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Wochnik A, Kajdrowicz T, Foltyńska G, Krzempek D, Krzempek K, Małecki K, Rydygier M, Swakoń J, Olko P, Kopeć R. Application of 3D-printed compensators for proton pencil beam scanning of shallowly localized pediatric tumors. Radiat Oncol 2025; 20:66. [PMID: 40301908 PMCID: PMC12042327 DOI: 10.1186/s13014-025-02646-3] [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: 01/14/2024] [Accepted: 04/23/2025] [Indexed: 05/01/2025] Open
Abstract
BACKGROUND In modern proton radiotherapy facilities with pencil beam scanning technology, the lowest energy of a proton beam typically ranges between 60 and 100 MeV, corresponding to a proton range in water of 3.1-7.5 cm. The irradiation of superficial lesions usually requires the application of a range shifter (RS) to further reduce the proton range. A certain distance from the patient to the RS increases the spot size, causing worse plan conformity. As an alternative solution, a patient-specific 3D-printed proton beam compensator (BC) can be applied to reduce the air gap and beam scattering. MATERIALS AND METHODS This study is based on treatment planning system simulations using retrospectively selected data from six pediatric patients with diagnosed sarcomas located in the head and neck area. For three of these patients, 3D-printed compensators were utilized during the treatment phase, prior to the retrospective analysis. Treatment plans for children with shallow lesions treated using RSs and BCs were compared. Planning target volume constraints (D98% >95%, D2%< 107%) and organs-at-risk (brainstem, spinal cord, visual organs, chiasm, cochlea) constraints (D2%, Dmax and DMean) were applied. The entire process of using a BCs in the treatment of pediatric superficial tumors is presented, including 3D printing procedure (via fused filament fabrication method), dosimetric verification of the material (Water Equivalent Ratio measurements) and assessment of its homogeneity, print quality and Hounsfield Unit specification. Beam parameters analysis including spot sizes and penumbras, were performed. Treatment plans were compared in terms of plan conformity and sparing of critical organs. RESULTS The application of BCs reduced the low-dose irradiation areas, improved conformity and reduced critical organs exposure. BCs decreased the lateral spot size by approximately 57% and the penumbras by 41-47% at different depths in the cube target. The variation in BC homogeneity was less than 3.5%, meeting the criteria for plan robustness evaluation. CONCLUSIONS Compared with RS placement at the nozzle, the placement of 3D-printed BCs in the near vicinity of the patient for the treatment of superficial tumors led to a more conformal dose distribution.
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Affiliation(s)
- Agnieszka Wochnik
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland.
| | - Tomasz Kajdrowicz
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
| | - Gabriela Foltyńska
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
| | - Dawid Krzempek
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
| | - Katarzyna Krzempek
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
| | | | - Marzena Rydygier
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
| | - Jan Swakoń
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
| | - Paweł Olko
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
| | - Renata Kopeć
- Institute of Nuclear Physics, Polish Academy of Sciences, Krakow, Poland
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Pan Z, Bao J, Wei S. Advancing medulloblastoma therapy: strategies and survival insights. Clin Exp Med 2025; 25:119. [PMID: 40237916 PMCID: PMC12003599 DOI: 10.1007/s10238-025-01648-5] [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: 02/09/2025] [Accepted: 03/22/2025] [Indexed: 04/18/2025]
Abstract
Medulloblastoma, the most common malignant brain tumor in children, presents unique challenges due to its molecular and histological heterogeneity. Advances in molecular profiling have refined risk stratification, enabling personalized treatment strategies and improved survival outcomes. This review synthesizes recent developments in the multimodal management of medulloblastoma, encompassing surgery, craniospinal radiation therapy, and chemotherapy, tailored to patient age and risk classification. Key highlights include subgroup-specific therapies, the role of molecular-targeted treatments, and the integration of genetic testing for germline mutations to guide clinical decision-making. Special emphasis is placed on minimizing treatment-related toxicity while preserving long-term quality of life. Additionally, this manuscript discusses the implications of novel therapeutic approaches for high-risk subgroups, including intensified regimens and systemic therapies for young children. Despite significant progress, challenges remain in addressing long-term complications such as neurocognitive impairments, endocrine dysfunction, and secondary malignancies. Future directions prioritize optimizing therapeutic efficacy while reducing morbidity, underscoring the importance of translating molecular discoveries into clinical practice.
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Affiliation(s)
- Zhenjiang Pan
- Department of Neurosurgery, Shidong Hospital, No. 999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Jing Bao
- Department of Neurosurgery, Shidong Hospital, No. 999, Shiguang Road, Yangpu District, Shanghai, 200438, China
| | - Shepeng Wei
- Department of Neurosurgery, Shidong Hospital, No. 999, Shiguang Road, Yangpu District, Shanghai, 200438, China.
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Thakkar JP, Luy DD, Pickles A, Refaat T, Prabhu VC. Chronic Neurological Complications of Brain Tumors and Brain Tumor Treatments. Curr Neurol Neurosci Rep 2025; 25:26. [PMID: 40116979 DOI: 10.1007/s11910-025-01411-z] [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] [Accepted: 02/28/2025] [Indexed: 03/23/2025]
Abstract
PURPOSE OF REVIEW Chronic complications of brain tumors and brain tumor treatments can lead to impairment of health-related quality of life and decreased functionality. These largely include cognitive decline, fatigue, headache, seizures, and secondary malignancies. Outpatient neurologists are an integral part of the multidisciplinary neuro-oncology team who help diagnose and manage chronic complications in this complex patient population. Timely diagnosis and treatment of these complications in outpatient neurology and neuro-oncology clinics helps improve quality of life and survival of brain tumor patients. RECENT FINDINGS We discuss updated information and management regarding various chronic neurologic complications among neuro-oncology patients. Understanding of chronic neurologic complications associated with central nervous system tumors and with common contemporary cancer treatments will facilitate neurologists management of these patient populations. While there are aspects analogous to the diagnosis and management in the non-oncologic population, a number of unique features discussed in this review should be considered.
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Affiliation(s)
- Jigisha P Thakkar
- Departments of Neurology and Neurological Surgery, Division of Neuro-Oncology, Loyola University Chicago Stritch School of Medicine, 2160 S. 1st Avenue Bldg 105, Room 2716, Maywood, IL, 60153, USA.
- Department of Neurosurgery, Loyola University Medical Center, Maywood, IL, USA.
| | - Diego D Luy
- Department of Neurosurgery, Loyola University Medical Center, Maywood, IL, USA
| | - Andrew Pickles
- Department of Neurosurgery, Loyola University Medical Center, Maywood, IL, USA
| | - Tamer Refaat
- Department of Radiation Oncology, Loyola University Medical Center, Maywood, IL, USA
| | - Vikram C Prabhu
- Department of Neurosurgery, Loyola University Medical Center, Maywood, IL, USA
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Otth M, Weiser A, Lee SY, Rudolf von Rohr L, Heesen P, Guerreiro Stucklin AS, Scheinemann K. Treatment of Medulloblastoma in the Adolescent and Young Adult Population: A Systematic Review. J Adolesc Young Adult Oncol 2025; 14:18-32. [PMID: 39178158 DOI: 10.1089/jayao.2024.0044] [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] [Indexed: 08/25/2024] Open
Abstract
Medulloblastoma is the most frequent high-grade tumor of the central nervous system in children but accounts for less than 1% of these tumors in adults. Adolescent and young adult (AYA) patients are between both age groups, and different approaches are used to treat medulloblastoma in this population. We performed a systematic review of studies published between 2007 and 2023 that reported treatment approaches and survival data of AYA patients with medulloblastoma, defined as 15 to 39 years of age at diagnosis. Due to the heterogeneity of data, a meta-analysis was not possible. Except for the omission of chemotherapy after radiotherapy in a few adult studies, the treatment backbone is very similar between studies starting enrolment during childhood and older adolescence or adulthood. Despite indications for a higher rate of early treatment termination due to toxicity in adults, survival data remain comparable between studies starting enrolment earlier or later in life. However, molecular subtyping was missing in most studies, so the survival data must be interpreted cautiously. Nevertheless, pediatric-inspired strategies in the AYA population are feasible, but individual dose adjustments may be necessary during treatment and should be considered upfront. Collaborative studies investigating the best treatment approach for medulloblastoma in the AYA population are needed in the future.
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Affiliation(s)
- Maria Otth
- Division of Hematology/Oncology, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland
- Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland
- Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
| | - Annette Weiser
- Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland
- Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Seok-Yun Lee
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Lukas Rudolf von Rohr
- Division of Hematology/Oncology, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland
- Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
| | - Philip Heesen
- Faculty of Medicine, University of Zurich, Zurich, Switzerland
| | - Ana S Guerreiro Stucklin
- Department of Oncology, University Children's Hospital Zurich, Zurich, Switzerland
- Children's Research Center, University Children's Hospital Zurich, Zurich, Switzerland
| | - Katrin Scheinemann
- Division of Hematology/Oncology, Children's Hospital of Eastern Switzerland, St. Gallen, Switzerland
- Faculty of Health Sciences and Medicine, University of Lucerne, Lucerne, Switzerland
- Division of Pediatric Hematology/Oncology, McMaster Children's Hospital and McMaster University, Hamilton, Canada
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Massimino M, Barretta F, Dossena C, Minasi S, Buttarelli FR, Biassoni V, Oriani M, Schiavello E, Ficorilli M, Nigro O, Pollo B, Antonelli M, Donofrio V, Maggioni M, Kool M, Pecori E, Vennarini S, Giangaspero F, Gianno F, Erbetta A, Chiapparini L, Luksch R, Barzanò E, Meazza C, Podda M, Spreafico F, Terenziani M, Bergamaschi L, Ferrari A, Casanova M, Chiaravalli S, Gattuso G, Modena P, Bailey S, De Cecco L. Long-term outcome of the Milano-hyperfractionated accelerated radiotherapy strategy for high-risk medulloblastoma, including the impact of molecular subtype. Neuro Oncol 2025; 27:209-218. [PMID: 39331528 PMCID: PMC11726337 DOI: 10.1093/neuonc/noae189] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2024] [Indexed: 09/29/2024] Open
Abstract
BACKGROUND We applied the strategy for M+ medulloblastoma across all high-risk subgroups, including LC/A histology, TP53 mutations, and MYC/MYCN amplification. METHODS Patients over 3 years old received, after surgery, staging and histo-biological analysis, sequential high-dose-methotrexate(HD-MTX), high-dose-etoposide(HD-VP16), high-dose-cyclophosphamide(HD-Cyclo), and high-dose-carboplatin(HD-Carbo). Hyperfractionated-accelerated-radiotherapy-craniospinal(HART-CSI), administered twice daily 1.3 Gy-fractions reached a total dose tailored to the patients' age and pre-radiation response to chemotherapy(CT): 31.2 Gy if under 10-years-old and complete response(CR) or partial response(PR) obtained or absence of metastatic disease, 39 Gy in other/older patients. Boosts to posterior fossa/residual metastatic(M+) deposits were given up to a total dose of 60 Gy/9 Gy, respectively, but avoided if metastatic nodules were very big or patients were very young. Two courses of high-dose-thiotepa were delivered in case of not CR/PR after the pre-radiotherapy (RT) phase and in all M0 patients either-pre/post-HART. Subgrouping was performed where the tissue was available. RESULTS Eighty-nine patients were enrolled, with a median age of 8.8 years, and a median follow-up of 136 months. Overall survival (OS) and event-free survival (EFS) at 5/15 years were 75.9/66.5% and 68.2/65.3%, respectively; 5/28 fatal events were not related to relapse(3 developed secondary malignancies). Sex, age less than 10 years, histological subtype, presence of MYC/MYCN amplification, reduction in CSI dose, omission of RT-boosts, implementation of myeloablative therapy, presence-absence of metastases did not impact prognosis.Patients progressing after pre-HART CT(14/89) and stable-disease(SD)+PD after HART(10/89) negatively affected outcome(P < .001).Subgrouping in 66/89 patients' samples demonstrated a significantly worse EFS for patients with Sonic Hedgehog(SHH)-tumors(#15, 2 with constitutional TP53-mutations) versus groups 3 and 4(15 and 29 patients, respectively, group3/4 in 7).Patients younger than 10 received lower CSI doses if stratified according to CT response. CONCLUSIONS This strategy, partly adopted in the ongoing SIOPE protocol, confirmed improved EFS and OS over previously reported outcomes in all high-risk categories; SHH tumors appeared the most aggressive.
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Affiliation(s)
- Maura Massimino
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Francesco Barretta
- Department of Clinical Epidemiology and Trial Organization, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Chiara Dossena
- Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Simone Minasi
- Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | | | - Veronica Biassoni
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Matilde Oriani
- Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | | | - Marica Ficorilli
- Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Olga Nigro
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Bianca Pollo
- Neuropathology Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Manila Antonelli
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, La Sapienza University, Rome, Italy
| | | | - Marco Maggioni
- Pathology Department, IRCCS Fondazione Policlinico, Milano, Italy
| | - Marcel Kool
- Hopp Children’s Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Princess Maxima Center, Amsterdam, Netherlands
| | - Emilia Pecori
- Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Sabina Vennarini
- Pediatric Radiotherapy Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Felice Giangaspero
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, La Sapienza University, Rome, Italy
| | - Francesca Gianno
- Department of Radiological, Oncological and Anatomo-Pathological Sciences, La Sapienza University, Rome, Italy
| | - Alessandra Erbetta
- Neuroradiology Department, Fondazione IRCCS Istituto Neurologico Carlo Besta, Milano, Italy
| | - Luisa Chiapparini
- Neuroradiology Department, Fondazione IRCCS Policlinico S. Matteo, Pavia, Italy
| | - Roberto Luksch
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Elena Barzanò
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Cristina Meazza
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Marta Podda
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Filippo Spreafico
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Monica Terenziani
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Luca Bergamaschi
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Andrea Ferrari
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Michela Casanova
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Stefano Chiaravalli
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | - Giovanna Gattuso
- Pediatric Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
| | | | - Simon Bailey
- Pediatric Oncology Department, Sir James Spence Institute of Child Health Royal Victoria Infirmary Queen Victoria Road Newcastle upon Tyne, UK
| | - Loris De Cecco
- Integrated Biology Platform, Department of Applied Research and Technology Development, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy
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Ronsley R, Cole B, Ketterl T, Wright J, Ermoian R, Hoffman LM, Margol AS, Leary SES. Pediatric Central Nervous System Embryonal Tumors: Presentation, Diagnosis, Therapeutic Strategies, and Survivorship-A Review. Pediatr Neurol 2024; 161:237-246. [PMID: 39447443 DOI: 10.1016/j.pediatrneurol.2024.09.031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/10/2024] [Revised: 05/28/2024] [Accepted: 09/29/2024] [Indexed: 10/26/2024]
Abstract
Central nervous system (CNS) embryonal tumors represent a diverse group of neoplasms and have a peak incidence in early childhood. These tumors can be located anywhere within the CNS, and presenting symptoms typically represent tumor location. These tumors display distinctive findings on neuroimaging and are staged using magnetic resonance imaging of the brain and spine as well as evaluation of cerebrospinal fluid. Diagnosis is made based on an integrated analysis of histologic and molecular features via tissue sampling. Risk stratification is based on integration of clinical staging and extent of resection with histologic and molecular risk factors. The therapeutic approach for these tumors is multimodal and includes surgery, chemotherapy, and radiation, tailored to the individual patient factors (including age) and specific tumor type. Comprehensive supportive care including management of nausea, nutrition support, pain, fertility preservation, and mitigation of therapy-related morbidity (including hearing protection) is imperative through treatment of CNS embryonal tumors. Despite advances in therapy and supportive care, the long-term consequences of current treatment strategies are substantial. Integration of less toxic, molecularly targeted therapies and a comprehensive, multidisciplinary approach to survivorship care are essential to improving survival and the overall quality of life for survivors.
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Affiliation(s)
- Rebecca Ronsley
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington; Division of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington; Fred Hutch Cancer Center, Seattle, Washington.
| | - Bonnie Cole
- Department of Laboratory Medicine and Pathology, University of Washington School of Medicine, Seattle, Washington; Department of Laboratories, Seattle Children's Hospital, Seattle, Washington
| | - Tyler Ketterl
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington; Division of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington; Fred Hutch Cancer Center, Seattle, Washington
| | - Jason Wright
- Department of Radiology, University of Washington School of Medicine and Seattle Children's Hospital, Seattle, Washington
| | - Ralph Ermoian
- Department of Radiation Oncology, University of Washington, Seattle, Washington
| | - Lindsey M Hoffman
- Center for Cancer and Blood Disorder, Phoenix Childrens Hospital, Arizona
| | - Ashley S Margol
- Keck School of Medicine of University of Southern California, Cancer and Blood Disease Institute at Children's Hospital Los Angeles, Los Angeles, California
| | - Sarah E S Leary
- Ben Towne Center for Childhood Cancer Research, Seattle Children's Research Institute, Seattle, Washington; Division of Hematology, Oncology and Bone Marrow Transplant, Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington; Fred Hutch Cancer Center, Seattle, Washington
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Piffer S, Greto D, Ubaldi L, Mortilla M, Ciccarone A, Desideri I, Genitori L, Livi L, Marrazzo L, Pallotta S, Retico A, Sardi I, Talamonti C. Radiomic- and dosiomic-based clustering development for radio-induced neurotoxicity in pediatric medulloblastoma. Childs Nerv Syst 2024; 40:2301-2310. [PMID: 38642113 PMCID: PMC11269375 DOI: 10.1007/s00381-024-06416-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/10/2024] [Accepted: 04/15/2024] [Indexed: 04/22/2024]
Abstract
BACKGROUND Texture analysis extracts many quantitative image features, offering a valuable, cost-effective, and non-invasive approach for individual medicine. Furthermore, multimodal machine learning could have a large impact for precision medicine, as texture biomarkers can underlie tissue microstructure. This study aims to investigate imaging-based biomarkers of radio-induced neurotoxicity in pediatric patients with metastatic medulloblastoma, using radiomic and dosiomic analysis. METHODS This single-center study retrospectively enrolled children diagnosed with metastatic medulloblastoma (MB) and treated with hyperfractionated craniospinal irradiation (CSI). Histological confirmation of medulloblastoma and baseline follow-up magnetic resonance imaging (MRI) were mandatory. Treatment involved helical tomotherapy (HT) delivering a dose of 39 Gray (Gy) to brain and spinal axis and a posterior fossa boost up to 60 Gy. Clinical outcomes, such as local and distant brain control and neurotoxicity, were recorded. Radiomic and dosiomic features were extracted from tumor regions on T1, T2, FLAIR (fluid-attenuated inversion recovery) MRI-maps, and radiotherapy dose distribution. Different machine learning feature selection and reduction approaches were performed for supervised and unsupervised clustering. RESULTS Forty-eight metastatic medulloblastoma patients (29 males and 19 females) with a mean age of 12 ± 6 years were enrolled. For each patient, 332 features were extracted. Greater level of abstraction of input data by combining selection of most performing features and dimensionality reduction returns the best performance. The resulting one-component radiomic signature yielded an accuracy of 0.73 with sensitivity, specificity, and precision of 0.83, 0.64, and 0.68, respectively. CONCLUSIONS Machine learning radiomic-dosiomic approach effectively stratified pediatric medulloblastoma patients who experienced radio-induced neurotoxicity. Strategy needs further validation in external dataset for its potential clinical use in ab initio management paradigms of medulloblastoma.
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Affiliation(s)
- Stefano Piffer
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy.
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy.
| | - Daniela Greto
- Radiation Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Leonardo Ubaldi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy
| | - Marzia Mortilla
- Radiology Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Antonio Ciccarone
- Medical Physics Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Isacco Desideri
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
| | - Lorenzo Genitori
- Neuro-Oncology Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Lorenzo Livi
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- Radiation Oncology Unit, Careggi University Hospital, Florence, Italy
| | - Livia Marrazzo
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy
| | - Stefania Pallotta
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy
| | | | - Iacopo Sardi
- Neuro-Oncology Unit, Meyer Children's Hospital IRCCS, Florence, Italy
| | - Cinzia Talamonti
- Department of Experimental and Clinical Biomedical Sciences "Mario Serio", University of Florence, Florence, Italy
- National Institute for Nuclear Physics (INFN), Florence Division, Florence, Italy
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Peterson K, Turos-Cabal M, Salvador AD, Palomo-Caturla I, Howell AJ, Vieira ME, Greiner SM, Barnoud T, Rodriguez-Blanco J. Mechanistic insights into medulloblastoma relapse. Pharmacol Ther 2024; 260:108673. [PMID: 38857789 PMCID: PMC11270902 DOI: 10.1016/j.pharmthera.2024.108673] [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: 01/08/2024] [Revised: 06/01/2024] [Accepted: 06/04/2024] [Indexed: 06/12/2024]
Abstract
Pediatric brain tumors are the leading cause of cancer-related deaths in children, with medulloblastoma (MB) being the most common type. A better understanding of these malignancies has led to their classification into four major molecular subgroups. This classification not only facilitates the stratification of clinical trials, but also the development of more effective therapies. Despite recent progress, approximately 30% of children diagnosed with MB experience tumor relapse. Recurrent disease in MB is often metastatic and responds poorly to current therapies. As a result, only a small subset of patients with recurrent MB survive beyond one year. Due to its dismal prognosis, novel therapeutic strategies aimed at preventing or managing recurrent disease are urgently needed. In this review, we summarize recent advances in our understanding of the molecular mechanisms behind treatment failure in MB, as well as those characterizing recurrent cases. We also propose avenues for how these findings can be used to better inform personalized medicine approaches for the treatment of newly diagnosed and recurrent MB. Lastly, we discuss the treatments currently being evaluated for MB patients, with special emphasis on those targeting MB by subgroup at diagnosis and relapse.
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Affiliation(s)
- Kendell Peterson
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Maria Turos-Cabal
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - April D Salvador
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | | | - Ashley J Howell
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Megan E Vieira
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA
| | - Sean M Greiner
- Department of Pediatrics, Johns Hopkins Children's Center, Baltimore, MD, USA
| | - Thibaut Barnoud
- Department of Biochemistry and Molecular Biology, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA
| | - Jezabel Rodriguez-Blanco
- Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC, USA; Hollings Cancer Center, Medical University of South Carolina, Charleston, SC, USA.
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Nejadi Orang F, Abdoli Shadbad M. CircRNA and lncRNA-associated competing endogenous RNA networks in medulloblastoma: a scoping review. Cancer Cell Int 2024; 24:248. [PMID: 39010056 PMCID: PMC11251335 DOI: 10.1186/s12935-024-03427-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2024] [Accepted: 07/02/2024] [Indexed: 07/17/2024] Open
Abstract
BACKGROUND Medulloblastoma is one of the common primary central nervous system (CNS) malignancies in pediatric patients. The main treatment is surgical resection preceded and/or followed by chemoradiotherapy. However, their serious side effects necessitate a better understanding of medulloblastoma biology to develop novel therapeutic options. MAIN BODY Circular RNA (circRNA) and long non-coding RNA (lncRNA) regulate gene expression via microRNA (miRNA) pathways. Although growing evidence has highlighted the significance of circRNA and lncRNA-associated competing endogenous RNA (ceRNA) networks in cancers, no study has comprehensively investigated them in medulloblastoma. For this aim, the Web of Science, PubMed, Scopus, and Embase were systematically searched to obtain the relevant papers published before 16 September 2023, adhering to the PRISMA-ScR statement. HOTAIR, NEAT1, linc-NeD125, HHIP-AS1, CRNDE, and TP73-AS1 are the oncogenic lncRNAs, and Nkx2-2as is a tumor-suppressive lncRNA that develop lncRNA-associated ceRNA networks in medulloblastoma. CircSKA3 and circRNA_103128 are upregulated oncogenic circRNAs that develop circRNA-associated ceRNA networks in medulloblastoma. CONCLUSION In summary, this study has provided an overview of the existing evidence on circRNA and lncRNA-associated ceRNA networks and their impact on miRNA and mRNA expression involved in various signaling pathways of medulloblastoma. Suppressing the oncogenic ceRNA networks and augmenting tumor-suppressive ceRNA networks can provide ample opportunities for medulloblastoma treatment.
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Affiliation(s)
| | - Mahdi Abdoli Shadbad
- Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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10
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Levy BB, Biasio MJD, Toledo NA, Das S, Bartling M, Aldahari F, de Almeida JR, Weinreb I, Chan Y. Sinonasal Malignancy Following Cranial Irradiation: A Scoping Review and Case Report of Sinonasal Teratocarcinosarcoma. J Neurol Surg Rep 2024; 85:e101-e111. [PMID: 38974921 PMCID: PMC11226344 DOI: 10.1055/s-0044-1788310] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2024] [Accepted: 06/17/2024] [Indexed: 07/09/2024] Open
Abstract
Background Radiation therapy is a mainstay of treatment for brain tumors, but delayed complications include secondary malignancy which may occur months to years after treatment completion. Methods We reviewed the medical records of a 41-year-old female treated with 60 Gy of radiation for a recurrent astrocytoma, who 6 years later developed a locally advanced sinonasal teratocarcinosarcoma. We searched MEDLINE, Embase, and Web of Science to conduct a scoping review of biopsy-proven sinonasal malignancy in patients who previously received cranial irradiation for a brain tumor. Results To our knowledge, this is the first report of a patient to present with a sinonasal teratocarcinosarcoma after receiving irradiation for a brain tumor. Our scoping review of 1,907 studies produced 14 similar cases of secondary sinonasal malignancy. Median age of primary cancer diagnosis was 39.5 years old (standard deviation [SD]: 21.9), and median radiation dose was 54 Gy (SD: 20.3). Median latency time between the primary cancer and secondary sinonasal cancer was 9.5 years (SD: 5.8). Olfactory neuroblastoma was the most common sinonasal cancer ( n = 4). Fifty percent of patients died from their sinonasal cancer within 1.5 years. Conclusion Patients who receive radiation exposure to the sinonasal region for treatment of a primary brain tumor, including low doses or scatter radiation, may be at risk of a secondary sinonasal malignancy later in life. Physicians who monitor at-risk patients must be vigilant of symptoms which may suggest sinonasal malignancy, and surveillance should include radiographic review with careful monitoring for a secondary malignancy throughout the entire irradiated field.
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Affiliation(s)
- Ben B. Levy
- Department of Otolaryngology–Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada
| | | | - Nilo Alvarez Toledo
- Division of Neurosurgery, Department of Surgery, St. Michael's Hospital, Unity Health, Toronto, Ontario, Canada
| | - Sunit Das
- Division of Neurosurgery, Department of Surgery, St. Michael's Hospital, Unity Health, Toronto, Ontario, Canada
| | - Mandolin Bartling
- Department of Otolaryngology–Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada
| | - Fahad Aldahari
- Department of Otolaryngology–Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada
| | - John R. de Almeida
- Department of Otolaryngology–Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada
- Department of Otolaryngology–Head and Neck Surgery, University Health Network, Toronto, Ontario, Canada
| | - Ilan Weinreb
- Department of Pathology, University Health Network, Toronto, Ontario, Canada
- Department of Pathobiology and Laboratory Medicine, University of Toronto, Toronto, Ontario, Canada
| | - Yvonne Chan
- Department of Otolaryngology–Head and Neck Surgery, University of Toronto, Toronto, Ontario, Canada
- Department of Otolaryngology–Head and Neck Surgery, St. Michael's Hospital, Unity Health, Toronto, Ontario, Canada
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11
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Baghani HR, Porouhan P. Secondary cancer risk assessment in healthy organs following craniospinal irradiation. Int J Radiat Biol 2024; 100:1174-1182. [PMID: 38889539 DOI: 10.1080/09553002.2024.2369110] [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: 11/28/2023] [Revised: 05/13/2024] [Accepted: 05/29/2024] [Indexed: 06/20/2024]
Abstract
INTRODUCTION Medulloblastoma is a central nerves tumor that often occurs in pediatrics. The main radiotherapy technique for this tumor type is craniospinal irradiation (CSI), through which the whole brain and spinal cord are exposed to radiation. Due to the immaturity of healthy organs in pediatrics, radiogenic side effects such as second cancer are more severe. Accordingly, the current study aimed to evaluate the risk of secondary cancer development in healthy organs following CSI. MATERIALS AND METHODS Seven organs at risk (OARs) including skin, eye lens, thyroid, lung, liver, stomach, bladder, colon, and gonads were considered and the dose received by each OAR during CSI was measured inside an anthropomorphic RANDO phantom by TLDs. Then, the mean obtained dose for each organ was used to estimate the probability of secondary malignancy development according to the recommended cancer risk coefficients for specific organs. RESULTS The results demonstrated that the stomach and colon are at high risk of secondary malignancy occurrence, while the skin has the lowest probability of secondary cancer development. The total received dose after the treatment course by all considered organs was lower than the corresponding tolerable dose levels. CONCLUSIONS From the results, it can be concluded that some OARs during CSI are highly at risk of secondary cancer development. This issue may be of concern due to organ immaturity in pediatrics which can intensify the radiogenic effects of radiation exposure. Accordingly, strict shielding the OARs during craniospinal radiotherapy and/or sparing them from the radiation field through modern techniques such as hadron therapy is highly recommended.
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Affiliation(s)
| | - Pejman Porouhan
- Radiation Oncology Department, Vasei Hospital, Sabzevar University of Medical Sciences, Sabzevar, Iran
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12
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Salceda-Rivera V, Tejocote-Romero I, Osorio DS, Bellido-Magaña R, López-Facundo A, Anaya-Aguirre SE, Ortiz-Morales D, Rivera-Luna R, Reyes-Gutiérrez E, Rivera-Gómez R, Velasco-Hidalgo L, Cortés-Alva D, Lagarda-Arrechea S, Arreguín-González FE, Benito-Reséndiz AE, Chávez-Gallegos S, Pérez-Rivera E, Gaytán-Fernández GJ, León-Espitia JA, Domínguez-Sánchez J, Leal-Cavazos C, Simón-González C, Larios-Farak TC, Macías-García NA, García-Espinosa AC, Guerrero-Maymes F, Casillas-Toral P, González-Ramella O. Impact of treatment and clinical characteristics on the survival of children with medulloblastoma in Mexico. Front Oncol 2024; 14:1376574. [PMID: 38756654 PMCID: PMC11096484 DOI: 10.3389/fonc.2024.1376574] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2024] [Accepted: 03/26/2024] [Indexed: 05/18/2024] Open
Abstract
Introduction Data on medulloblastoma outcomes and experiences in low- and middle-income countries, especially in Latin America, is limited. This study examines challenges in Mexico's healthcare system, focusing on assessing outcomes for children with medulloblastoma in a tertiary care setting. Methods A retrospective analysis was conducted, involving 284 patients treated at 21 pediatric oncology centers in Mexico. Results High-risk patients exhibited markedly lower event-free survival than standard-risk patients (43.5% vs. 78.3%, p<0.001). Influential factors on survival included anaplastic subtype (HR 2.4, p=0.003), metastatic disease (HR 1.9, p=0.001); residual tumor >1.5cm², and lower radiotherapy doses significantly impacted event-free survival (EFS) and overall survival (OS). Platinum-based chemotherapy showed better results compared to the ICE protocol in terms of OS and EFS, which was associated with higher toxicity. Patients under 3 years old displayed notably lower OS and EFS compared to older children (36.1% vs. 55.9%, p=0.01).
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Affiliation(s)
- Violeta Salceda-Rivera
- Hospital Civil de Guadalajara “Dr. Juan I. Menchaca”, Department of Pediatrics, Divisions of Pediatric Hematology-Oncology, Guadalajara, Jalisco, Mexico
| | - Isidoro Tejocote-Romero
- IMIEM, Instituto Materno Infantil del Estado de Mexico, Secretaria de Salud, Toluca, Estado de Mexico, Mexico
- Department of Pediatric Oncology, ISSEMYM, Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Estado de Mexico, Mexico
| | | | | | - Araceli López-Facundo
- Department of Pediatric Oncology, ISSEMYM, Instituto de Seguridad Social del Estado de México y Municipios, Toluca, Estado de Mexico, Mexico
| | | | - Daniel Ortiz-Morales
- Department of Pediatric Oncology, Hospital General de México “Dr. Eduardo Liceaga”, Mexico City, Mexico
- Department of Pediatric Oncology, Hospital Militar de Especialidades de la Mujer y Neonatología, Mexico City, Mexico
| | - Roberto Rivera-Luna
- Department of Pediatric Oncology, Instituto Nacional de Pediatria, Mexico City, Mexico
| | | | - Rebeca Rivera-Gómez
- Hospital General de Tijuana, Universidad Autonoma de Baja California, Tijuana, Baja California, Mexico
| | | | - Deyanira Cortés-Alva
- Hospital del Niño DIF Hidalgo, Sistema Nacional para el Desarrollo Integral de la Familia, Hidalgo, Mexico
| | | | - Farina E. Arreguín-González
- Centro Médico Nacional “20 de Noviembre” del Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Mexico City, Mexico
| | - Alma E. Benito-Reséndiz
- Centro Médico Nacional “20 de Noviembre” del Instituto de Seguridad y Servicios Sociales de los Trabajadores del Estado (ISSSTE), Mexico City, Mexico
| | - Silvia Chávez-Gallegos
- Department of Pediatric Oncology, Hospital Infantil “Eva Samano de López Mateos”, Morelia, Michoacan, Mexico
| | - Eloy Pérez-Rivera
- Department of Pediatric Oncology, Hospital Infantil “Eva Samano de López Mateos”, Morelia, Michoacan, Mexico
| | - Guillermo J. Gaytán-Fernández
- Hospital General Regional de Leon, Leon, Guanajuato, Mexico
- Department of Pediatric Oncology, Hospital Regional de Alta Especialidad del Bajío, Leon, Guanajuato, Mexico
| | | | | | - Carlos Leal-Cavazos
- Hospital Universitario “Dr. José Eleuterio González”, Universidad Autónoma de Nuevo Leon, Nuevo Leon, Mexico
| | - Citlalli Simón-González
- Department of Pediatric Oncology, Hospital Regional de Alta Especialidad del Niño “ Dr. Rodolfo Nieto Padrón”, Tabasco, Mexico
| | - Tania C. Larios-Farak
- Department of Pediatric Oncology, Hospital Infantil del Estado de Sonora, Hermosillo, Sonora, Mexico
| | - Nubia A. Macías-García
- Department of Pediatric Oncology, Hospital del Niño “Dr. Federico Gómez Santos”, Saltillo, Coahuila, Mexico
| | - Ana C. García-Espinosa
- Department of Pediatric Oncology, Hospital Infantil de Especialidades de Chihuahua, Chihuahua, Chihuahua, Mexico
| | | | - Paola Casillas-Toral
- Hospital Civil de Guadalajara “Dr. Juan I. Menchaca”, Department of Pediatrics, Divisions of Pediatric Hematology-Oncology, Guadalajara, Jalisco, Mexico
| | - Oscar González-Ramella
- Hospital Civil de Guadalajara “Dr. Juan I. Menchaca”, Department of Pediatrics, Divisions of Pediatric Hematology-Oncology, Guadalajara, Jalisco, Mexico
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13
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Savagner J, Ducassou A, Cabarrou B, Hangard G, Gambart M, Bertozzi AI, Baudou E, Boetto S, Larrieu D, Laprie A. Helical tomotherapy craniospinal irradiation in primary brain tumours: Toxicities and outcomes in a peadiatric and adult population. Clin Transl Radiat Oncol 2024; 46:100777. [PMID: 38628594 PMCID: PMC11019098 DOI: 10.1016/j.ctro.2024.100777] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2023] [Revised: 03/30/2024] [Accepted: 04/04/2024] [Indexed: 04/19/2024] Open
Abstract
Objective As craniospinal irradiation (CSI) is delivered more frequently by helical tomotherapy (HT) with few reports about late effects, we analysed all patients treated in our centre over an 11-year period. Methods and materials Our study included all patients that underwent CSI by HT, between September 2009 and January 2020, in the Department of Radiation Oncology of the Toulouse Cancer Institute. Acute radiotherapy toxicities were reported and medium- to long-term outcomes analysed. Results Among the 79 patients included, 70.9 % were younger than 18 years at diagnosis, the median age was 13 (range: 1-52) at the time of radiation therapy, 67.1 % of patients had medulloblastoma. Half of them (49.4 %) had a metastatic disease at diagnosis. The median dose of CSI was 36 Gy (range, 18-36). Seventy-seven patients received a radiation boost to the original location of the primary tumour (97.5 %), 32 patients also received a boost to their metastatic sites (40.5 %). Median follow-up was 55.5 months (95 %CI = [41.2; 71.8]). The 3-year event-free survival rate was 66.3 % (95 %CI = [54.2; 75.9]). Most patients presented with acute haematological toxicities during CSI (85.9 %), predominantly severe thrombocytopenia (39.7 %). Among the 64 patients assessed for medium- and long-term outcomes, 52 survived and 47 were alive and disease-free at the latest follow-up visit on record. There were 3.8 % secondary tumours: two meningiomas and one diffuse intrinsic pontine glioma. Adult and paediatric patients respectively presented with secondary cataract (4.3 % vs 22.0 %), persistent hearing disorders (26.1 % vs 29.3 %), pulmonary or cardiac late effects (4.3 % vs 2.4 %), hormonal pituitary gland deficiencies (30.0 % vs 56.8 %) and psycho-cognitive disorders (56.5 % vs 53.7 %). Conclusion CSI dispensed by HT, did not result in any additional acute or late toxicities when compared to 3D-CSI. There was no increase in the secondary tumour rate compared to that reported in the literature.
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Affiliation(s)
- Julie Savagner
- Department of Paediatric Neurology, Children’s Hospital of Toulouse, 330 Avenue de Grande Bretagne, 31300 Toulouse, France
| | - Anne Ducassou
- Department of Radiation Oncology, Toulouse Cancer Institute (IUCT), 1 avenue Irene Joliot-Curie, 31100 Toulouse, France
| | - Bastien Cabarrou
- Department of Biostatistics, Toulouse Cancer Institute (IUCT), 1 avenue Irene Joliot-Curie, 31100 Toulouse, France
| | - Gregory Hangard
- Department of Radiation Oncology, Toulouse Cancer Institute (IUCT), 1 avenue Irene Joliot-Curie, 31100 Toulouse, France
| | - Marion Gambart
- Department of Paediatric Oncology, Children’s Hospital of Toulouse, 330 Avenue de Grande Bretagne, 31300 Toulouse, France
| | - Anne-Isabelle Bertozzi
- Department of Paediatric Oncology, Children’s Hospital of Toulouse, 330 Avenue de Grande Bretagne, 31300 Toulouse, France
| | - Eloise Baudou
- Department of Paediatric Neurology, Children’s Hospital of Toulouse, 330 Avenue de Grande Bretagne, 31300 Toulouse, France
| | - Sergio Boetto
- Department of Neurosurgery, Toulouse University Hospital, Pierre-Paul Riquet Hospital, Place du Docteur Baylac, Toulouse, France
| | - Delphine Larrieu
- Department of Oncology, Toulouse Cancer Institute (IUCT), 1 avenue Irene Joliot-Curie, 31100 Toulouse, France
| | - Anne Laprie
- Department of Radiation Oncology, Toulouse Cancer Institute (IUCT), 1 avenue Irene Joliot-Curie, 31100 Toulouse, France
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14
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Ahn WK, Hahn SM, Yoon HI, Lee J, Park EK, Shim KW, Kim DS, Suh CO, Kim SH, Lyu CJ, Han JW. Long-term Outcomes of Protocol-Based Treatment for Newly Diagnosed Medulloblastoma. Cancer Res Treat 2024; 56:652-664. [PMID: 38037318 PMCID: PMC11016662 DOI: 10.4143/crt.2023.865] [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: 07/23/2023] [Accepted: 11/29/2023] [Indexed: 12/02/2023] Open
Abstract
PURPOSE The Korean Society of Pediatric Neuro-Oncology (KSPNO) conducted treatment strategies for children with medulloblastoma (MB) by using alkylating agents for maintenance chemotherapy or tandem high-dose chemotherapy (HDC) with autologous stem cell rescue (ASCR) according to the risk stratification. The purpose of the study was to assess treatment outcomes and complications based on risk-adapted treatment and HDC. MATERIALS AND METHODS Fifty-nine patients diagnosed with MB were enrolled in this study. Patients in the standard-risk (SR) group received radiotherapy (RT) after surgery and chemotherapy using the KSPNO M051 regimen. Patients in the high-risk (HR) group received two and four chemotherapy cycles according to the KSPNO S081 protocol before and after reduced RT for age following surgery and two cycles of tandem HDC with ASCR consolidation treatment. RESULTS In the SR group, 24 patients showed 5-year event-free survival (EFS) and overall survival (OS) estimates of 86.7% (95% confidence interval [CI], 73.6 to 100) and 95.8% (95% CI, 88.2 to 100), respectively. In the HR group, more infectious complications and mortality occurred during the second HDC than during the first. In the HR group, the 5-year EFS and OS estimates were 65.5% (95% CI, 51.4 to 83.4) and 72.3% (95% CI, 58.4 to 89.6), respectively. CONCLUSION High intensity of alkylating agents for SR resulted in similar outcomes but with a high incidence of hematologic toxicity. Tandem HDC with ASCR for HR induced favorable EFS and OS estimates compared to those reported previously. However, infectious complications and treatment-related mortalities suggest that a reduced chemotherapy dose is necessary, especially for the second HDC.
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Affiliation(s)
- Won Kee Ahn
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Yonsei University Health System, Yonsei University College of Medicine, Seoul
- Department of Pediatric Hemato-Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
| | - Seung Min Hahn
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Yonsei University Health System, Yonsei University College of Medicine, Seoul
- Department of Pediatric Hemato-Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
| | - Hong In Yoon
- Department of Radiation Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
| | - Jeongshim Lee
- Department of Radiation Oncology, Inha University Hospital, Incheon, Korea
| | - Eun Kyung Park
- Department of Neurosurgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul
| | - Kyu Won Shim
- Department of Neurosurgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul
| | - Dong Seok Kim
- Department of Neurosurgery, Yonsei University Health System, Yonsei University College of Medicine, Seoul
| | - Chang-Ok Suh
- Department of Radiation Oncology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea
| | - Se Hoon Kim
- Department of Pathology, Yonsei University Health System, Yonsei University College of Medicine, Seoul, Korea
| | - Chuhl Joo Lyu
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Yonsei University Health System, Yonsei University College of Medicine, Seoul
- Department of Pediatric Hemato-Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
| | - Jung Woo Han
- Division of Pediatric Hematology and Oncology, Department of Pediatrics, Yonsei University Health System, Yonsei University College of Medicine, Seoul
- Department of Pediatric Hemato-Oncology, Yonsei Cancer Center, Yonsei University Health System, Seoul, Korea
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15
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Dinikina YV, Zheludkova OG, Belogurova MB, Spelnikov DM, Osipov NN, Nikitina IL. Personalized treatment options of refractory and relapsed medulloblastoma in children: literature review. JOURNAL OF MODERN ONCOLOGY 2024; 25:454-465. [DOI: 10.26442/18151434.2023.4.202521] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
Medulloblastoma (MB) is the most common malignant tumor of the central nervous system in pediatric patients. Despite the complex anticancer therapy approach, refractory and relapsing forms of the disease remain fatal in most cases and account for approximately 30%. To date, repeated surgery, radiation, and chemotherapy can be used as life-prolonging treatment options; nevertheless, it should be emphasized that there are no standardized approaches based on existing data of molecular variants of MB. It is obvious that only a deep understanding of the biological mechanisms in association with clinical aspects in refractory and relapsing forms of MB would make it possible to personalize second- and subsequent-line therapy in order to achieve maximum efficiency and minimize early and long-term toxicity. The article presents the current understanding of prognostic factors in relapsed/refractory forms of MB, methods of modern diagnostics, as well as existing and perspective treatment options based on the biological and clinical aspects of the disease.
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16
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Green S, Hoover T, Doss D, Davidow K, Walter AW, Cottrell CE, Mahapatra S. WNT-activated, MYC-amplified medulloblastoma displaying intratumoural heterogeneity. Neuropathol Appl Neurobiol 2024; 50:e12945. [PMID: 38093348 DOI: 10.1111/nan.12945] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2023] [Revised: 10/16/2023] [Accepted: 12/05/2023] [Indexed: 02/21/2024]
Affiliation(s)
- Sage Green
- Dell Children's Medical Center, Austin, TX, 78723, USA
- Nemours Children's Health, Wilmington, DE, 19803, USA
| | - Travis Hoover
- Pennsylvania State University College of Medicine, Philadelphia, PA, 17033, USA
| | - David Doss
- Creighton University School of Medicine, Omaha, NE, 68124, USA
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17
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Abstract
PURPOSE OF REVIEW Review recent advances in the understanding of pediatric medulloblastoma including etiology, biology, radiology, and management of pediatric medulloblastoma. RECENT FINDINGS The classic four subgroups have been reclassified and further subdivided based on new molecular findings. Research is revealing the cell origins of the different subtypes of medulloblastoma. There has been continued personalization of management based on molecular parameters. While many advances have been made in the knowledge base of this most common malignant pediatric brain tumor, there has not yet been translation into more effective therapies to prolong survival in all subgroups with the possible exception of children with group 3 disease. Quality of life remains a major challenge for long-term survivors.
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Affiliation(s)
- Kasey Jackson
- Brain Tumor Institute, Children's National Hospital, Washington D C, USA.
- Division of Hematology and Oncology, Children's National Hospital, Washington D C, USA.
| | - Roger J Packer
- Brain Tumor Institute, Children's National Hospital, Washington D C, USA
- Center for Neuroscience and Behavioral Medicine, Children's National Hospital, Washington D C, USA
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18
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Mariotto E, Rampazzo E, Bortolozzi R, Rruga F, Zeni I, Manfreda L, Marchioro C, Canton M, Cani A, Magni R, Luchini A, Bresolin S, Viola G, Persano L. Molecular and functional profiling of chemotolerant cells unveils nucleoside metabolism-dependent vulnerabilities in medulloblastoma. Acta Neuropathol Commun 2023; 11:183. [PMID: 37978570 PMCID: PMC10655385 DOI: 10.1186/s40478-023-01679-7] [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: 08/03/2023] [Accepted: 10/26/2023] [Indexed: 11/19/2023] Open
Abstract
Chemotherapy resistance is considered one of the main causes of tumor relapse, still challenging researchers for the identification of the molecular mechanisms sustaining its emergence. Here, we setup and characterized chemotherapy-resistant models of Medulloblastoma (MB), one of the most lethal pediatric brain tumors, to uncover targetable vulnerabilities associated to their resistant phenotype. Integration of proteomic, transcriptomic and kinomic data revealed a significant deregulation of several pathways in resistant MB cells, converging to cell metabolism, RNA/protein homeostasis, and immune response, eventually impacting on patient outcome. Moreover, resistant MB cell response to a large library of compounds through a high-throughput screening (HTS), highlighted nucleoside metabolism as a relevant vulnerability of chemotolerant cells, with peculiar antimetabolites demonstrating increased efficacy against them and even synergism with conventional chemotherapeutics. Our results suggest that drug-resistant cells significantly rewire multiple cellular processes, allowing their adaptation to a chemotoxic environment, nevertheless exposing alternative actionable susceptibilities for their specific targeting.
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Affiliation(s)
- Elena Mariotto
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
- Unit of Biostatistics, Department of Cardiac, Thoracic and Vascular Sciences and Public Health, University of Padova, Via Loredan 18, 35131, Padua, Italy
| | - Elena Rampazzo
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy.
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy.
| | - Roberta Bortolozzi
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy.
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy.
- Section of Pharmacology, Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Largo Meneghetti 2, 35131, Padua, Italy.
| | - Fatlum Rruga
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Ilaria Zeni
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
| | - Lorenzo Manfreda
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Chiara Marchioro
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Martina Canton
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Alice Cani
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Ruben Magni
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, MSN 1A9, Manassas, VA, 20110, USA
| | - Alessandra Luchini
- Center for Applied Proteomics and Molecular Medicine, George Mason University, 10920 George Mason Circle, MSN 1A9, Manassas, VA, 20110, USA
| | - Silvia Bresolin
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Giampietro Viola
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
| | - Luca Persano
- Department of Women's and Children's Health, University of Padova, Via Giustiniani 3, 35128, Padua, Italy
- Pediatric Research Institute, Corso Stati Uniti 4, 35127, Padua, Italy
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19
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Singh R, Yu S, Osman M, Inde Z, Fraser C, Cleveland AH, Almanzar N, Lim CB, Joshi GN, Spetz J, Qin X, Toprani SM, Nagel Z, Hocking MC, Cormack RA, Yock TI, Miller JW, Yuan ZM, Gershon T, Sarosiek KA. Radiotherapy-Induced Neurocognitive Impairment Is Driven by Heightened Apoptotic Priming in Early Life and Prevented by Blocking BAX. Cancer Res 2023; 83:3442-3461. [PMID: 37470810 PMCID: PMC10570680 DOI: 10.1158/0008-5472.can-22-1337] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 04/23/2023] [Accepted: 07/17/2023] [Indexed: 07/21/2023]
Abstract
Although external beam radiotherapy (xRT) is commonly used to treat central nervous system (CNS) tumors in patients of all ages, young children treated with xRT frequently experience life-altering and dose-limiting neurocognitive impairment (NI) while adults do not. The lack of understanding of mechanisms responsible for these differences has impeded the development of neuroprotective treatments. Using a newly developed mouse model of xRT-induced NI, we found that neurocognitive function is impaired by ionizing radiation in a dose- and age-dependent manner, with the youngest animals being most affected. Histologic analysis revealed xRT-driven neuronal degeneration and cell death in neurogenic brain regions in young animals but not adults. BH3 profiling showed that neural stem and progenitor cells, neurons, and astrocytes in young mice are highly primed for apoptosis, rendering them hypersensitive to genotoxic damage. Analysis of single-cell RNA sequencing data revealed that neural cell vulnerability stems from heightened expression of proapoptotic genes including BAX, which is associated with developmental and mitogenic signaling by MYC. xRT induced apoptosis in primed neural cells by triggering a p53- and PUMA-initiated, proapoptotic feedback loop requiring cleavage of BID and culminating in BAX oligomerization and caspase activation. Notably, loss of BAX protected against apoptosis induced by proapoptotic signaling in vitro and prevented xRT-induced apoptosis in neural cells in vivo as well as neurocognitive sequelae. On the basis of these findings, preventing xRT-induced apoptosis specifically in immature neural cells by blocking BAX, BIM, or BID via direct or upstream mechanisms is expected to ameliorate NI in pediatric patients with CNS tumor. SIGNIFICANCE Age- and differentiation-dependent apoptotic priming plays a pivotal role in driving radiotherapy-induced neurocognitive impairment and can be targeted for neuroprotection in pediatric patients.
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Affiliation(s)
- Rumani Singh
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Stacey Yu
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Marwa Osman
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Zintis Inde
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Cameron Fraser
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Abigail H. Cleveland
- Department of Neurology, University of North Carolina, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, North Carolina Cancer Hospital, Chapel Hill, North Carolina
| | - Nicole Almanzar
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Chuan Bian Lim
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Gaurav N. Joshi
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Johan Spetz
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Xingping Qin
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Sneh M. Toprani
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Zachary Nagel
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Matthew C. Hocking
- Department of Psychiatry, University of Pennsylvania, Philadelphia, Pennsylvania
- Cancer Center, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania
| | - Robert A. Cormack
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Radiation Oncology, Brigham and Women's Hospital, Boston, Massachusetts
| | - Torunn I. Yock
- Department of Medicine, Harvard Medical School, Boston, Massachusetts
- Pediatric Radiation Oncology, Francis H. Burr Proton Therapy Center, Massachusetts General Hospital, Boston, Massachusetts
| | - Jeffrey W. Miller
- Department of Biostatistics, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Zhi-Min Yuan
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
| | - Timothy Gershon
- Department of Neurology, University of North Carolina, Chapel Hill, North Carolina
- Lineberger Comprehensive Cancer Center, North Carolina Cancer Hospital, Chapel Hill, North Carolina
| | - Kristopher A. Sarosiek
- John B. Little Center for Radiation Sciences, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Department of Systems Biology, Harvard Medical School, Boston, Massachusetts
- Molecular and Integrative Physiological Sciences Program, Harvard T.H. Chan School of Public Health, Boston, Massachusetts
- Department of Medical Oncology, Dana-Farber Cancer Institute/Harvard Cancer Center, Boston, Massachusetts
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20
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Gallo-Oller G, de Ståhl TD, Alaiya A, Nilsson S, Holmberg AR, Márquez-Méndez M. Cytotoxicity of poly-guanidine in medulloblastoma cell lines. Invest New Drugs 2023; 41:688-698. [PMID: 37556022 PMCID: PMC10560188 DOI: 10.1007/s10637-023-01386-z] [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: 06/05/2023] [Accepted: 07/14/2023] [Indexed: 08/10/2023]
Abstract
Medulloblastoma (MB) is the most common pediatric brain tumor. The therapy frequently causes serious side effects, and new selective therapies are needed. MB expresses hyper sialylation, a possible target for selective therapy. The cytotoxic efficacy of a poly guanidine conjugate (GuaDex) incubated with medulloblastoma cell cultures (DAOY and MB-LU-181) was investigated. The cells were incubated with 0.05-8 µM GuaDex from 15 min to 72 h. A fluorometric cytotoxicity assay (FMCA) measured the cytotoxicity. Labeled GuaDex was used to study tumor cell interaction. FITC-label Sambucus nigra confirmed high expression of sialic acid (Sia). Immunofluorescence microscopy was used to visualize the cell F-actin and microtubules. The cell interactions were studied by confocal and fluorescence microscopy. Annexin-V assay was used to detect apoptosis. Cell cycle analysis was done by DNA content determination. A wound-healing migration assay determined the effects on the migratory ability of DAOY cells after GuaDex treatment. IC50 for GuaDex was 223.4 -281.1 nM. FMCA showed potent growth inhibition on DAOY and MB-LU-181 cells at 5 uM GuaDex after 4 h of incubation. GuaDex treatment induced G2/M phase cell cycle arrest. S. nigra FITC-label lectin confirmed high expression of Sia on DAOY medulloblastoma cells. The GuaDex treatment polymerized the cytoskeleton (actin filaments and microtubules) and bound to DNA, inducing condensation. The Annexin V assay results were negative. Cell migration was inhibited at 0.5 µM GuaDex concentration after 24 h of incubation. GuaDex showed potent cytotoxicity and invasion-inhibitory effects on medulloblastoma cells at low micromolar concentrations. GuaDex efficacy was significant and warrants further studies.
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Affiliation(s)
- Gabriel Gallo-Oller
- Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden
| | | | - Ayodele Alaiya
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
- Cell Therapy and Immunobiology Department, King Faisal Specialist Hospital and Research Centre Oncology Centre, Riyadh, Saudi Arabia
| | - Sten Nilsson
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Anders R Holmberg
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden
| | - Marcela Márquez-Méndez
- Department of Oncology-Pathology, Karolinska Institutet, Stockholm, Sweden.
- Center for Research and Development in Health Sciences, Autonomous University of Nuevo León, Monterrey, N.L., Mexico.
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21
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Perek-Polnik M, Cochrane A, Wang J, Chojnacka M, Drogosiewicz M, Filipek I, Swieszkowska E, Tarasinska M, Grajkowska W, Trubicka J, Kowalczyk P, Dembowska-Bagińskai B, Abdelbaki MS. Risk-Adapted Treatment Strategies with Pre-Irradiation Chemotherapy in Pediatric Medulloblastoma: Outcomes from the Polish Pediatric Neuro-Oncology Group. CHILDREN (BASEL, SWITZERLAND) 2023; 10:1387. [PMID: 37628386 PMCID: PMC10453075 DOI: 10.3390/children10081387] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/26/2023] [Accepted: 08/09/2023] [Indexed: 08/27/2023]
Abstract
Craniospinal irradiation (CSI) has been a major component of the standard of care treatment backbone for childhood medulloblastoma. However, chemotherapy regimens have varied based on protocol, patient age, and molecular subtyping. In one of the largest studies to date, we analyzed treatment outcomes in children with newly-diagnosed medulloblastoma treated with pre-irradiation chemotherapy followed by risk-adapted radiotherapy and maintenance chemotherapy. A total of 153 patients from the Polish Pediatric Neuro-Oncology Group were included in the analysis. The median age at diagnosis was 8.0 years, and median follow-up time was 6.4 years. Sixty-seven patients were classified as standard-risk and eighty-six as high-risk. Overall survival (OS) and event-free survival (EFS) for standard-risk patients at 5 years (±standard error) were 87 ± 4.3% and 84 ± 4.6%, respectively, while 5-year OS and EFS for high-risk patients were 81 ± 4.3% and 79 ± 4.5%, respectively. Only one patient had disease progression prior to radiotherapy. This study demonstrates promising survival outcomes in patients treated with pre-irradiation chemotherapy followed by risk-adapted CSI and adjuvant chemotherapy. Such an approach may be useful in cases where the initiation of radiotherapy may need to be delayed, a common occurrence in many institutions globally.
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Affiliation(s)
- Marta Perek-Polnik
- Department of Oncology, Children’s Memorial Health Institute, 01-211 Warsaw, Poland; (M.D.); (I.F.); (E.S.); (M.T.); (B.D.-B.)
| | - Anne Cochrane
- Division of Hematology and Oncology, Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO 63110, USA
| | - Jinli Wang
- Center for Biostatistics and Data Science, Washington University School of Medicine, St. Louis, MO 63110, USA
| | - Marzanna Chojnacka
- Maria Sklodowska-Curie National Research Institute of Oncology, Pediatric Radiotherapy Centre, 00-001 Warsaw, Poland
| | - Monika Drogosiewicz
- Department of Oncology, Children’s Memorial Health Institute, 01-211 Warsaw, Poland; (M.D.); (I.F.); (E.S.); (M.T.); (B.D.-B.)
| | - Iwona Filipek
- Department of Oncology, Children’s Memorial Health Institute, 01-211 Warsaw, Poland; (M.D.); (I.F.); (E.S.); (M.T.); (B.D.-B.)
| | - Ewa Swieszkowska
- Department of Oncology, Children’s Memorial Health Institute, 01-211 Warsaw, Poland; (M.D.); (I.F.); (E.S.); (M.T.); (B.D.-B.)
| | - Magdalena Tarasinska
- Department of Oncology, Children’s Memorial Health Institute, 01-211 Warsaw, Poland; (M.D.); (I.F.); (E.S.); (M.T.); (B.D.-B.)
| | - Wiesława Grajkowska
- Department of Pathology, Children’s Memorial Health Institute, 01-211 Warsaw, Poland; (W.G.); (J.T.)
| | - Joanna Trubicka
- Department of Pathology, Children’s Memorial Health Institute, 01-211 Warsaw, Poland; (W.G.); (J.T.)
| | - Paweł Kowalczyk
- Department of Neurosurgery, Children’s Memorial Health Institute, 01-211 Warsaw, Poland;
| | - Bożenna Dembowska-Bagińskai
- Department of Oncology, Children’s Memorial Health Institute, 01-211 Warsaw, Poland; (M.D.); (I.F.); (E.S.); (M.T.); (B.D.-B.)
| | - Mohamed S. Abdelbaki
- Division of Hematology and Oncology, Department of Pediatrics, School of Medicine, Washington University, St. Louis, MO 63110, USA
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22
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Isik Bedir S, Karabagli P, Batur A, Ozturk M, Karabagli H, Yavas G, Koksal Y. Radiation-induced Desmoid Tumor Development in the Radiotherapy Field in a Child With Pineoblastoma: A Case Report. J Pediatr Hematol Oncol 2023; 45:e639-e642. [PMID: 37278565 DOI: 10.1097/mph.0000000000002680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2022] [Accepted: 03/31/2023] [Indexed: 06/07/2023]
Abstract
Although treatment-related secondary malignancies are rare, they are important problems after the treatment of childhood malignant diseases. Irradiation-induced sarcomas are the development of sarcoma different from the primary tumor after a latent period of ≥3 years or more in the radiotherapy field. Desmoid tumor is extremely rare as irradiation-induced tumor. A 7.5-year-old girl was referred to our hospital after a subtotal mass excision for a solid lesion with a cystic component located in the pineal gland. Pathologic examination revealed pineoblastoma. After surgery, craniospinal radiotherapy, and chemotherapy consisting of vincristine, cisplatin, and etoposide were performed. Painless swelling in the left parieto-occipital region ~75 months after the end of the treatment developed in the patient. A mass was detected in the intracranial but extra-axial region by radiologic imaging methods. Due to the total removal of the mass and the absence of a tumor in the surgical margins, she was followed up without additional treatment. The pathologic diagnosis was a desmoid tumor. She was followed up disease free for ~7 years after the primary tumor and ~7 months after the secondary tumor. Treatment-related desmoid tumor development after treatment for a central nervous system tumor in a child is extremely rare.
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Affiliation(s)
| | | | | | | | | | - Guler Yavas
- Department of Radiation Oncology, Baskent University, Ankara, Turkey
| | - Yavuz Koksal
- Department of Pediatric Hematology and Oncology, Selcuk University, Konya
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23
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Osuna-Marco MP, Martín-López LI, Tejera ÁM, López-Ibor B. Questions and answers in the management of children with medulloblastoma over the time. How did we get here? A systematic review. Front Oncol 2023; 13:1229853. [PMID: 37456257 PMCID: PMC10340518 DOI: 10.3389/fonc.2023.1229853] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2023] [Accepted: 06/13/2023] [Indexed: 07/18/2023] Open
Abstract
Introduction Treatment of children with medulloblastoma (MB) includes surgery, radiation therapy (RT) and chemotherapy (CT). Several treatment protocols and clinical trials have been developed over the time to maximize survival and minimize side effects. Methods We performed a systematic literature search in May 2023 using PubMed. We selected all clinical trials articles and multicenter studies focusing on MB. We excluded studies focusing exclusively on infants, adults, supratentorial PNETs or refractory/relapsed tumors, studies involving different tumors or different types of PNETs without differentiating survival, studies including <10 cases of MB, solely retrospective studies and those without reference to outcome and/or side effects after a defined treatment. Results 1. The main poor-prognosis factors are: metastatic disease, anaplasia, MYC amplification, age younger than 36 months and some molecular subgroups. The postoperative residual tumor size is controversial.2. MB is a collection of diseases.3. MB is a curable disease at diagnosis, but survival is scarce upon relapse.4. Children should be treated by experienced neurosurgeons and in advanced centers.5. RT is an essential treatment for MB. It should be administered craniospinal, early and without interruptions.6. Craniospinal RT dose could be lowered in some low-risk patients, but these reductions should be done with caution to avoid relapses.7. Irradiation of the tumor area instead of the entire posterior fossa is safe enough.8. Hyperfractionated RT is not superior to conventional RT9. Both photon and proton RT are effective.10. CT increases survival, especially in high-risk patients.11. There are multiple drugs effective in MB. The combination of different drugs is appropriate management.12. CT should be administered after RT.13. The specific benefit of concomitant CT to RT is unknown.14. Intensified CT with stem cell rescue has no benefit compared to standard CT regimens.15. The efficacy of intraventricular/intrathecal CT is controversial.16. We should start to think about incorporating targeted therapies in front-line treatment.17. Survivors of MB still have significant side effects. Conclusion Survival rates of MB improved greatly from 1940-1970, but since then the improvement has been smaller. We should consider introducing targeted therapy as front-line therapy.
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Affiliation(s)
- Marta P. Osuna-Marco
- Pediatric Oncology Unit, Centro Integral Oncológico Clara Campal (CIOCC), Hospital Universitario HM Montepríncipe, HM Hospitales, Madrid, Spain
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
| | - Laura I. Martín-López
- Pediatric Oncology Unit, Centro Integral Oncológico Clara Campal (CIOCC), Hospital Universitario HM Montepríncipe, HM Hospitales, Madrid, Spain
| | - Águeda M. Tejera
- Faculty of Experimental Sciences, Universidad Francisco de Vitoria, Madrid, Spain
| | - Blanca López-Ibor
- Pediatric Oncology Unit, Centro Integral Oncológico Clara Campal (CIOCC), Hospital Universitario HM Montepríncipe, HM Hospitales, Madrid, Spain
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24
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Funakoshi Y, Sugihara Y, Uneda A, Nakashima T, Suzuki H. Recent advances in the molecular understanding of medulloblastoma. Cancer Sci 2023; 114:741-749. [PMID: 36520034 PMCID: PMC9986075 DOI: 10.1111/cas.15691] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/03/2022] [Revised: 11/25/2022] [Accepted: 12/08/2022] [Indexed: 12/23/2022] Open
Abstract
Medulloblastoma is the most common pediatric malignant brain tumor composed of four molecular subgroups. Recent intensive genomics has greatly contributed to our understanding of medulloblastoma pathogenesis. Sequencing studies identified novel mutations involved in the cyclic AMP-dependent pathway or RNA processing in the Sonic Hedgehog (SHH) subgroup, and core-binding factor subunit alpha (CBFA) complex in the group 4 subgroup. Likewise, single-cell sequencing provided detailed insights into the cell of origin associated with brain development. In this review, we will summarize recent findings by sequencing analyses for medulloblastoma.
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Affiliation(s)
- Yusuke Funakoshi
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Japan
| | - Yuriko Sugihara
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Japan
| | - Atsuhito Uneda
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Japan
| | - Takuma Nakashima
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Japan
| | - Hiromichi Suzuki
- Division of Brain Tumor Translational Research, National Cancer Center Research Institute, Chuo-ku, Japan
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25
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Marquardt V, Theruvath J, Pauck D, Picard D, Qin N, Blümel L, Maue M, Bartl J, Ahmadov U, Langini M, Meyer FD, Cole A, Cruz-Cruz J, Graef CM, Wölfl M, Milde T, Witt O, Erdreich-Epstein A, Leprivier G, Kahlert U, Stefanski A, Stühler K, Keir ST, Bigner DD, Hauer J, Beez T, Knobbe-Thomsen CB, Fischer U, Felsberg J, Hansen FK, Vibhakar R, Venkatraman S, Cheshier SH, Reifenberger G, Borkhardt A, Kurz T, Remke M, Mitra S. Tacedinaline (CI-994), a class I HDAC inhibitor, targets intrinsic tumor growth and leptomeningeal dissemination in MYC-driven medulloblastoma while making them susceptible to anti-CD47-induced macrophage phagocytosis via NF-kB-TGM2 driven tumor inflammation. J Immunother Cancer 2023; 11:jitc-2022-005871. [PMID: 36639156 PMCID: PMC9843227 DOI: 10.1136/jitc-2022-005871] [Citation(s) in RCA: 24] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 12/13/2022] [Indexed: 01/15/2023] Open
Abstract
BACKGROUND While major advances have been made in improving the quality of life and survival of children with most forms of medulloblastoma (MB), those with MYC-driven tumors (Grp3-MB) still suffer significant morbidity and mortality. There is an urgent need to explore multimodal therapeutic regimens which are effective and safe for children. Large-scale studies have revealed abnormal cancer epigenomes caused by mutations and structural alterations of chromatin modifiers, aberrant DNA methylation, and histone modification signatures. Therefore, targeting epigenetic modifiers for cancer treatment has gained increasing interest, and inhibitors for various epigenetic modulators have been intensively studied in clinical trials. Here, we report a cross-entity, epigenetic drug screen to evaluate therapeutic vulnerabilities in MYC amplified MB, which sensitizes them to macrophage-mediated phagocytosis by targeting the CD47-signal regulatory protein α (SIRPα) innate checkpoint pathway. METHODS We performed a primary screen including 78 epigenetic inhibitors and a secondary screen including 20 histone deacetylase inhibitors (HDACi) to compare response profiles in atypical teratoid/rhabdoid tumor (AT/RT, n=11), MB (n=14), and glioblastoma (n=14). This unbiased approach revealed the preferential activity of HDACi in MYC-driven MB. Importantly, the class I selective HDACi, CI-994, showed significant cell viability reduction mediated by induction of apoptosis in MYC-driven MB, with little-to-no activity in non-MYC-driven MB, AT/RT, and glioblastoma in vitro. We tested the combinatorial effect of targeting class I HDACs and the CD47-SIRPa phagocytosis checkpoint pathway using in vitro phagocytosis assays and in vivo orthotopic xenograft models. RESULTS CI-994 displayed antitumoral effects at the primary site and the metastatic compartment in two orthotopic mouse models of MYC-driven MB. Furthermore, RNA sequencing revealed nuclear factor-kB (NF-κB) pathway induction as a response to CI-994 treatment, followed by transglutaminase 2 (TGM2) expression, which enhanced inflammatory cytokine secretion. We further show interferon-γ release and cell surface expression of engulfment ('eat-me') signals (such as calreticulin). Finally, combining CI-994 treatment with an anti-CD47 mAb targeting the CD47-SIRPα phagocytosis checkpoint enhanced in vitro phagocytosis and survival in tumor-bearing mice. CONCLUSION Together, these findings suggest a dynamic relationship between MYC amplification and innate immune suppression in MYC amplified MB and support further investigation of phagocytosis modulation as a strategy to enhance cancer immunotherapy responses.
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Affiliation(s)
- Viktoria Marquardt
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Johanna Theruvath
- Department of Neurosurgery, Institute for StemCell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA
- Stanford University School of Medicine, Stanford, California, USA
| | - David Pauck
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Daniel Picard
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Nan Qin
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Lena Blümel
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Mara Maue
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Jasmin Bartl
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Ulvi Ahmadov
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Maike Langini
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany
| | - Frauke-Dorothee Meyer
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Allison Cole
- Pediatrics, University of Colorado Denver, Aurora, Colorado, USA
| | | | - Claus M Graef
- Department of Neurosurgery, Institute for StemCell Biology and Regenerative Medicine and Division of Pediatric Neurosurgery, Lucile Packard Children's Hospital, Stanford University, Stanford, California, USA
| | - Matthias Wölfl
- Department of Pediatric Oncology, University Children's Hospital Würzburg, Würzburg, Germany
| | - Till Milde
- Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany
- Department of Pediatric Hematology and Oncology, Heidelberg University Hospital, Heidelberg, Germany
| | - Olaf Witt
- 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
| | - Anat Erdreich-Epstein
- Division of Hematology-Oncology and Blood and Marrow Transplantation, Department of Pediatrics and the Department of Pathology, Children's Hospital Los Angeles, and the Norris Comprehensive Cancer Center, Keck School of Medicine, University of Southern California, Los Angeles, California, USA
| | - Gabriel Leprivier
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Ulf Kahlert
- Department of Neurosurgery, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Anja Stefanski
- Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany
| | - Kai Stühler
- Molecular Proteomics Laboratory, Biomedical Research Centre (BMFZ), Heinrich-Heine University, Düsseldorf, Germany, Düsseldorf, Germany
| | - Stephen T Keir
- Department of Neurosurgery, Duke University, Durham, North Carolina, USA
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA
| | - Darell D Bigner
- Department of Neurosurgery, Duke University, Durham, North Carolina, USA
- Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina, USA
| | - Julia Hauer
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Thomas Beez
- Department of Neurosurgery, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf, Germany
| | - Christiane B Knobbe-Thomsen
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Ute Fischer
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Jörg Felsberg
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Finn K Hansen
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University, Leipzig, Germany
| | - Rajeev Vibhakar
- Pediatrics, University of Colorado Denver, Aurora, Colorado, USA
| | | | - Samuel H Cheshier
- Department of Neurosurgery, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA
| | - Guido Reifenberger
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Institute of Neuropathology, Medical Faculty, Heinrich-Heine University Düsseldorf, Düsseldorf; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Arndt Borkhardt
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology and Clinical Immunology, Medical Faculty, Heinrich-Heine-University, Düsseldorf, Germany
| | - Thomas Kurz
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Marc Remke
- Division of Pediatric Neuro-Oncogenomics, German Cancer Research Center (DKFZ), Heidelberg, Germany, and German Cancer Consortium (DKTK), partner site Essen/Düsseldorf, Düsseldorf, Germany
- Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and DKTK, partner site Essen/Düsseldorf, Germany, Düsseldorf, Germany
| | - Siddhartha Mitra
- Pediatrics, University of Colorado Denver, Aurora, Colorado, USA
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Lim DH. Role of Radiotherapy in Patients With Relapsed Medulloblastoma. Brain Tumor Res Treat 2023; 11:22-27. [PMID: 36762805 PMCID: PMC9911706 DOI: 10.14791/btrt.2022.0033] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2022] [Revised: 01/10/2023] [Accepted: 01/16/2023] [Indexed: 02/05/2023] Open
Abstract
During the last three decades, the management of medulloblastoma (MBL) has made enormous progress with a multidisciplinary approach, incorporating surgery, radiotherapy (RT), and chemotherapy. Despite this improvement, 20%-30% of patients with MBL remain at risk of disease recurrence, with its relapse being possibly fatal. To date, the salvage treatment for relapse remains challenging, and various approaches have been suggested for the retreatment. In this review, I have described the characteristics of patients with relapsed MBL, patterns of relapse and the most commonly prescribed treatment. Further, I have reviewed the studies on re-irradiation and its associated issues to conclusively suggest the RT recommendations for patients with relapsed MBL.
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Affiliation(s)
- Do Hoon Lim
- Department of Radiation Oncology, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea.
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27
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Giakoumettis G, Mantzavinou A, Moschos G, Giakoumettis D, Capizzello A. Re-irradiation of Pediatric Medulloblastoma: A Case Report and Systematic Review. Cureus 2022; 14:e31585. [PMID: 36540431 PMCID: PMC9757891 DOI: 10.7759/cureus.31585] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/14/2022] [Indexed: 11/17/2022] Open
Abstract
Despite the optimal treatment given to children with medulloblastoma, many relapses are seen after combining treatments. Re-irradiation is part of salvage therapy for children who relapse and might provide long-term disease control. Nevertheless, it is challenging because there is a concern about exceeding radiation tolerances and late treatment toxicities. Re-irradiation is an option for many brain tumors, including medulloblastoma in children. This study presents a case of recurrent medulloblastoma treated with re-irradiation. A systematic review of the literature provided up-to-date data on the re-irradiation of medulloblastoma in children. This study aims to contribute to the scarce literature on the treatment strategy, which may help improve patients' outcomes.
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Affiliation(s)
| | - Artemis Mantzavinou
- Medicine, Barts and The London School of Medicine and Dentistry, London, GBR
| | - Georgios Moschos
- Department of Radiation Oncology, AHEPA University Hospital, Thessaloniki, GRC
| | | | - Antonio Capizzello
- Department of Radiation Oncology, AHEPA University Hospital, Thessaloniki, GRC
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28
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Lazow MA, Palmer JD, Fouladi M, Salloum R. Medulloblastoma in the Modern Era: Review of Contemporary Trials, Molecular Advances, and Updates in Management. Neurotherapeutics 2022; 19:1733-1751. [PMID: 35859223 PMCID: PMC9723091 DOI: 10.1007/s13311-022-01273-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/04/2022] [Indexed: 12/13/2022] Open
Abstract
Critical discoveries over the past two decades have transformed our understanding of medulloblastoma from a single entity into a clinically and biologically heterogeneous disease composed of at least four molecularly distinct subgroups with prognostically and therapeutically relevant genomic signatures. Contemporary clinical trials also have provided valuable insight guiding appropriate treatment strategies. Despite therapeutic and biological advances, medulloblastoma patients across the age spectrum experience tumor- and treatment-related morbidity and mortality. Using an updated risk stratification approach integrating both clinical and molecular features, ongoing research seeks to (1) cautiously reduce therapy and mitigate toxicity in low-average risk patients, and (2) thoughtfully intensify treatment with incorporation of novel, biologically guided agents for patients with high-risk disease. Herein, we review important historical and contemporary studies, discuss management updates, and summarize current knowledge of the biological landscape across unique pediatric, infant, young adult, and relapsed medulloblastoma populations.
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Affiliation(s)
- Margot A Lazow
- Pediatric Brain Tumor Program, Division of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
- The Ohio State University College of Medicine, Columbus, OH, USA
| | - Joshua D Palmer
- The Ohio State University College of Medicine, Columbus, OH, USA
- The James Cancer Centre, Ohio State University, Columbus, OH, USA
| | - Maryam Fouladi
- Pediatric Brain Tumor Program, Division of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA
- The Ohio State University College of Medicine, Columbus, OH, USA
| | - Ralph Salloum
- Pediatric Brain Tumor Program, Division of Hematology, Oncology, and Bone Marrow Transplant, Nationwide Children's Hospital, 700 Children's Drive, Columbus, OH, 43205, USA.
- The Ohio State University College of Medicine, Columbus, OH, USA.
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29
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Eibl RH, Schneemann M. Liquid biopsy for monitoring medulloblastoma. EXTRACELLULAR VESICLES AND CIRCULATING NUCLEIC ACIDS 2022; 3:280-291. [PMID: 39697492 PMCID: PMC11648495 DOI: 10.20517/evcna.2022.36] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 07/31/2022] [Revised: 08/31/2022] [Accepted: 09/14/2022] [Indexed: 12/20/2024]
Abstract
Despite recent progress in molecular diagnostics defining four distinct medulloblastoma groups, the clinical management of these malignant childhood tumors of the cerebellum remains challenging. After surgical removal of the tumor, both cytotoxic chemotherapy and irradiation can offer additional curative benefits, but they also include a significant risk of long-term damage. Early molecular profiling aims to predict the outcome of such aggressive therapies. This prevents unnecessary damage to patients who may not need it and helps to identify those patients with remaining tumor cells who may benefit from more aggressive treatment with the intent to cure. Monitoring tumor evolution in real time allows personalized precision medicine with an immediate clinical response resulting in a better outcome. Liquid biopsy includes various methodologies already applied in numerous studies and clinical trials for common cancers including brain tumors, but information on medulloblastomas is limited. This review summarizes the recent developments of how liquid biopsy can support or even replace the standard monitoring of medulloblastomas by medical imaging or cytology and discusses what will be needed to make liquid biopsy a new gold standard in diagnosis, therapy, and follow-up of medulloblastomas for the benefit of the patients.
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Affiliation(s)
- Robert H. Eibl
- c/o M. Schneemann, Department of Internal Medicine, Hospitals of Schaffhausen, 8208 Schaffhausen, Switzerland
| | - Markus Schneemann
- Department of Internal Medicine, Hospitals of Schaffhausen, 8208 Schaffhausen, Switzerland
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30
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Upadhyay R, Yadav D, Venkatesulu BP, Singh R, Baliga S, Raval RR, Lazow MA, Salloum R, Fouladi M, Mardis ER, Zaorsky NG, Trifiletti DM, Paulino AC, Palmer JD. Risk of secondary malignant neoplasms in children following proton therapy vs. photon therapy for primary CNS tumors: A systematic review and meta-analysis. Front Oncol 2022; 12:893855. [PMID: 36033525 PMCID: PMC9413159 DOI: 10.3389/fonc.2022.893855] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2022] [Accepted: 07/21/2022] [Indexed: 11/20/2022] Open
Abstract
Background Central nervous system tumors are now the most common primary neoplasms seen in children, and radiation therapy is a key component in management. Secondary malignant neoplasms (SMNs) are rare, but dreaded complications. Proton beam therapy (PBT) can potentially minimize the risk of SMNs compared to conventional photon radiation therapy (RT), and multiple recent studies with mature data have reported the risk of SMNs after PBT. We performed this systematic review and meta-analysis to characterize and compare the incidence of SMNs after proton and photon-based radiation for pediatric CNS tumors. Methods A systematic search of literature on electronic (PubMed, Cochrane Central, and Embase) databases was conducted in accordance with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) method. We included studies reporting the incidence and nature of SMNs in pediatric patients with primary CNS tumors. The crude incidence of SMNs and all secondary neoplasms were separately extracted, and the random-effects model was used for pooled analysis and subgroup comparison was performed between studies using photons vs. protons. Results Twenty-four studies were included for analysis. A total of 418 SMNs were seen in 38,163 patients. The most common SMN were gliomas (40.6%) followed by meningiomas (38.7%), sarcomas (4.8%), and thyroid cancers (4.2%). The median follow-up was 8.8 years [3.3–23.2].The median latency to SMN for photons and protons were 11.9 years [5-23] and 5.9 years [5-6.7], respectively. The pooled incidence of SMNs was 1.8% (95% CI: 1.1%–2.6%, I2 = 94%) with photons and 1.5% (95% CI: 0%–4.5%, I2 = 81%) with protons. The pooled incidence of all SNs was not different [photons: 3.6% (95% CI: 2.5%–4.8%, I2 = 96%) vs. protons: 1.5% (95% CI: 0–4.5%, I2 = 80%); p = 0.21]. Conclusion We observed similar rates of SMN with PBT at 1.5% compared to 1.8% with photon-based RT for pediatric CNS tumors. We observed a shorter latency to SMN with PBT compared to RT. With increasing use of pencil beam scanning PBT and VMAT, further studies are warranted to evaluate the risk of secondary cancers in patients treated with these newer modalities.
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Affiliation(s)
- Rituraj Upadhyay
- Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
| | - Divya Yadav
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | | | - Raj Singh
- Department of Radiation Oncology, Virginia Commonwealth University, Richmond, VA, United States
| | - Sujith Baliga
- Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
| | - Raju R. Raval
- Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
| | - Margot A. Lazow
- Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Ralph Salloum
- Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Maryam Fouladi
- Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Elaine R. Mardis
- Department of Pediatrics, Nationwide Children’s Hospital, Columbus, OH, United States
| | - Nicholas G. Zaorsky
- Department of Radiation Oncology, University Hospitals Seidman Cancer Center, Case Western Reserve School of Medicine, Cleveland, OH, United States
| | | | - Arnold C. Paulino
- Department of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, United States
| | - Joshua D. Palmer
- Department of Radiation Oncology, The James Comprehensive Cancer Center, Ohio State University, Columbus, OH, United States
- *Correspondence: Joshua D. Palmer,
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31
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Zhang M, Liu C, Zhou H, Wang W, Wang L, Shi B, Xue X. Meta of classical chemotherapy compared with high-dose chemotherapy and autologous stem cell rescue in newly diagnosed medulloblastoma after radiotherapy. Medicine (Baltimore) 2022; 101:e29372. [PMID: 35905255 PMCID: PMC9333539 DOI: 10.1097/md.0000000000029372] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023] Open
Abstract
BACKGROUND High-dose chemotherapy combined with autologous stem cell rescue (HDCT + ASCR) has been used to treat newly diagnosed medulloblastoma, but there was no high-level evidence to support its efficacy. METHODS Databases were retrieved, and patients were divided into 2 groups: group A was radiotherapy combined with HCDT + ASCR, and group B was classical radiotherapy and chemotherapy. The clinical benefit rate, progression-free survival (PFS), overall survival (OS) and toxicities data were extracted. RESULTS 22 clinical trials met the inclusion criteria, 416 in group A and 2331 in group B. There was no difference in CBR between 2 groups (80.0% vs 71.5%, P.262). The 3-year PFS (3-y PFS) of group A was significantly better than group B (79.0% vs 69.5%, P = .004). The analysis found that there was no difference between the 2 groups of the standard risk group or the high-risk group. In the standard risk group, the 5-y PFS of group A was significantly better than group B (83.6% vs75.6%, P = .004). Comparison of 3-y OS and 5-y OS between 2 groups of all MB patients showed no difference (P = .086; P = .507), stratified analysis was the same result. The gastrointestinal toxicity in group A was significantly higher than that in group B (P = .016), and the level 3/4 ototoxicity in high-risk group A was higher than that in group B (P = .001). CONCLUSIONS HDCT + ASCR can prolong 3-year PFS significantly, and prolong 5-y PFS significantly in the standard risk group, but increase gastrointestinal toxicity significantly for newly diagnosed medulloblastoma.
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Affiliation(s)
- Mengting Zhang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Oncology, Handan Central Hospital, Handan, Hebei, China
| | - Chunmei Liu
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Huandi Zhou
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Central Laboratory, The Second Hospital of Hebei Medical University, Shijiazhuang, China
- Center of Metabolic Diseases and Cancer Research (CMCR), Hebei Medical University, Shijiazhuang, Hebei, China
| | - Wenyan Wang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Lixin Wang
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Baojun Shi
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Xiaoying Xue
- Department of Radiotherapy, The Second Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
- *Correspondence: Xiaoying Xue, Department of Radiotherapy, The Second Hospital Of Hebei Medical University, No. 215 Heping West Road, Shijiazhuang 050000, Hebei, China (e-mail: )
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Shi HM, Sun ZC, Ju FH. Recommendations for reducing exposure to medical X-ray irradiation (Review). MEDICINE INTERNATIONAL 2022; 2:22. [PMID: 36699506 PMCID: PMC9829209 DOI: 10.3892/mi.2022.47] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 02/18/2022] [Accepted: 07/08/2022] [Indexed: 02/01/2023]
Abstract
With the increasing frequency of X-ray examinations in clinical medicine, public concern regarding the harm caused by exposure to X-ray radiation is also increasing. However, some physicians are not completely aware of the dangers of exposure to X-ray irradiation. Individuals specialized in this field, including physicians, have a better understanding of these dangers, which limits the use of X-rays in medicine. The present study aimed to address strategies for reducing the harm caused by exposure to medical X-rays and increase public awareness regarding X-ray radiation. Through a literature search and review, combined with the current status of clinical X-ray examination and the authors' professional experience, the present study highlights the importance of reducing X-ray exposure, and proposes several specific recommendations and measures for reducing the frequency or dose of X-ray irradiation. On the whole, the finding discussed in the present review suggest the minimal use of medical X-ray examinations and that alternative tests should be selected whenever possible. When medical X-ray screening and treatments are necessary, the risk-benefit ratio should be assessed, possibly aiming to achieve avoidable exposure. Further attention should be paid to protect sensitive glands and reduce the risks in children.
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Affiliation(s)
- Hai-Min Shi
- Department of Gynecology and Obstetrics Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China,Department of Gynecology and Obstetrics Medicine, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Zhi-Chao Sun
- Department of Medical Imaging, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China,Department of Medical Imaging, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310006, P.R. China
| | - Fang-He Ju
- Department of Respiratory Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, Hangzhou, Zhejiang 310006, P.R. China,Department of Respiratory Medicine, Zhejiang Provincial Hospital of Traditional Chinese Medicine, Hangzhou, Zhejiang 310006, P.R. China,Correspondence to: Dr Fang-He Ju, Department of Respiratory Medicine, The First Affiliated Hospital of Zhejiang Chinese Medical University, 54 Youdian Road, Hangzhou, Zhejiang 310006, P.R. China
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The Current State of Radiotherapy for Pediatric Brain Tumors: An Overview of Post-Radiotherapy Neurocognitive Decline and Outcomes. J Pers Med 2022; 12:jpm12071050. [PMID: 35887547 PMCID: PMC9315742 DOI: 10.3390/jpm12071050] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2022] [Revised: 06/10/2022] [Accepted: 06/13/2022] [Indexed: 11/17/2022] Open
Abstract
Tumors of the central nervous system are the most common solid malignancies diagnosed in children. While common, they are also found to have some of the lowest survival rates of all malignancies. Treatment of childhood brain tumors often consists of operative gross total resection with adjuvant chemotherapy or radiotherapy. The current body of literature is largely inconclusive regarding the overall benefit of adjuvant chemo- or radiotherapy. However, it is known that both are associated with conditions that lower the quality of life in children who undergo those treatments. Chemotherapy is often associated with nausea, emesis, significant fatigue, immunosuppression, and alopecia. While radiotherapy can be effective for achieving local control, it is associated with late effects such as endocrine dysfunction, secondary malignancy, and neurocognitive decline. Advancements in radiotherapy grant both an increase in lifetime survival and an increased lifetime for survivors to contend with these late effects. In this review, the authors examined all the published literature, analyzing the results of clinical trials, case series, and technical notes on patients undergoing radiotherapy for the treatment of tumors of the central nervous system with a focus on neurocognitive decline and survival outcomes.
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El Moukhtari SH, Garbayo E, Fernández-Teijeiro A, Rodríguez-Nogales C, Couvreur P, Blanco-Prieto MJ. Nanomedicines and cell-based therapies for embryonal tumors of the nervous system. J Control Release 2022; 348:553-571. [PMID: 35705114 DOI: 10.1016/j.jconrel.2022.06.010] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2022] [Revised: 06/05/2022] [Accepted: 06/08/2022] [Indexed: 11/26/2022]
Abstract
Embryonal tumors of the nervous system are neoplasms predominantly affecting the pediatric population. Among the most common and aggressive ones are neuroblastoma (NB) and medulloblastoma (MB). NB is a sympathetic nervous system tumor, which is the most frequent extracranial solid pediatric cancer, usually detected in children under two. MB originates in the cerebellum and is one of the most lethal brain tumors in early childhood. Their tumorigenesis presents some similarities and both tumors often have treatment resistances and poor prognosis. High-risk (HR) patients require high dose chemotherapy cocktails associated with acute and long-term toxicities. Nanomedicine and cell therapy arise as potential solutions to improve the prognosis and quality of life of children suffering from these tumors. Indeed, nanomedicines have been demonstrated to efficiently reduce drug toxicity and improve drug efficacy. Moreover, these systems have been extensively studied in cancer research over the last few decades and an increasing number of anticancer nanocarriers for adult cancer treatment has reached the clinic. Among cell-based strategies, the clinically most advanced approach is chimeric-antigen receptor (CAR) T therapy for both pathologies, which is currently under investigation in phase I/II clinical trials. However, pediatric drug research is especially hampered due not only to ethical issues but also to the lack of efficient pre-clinical models and the inadequate design of clinical trials. This review provides an update on progress in the treatment of the main embryonal tumors of the nervous system using nanotechnology and cell-based therapies and discusses key issues behind the gap between preclinical studies and clinical trials in this specific area. Some directions to improve their translation into clinical practice and foster their development are also provided.
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Affiliation(s)
- Souhaila H El Moukhtari
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain
| | - Elisa Garbayo
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain
| | - Ana Fernández-Teijeiro
- Pediatric Onco-Hematology Unit, Hospital Universitario Virgen Macarena, School of Medicine, Universidad de Sevilla, Avenida Dr, Fedriani 3, 41009 Sevilla, Spain; Sociedad Española de Hematología y Oncología Pediátricas (SEHOP), Spain
| | - Carlos Rodríguez-Nogales
- School of Pharmaceutical Sciences, University of Geneva, Rue Michel-Servet 1, 1206 Geneva, Switzerland
| | - Patrick Couvreur
- Institut Galien Paris-Sud, UMRCNRS8612,Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry 92296, France
| | - María J Blanco-Prieto
- Department of Pharmaceutical Technology and Chemistry, School of Pharmacy and Nutrition, Universidad de Navarra, C/Irunlarrea 1, 31008 Pamplona, Spain; Instituto de Investigación Sanitaria de Navarra, IdiSNA, C/Irunlarrea 3, 31008 Pamplona, Spain.
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Ruggi A, Melchionda F, Sardi I, Pavone R, Meneghello L, Kitanovski L, Zaletel LZ, Farace P, Zucchelli M, Scagnet M, Toni F, Righetto R, Cianchetti M, Prete A, Greto D, Cammelli S, Morganti AG, Rombi B. Toxicity and Clinical Results after Proton Therapy for Pediatric Medulloblastoma: A Multi-Centric Retrospective Study. Cancers (Basel) 2022; 14:2747. [PMID: 35681727 PMCID: PMC9179586 DOI: 10.3390/cancers14112747] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2022] [Revised: 05/28/2022] [Accepted: 05/30/2022] [Indexed: 02/04/2023] Open
Abstract
Medulloblastoma is the most common malignant brain tumor in children. Even if current treatment dramatically improves the prognosis, survivors often develop long-term treatment-related sequelae. The current radiotherapy standard for medulloblastoma is craniospinal irradiation with a boost to the primary tumor site and to any metastatic sites. Proton therapy (PT) has similar efficacy compared to traditional photon-based radiotherapy but might achieve lower toxicity rates. We report on our multi-centric experience with 43 children with medulloblastoma (median age at diagnosis 8.7 years, IQR 6.6, M/F 23/20; 26 high-risk, 14 standard-risk, 3 ex-infant), who received active scanning PT between 2015 and 2021, with a focus on PT-related acute-subacute toxicity, as well as some preliminary data on late toxicity. Most acute toxicities were mild and manageable with supportive therapy. Hematological toxicity was limited, even among HR patients who underwent hematopoietic stem-cell transplantation before PT. Preliminary data on late sequelae were also encouraging, although a longer follow-up is needed.
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Affiliation(s)
- Alessandro Ruggi
- Specialty School of Paediatrics-Alma Mater Studiorum, Università di Bologna, 40138 Bologna, Italy;
| | - Fraia Melchionda
- Pediatric Onco-Hematology, IRCCS Sant’Orsola SSD, University Hospital of Bologna, 40138 Bologna, Italy; (F.M.); (A.P.)
| | - Iacopo Sardi
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (I.S.); (R.P.)
| | - Rossana Pavone
- Neuro-Oncology Unit, Department of Pediatric Oncology, Meyer Children’s Hospital, 50139 Florence, Italy; (I.S.); (R.P.)
| | - Linda Meneghello
- Pediatric Onco-Hematology Service, Pediatric Unit, Santa Chiara Hospital, 38123 Trento, Italy;
| | - Lidija Kitanovski
- Department of Oncology and Haematology, University Children’s Hospital, University Medical Centre Ljubljana, 1000 Ljubljana, Slovenia;
| | | | - Paolo Farace
- Proton Therapy Unit, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), 38123 Trento, Italy; (P.F.); (R.R.); (M.C.)
| | - Mino Zucchelli
- Pediatric Neurosurgery, Institute of Neurological Science, IRCCS Bellaria Hospital, 40139 Bologna, Italy;
| | - Mirko Scagnet
- Department of Neurosurgery, Meyer Children’s Hospital, 50139 Florence, Italy;
| | - Francesco Toni
- Neuroradiology Unit, IRCCS Istituto delle Scienze Neurologiche di Bologna, 40139 Bologna, Italy;
| | - Roberto Righetto
- Proton Therapy Unit, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), 38123 Trento, Italy; (P.F.); (R.R.); (M.C.)
| | - Marco Cianchetti
- Proton Therapy Unit, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), 38123 Trento, Italy; (P.F.); (R.R.); (M.C.)
| | - Arcangelo Prete
- Pediatric Onco-Hematology, IRCCS Sant’Orsola SSD, University Hospital of Bologna, 40138 Bologna, Italy; (F.M.); (A.P.)
| | - Daniela Greto
- Azienda Ospedaliero-Universitaria Careggi, 50134 Florence, Italy;
| | - Silvia Cammelli
- Radiation Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.C.); (A.G.M.)
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Alessio Giuseppe Morganti
- Radiation Oncology, IRCCS Azienda Ospedaliero-Universitaria di Bologna, 40138 Bologna, Italy; (S.C.); (A.G.M.)
- Department of Experimental, Diagnostic and Specialty Medicine-DIMES, Alma Mater Studiorum, University of Bologna, 40138 Bologna, Italy
| | - Barbara Rombi
- Proton Therapy Unit, Santa Chiara Hospital, Azienda Provinciale per i Servizi Sanitari (APSS), 38123 Trento, Italy; (P.F.); (R.R.); (M.C.)
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Radiomics signature for the prediction of progression-free survival and radiotherapeutic benefits in pediatric medulloblastoma. Childs Nerv Syst 2022; 38:1085-1094. [PMID: 35394210 DOI: 10.1007/s00381-022-05507-6] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2021] [Accepted: 03/18/2022] [Indexed: 11/03/2022]
Abstract
PURPOSE To develop and validate a radiomics signature for progression-free survival (PFS) and radiotherapeutic benefits in pediatric medulloblastoma. MATERIALS AND METHODS We retrospectively enrolled 253 consecutive children with medulloblastoma from two hospitals. A total of 1294 radiomic features were extracted from the region of tumor on the T1-weighted and contrast-enhanced T1-weighted (CE-T1w) MRI. Radiomic feature selection and machine learning modelling were performed to build radiomics signature for the prediction of PFS on the training set. Moreover, the prognostic performance of the clinical parameters was investigated for PFS. The Concordance index (a value of 0.5 indicates no predictive discrimination, and a value of 1 indicates perfect predictive discrimination) was used to measure and compare the prognostic performance of these models. RESULTS The radiomics signature for the prediction of the PFS yielded Concordance indices of 0.711, 0.707, and 0.717 on the training and held-out test sets 1 and 2, respectively. The radiomics nomogram integrating the radiomics signature, age, and metastasis performed better than the nomogram incorporating only clinicopathological factors (C-index, 0.723 vs. 0.665 and 0.722 vs. 0.677 on the held-out test sets 1 and 2, respectively), which was also validated by the good calibration and decision curve analysis. Further analysis demonstrated that patients with lower value of radiomics signature were associated with better clinical outcomes after postoperative radiotherapy (p < 0.001). CONCLUSION The radiomics signature and nomogram performed well for the prediction of PFS and could stratify patients underwent postoperative radiotherapy into the high- and low-risk groups with significantly different clinical outcomes.
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Al Dahhan NZ, Cox E, Nieman BJ, Mabbott DJ. Cross-translational models of late-onset cognitive sequelae and their treatment in pediatric brain tumor survivors. Neuron 2022; 110:2215-2241. [PMID: 35523175 DOI: 10.1016/j.neuron.2022.04.009] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/09/2021] [Revised: 03/21/2022] [Accepted: 04/08/2022] [Indexed: 10/18/2022]
Abstract
Pediatric brain tumor treatments have a high success rate, but survivors are at risk of cognitive sequelae that impact long-term quality of life. We summarize recent clinical and animal model research addressing pathogenesis or evaluating candidate interventions for treatment-induced cognitive sequelae. Assayed interventions encompass a broad range of approaches, including modifications to radiotherapy, modulation of immune response, prevention of treatment-induced cell loss or promotion of cell renewal, manipulation of neuronal signaling, and lifestyle/environmental adjustments. We further emphasize the potential of neuroimaging as a key component of cross-translation to contextualize laboratory research within broader clinical findings. This cross-translational approach has the potential to accelerate discovery to improve pediatric cancer survivors' long-term quality of life.
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Affiliation(s)
- Noor Z Al Dahhan
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada
| | - Elizabeth Cox
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada
| | - Brian J Nieman
- Translational Medicine, Hospital for Sick Children, Toronto, ON, Canada; Mouse Imaging Centre, Hospital for Sick Children, Toronto, ON, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada; Ontario Institute for Cancer Research, Toronto, ON, Canada
| | - Donald J Mabbott
- Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada; Department of Psychology, University of Toronto, Toronto, ON, Canada; Department of Psychology, Hospital for Sick Children, Toronto, ON, Canada.
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Rozowsky JS, Meesters-Ensing JI, Lammers JAS, Belle ML, Nierkens S, Kranendonk MEG, Kester LA, Calkoen FG, van der Lugt J. A Toolkit for Profiling the Immune Landscape of Pediatric Central Nervous System Malignancies. Front Immunol 2022; 13:864423. [PMID: 35464481 PMCID: PMC9022116 DOI: 10.3389/fimmu.2022.864423] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2022] [Accepted: 03/11/2022] [Indexed: 11/13/2022] Open
Abstract
The prognosis of pediatric central nervous system (CNS) malignancies remains dismal due to limited treatment options, resulting in high mortality rates and long-term morbidities. Immunotherapies, including checkpoint inhibition, cancer vaccines, engineered T cell therapies, and oncolytic viruses, have promising results in some hematological and solid malignancies, and are being investigated in clinical trials for various high-grade CNS malignancies. However, the role of the tumor immune microenvironment (TIME) in CNS malignancies is mostly unknown for pediatric cases. In order to successfully implement immunotherapies and to eventually predict which patients would benefit from such treatments, in-depth characterization of the TIME at diagnosis and throughout treatment is essential. In this review, we provide an overview of techniques for immune profiling of CNS malignancies, and detail how they can be utilized for different tissue types and studies. These techniques include immunohistochemistry and flow cytometry for quantifying and phenotyping the infiltrating immune cells, bulk and single-cell transcriptomics for describing the implicated immunological pathways, as well as functional assays. Finally, we aim to describe the potential benefits of evaluating other compartments of the immune system implicated by cancer therapies, such as cerebrospinal fluid and blood, and how such liquid biopsies are informative when designing immune monitoring studies. Understanding and uniformly evaluating the TIME and immune landscape of pediatric CNS malignancies will be essential to eventually integrate immunotherapy into clinical practice.
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Affiliation(s)
| | | | | | - Muriël L. Belle
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
| | - Stefan Nierkens
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
- Center for Translational Immunology, University Medical Center Utrecht, Utrecht, Netherlands
| | | | | | - Friso G. Calkoen
- Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
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Boukhellout A, Ounoughi N, Kharfi F. MONTE-CARLO SIMULATION USING PHITS OF SECONDARY NEUTRONS PRODUCED IN-PATIENT DURING 16O ION THERAPY. RADIATION PROTECTION DOSIMETRY 2022; 198:31-36. [PMID: 35037066 DOI: 10.1093/rpd/ncab188] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/25/2021] [Revised: 12/15/2021] [Accepted: 12/20/2021] [Indexed: 06/14/2023]
Abstract
In hadrontherapy, oxygen ions 16O can be currently considered as an alternative to carbon ions 12C designed specifically for the treatment of deep and radioresistant tumors. Secondary particles, particularly neutrons constitute a serious problem of undesirable additional irradiation to surrounding healthy tissue. The objective of this study is to evaluate, by Monte-Carlo simulation [code Particle and Heavy Ion Transport code System (PHITS)], the contribution in terms of dose of secondary neutrons produced during interaction 16O ion of 300 MeV u-1 in a soft tissue phantom. The dose of 16O ion, secondary particles and neutrons is evaluated, as well as the particle fluence and energy spectra of neutrons. The contribution to the total dose of secondary neutrons in a soft tissue phantom represents 0.1%. This dose, although apparently insignificant, is essential to conduct even more in-depth studies to understand the long-term effects of these secondary neutrons on the patient's body especially in pediatric case.
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Affiliation(s)
- A Boukhellout
- Radiation Physics and Applications Laboratory, Mohammed Seddik Benyahia University, BP 98, Ouled, Aissa Jijel 18000, Algeria
| | - N Ounoughi
- Radiation Physics and Applications Laboratory, Mohammed Seddik Benyahia University, BP 98, Ouled, Aissa Jijel 18000, Algeria
| | - F Kharfi
- Laboratory of Dosing, Analysis and Characterization in High Resolution (DAC), Ferhat Abbas, Setif1 University, Setif 19000, Algeria
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Lafay-Cousin L, Dufour C. High-Dose Chemotherapy in Children with Newly Diagnosed Medulloblastoma. Cancers (Basel) 2022; 14:837. [PMID: 35159104 PMCID: PMC8834150 DOI: 10.3390/cancers14030837] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/11/2022] [Accepted: 01/26/2022] [Indexed: 12/24/2022] Open
Abstract
High-dose chemotherapy with stem cell rescue has been used as an adjuvant therapy or as salvage therapy to treat pediatric patients with brain tumors, and to avoid deleterious side effects of radiotherapy in infants and very young children. Here, we present the most recent trials using high-dose chemotherapy regimens for medulloblastoma in children, and we discuss their contribution to improved survival and describe their toxicity profile and limitations.
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Affiliation(s)
- Lucie Lafay-Cousin
- Section of Pediatric Hematology Oncology and Bone Marrow Transplantation, Alberta Children’s Hospital, Calgary, AB T3B 6A8, Canada
| | - Christelle Dufour
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, 96805 Villejuif, France;
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Normal tissue exposure and second malignancy risk in vertebral-body-sparing craniospinal irradiation. Med Dosim 2022; 47:142-145. [PMID: 34996678 DOI: 10.1016/j.meddos.2021.12.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Revised: 11/22/2021] [Accepted: 12/01/2021] [Indexed: 11/20/2022]
Abstract
The purpose of this study was to compare dose to anterior organs at risk (OARs) and quantify the risk of developing secondary malignancy (SMN) in pediatric patients treated with vertebral-body-sparing (VBS) vs vertebral body (VB) pencil beam scanning proton craniospinal irradiation (CSI). Comparative plans of VBS and VB CSI were created for 10 previously treated patients. Dose-volume histograms were used to evaluate dose to OARs. Absolute excess risk of SMN was calculated according to the organ-specific, radiation-induced cancer incidence based on the organ equivalent dose. OAR dosimetric parameters and absolute excess risk of SMN were compared for VBS and VB plans using the Kruskal-Wallis H test (α = 0.05). VBS CSI leads to significantly lower radiation dose to the heart, esophagus, kidney, liver and bowel. Excluding the vertebral body also significantly decreases the absolute excess risk of SMN for liver, esophagus and bowel. For these reasons, implementation of VBS pencil beam scanning proton CSI should be considered.
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Hill RM, Plasschaert SLA, Timmermann B, Dufour C, Aquilina K, Avula S, Donovan L, Lequin M, Pietsch T, Thomale U, Tippelt S, Wesseling P, Rutkowski S, Clifford SC, Pfister SM, Bailey S, Fleischhack G. Relapsed Medulloblastoma in Pre-Irradiated Patients: Current Practice for Diagnostics and Treatment. Cancers (Basel) 2021; 14:126. [PMID: 35008290 PMCID: PMC8750207 DOI: 10.3390/cancers14010126] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2021] [Revised: 12/23/2021] [Accepted: 12/24/2021] [Indexed: 02/07/2023] Open
Abstract
Relapsed medulloblastoma (rMB) accounts for a considerable, and disproportionate amount of childhood cancer deaths. Recent advances have gone someway to characterising disease biology at relapse including second malignancies that often cannot be distinguished from relapse on imaging alone. Furthermore, there are now multiple international early-phase trials exploring drug-target matches across a range of high-risk/relapsed paediatric tumours. Despite these advances, treatment at relapse in pre-irradiated patients is typically non-curative and focuses on providing life-prolonging and symptom-modifying care that is tailored to the needs and wishes of the individual and their family. Here, we describe the current understanding of prognostic factors at disease relapse such as principal molecular group, adverse molecular biology, and timing of relapse. We provide an overview of the clinical diagnostic process including signs and symptoms, staging investigations, and molecular pathology, followed by a summary of treatment modalities and considerations. Finally, we summarise future directions to progress understanding of treatment resistance and the biological mechanisms underpinning early therapy-refractory and relapsed disease. These initiatives include development of comprehensive and collaborative molecular profiling approaches at relapse, liquid biopsies such as cerebrospinal fluid (CSF) as a biomarker of minimal residual disease (MRD), modelling strategies, and the use of primary tumour material for real-time drug screening approaches.
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Affiliation(s)
- Rebecca M. Hill
- Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne NE1 7RU, UK; (S.C.C.); (S.B.)
| | - Sabine L. A. Plasschaert
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (S.L.A.P.); (M.L.); (P.W.)
| | - Beate Timmermann
- Department of Particle Therapy, West German Proton Therapy Centre Essen (WPE), West German Cancer Center (WTZ), University Hospital Essen, 45147 Essen, Germany;
| | - Christelle Dufour
- Department of Pediatric and Adolescent Oncology, Gustave Roussy, 94800 Villejuif, France;
| | - Kristian Aquilina
- Department of Neurosurgery, Great Ormond Street Hospital, London WC1N 3JH, UK;
| | - Shivaram Avula
- Department of Radiology, Alder Hey Children’s NHS Foundation Trust, Liverpool L12 2AP, UK;
| | - Laura Donovan
- UCL Great Ormond Street Institute of Child Health, London WC1N 1EH, UK;
| | - Maarten Lequin
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (S.L.A.P.); (M.L.); (P.W.)
| | - Torsten Pietsch
- Institute of Neuropathology, DGNN Brain Tumor Reference Center, University of Bonn, 53127 Bonn, Germany;
| | - Ulrich Thomale
- Department of Neurosurgery, Charité-Universitätsmedizin Berlin, 13353 Berlin, Germany;
| | - Stephan Tippelt
- Department of Pediatrics III, Center for Translational Neuro- and Behavioral Sciences (CTNBS), University Hospital of Essen, 45147 Essen, Germany;
| | - Pieter Wesseling
- Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands; (S.L.A.P.); (M.L.); (P.W.)
- Department of Pathology, Amsterdam University Medical Centers/VUmc, 1081 HV Amsterdam, The Netherlands
| | - Stefan Rutkowski
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, 20246 Hamburg, Germany;
| | - Steven C. Clifford
- Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne NE1 7RU, UK; (S.C.C.); (S.B.)
| | - Stefan M. Pfister
- Hopp Children’s Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany;
- Division of Pediatric Neurooncology, German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany
- Department of Pediatric Oncology and Hematology, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Simon Bailey
- Wolfson Childhood Cancer Research Centre, Newcastle University Centre for Cancer, Newcastle upon Tyne NE1 7RU, UK; (S.C.C.); (S.B.)
| | - Gudrun Fleischhack
- Department of Pediatrics III, Center for Translational Neuro- and Behavioral Sciences (CTNBS), University Hospital of Essen, 45147 Essen, Germany;
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Pagnuzzi-Boncompagni M, Picco V, Vial V, Planas-Bielsa V, Vandenberghe A, Daubon T, Derieppe MA, Montemagno C, Durivault J, Grépin R, Martial S, Doyen J, Gavard J, Pagès G. Antiangiogenic Compound Axitinib Demonstrates Low Toxicity and Antitumoral Effects against Medulloblastoma. Cancers (Basel) 2021; 14:cancers14010070. [PMID: 35008234 PMCID: PMC8750527 DOI: 10.3390/cancers14010070] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 01/06/2023] Open
Abstract
Simple Summary Medulloblastoma is the most frequent pediatric brain cancer. Despite great improvements in the treatment of this disease over the last decades, survivors are subject to debilitating adverse effects that strongly impair their quality of life. There is an urgent need to find efficient anticancer therapies with fewer toxic effects. In this study, we suggest that an FDA- and EMA-approved antiangiogenic compound named axitinib may display effective antitumoral effects and low toxicity towards children as compared to a reference treatment currently used in clinical protocols. We also show that this compound can enter the brain compartment and exert antitumoral effects in vivo. Our study paves the way towards a clinical trial of repurposing axitinib to a pediatric brain cancer indication. Abstract Background: Despite the improvement of medulloblastoma (MB) treatments, survivors face severe long-term adverse effects and associated morbidity following multimodal treatments. Moreover, relapses are fatal within a few months. Therefore, chemotherapies inducing fewer adverse effects and/or improving survival at relapse are key for MB patients. Our purpose was to evaluate the last-generation antiangiogenic drugs for their relevance in the therapeutic arsenal of MB. Methods: We screened three EMA- and FDA-approved antiangiogenic compounds (axitinib, cabozantinib and sunitinib) for their ability to reduce cell viability of five MB cell lines and their low toxicity towards two normal cell lines in vitro. Based on this screening, single-agent and combination therapies were designed for in vivo validation. Results: Axitinib, cabozantinib and sunitinib decreased viability of all the tested tumor cells. Although sunitinib was the most efficient in tumor cells, it also impacted normal cells. Therefore, axitinib showed the highest selectivity index for MB cells as compared to normal cells. The compound did not lead to acute toxicity in juvenile rats and crossed the blood–brain barrier. Moreover, axitinib efficiently reduced the growth rate of experimental brain tumors. Analysis of public databases showed that high expression of axitinib targets correlates with poor prognosis. Conclusion: Our results suggest that axitinib is a compelling candidate for MB treatment.
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Affiliation(s)
- Marina Pagnuzzi-Boncompagni
- Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (M.P.-B.); (V.V.); (A.V.); (C.M.); (J.D.); (R.G.)
| | - Vincent Picco
- Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (M.P.-B.); (V.V.); (A.V.); (C.M.); (J.D.); (R.G.)
- Correspondence: (V.P.); (G.P.); Tel.: +377-97-77-44-15 (V.P.); +33-4-92-03-12-39 (G.P.)
| | - Valérie Vial
- Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (M.P.-B.); (V.V.); (A.V.); (C.M.); (J.D.); (R.G.)
| | | | - Ashaina Vandenberghe
- Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (M.P.-B.); (V.V.); (A.V.); (C.M.); (J.D.); (R.G.)
| | - Thomas Daubon
- Institut de Biochimie et Génétique Cellulaires (IBGC), CNRS, University of Bordeaux, UMR 5095, 33000 Bordeaux, France;
| | - Marie-Alix Derieppe
- Animalerie Mutualisée, Service Commun des Animaleries, University of Bordeaux, 33600 Pessac, France;
| | - Christopher Montemagno
- Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (M.P.-B.); (V.V.); (A.V.); (C.M.); (J.D.); (R.G.)
| | - Jérôme Durivault
- Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (M.P.-B.); (V.V.); (A.V.); (C.M.); (J.D.); (R.G.)
| | - Renaud Grépin
- Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (M.P.-B.); (V.V.); (A.V.); (C.M.); (J.D.); (R.G.)
| | - Sonia Martial
- Centre Antoine Lacassagne, Institute for Research on Cancer and Aging of Nice (IRCAN), University Nice Cote d’Azur, CNRS UMR 7284, INSERM U1081, 06189 Nice, France;
| | - Jérôme Doyen
- Department of Radiation Oncology, Centre Antoine-Lacassagne, University of Côte d’Azur, Fédération Claude Lalanne, 06189 Nice, France;
| | - Julie Gavard
- Team SOAP, CRCINA, INSERM, CNRS, Université de Nantes, 44000 Nantes, France;
- Integrated Center of Oncology, 44800 St. Herblain, France
| | - Gilles Pagès
- Biomedical Department, Centre Scientifique de Monaco, 98000 Monaco, Monaco; (M.P.-B.); (V.V.); (A.V.); (C.M.); (J.D.); (R.G.)
- Centre Antoine Lacassagne, Institute for Research on Cancer and Aging of Nice (IRCAN), University Nice Cote d’Azur, CNRS UMR 7284, INSERM U1081, 06189 Nice, France;
- Correspondence: (V.P.); (G.P.); Tel.: +377-97-77-44-15 (V.P.); +33-4-92-03-12-39 (G.P.)
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Perumal N, Kanchan RK, Doss D, Bastola N, Atri P, Chirravuri-Venkata R, Thapa I, Vengoji R, Maurya SK, Klinkebiel D, Talmon GA, Nasser MW, Batra SK, Mahapatra S. MiR-212-3p functions as a tumor suppressor gene in group 3 medulloblastoma via targeting nuclear factor I/B (NFIB). Acta Neuropathol Commun 2021; 9:195. [PMID: 34922631 PMCID: PMC8684142 DOI: 10.1186/s40478-021-01299-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2021] [Accepted: 12/01/2021] [Indexed: 12/30/2022] Open
Abstract
Haploinsufficiency of chromosome 17p and c-Myc amplification distinguish group 3 medulloblastomas which are associated with early metastasis, rapid recurrence, and swift mortality. Tumor suppressor genes on this locus have not been adequately characterized. We elucidated the role of miR-212-3p in the pathophysiology of group 3 tumors. First, we learned that miR-212-3p undergoes epigenetic silencing by histone modifications in group 3 tumors. Restoring its expression reduced cancer cell proliferation, migration, colony formation, and wound healing in vitro and attenuated tumor burden and improved survival in vivo. MiR-212-3p also triggered c-Myc destabilization and degradation, leading to elevated apoptosis. We then isolated an oncogenic target of miR-212-3p, i.e. NFIB, a nuclear transcription factor implicated in metastasis and recurrence in various cancers. Increased expression of NFIB was confirmed in group 3 tumors and associated with poor survival. NFIB silencing reduced cancer cell proliferation, migration, and invasion. Concurrently, reduced medullosphere formation and stem cell markers (Nanog, Oct4, Sox2, CD133) were noted. These results substantiate the tumor-suppressive role of miR-212-3p in group 3 MB and identify a novel oncogenic target implicated in metastasis and tumor recurrence.
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Affiliation(s)
- Naveenkumar Perumal
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Ranjana K Kanchan
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Doss
- Department of Biomedical Sciences, Creighton University School of Medicine, Omaha, NE, 68124, USA
| | - Noah Bastola
- Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, St. Louis, MO, 63110, USA
| | - Pranita Atri
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | | | - Ishwor Thapa
- School of Interdisciplinary Informatics, University of Nebraska at Omaha, Omaha, NE, 68182, USA
| | - Raghupathy Vengoji
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Shailendra K Maurya
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - David Klinkebiel
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Geoffrey A Talmon
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Mohd W Nasser
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Surinder K Batra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA
| | - Sidharth Mahapatra
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
- Department of Pediatrics, University of Nebraska Medical Center, Omaha, NE, 68198, USA.
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Kloth K, Obrecht D, Sturm D, Pietsch T, Warmuth-Metz M, Bison B, Mynarek M, Rutkowski S. Defining the Spectrum, Treatment and Outcome of Patients With Genetically Confirmed Gorlin Syndrome From the HIT-MED Cohort. Front Oncol 2021; 11:756025. [PMID: 34888241 PMCID: PMC8649840 DOI: 10.3389/fonc.2021.756025] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Accepted: 11/04/2021] [Indexed: 12/27/2022] Open
Abstract
Gorlin syndrome is a genetic condition associated with the occurrence of SHH activated medulloblastoma, basal cell carcinoma, macrocephaly and other congenital anomalies. It is caused by heterozygous pathogenic variants in PTCH1 or SUFU. In this study we included 16 patients from the HIT2000, HIT2000interim, I-HIT-MED, observation registry and older registries such as HIT-SKK87, HIT-SKK92 (1987 – 2020) with genetically confirmed Gorlin syndrome, harboring 10 PTCH1 and 6 SUFU mutations. Nine patients presented with desmoplastic medulloblastomas (DMB), 6 with medulloblastomas with extensive nodularity (MBEN) and one patient with classic medulloblastoma (CMB); all tumors affected the cerebellum, vermis or the fourth ventricle. SHH activation was present in all investigated tumors (14/16); DNA methylation analysis (when available) classified 3 tumors as iSHH-I and 4 tumors as iSHH-II. Age at diagnosis ranged from 0.65 to 3.41 years. All but one patient received chemotherapy according to the HIT-SKK protocol. Ten patients were in complete remission after completion of primary therapy; four subsequently presented with PD. No patient received radiotherapy during initial treatment. Five patients acquired additional neoplasms, namely basal cell carcinomas, odontogenic tumors, ovarian fibromas and meningioma. Developmental delay was documented in 5/16 patients. Overall survival (OS) and progression-free survival (PFS) between patients with PTCH1 or SUFU mutations did not differ statistically (10y-OS 90% vs. 100%, p=0.414; 5y-PFS 88.9% ± 10.5% vs. 41.7% ± 22.2%, p=0.139). Comparing the Gorlin patients to all young, SHH activated MBs in the registries (10y-OS 93.3% ± 6.4% vs. 92.5% ± 3.3%, p=0.738; 10y-PFS 64.9%+-16.7% vs. 83.8%+-4.5%, p=0.228) as well as comparing Gorlin M0 SKK-treated patients to all young, SHH activated, M0, SKK-treated MBs in the HIT-MED database did not reveal significantly different clinical outcomes (10y-OS 88.9% ± 10.5% vs. 88% ± 4%, p=0.812; 5y-PFS 87.5% ± 11.7% vs. 77.7% ± 5.1%, p=0.746). Gorlin syndrome should be considered in young children with SHH activated medulloblastoma, especially DMB and MBEN but cannot be ruled out for CMB. Survival did not differ to patients with SHH-activated medulloblastoma with unknown germline status or between PTCH1 and SUFU mutated patients. Additional neoplasms, especially basal cell carcinomas, need to be expected and screened for. Genetic counselling should be provided for families with young medulloblastoma patients with SHH activation.
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Affiliation(s)
- Katja Kloth
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Denise Obrecht
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Dominik Sturm
- Hopp Children's Cancer Center (KiTZ) Heidelberg, Heidelberg, Germany.,Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) Heidelberg, Heidelberg, Germany.,Department of Pediatric Oncology, Hematology, and Immunology, Heidelberg University Hospital, Heidelberg, Germany
| | - Torsten Pietsch
- Department of Neuropathology, Deutsche Gesellschaft für Neuropathologie und Neuroanatomie (DGNN) Brain Tumor Reference Center, Bonn, Germany
| | - Monika Warmuth-Metz
- Institute of Diagnostic and Interventional Neuroradiology, University Hospital Wuerzburg, Wuerzburg, Germany
| | - Brigitte Bison
- Department of Diagnostic and Interventional Neuroradiology, University Hospital Augsburg, Augsburg, Germany
| | - Martin Mynarek
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Rutkowski
- Department of Pediatric Hematology and Oncology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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Experimental Assessment of Leptomeningeal Metastasis Diagnosis in Medulloblastoma Using Cerebrospinal Fluid Metabolomic Profiles. Metabolites 2021; 11:metabo11120851. [PMID: 34940608 PMCID: PMC8708677 DOI: 10.3390/metabo11120851] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 12/02/2021] [Accepted: 12/04/2021] [Indexed: 11/17/2022] Open
Abstract
Diagnosing leptomeningeal metastasis (LM) in medulloblastoma is currently based on positive cerebrospinal fluid (CSF) cytology or magnetic resonance imaging (MRI) finding. However, the relevance of discordant results has not been established. We evaluated the diagnostic potential of CSF metabolomic profiles in the medulloblastoma LM assessment. A total of 83 CSF samples from medulloblastoma patients with documented MRI and CSF cytology results at the time of sampling for LM underwent low-mass ions (LMIs) analysis using liquid chromatography-mass spectrometry. Discriminating LMIs were selected by a summed sensitivity and specificity (>160%) and LMI discriminant equation (LOME) algorithms, evaluated by measuring diagnostic accuracy for verifying LM groups of different MRI/cytology results. Diagnostic accuracy of LM in medulloblastoma was 0.722 for cytology and 0.889 for MRI. Among 6572 LMIs identified in all sample, we identified 27 discriminative LMIs differentiating MRI (+)/cytology (+) from MRI (-)/cytology (-). Using LMI discriminant equation (LOME) analysis, we selected 9 LMIs with a sensitivity of 100% and a specificity of 93.6% for differentiating MRI (+)/cytology (+) from MRI (-)/cytology (-). Another LOME of 20 LMIs significantly differentiated sampling time relative to treatment (p = 0.007) and the presence or absence of LM-related symptoms (p = 0.03) in the MRI (+)/cytology (-) group. CSF metabolomics of medulloblastoma patients revealed significantly different profiles among LM diagnosed with different test results. We suggest that LM patients could be screened by appropriately selected LOME-generated LMIs to support LM diagnosis by either MRI or cytology alone.
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Friedman GK, Dhall G. Potential role of carbon ion radiotherapy in chromothripsis-induced medulloblastoma and other malignancies. Neuro Oncol 2021; 23:1991. [PMID: 34605541 DOI: 10.1093/neuonc/noab232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Affiliation(s)
- Gregory K Friedman
- Department of Pediatrics, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Girish Dhall
- Department of Pediatrics, Division of Hematology/Oncology, University of Alabama at Birmingham, Birmingham, Alabama, USA
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Baliga S, Gallotto S, Bajaj B, Lewy J, Weyman E, Lawell M, Yeap BY, Ebb DE, Huang M, Caruso P, Perry A, Jones RM, MacDonald SM, Tarbell NJ, Yock TI. Decade Long Disease, Secondary Malignancy, and Brainstem Injury Outcomes in Pediatric and Young Adult Medulloblastoma Patients Treated with Proton Radiotherapy. Neuro Oncol 2021; 24:1010-1019. [PMID: 34788463 DOI: 10.1093/neuonc/noab257] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/12/2022] Open
Abstract
BACKGROUND Survivors of pediatric medulloblastoma experience long term morbidity associated with the toxic effects of post-operative radiotherapy. Proton radiotherapy limits radiation dose to normal tissues thereby reducing side effects of treatment while maintaining high cure rates. However, long term data on disease outcomes and long-term effects of proton radiotherapy remain limited. METHODS 178 Pediatric medulloblastoma patients treated with proton radiotherapy between 2002-2016 at the Massachusetts General Hospital comprise the cohort of patients who were treated with surgery, radiation therapy and chemotherapy. We evaluated EFS, OS, and LC using the Kaplan Meier method. The cumulative incidence of brainstem injury and secondary malignancies was assessed. RESULTS Median follow-up was 9.3 years. 159 patients (89.3%) underwent a gross total resection (GTR). The 10-year OS for the entire cohort, standard risk, and intermediate/high risk patients was 79.3%, 86.9%, and 68.9% respectively. The 10-year EFS for entire cohort, SR, and IR/HR cohorts was 73.8%, 79.5%, and 66.2%. The 10-year EFS and OS for patients with GTR/NTR were 75.3% and 81.0% versus 57.7% and 61.0% for STR. On univariate analysis, IR/HR status was associated with inferior EFS, while both anaplastic histology and IR/HR status was associated with worse overall survival. The 10-year cumulative incidence of secondary tumors and brainstem injury was 5.6% and 2.1%, respectively. CONCLUSIONS In this cohort study of pediatric medulloblastoma, proton radiotherapy was effective and disease outcomes were comparable to historically treated photon cohorts. The incidence of secondary malignancies and brainstem injury was low in this cohort with mature follow up.
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Affiliation(s)
- Sujith Baliga
- Department of Radiation Oncology, The Ohio State University Wexner Medical Center, Columbus, OH
| | - Sara Gallotto
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Benjamin Bajaj
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Jaqueline Lewy
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Elizabeth Weyman
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Miranda Lawell
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Beow Y Yeap
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - David E Ebb
- Department of Pediatric Hematology Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Mary Huang
- Department of Pediatric Hematology Oncology, Massachusetts General Hospital, Boston, Massachusetts
| | - Paul Caruso
- Department of Pediatric Neuroradiology, Massachusetts General Hospital, Boston, Massachusetts
| | - Alisa Perry
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Robin M Jones
- Department of Pediatric Neurology, Massachusetts General Hospital, Boston, Massachusetts
| | - Shannon M MacDonald
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Nancy J Tarbell
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
| | - Torunn I Yock
- Department of Radiation Oncology, Massachusetts General Hospital/Harvard Medical School, Boston, Massachusetts
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49
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Izmailov TR, Melnik SY. [Early and long-term outcomes of treatment in patients with medulloblastoma]. ZHURNAL VOPROSY NEĬROKHIRURGII IMENI N. N. BURDENKO 2021; 85:57-62. [PMID: 34714004 DOI: 10.17116/neiro20218505157] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
OBJECTIVE To compare the modes of craniospinal irradiation (CSI) and to determine possible factors improving the outcome in patients with medulloblastoma. MATERIAL AND METHODS The study included 92 patients with medulloblastoma who were treated at the Russian Research Radiology Center between 2008 and 2019. Mean age of patients was 12 years. Classical morphological variant of medulloblastoma prevailed (48.4%). After surgery, 78 patients underwent radiotherapy (CSI + full-volume «boost» on the tumor site). Standard risk patients received CSI in a reduced dose after tumor resection. Weekly modification of radiotherapy with vincristine was performed in 73 (79.3%) patients. RESULTS We significantly (p<0.05) determined the total focal doses for CSI in patients with medulloblastoma. Total resection of posterior cranial fossa tumor improved relapse-free survival by several times. Complete CSI up to total dose of 36/54 Gy ensures the most positive effect compared to irradiation in reduced dose. CONCLUSION Relapse-free survival significantly depends on total focal dose of CSI. Single focal dose, chemotherapeutic modification of radiotherapy and M-stage had no significant effect on relapse-free survival. Perhaps, this is due to small sample size.
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Affiliation(s)
- T R Izmailov
- Russian Research Radiology Center, Moscow, Russia.,Pirogov Russian National Research Medical University, Moscow, Russia
| | - S Yu Melnik
- Russian Research Radiology Center, Moscow, Russia
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50
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Thomas P, Galopin N, Bonérandi E, Clémenceau B, Fougeray S, Birklé S. CAR T Cell Therapy's Potential for Pediatric Brain Tumors. Cancers (Basel) 2021; 13:cancers13215445. [PMID: 34771608 PMCID: PMC8582542 DOI: 10.3390/cancers13215445] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2021] [Revised: 10/11/2021] [Accepted: 10/25/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary T cells that are genetically engineered to express chimeric antigen receptors constitute an effective new therapy with curative potential for patients with hematological tumors. The value of chimeric antigen receptor T cells in childhood brain tumors, the leading cause of cancer death in children, is less clear. In this context, the main obstacles for these engineered T cells remain how to find them, allow them to infiltrate, and induce them to remain active in the tumor site. Here, we discuss recent progress in the field and examine future directions for realizing the potential of this therapy. Abstract Malignant central nervous system tumors are the leading cause of cancer death in children. Progress in high-throughput molecular techniques has increased the molecular understanding of these tumors, but the outcomes are still poor. Even when efficacious, surgery, radiation, and chemotherapy cause neurologic and neurocognitive morbidity. Adoptive cell therapy with autologous CD19 chimeric antigen receptor T cells (CAR T) has demonstrated remarkable remission rates in patients with relapsed refractory B cell malignancies. Unfortunately, tumor heterogeneity, the identification of appropriate target antigens, and location in a growing brain behind the blood–brain barrier within a specific suppressive immune microenvironment restrict the efficacy of this strategy in pediatric neuro-oncology. In addition, the vulnerability of the brain to unrepairable tissue damage raises important safety concerns. Recent preclinical findings, however, have provided a strong rationale for clinical trials of this approach in patients. Here, we examine the most important challenges associated with the development of CAR T cell immunotherapy and further present the latest preclinical strategies intending to optimize genetically engineered T cells’ efficiency and safety in the field of pediatric neuro-oncology.
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Affiliation(s)
- Pauline Thomas
- Université de Nantes, INSERM, CRCINA, F-44000 Nantes, France; (P.T.); (N.G.); (E.B.); (S.F.)
| | - Natacha Galopin
- Université de Nantes, INSERM, CRCINA, F-44000 Nantes, France; (P.T.); (N.G.); (E.B.); (S.F.)
| | - Emma Bonérandi
- Université de Nantes, INSERM, CRCINA, F-44000 Nantes, France; (P.T.); (N.G.); (E.B.); (S.F.)
| | - Béatrice Clémenceau
- Université de Nantes, CHU Nantes, CNRS, INSERM, CRCINA, F-44000 Nantes, France;
| | - Sophie Fougeray
- Université de Nantes, INSERM, CRCINA, F-44000 Nantes, France; (P.T.); (N.G.); (E.B.); (S.F.)
| | - Stéphane Birklé
- Université de Nantes, INSERM, CRCINA, F-44000 Nantes, France; (P.T.); (N.G.); (E.B.); (S.F.)
- Correspondence: ; Tel.: +33-228-08-03-00
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