer Research Center and University of Heidelberg, Heidelberg, Germany; and Nicholas G. Gottardo, Princess Margaret Hospital for Children and The University of Western Australia, Perth, Western Australia, Australia
| | - Hendrik Witt
- Amar Gajjar, St Jude Children's Research Hospital, Memphis, TN; Daniel C. Bowers, University of Texas Southwestern Medical Center, Dallas, TX; Matthias A. Karajannis, New York University (NYU) Perlmutter Cancer Center and NYU Langone Medical Center, New York, NY; Sarah Leary, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, WA; Hendrik Witt, German Cancer Research Center and University of Heidelberg, Heidelberg, Germany; and Nicholas G. Gottardo, Princess Margaret Hospital for Children and The University of Western Australia, Perth, Western Australia, Australia
| | - Nicholas G Gottardo
- Amar Gajjar, St Jude Children's Research Hospital, Memphis, TN; Daniel C. Bowers, University of Texas Southwestern Medical Center, Dallas, TX; Matthias A. Karajannis, New York University (NYU) Perlmutter Cancer Center and NYU Langone Medical Center, New York, NY; Sarah Leary, University of Washington School of Medicine and Fred Hutchinson Cancer Research Center, Seattle, WA; Hendrik Witt, German Cancer Research Center and University of Heidelberg, Heidelberg, Germany; and Nicholas G. Gottardo, Princess Margaret Hospital for Children and The University of Western Australia, Perth, Western Australia, Australia
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Jalali R, Rishi A, Goda JS, Sridhar E, Gurav M, Sharma P, Moiyadi A, Shetty P, Gupta T. Clinical outcome and molecular characterization of pediatric glioblastoma treated with postoperative radiotherapy with concurrent and adjuvant temozolomide: a single institutional study of 66 children. Neurooncol Pract 2015; 3:39-47. [PMID: 31579520 DOI: 10.1093/nop/npv024] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Indexed: 11/12/2022] Open
Abstract
Background Glioblastoma (GBM) in children is rare. Pediatric GBM have a distinct molecular profile as compared to adult GBM. There are relatively few studies of pediatric GBMs and no standard of care on adjuvant therapy. We aimed to evaluate the clinical outcome and molecular profile of pediatric GBM. Methods and Materials Between 2004 and 2013, 66 consecutive children with histologically proven GBM were identified from our database. The majority of the children underwent maximal safe resection followed by focal radiotherapy with concurrent and adjuvant temozolomide. Immunohistochemical staining was performed for p53, MIB-1 labeling index, MGMT overexpression, and EGFR amplification and isocitrate dehydrogenase (IDH1) R132H point mutation. Survival and impact of possible prognostic factors on outcomes were analyzed. Result Median survival was 15 months. The overall survival rate at 1 year was 62%, at 2 years was 30%, and at 3 years was 27%. Patients with thalamic tumors (P < .001), incompletely resected tumors (P < .00001), and tumors with MIB-1 labeling index >25% (P < .002) had poor overall survival rates. p53 was overexpressed in 74% of patients, MGMT promoter methylation was seen in 37% of patients, IDH1 mutation was seen in 4% of patients, and no patients had EGFR amplification. MGMT methylation and p53 overexpression did not impact survival. Conclusions Clinical outcome of pediatric GBM is similar to that reported for adult GBM. The frequency of p53 overexpression is higher than in adult GBM, while MGMT methylation, IDH1 mutations and EGFR amplification is lower than in adult GBM. MGMT methylation and p53 expression status do not have any prognostic significance.
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Affiliation(s)
- Rakesh Jalali
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
| | - Anupam Rishi
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
| | - Jayant S Goda
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
| | - Epari Sridhar
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
| | - Mamta Gurav
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
| | - Pravin Sharma
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
| | - Aliasgar Moiyadi
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
| | - Prakash Shetty
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
| | - Tejpal Gupta
- Neuro Oncology Group, Tata Memorial Centre, Mumbai, India (R.J., A.R., J.S.G., P.S., T.G.); Molecular Pathology, Tata Memorial Centre, Mumbai, India (E.S., M.G.); Neurosurgery, Tata Memorial Centre, Mumbai, India (A.M., P.S.)
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Confirmation of Bevacizumab Activity, and Maintenance of Efficacy in Retreatment After Subsequent Relapse, in Pediatric Low-grade Glioma. J Pediatr Hematol Oncol 2015; 37:e341-6. [PMID: 26056795 DOI: 10.1097/mph.0000000000000371] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
BACKGROUND Management of low-grade gliomas (LGG) can be a challenge, particularly when not resectable and refractory or recurrent following standard treatments. We undertook a retrospective analysis of 2 institutions' experiences treating children for refractory or progressive LGG with bevacizumab-based therapy (BBT). PROCEDURE Inclusion criteria were patients younger than 18 years of age who had previously failed one or more lines of therapy. Treatment was intravenous bevacizumab 10 mg/kg and intravenous irinotecan 125 to 150 mg/m2 every 2 weeks. RESULTS Sixteen children (median age of 8.6 y), 5 with neurofibromatosis type 1 and 8 with disseminated disease were treated between 2009 and 2013. Median duration of treatment was 12 months (range, 3 to 45 mo). Seven patients (44%) showed clinical improvement (3 patients within a month) and 8 patients (50%) remained clinically stable during BBT. Imaging studies showed 3 (19%) had a partial response, 11 (69%) stable disease, and 2 (12%) had progressive disease. Four patients had progressive disease after stopping BBT (median duration of 5 mo). Three of these 4 were able to be retreated with BBT and all achieved an objective response. Treatment was well tolerated with no grade 3 or 4 toxicities related to bevacizumab. Irinotecan was discontinued in 4 patients because of grade 2-3 toxicities. CONCLUSIONS We conclude that BBT is well tolerated and led to disease control in patients with refractory or recurrent cases of LGG. Retreatment with BBT led to disease control in most of these cases. Larger, prospective studies are warranted to confirm these results.
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Panditharatna E, Yaeger K, Kilburn LB, Packer RJ, Nazarian J. Clinicopathology of diffuse intrinsic pontine glioma and its redefined genomic and epigenomic landscape. Cancer Genet 2015. [PMID: 26206682 DOI: 10.1016/j.cancergen.2015.04.008] [Citation(s) in RCA: 36] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
Diffuse intrinsic pontine glioma (DIPG) is one of the most lethal pediatric central nervous system (CNS) cancers. Recently, a surge in molecular studies of DIPG has occurred, in large part due to the increased availability of tumor tissue through donation of post-mortem specimens. These new discoveries have established DIPGs as biologically distinct from adult gliomas, harboring unique genomic aberrations. Mutations in histone encoding genes are shown to be associated with >70% of DIPG cases. However, the exact molecular mechanisms of the tumorigenicity of these mutations remain elusive. Understanding the driving mutations and genomic landscape of DIPGs can now guide the development of targeted therapies for this incurable childhood cancer.
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Affiliation(s)
- Eshini Panditharatna
- Institute for Biomedical Sciences, George Washington University School of Medicine, Washington, DC, USA; Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA
| | - Kurt Yaeger
- Department of Neurosurgery, Georgetown University School of Medicine, Washington, DC, USA
| | - Lindsay B Kilburn
- Division of Oncology, Center for Cancer and Immunology Research, Children's National Health System, Washington, DC, USA
| | - Roger J Packer
- Brain Tumor Institute, Center for Neuroscience and Behavioral Medicine, Children's National Health System, Washington, DC, USA
| | - Javad Nazarian
- Research Center for Genetic Medicine, Children's National Health System, Washington, DC, USA; Department of Integrative Systems Biology, George Washington University School of Medicine and Health Sciences, Washington, DC, USA.
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Capitini CM, Otto M, DeSantes KB, Sondel PM. Immunotherapy in pediatric malignancies: current status and future perspectives. Future Oncol 2015; 10:1659-78. [PMID: 25145434 DOI: 10.2217/fon.14.62] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Novel immune-based therapies are becoming available as additions to, and in some cases as alternatives to, the traditional treatment modalities such as chemotherapy, surgery and radiation that have improved outcomes for childhood cancer for decades. In this article, we will discuss what immunotherapies are being tested in the clinic, barriers to widespread application, and the future of immuno-oncology for childhood cancer. While in many cases, these therapies have shown dramatic responses in the setting of refractory or relapsed cancer, much remains to be learned about how to integrate these therapies into existing upfront regimens. The progress and challenges of developing immunotherapies for childhood cancer in a timely and cost-effective fashion will be discussed.
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Affiliation(s)
- Christian M Capitini
- Department of Pediatrics & Carbone Cancer Center, University of Wisconsin School of Medicine & Public Health, 1111 Highland Avenue, WIMR 4137, Madison, WI 53705, USA
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Patterns of progression in pediatric patients with high-grade glioma or diffuse intrinsic pontine glioma treated with Bevacizumab-based therapy at diagnosis. J Neurooncol 2014; 121:591-8. [DOI: 10.1007/s11060-014-1671-3] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2014] [Accepted: 11/23/2014] [Indexed: 12/11/2022]
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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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D'Asti E, Kool M, Pfister SM, Rak J. Coagulation and angiogenic gene expression profiles are defined by molecular subgroups of medulloblastoma: evidence for growth factor-thrombin cross-talk. J Thromb Haemost 2014; 12:1838-49. [PMID: 25163932 DOI: 10.1111/jth.12715] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2014] [Accepted: 08/22/2014] [Indexed: 12/21/2022]
Abstract
BACKGROUND The coagulation system becomes activated during progression and therapy of high-grade brain tumors. Triggering tissue factor (F3/TF) and thrombin receptors (F2R/PAR-1) may influence the vascular tumor microenvironment and angiogenesis irrespective of clinically apparent thrombosis. These processes are poorly understood in medulloblastoma (MB), in which diverse oncogenic pathways define at least four molecular disease subtypes (WNT, SHH, Group 3 and Group 4). We asked whether there is a link between molecular subtype and the network of vascular regulators expressed in MB. METHODS Using R2 microarray analysis and visualization platform, we mined MB datasets for differential expression of vascular (coagulation and angiogenesis)-related genes, and explored their link to known oncogenic drivers. We evaluated the functional significance of this link in DAOY cells in vitro following growth factor and thrombin stimulation. RESULTS The coagulome and angiome differ across MB subtypes. F3/TF and F2R/PAR-1 mRNA expression are upregulated in SHH tumors and correlate with higher levels of hepatocyte growth factor receptor (MET). Cultured DAOY (MB) cells exhibit an up-regulation of F3/TF and F2R/PAR-1 following combined SHH and MET ligand (HGF) treatment. These factors cooperate with thrombin, impacting the profile of vascular regulators, including interleukin 1β (IL1B) and chondromodulin 1 (LECT1). CONCLUSIONS Coagulation pathway sensors (F3/TF, F2R/PAR-1) are expressed in MB in a subtype-specific manner, and may be functionally linked to SHH and MET circuitry. Thus coagulation system perturbations may elicit subtype/context-specific changes in vascular and cellular responses in MB.
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Affiliation(s)
- E D'Asti
- Cancer and Angiogenesis Laboratory, Montreal Children's Hospital, McGill University, Montreal, QC, Canada
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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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Saletta F, Wadham C, Ziegler DS, Marshall GM, Haber M, McCowage G, Norris MD, Byrne JA. Molecular profiling of childhood cancer: Biomarkers and novel therapies. BBA CLINICAL 2014; 1:59-77. [PMID: 26675306 PMCID: PMC4633945 DOI: 10.1016/j.bbacli.2014.06.003] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/20/2013] [Revised: 06/16/2014] [Accepted: 06/24/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Technological advances including high-throughput sequencing have identified numerous tumor-specific genetic changes in pediatric and adolescent cancers that can be exploited as targets for novel therapies. SCOPE OF REVIEW This review provides a detailed overview of recent advances in the application of target-specific therapies for childhood cancers, either as single agents or in combination with other therapies. The review summarizes preclinical evidence on which clinical trials are based, early phase clinical trial results, and the incorporation of predictive biomarkers into clinical practice, according to cancer type. MAJOR CONCLUSIONS There is growing evidence that molecularly targeted therapies can valuably add to the arsenal available for treating childhood cancers, particularly when used in combination with other therapies. Nonetheless the introduction of molecularly targeted agents into practice remains challenging, due to the use of unselected populations in some clinical trials, inadequate methods to evaluate efficacy, and the need for improved preclinical models to both evaluate dosing and safety of combination therapies. GENERAL SIGNIFICANCE The increasing recognition of the heterogeneity of molecular causes of cancer favors the continued development of molecularly targeted agents, and their transfer to pediatric and adolescent populations.
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Key Words
- ALK, anaplastic lymphoma kinase
- ALL, acute lymphoblastic leukemia
- AML, acute myeloid leukemia
- ARMS, alveolar rhabdomyosarcoma
- AT/RT, atypical teratoid/rhabdoid tumor
- AURKA, aurora kinase A
- AURKB, aurora kinase B
- BET, bromodomain and extra terminal
- Biomarkers
- CAR, chimeric antigen receptor
- CML, chronic myeloid leukemia
- Childhood cancer
- DFMO, difluoromethylornithine
- DIPG, diffuse intrinsic pontine glioma
- EGFR, epidermal growth factor receptor
- ERMS, embryonal rhabdomyosarcoma
- HDAC, histone deacetylases
- Hsp90, heat shock protein 90
- IGF-1R, insulin-like growth factor type 1 receptor
- IGF/IGFR, insulin-like growth factor/receptor
- Molecular diagnostics
- NSCLC, non-small cell lung cancer
- ODC1, ornithine decarboxylase 1
- PARP, poly(ADP-ribose) polymerase
- PDGFRA/B, platelet derived growth factor alpha/beta
- PI3K, phosphatidylinositol 3′-kinase
- PLK1, polo-like kinase 1
- Ph +, Philadelphia chromosome-positive
- RMS, rhabdomyosarcoma
- SHH, sonic hedgehog
- SMO, smoothened
- SYK, spleen tyrosine kinase
- TOP1/TOP2, DNA topoisomerase 1/2
- TRAIL, TNF-related apoptosis-inducing ligand
- Targeted therapy
- VEGF/VEGFR, vascular endothelial growth factor/receptor
- mAb, monoclonal antibody
- mAbs, monoclonal antibodies
- mTOR, mammalian target of rapamycin
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Affiliation(s)
- Federica Saletta
- Children's Cancer Research Unit, Kids Research Institute, Westmead 2145, New South Wales, Australia
| | - Carol Wadham
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick 2031, New South Wales, Australia
| | - David S. Ziegler
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick 2031, New South Wales, Australia
- Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, New South Wales, Australia
| | - Glenn M. Marshall
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick 2031, New South Wales, Australia
- Kids Cancer Centre, Sydney Children's Hospital, Randwick 2031, New South Wales, Australia
| | - Michelle Haber
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick 2031, New South Wales, Australia
| | - Geoffrey McCowage
- The Children's Hospital at Westmead, Westmead 2145, New South Wales, Australia
| | - Murray D. Norris
- Children's Cancer Institute Australia, Lowy Cancer Research Centre, UNSW, Randwick 2031, New South Wales, Australia
| | - Jennifer A. Byrne
- Children's Cancer Research Unit, Kids Research Institute, Westmead 2145, New South Wales, Australia
- The University of Sydney Discipline of Paediatrics and Child Health, The Children's Hospital at Westmead, Westmead 2145, New South Wales, Australia
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Sie M, den Dunnen WF, Hoving EW, de Bont ES. Anti-angiogenic therapy in pediatric brain tumors: An effective strategy? Crit Rev Oncol Hematol 2014; 89:418-32. [DOI: 10.1016/j.critrevonc.2013.09.005] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2013] [Revised: 08/10/2013] [Accepted: 09/27/2013] [Indexed: 12/15/2022] Open
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Olar A, Aldape KD. Using the molecular classification of glioblastoma to inform personalized treatment. J Pathol 2014; 232:165-77. [PMID: 24114756 PMCID: PMC4138801 DOI: 10.1002/path.4282] [Citation(s) in RCA: 206] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2013] [Revised: 08/23/2013] [Accepted: 09/24/2013] [Indexed: 12/19/2022]
Abstract
Glioblastoma is the most common and most aggressive diffuse glioma, associated with short survival and uniformly fatal outcome, irrespective of treatment. It is characterized by morphological, genetic and gene-expression heterogeneity. The current standard of treatment is maximal surgical resection, followed by radiation, with concurrent and adjuvant chemotherapy. Due to the heterogeneity, most tumours develop resistance to treatment and shortly recur. Following recurrence, glioblastoma is quickly fatal in the majority of cases. Recent genetic molecular advances have contributed to a better understanding of glioblastoma pathophysiology and disease stratification. In this paper we review basic glioblastoma pathophysiology, with emphasis on clinically relevant genetic molecular alterations and potential targets for further drug development.
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Affiliation(s)
- Adriana Olar
- Department of Pathology, University of Texas MD Anderson Cancer Centre, Houston, TX, USA
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Cabanas R, Saurez G, Rios M, Alert J, Reyes A, Valdes J, Gonzalez MC, Pedrayes JL, Avila M, Herrera R, Infante M, Echevarria E, Moreno M, Luaces PL, Ramos TC. Treatment of children with high grade glioma with nimotuzumab: a 5-year institutional experience. MAbs 2013; 5:202-7. [PMID: 23575267 DOI: 10.4161/mabs.22970] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Brain tumors are a major cause of cancer-related mortality in children. Overexpression of epidermal growth factor receptor (EGFR) is detected in pediatric brain tumors and receptor density appears to increase with tumor grading. Nimotuzumab is an IgG1 antibody that targets EGFR. Twenty-three children with high-grade glioma (HGG) were enrolled in an expanded access program in which nimotuzumab was administered alone or with radio-chemotherapy. The mean number of doses was 39. Nimotuzumab was well-tolerated and treatment with the antibody yielded a survival benefit: median survival time was 32.66 mo and the 2-y survival rate was 54.2%. This study demonstrated the feasibility of prolonged administration of nimotuzumab and showed preliminary evidence of clinical benefit in HGG patients with poor prognosis.
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Affiliation(s)
- Ricardo Cabanas
- Oncohematology, Juan Manuel Márquez Pediatric Hospital, Havana, Cuba
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Abstract
The prognosis for children with diffuse intrinsic pontine gliomas (DIPGs) is dismal. Although DIPGs constitute only 10-15 % of all pediatric brain tumors, they are the main cause of death in this group with a median survival of less than 12 months. Standard therapy involves radiotherapy, which produces transient neurologic improvement. Despite several clinical trials having been conducted, including trials on targeted agents to assess their efficacy, there is no clear improvement in prognosis. However, knowledge of DIPG biology is increasing, mainly as a result of research using biopsy and autopsy samples. In this review, we discuss recent studies in which systemic therapy was administered prior to, concomitantly with, or after radiotherapy. The discussion also includes novel therapeutic options in DIPG. Continuing multimodal and multitargeted therapies might lead to an improvement in the dismal prognosis of the disease.
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Affiliation(s)
- Rejin Kebudi
- Istanbul University Cerrahpasa Medical Faculty Pediatric Hematology-Oncology, P.C: 34090, Millet Street, Capa, Istanbul, Turkey,
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Okada K, Yamasaki K, Tanaka C, Fujisaki H, Osugi Y, Hara J. Phase I study of bevacizumab plus irinotecan in pediatric patients with recurrent/refractory solid tumors. Jpn J Clin Oncol 2013; 43:1073-9. [PMID: 24002900 DOI: 10.1093/jjco/hyt124] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
OBJECTIVE Studies have suggested that bevacizumab has shown activity against various pediatric solid tumors. We, therefore, conducted a Phase I study of bevacizumab plus irinotecan in Japanese children with recurrent, progressive or refractory solid tumors. METHODS The starting dose was bevacizumab 10 mg/kg over 60-90 min and irinotecan 125 mg/m(2) over 90 min intravenously on Days 1, 15 and 29. The dose of irinotecan was 340 mg/m(2) for patients receiving enzyme-inducing antiepileptic drugs. Treatment was repeated every 6 weeks for up to three courses in the absence of disease progression or unacceptable toxicity. RESULTS Of 11 patients, 9 (median age, 9 years) were fully assessable for toxicity and received 24 courses. Dose-limiting toxicities were Grade 2 diarrhea and Grade 4 neutropenia/thrombocytopenia in two of the five patients at dose level 1. No dose-limiting toxicities were observed in four patients at dose level -1 at bevacizumab 10 mg/kg and irinotecan 100 mg/m(2) (270 mg/m(2) for patients taking enzyme-inducing antiepileptic drugs). The maximum-tolerated dose was bevacizumab 10 mg/kg and irinotecan 100 mg/m(2). The most frequent non-dose-limiting toxicities were Grade 1 or 2 hypertension, bleeding and hematologic toxicity. One patient with optic nerve glioma had a partial response. Three patients with medulloblastoma, optic nerve glioma and diffuse intrinsic pontine glioma had stable disease. CONCLUSIONS Combination chemotherapy of bevacizumab plus irinotecan was well tolerated in children. We plan Phase II pediatric studies at doses of bevacizumab 10 mg/kg and irinotecan 100 mg/m(2) every 2 weeks (270 mg/m(2) for patients taking enzyme-inducing antiepileptic drugs).
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Affiliation(s)
- Keiko Okada
- *2-13-22 Miyakojima-Hondori, Miyakojima-ku, Osaka 534-0021, Japan.
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Venkatramani R, Malogolowkin M, Davidson TB, May W, Sposto R, Mascarenhas L. A phase I study of vincristine, irinotecan, temozolomide and bevacizumab (vitb) in pediatric patients with relapsed solid tumors. PLoS One 2013; 8:e68416. [PMID: 23894304 PMCID: PMC3718768 DOI: 10.1371/journal.pone.0068416] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2013] [Accepted: 05/28/2013] [Indexed: 12/03/2022] Open
Abstract
Background To determine the maximum tolerated dose (MTD) and dose limiting toxicity (DLT) of irinotecan administered in combination with vincristine, temozolomide and bevacizumab in children with refractory solid tumors. Methods The study design included two dose levels (DL) of irinotecan given intravenously once daily for 5 consecutive days (DL1: 30 mg/m2, and DL2: 50 mg/m2), combined with vincristine 1.5 mg/m2 on days 1 and 8, temozolomide 100 mg/m2 on days 1-5, and bevacizumab 15mg/kg on day 1, administered every 21 days for a maximum of 12 cycles. Results Thirteen patients were enrolled and 12 were evaluable for toxicity Dose limiting toxicity observed included grade 3 hyperbilirubinemia in 1 of 6 patients on DL1, and grade 3 colitis in 1 of 6 patients on DL2. DL 2 was the determined MTD. A total of 87 cycles were administered. Myelosuppression was mild. Grade 1-2 diarrhea occurred in the majority of cycles with grade 3 diarrhea occurring in only one cycle. Grade 2 hypertension developed in two patients. Severe hemorrhage, intestinal perforation, posterior leukoencephalopathy or growth plate abnormalities were not observed. Objective responses were noted in three Wilms tumor patients and one each of medulloblastoma and hepatocellular carcinoma. Five patients completed all 12 cycles of protocol therapy. Conclusions Irinotecan 50 mg/m2/day for 5 days was the MTD when combined with vincristine, temozolomide and bevacizumab administered on a 21 day schedule. Encouraging anti-tumor activity was noted. Trial Registration ClinicalTrials.gov; NCT00993044; http://clinicaltrials.gov/show/NCT00993044
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Affiliation(s)
- Rajkumar Venkatramani
- Division of Hematology/Oncology, Children's Hospital Los Angeles, Los Angeles, California, USA.
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Abstract
Angiogenesis, recruitment of new blood vessels, is an essential component of the metastatic pathway. These vessels provide the principal route by which tumor cells exit the primary tumor site and enter the circulation. For many tumors, the vascular density can provide a prognostic indicator of metastatic potential, with the highly vascular primary tumors having a higher incidence of metastasis than poorly vascular tumors. The discovery and characterization of tumor-derived angiogenesis modulators greatly contributed to our understanding of how tumors regulate angiogenesis. However, although angiogenesis appears to be a rate-limiting event in tumor growth and metastatic dissemination, a direct connection between the induction of angiogenesis and the progression to tumor malignancy is less well understood. In this review, we discuss the observations concerning the modulation of angiogenesis and their implications in various neurological disorders, as well as their potential impact on cancer therapy.
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Affiliation(s)
- Göksemin Acar
- Department of Neurology, Faculty of Medicine, Pamukkale University, Denizli, Turkey.
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Taylor J, Gerstner ER. Anti-angiogenic therapy in high-grade glioma (treatment and toxicity). Curr Treat Options Neurol 2013; 15:328-37. [PMID: 23417315 DOI: 10.1007/s11940-013-0224-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OPINION STATEMENT Malignant gliomas continue to have a very poor prognosis and treatment responses at recurrence are very limited. Though anti-angiogenic therapy has not yet been shown to extend overall survival in this patient population, there is likely substantial benefit to reducing vasogenic edema, allowing for temporary improvement in neurologic function, and minimizing the side effects of prolonged corticosteroid use. A trial of bevacizumab should be considered in those with worsening vasogenic cerebral edema such as seen in recurrent malignant gliomas, radiation necrosis, or progressive brain metastases. However, not all patients respond to anti-angiogenic treatment and if no radiographic or clinical responses are seen, then patients are not likely to benefit from further infusions. Though it is commonly well tolerated, some side effects, while rare, may be life threatening, and should be discussed with patients and their families. These discussions should also outline the goals of initiating therapy and when treatment should be stopped.
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Affiliation(s)
- Jennie Taylor
- Stephen E. and Catherine Pappas Center for Neuro-Oncology, Massachusetts General Hospital Cancer Center, Yawkey 9E, 55 Fruit Street, Boston, MA, 02114, USA
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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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Barone A, Rubin JB. Opportunities and challenges for successful use of bevacizumab in pediatrics. Front Oncol 2013; 3:92. [PMID: 23641361 PMCID: PMC3638307 DOI: 10.3389/fonc.2013.00092] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2012] [Accepted: 04/05/2013] [Indexed: 11/13/2022] Open
Abstract
Bevacizumab (Avastin) has rapidly gained status as a broadly active agent for malignancies of several different histologies in adults. This activity has spawned a range of uses in pediatrics for both oncologic and non-oncologic indications. Early analyses indicate that pediatric cancers exhibit a spectrum of responses to bevacizumab that suggest its activity may be more limited than in adult oncology. Most exciting, is that for low-grade tumors that threaten vision and hearing, there is not only evidence for objective tumor response but for recovery of lost function as well. In addition to oncological indications, there is a range of uses for non-oncologic disease for which bevacizumab has clear activity. Finally, a number of mechanisms have been identified as contributing to bevacizumab resistance in cancer. Elucidating these mechanisms will guide the development of future clinical trials of bevacizumab in pediatric oncology.
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Affiliation(s)
- Amy Barone
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, St. Louis Children's Hospital, Washington University School of Medicine St. Louis, MO, USA
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