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Vetsika EK, Katsianou MA, Sarantis P, Palamaris K, Papavassiliou AG, Piperi C. Pediatric gliomas immunity challenges and immunotherapy advances. Cancer Lett 2025; 618:217640. [PMID: 40090572 DOI: 10.1016/j.canlet.2025.217640] [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: 02/11/2025] [Revised: 03/11/2025] [Accepted: 03/12/2025] [Indexed: 03/18/2025]
Abstract
Pediatric gliomas, the most frequent brain tumors in children, are characterized by heterogeneity and a unique tumor immune microenvironment. They are categorized into different subtypes, including low-grade gliomas like pilocytic astrocytomas and high-grade gliomas such as diffuse midline gliomas and diffuse intrinsic pontine gliomas, each exhibiting distinct immunological profiles. The tumor immune microenvironment in pediatric gliomas is shaped by cellular and non-cellular components, including immune cells, cytokines, and the extracellular matrix, involved in tumor progression, immune evasion, and response to therapy. While pediatric low-grade gliomas often display an immunosuppressed microenvironment, high-grade gliomas are characterized by complex immune infiltrates and intricate immunosuppressive mechanisms. The blood-brain barrier further obscures immune cell recruitment and therapeutic delivery. Despite advances in understanding adult gliomas, the immunobiology of pediatric tumors is poorly investigated, with limited data on the interactions between glioma cells and immune populations such as T and natural killer cells, as well as tumor-associated macrophages. Herein, we provide an update of the current knowledge on tumor immune microenvironment interactions in pediatric gliomas, highlighting the immunosuppressive mechanisms and emerging immunotherapeutic strategies aiming at overcoming these barriers to improve clinical outcomes for affected children.
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Affiliation(s)
- Eleni-Kyriaki Vetsika
- Centre of New Biotechnologies and Precision Medicine (CNBPM), School of Medicine, National and Kapodistrian University of Athens, Athens, Greece
| | - Maria A Katsianou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Panagiotis Sarantis
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Kostas Palamaris
- First Department of Pathology, School of Medicine, National and Kapodistrian University of Athens, 10679, Athens, Greece
| | - Athanasios G Papavassiliou
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - Christina Piperi
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Athens, Greece.
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Mwebe VK, Wegoye E, Ssekabunga J, Onen J, Kibudde S, Chintagumpala M, Lubega J. A Case Series of Children With Medulloblastoma Depicting the Disparities in Care and the Challenges in the Detection and Treatment of Pediatric Central Nervous System Tumors in Low-Resource Settings: A Case Study of Uganda. Pediatr Neurol 2024; 161:67-72. [PMID: 39305574 DOI: 10.1016/j.pediatrneurol.2024.08.006] [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: 01/24/2024] [Revised: 07/27/2024] [Accepted: 08/16/2024] [Indexed: 11/29/2024]
Abstract
BACKGROUND Primary central nervous system tumors are the second most common cancer among children in high-income countries (HICs). These tumors are also the leading cause of cancer-related deaths in children in this setting. Studies from HICs report gliomas as the most common pediatric cancer. However, there is paucity of data from low- and middle-income countries as not many publications have been made in this field. METHODS The objective was to describe the disparities in detection, treatment, and survival of children with central nervous system tumors in low-income countries (LICs) when compared with HICs, using a case series. A retrospective chart review of three children treated for medulloblastoma in Uganda was done. In addition, a review of the literature about management of pediatric central nervous system tumors in both LICs and HICs was conducted. RESULTS There are no quantifiable results for this case series. CONCLUSION There are notable differences in the quality of care for children with pediatric central nervous system tumors in LICs when compared with HICs. In Uganda, the challenges in management of these children include few multidisciplinary specialists, long distance from the neurosurgery centers, and difficulties in making a correct pathologic diagnosis, among others.
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Affiliation(s)
- Victoria Katasi Mwebe
- Department of Pediatrics and Child Health, Pediatric Hematology/Oncology, Mulago National Referral Hospital, Kampala, Uganda.
| | - Emmanuel Wegoye
- Department of Neurosurgery, CURE Children's Hospital of Uganda, Mbale, Uganda
| | - Julie Ssekabunga
- Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda
| | - Justine Onen
- Department of Neurosurgery, Mulago National Referral Hospital, Kampala, Uganda
| | - Solomon Kibudde
- Department of Radiation Oncology, Uganda Cancer Institute, Kampala, Uganda
| | - Murali Chintagumpala
- Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas
| | - Joseph Lubega
- Department of Pediatrics, Baylor College of Medicine/Texas Children's Hospital, Houston, Texas
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Kurzbuch AR, Wahedi A, Calisto A, Magdum S. Symptomatic cerebral vasospasm after posterior fossa surgery in pediatric patients: single-center study and systematic literature review. Childs Nerv Syst 2024; 40:4211-4223. [PMID: 39325181 DOI: 10.1007/s00381-024-06630-2] [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: 06/25/2024] [Accepted: 09/20/2024] [Indexed: 09/27/2024]
Abstract
PURPOSE The most common cause of cerebral vasospasm is subarachnoid hemorrhage, less frequently it occurs after trauma, infection, and tumor resection. Vasospasm in children is rare and has not been systematically investigated in posterior fossa surgery. METHODS The authors undertook a single-center retrospective study of all the pediatric patients who underwent surgery on the posterior fossa and presented with postoperative symptomatic vasospasm in the period from January 2018 to February 2024. Subsequently, a systematic literature review in accordance with the PRISMA guidelines was performed in the PubMed and Scopus databases to identify the published papers on symptomatic vasospasm after posterior fossa surgery in children. RESULTS Of the 178 patients who underwent surgery on the posterior fossa, only one patient was diagnosed with symptomatic diffuse vasospasm on postoperative day 21. The systematic literature review provided further 9 children. The underlying pathology comprised 8 intra-axial lesions with 4 medulloblastomas, 1 schwannoma in the medulla oblongata, 1 pilocytic astrocytoma, 1 primitive neuroectodermal tumor, and 1 arteriovenous malformation. The extra-axial lesions were 1 hypoglossal schwannoma and 1 oculomotor nerve schwannoma. CONCLUSION Iatrogenic symptomatic vasospasm after posterior fossa surgery in children is a rare complication with an outcome ranging from complete recovery to the death of the patient. It is important for all staff involved in the care of patients undergoing surgery on the posterior fossa to be aware of this rare postoperative complication. The small number of patients affected does not allow a substantiated conclusion to be drawn about predictive risk factors.
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Affiliation(s)
- Arthur R Kurzbuch
- Department of Pediatric Neurosurgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK.
| | - Azizia Wahedi
- Medical Sciences Division, University of Oxford, Oxford, OX3 9DU, UK
| | - Amedeo Calisto
- Department of Pediatric Neurosurgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK
| | - Shailendra Magdum
- Department of Pediatric Neurosurgery, Oxford University Hospitals NHS Foundation Trust, John Radcliffe Hospital, Oxford, OX3 9DU, UK
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Huang ZL, Liu ZG, Lin Q, Tao YL, Li X, Baxter P, Su JM, Adesina AM, Man C, Chintagumpala M, Teo WY, Du YC, Xia YF, Li XN. Fractionated radiation therapy alters energy metabolism and induces cellular quiescence exit in patient-derived orthotopic xenograft models of high-grade glioma. Transl Oncol 2024; 45:101988. [PMID: 38733642 PMCID: PMC11101904 DOI: 10.1016/j.tranon.2024.101988] [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: 11/29/2023] [Revised: 04/23/2024] [Accepted: 05/06/2024] [Indexed: 05/13/2024] Open
Abstract
Radiation is one of the standard therapies for pediatric high-grade glioma (pHGG), of which the prognosis remains poor. To gain an in-depth understanding of biological consequences beyond the classic DNA damage, we treated 9 patient-derived orthotopic xenograft (PDOX) models, including one with DNA mismatch repair (MMR) deficiency, with fractionated radiations (2 Gy/day x 5 days). Extension of survival time was noted in 5 PDOX models (P < 0.05) accompanied by γH2AX positivity in >95 % tumor cells in tumor core and >85 % in the invasive foci as well as ∼30 % apoptotic and mitotic catastrophic cell death. The model with DNA MMR (IC-1406HGG) was the most responsive to radiation with a reduction of Ki-67(+) cells. Altered metabolism, including mitochondria number elevation, COX IV activation and reactive oxygen species accumulation, were detected together with the enrichment of CD133+ tumor cells. The latter was caused by the entry of quiescent G0 cells into cell cycle and the activation of self-renewal (SOX2 and BMI1) and epithelial mesenchymal transition (fibronectin) genes. These novel insights about the cellular and molecular mechanisms of fractionated radiation in vivo should support the development of new radio-sensitizing therapies.
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Affiliation(s)
- Zi-Lu Huang
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510060, PR China; Department of Pediatrics, Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Zhi-Gang Liu
- Cancer Center, The 10th Affiliated Hospital of Southern Medical University (Dongguan People's Hospital), Southern Medical University, China; Dongguan Key Laboratory of Precision Diagnosis and Treatment for Tumors, The 10th Affiliated Hospital of Southern Medical University, Southern Medical University, China; Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States.
| | - Qi Lin
- Department of Pediatrics, Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Department of Pharmacology, School of Medicine, Sun Yat-Sen University, Guangzhou, Guangdong 510080, China
| | - Ya-Lan Tao
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510060, PR China
| | - Xinzhuoyun Li
- Department of Pediatrics, Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States
| | - Patricia Baxter
- Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Jack Mf Su
- Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Adekunle M Adesina
- Department of Pathology, Texas Children's Hospital, Houston, TX, United States
| | - Chris Man
- Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Murali Chintagumpala
- Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States
| | - Wan Yee Teo
- Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States; The Laboratory of Pediatric Brain Tumor Research Office, SingHealth Duke-NUS Academic Medical Center, 169856, Singapore; Cancer and Stem Cell Biology Program, Duke-NUS Medical School Singapore, A*STAR, KK Women's & Children's Hospital Singapore, Institute of Molecular and Cell Biology, Singapore
| | - Yu-Chen Du
- Department of Pediatrics, Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States.
| | - Yun-Fei Xia
- Department of Radiation Oncology, State Key Laboratory of Oncology in South China, Guangdong Provincial Clinical Research Center for Cancer, Sun Yat-Sen University Cancer Center, Guangzhou 510060, PR China.
| | - Xiao-Nan Li
- Department of Pediatrics, Program of Precision Medicine PDOX Modeling of Pediatric Tumors, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States; Texas Children's Cancer Center and Department of Pediatrics, Baylor College of Medicine, Houston, TX, United States; Robert H. Lurie Comprehensive Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, United States.
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Almalki YE, Basha MAA, Metwally MI, Zeed NA, Nada MG, Alduraibi SK, Morsy AA, Balata R, Al Attar AZ, Amer MM, Farag MAEAM, Aly SA, Basha AMA, Hamed EM. Validating Brain Tumor Reporting and Data System (BT-RADS) as a Diagnostic Tool for Glioma Follow-Up after Surgery. Biomedicines 2024; 12:887. [PMID: 38672241 PMCID: PMC11048183 DOI: 10.3390/biomedicines12040887] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2024] [Revised: 04/03/2024] [Accepted: 04/09/2024] [Indexed: 04/28/2024] Open
Abstract
Gliomas are a type of brain tumor that requires accurate monitoring for progression following surgery. The Brain Tumor Reporting and Data System (BT-RADS) has emerged as a potential tool for improving diagnostic accuracy and reducing the need for repeated operations. This prospective multicenter study aimed to evaluate the diagnostic accuracy and reliability of BT-RADS in predicting tumor progression (TP) in postoperative glioma patients and evaluate its acceptance in clinical practice. The study enrolled patients with a history of partial or complete resection of high-grade glioma. All patients underwent two consecutive follow-up brain MRI examinations. Five neuroradiologists independently evaluated the MRI examinations using the BT-RADS. The diagnostic accuracy of the BT-RADS for predicting TP was calculated using histopathology after reoperation and clinical and imaging follow-up as reference standards. Reliability based on inter-reader agreement (IRA) was assessed using kappa statistics. Reader acceptance was evaluated using a short survey. The final analysis included 73 patients (male, 67.1%; female, 32.9%; mean age, 43.2 ± 12.9 years; age range, 31-67 years); 47.9% showed TP, and 52.1% showed no TP. According to readers, TP was observed in 25-41.7% of BT-3a, 61.5-88.9% of BT-3b, 75-90.9% of BT-3c, and 91.7-100% of BT-RADS-4. Considering >BT-RADS-3a as a cutoff value for TP, the sensitivity, specificity, and accuracy of the BT-RADS were 68.6-85.7%, 84.2-92.1%, and 78.1-86.3%, respectively, according to the reader. The overall IRA was good (κ = 0.75) for the final BT-RADS classification and very good for detecting new lesions (κ = 0.89). The readers completely agreed with the statement "the application of the BT-RADS should be encouraged" (score = 25). The BT-RADS has good diagnostic accuracy and reliability for predicting TP in postoperative glioma patients. However, BT-RADS 3 needs further improvements to increase its diagnostic accuracy.
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Affiliation(s)
- Yassir Edrees Almalki
- Division of Radiology, Department of Internal Medicine, Medical College, Najran University, Najran 61441, Saudi Arabia;
| | - Mohammad Abd Alkhalik Basha
- Department of Diagnostic Radiology, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt; (M.I.M.); (N.A.Z.); (M.G.N.); (E.M.H.)
| | - Maha Ibrahim Metwally
- Department of Diagnostic Radiology, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt; (M.I.M.); (N.A.Z.); (M.G.N.); (E.M.H.)
| | - Nesma Adel Zeed
- Department of Diagnostic Radiology, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt; (M.I.M.); (N.A.Z.); (M.G.N.); (E.M.H.)
| | - Mohamad Gamal Nada
- Department of Diagnostic Radiology, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt; (M.I.M.); (N.A.Z.); (M.G.N.); (E.M.H.)
| | | | - Ahmed A. Morsy
- Department of Neurosurgery, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt;
| | - Rawda Balata
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt; (R.B.); (A.Z.A.A.)
| | - Ahmed Z. Al Attar
- Department of Clinical Oncology and Nuclear Medicine, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt; (R.B.); (A.Z.A.A.)
| | - Mona M. Amer
- Department of Neurology, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt;
| | | | - Sameh Abdelaziz Aly
- Department of Diagnostic Radiology, Faculty of Human Medicine, Benha University, Benha 13511, Egypt;
| | | | - Enas Mahmoud Hamed
- Department of Diagnostic Radiology, Faculty of Human Medicine, Zagazig University, Zagazig 44519, Egypt; (M.I.M.); (N.A.Z.); (M.G.N.); (E.M.H.)
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del Río RJ, Cicutti SE, Moreira DC, Ramos JDG. New CNS tumor classification: The importance in pediatric neurosurgical practice. Surg Neurol Int 2024; 15:130. [PMID: 38742003 PMCID: PMC11090558 DOI: 10.25259/sni_681_2023] [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: 08/12/2023] [Accepted: 03/26/2024] [Indexed: 05/16/2024] Open
Abstract
Background The management of the central nervous system (CNS) tumors in the pediatric population is crucial in neurosurgical practice. The World Health Organization (WHO) has evolved its classification of CNS tumors from the 19th century to the 5th edition, published in 2021, incorporating molecular advancements. This transition from morphology to molecular characterization is ongoing. Methods This manuscript analyzes the modifications introduced in the 5th edition of WHO's CNS tumor classification, particularly focusing on pediatric tumor families. The paper integrates clinical, morphological, and molecular information, aiming to guide pediatric neurosurgeons in their daily practice and interdisciplinary discussions. Results The 5th edition of the WHO classification introduces a hybrid taxonomy that incorporates both molecular and histological components. The terminology shifts from "entity" to "type" and "subtype," aiming to standardize terminology. Tumor grading experiences changes, integrating molecular biomarkers for prognosis. The concept of integrated layered diagnosis is emphasized, where molecular and histological information is combined systematically. Conclusion The 5th edition of the WHO CNS classification signifies a paradigm shift toward molecular characterization. The incorporation of molecular advances, the layered diagnostic approach, and the inclusion of clinical, morphological, and molecular information aim to provide comprehensive insights into pediatric CNS tumors. This classification offers valuable guidance for pediatric neurosurgeons, aiding in precise diagnosis and treatment planning for these complex neoplasms.
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Affiliation(s)
- Ramiro José del Río
- Department of Neurosurgery, Hospital de Pediatría Juan P. Garrahan, Ciudad Autónoma de Buenos Aires, Argentina
| | - Santiago Ezequiel Cicutti
- Department of Neurosurgery, Hospital de Pediatría Juan P. Garrahan, Ciudad Autónoma de Buenos Aires, Argentina
| | - Daniel C. Moreira
- Department of Oncology, St. Jude Children’s Research Hospital, Memphis, United States
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Huang HM, Yeh TC, Lee TY. Taiwanese fathers' experiences of caring for their children during childhood cancer treatment. Eur J Oncol Nurs 2024; 69:102543. [PMID: 38457933 DOI: 10.1016/j.ejon.2024.102543] [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: 12/23/2022] [Revised: 02/21/2024] [Accepted: 02/24/2024] [Indexed: 03/10/2024]
Abstract
PURPOSE Parents must manage their own stress and help their child with cancer during the treatment process, both physically and emotionally. With the increased involvement of fathers in caring for the family, how fathers adjust to the stress and play a role in care responsibilities is unknown. This study aimed to explore the fathers' experiences of caring for their ill child during the cancer diagnosis and treatment process. METHOD This study adopted a qualitative descriptive design and conducted in-depth interviews with 21 fathers with a diagnosed child recruited from a northern Taiwan medical center. Data were managed and analysed using content analysis. RESULTS Two main categories in the Taiwanese fathers' experiences of caring for their ill child during the cancer diagnosis and treatment process emerged: 1) the maintainer of family stability, and 2) thoughts and value adjustment. Each main category consists of 3-4 generic categories. They make the necessary adjustments between work and family, actively participate in caring for the entire family, and redefine family values. They convey information about the illness to their children, pay attention to the physical and psychological development of the child with cancer, and cherish the time spent together as a family. CONCLUSIONS During the cancer treatment process, fathers play the roles of the protector and maintainer of family stability and adjust their attitudes and thoughts toward the family members and family life. Healthcare professionals can offer the fathers comprehensive support and improve the family's overall well-being during this demanding period.
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Affiliation(s)
- Hsiu-Mei Huang
- School of Nursing, National Taipei University of Nursing and Health Sciences, Taiwan
| | - Ting-Chi Yeh
- Division of Pediatric Hematology-Oncology, Department of Pediatrics, Mackay Children's Hospital and Mackay Medical College, Taipei, Taiwan
| | - Tzu-Ying Lee
- School of Nursing, National Taipei University of Nursing and Health Sciences, Taiwan.
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Ravi Kiran AVVV, Kumari GK, Krishnamurthy PT, Johnson AP, Kenchegowda M, Osmani RAM, Abu Lila AS, Moin A, Gangadharappa HV, Rizvi SMD. An Update on Emergent Nano-Therapeutic Strategies against Pediatric Brain Tumors. Brain Sci 2024; 14:185. [PMID: 38391759 PMCID: PMC10886772 DOI: 10.3390/brainsci14020185] [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: 12/16/2023] [Revised: 02/07/2024] [Accepted: 02/13/2024] [Indexed: 02/24/2024] Open
Abstract
Pediatric brain tumors are the major cause of pediatric cancer mortality. They comprise a diverse group of tumors with different developmental origins, genetic profiles, therapeutic options, and outcomes. Despite many technological advancements, the treatment of pediatric brain cancers has remained a challenge. Treatment options for pediatric brain cancers have been ineffective due to non-specificity, inability to cross the blood-brain barrier, and causing off-target side effects. In recent years, nanotechnological advancements in the medical field have proven to be effective in curing challenging cancers like brain tumors. Moreover, nanoparticles have emerged successfully, particularly in carrying larger payloads, as well as their stability, safety, and efficacy monitoring. In the present review, we will emphasize pediatric brain cancers, barriers to treating these cancers, and novel treatment options.
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Affiliation(s)
- Ammu V V V Ravi Kiran
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rocklands, Ooty 643001, The Nilgiris, Tamil Nadu, India
| | - G Kusuma Kumari
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rocklands, Ooty 643001, The Nilgiris, Tamil Nadu, India
| | - Praveen T Krishnamurthy
- Department of Pharmacology, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Rocklands, Ooty 643001, The Nilgiris, Tamil Nadu, India
| | - Asha P Johnson
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Madhuchandra Kenchegowda
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Riyaz Ali M Osmani
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Amr Selim Abu Lila
- Department of Pharmaceutics, College of Pharmacy, University of Ha'il, Ha'il 81442, Saudi Arabia
| | - Afrasim Moin
- Department of Pharmaceutics, College of Pharmacy, University of Ha'il, Ha'il 81442, Saudi Arabia
| | - H V Gangadharappa
- Department of Pharmaceutics, JSS College of Pharmacy, JSS Academy of Higher Education & Research, Mysuru 570015, Karnataka, India
| | - Syed Mohd Danish Rizvi
- Department of Pharmaceutics, College of Pharmacy, University of Ha'il, Ha'il 81442, Saudi Arabia
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Pascual Morales C, Vasquez Ponce L, Hernandez Briceño J, Leon Lopez E, Guevara Guevara J, Jimenez Vargas J, Diaz Coronado R, Flores JD, Lazon Ayala M. Clinical Factors, Management, and Outcomes of Patients Under 18 Years Old With Central Nervous System Tumors: Single-center Experience in Peru. J Pediatr Hematol Oncol 2023; 45:e345-e349. [PMID: 36731067 DOI: 10.1097/mph.0000000000002563] [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: 03/14/2022] [Accepted: 08/04/2022] [Indexed: 02/04/2023]
Abstract
Few reports on clinical factors, treatment, and survival in children and adolescents with Central nervous system tumors in low-income and middle-income countries in Latin America exist. We retrospectively reviewed such data in all cases of patients younger than 18 years with brain tumors diagnosed in a single tertiary care center in Peru from 2007 through 2017. Variables were analyzed for association with overall survival and event-free survival by using the Kaplan-Meier method and the Cox hazards ratio regression. Seventy-five patients' data were analyzed (40 boys, 35 girls; mean age=7.7 y). The main clinical symptoms were headache, vomiting, difficulty walking, and visual disturbances. The most frequent clinical signs were hydrocephalus, cerebellar signs, visual abnormalities, and focal motor signs. The median time to diagnosis was 12 weeks. Tumor resection was performed in 68 patients, and 37 patients received postoperative radiotherapy. The most frequent histologic subtypes were low-grade gliomas and medulloblastomas. Overall survival rates at 1 and 5 years of disease were 78% (CI 95%, 0.67 to 0.86) and 74% (CI 95%, 0.62 to 0.82), respectively, and the 5-year event-free survival rate was 62% (CI 95%, 0.47 to 0.73). Although diagnosis occurred late in our cohort, the survival rate was higher than that in other Latin American countries.
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Affiliation(s)
| | - Liliana Vasquez Ponce
- "Medicina de Precision" Research Center, Universidad de San Martín de Porres, Facultad de Medicina
| | | | | | | | | | | | - Jose D Flores
- Neurosurgery Department, Guillermo Almenara Hospital
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Dang H, Khan AB, Gadgil N, Sharma H, Trandafir C, Malbari F, Weiner HL. Behavioral Improvements following Lesion Resection for Pediatric Epilepsy: Pediatric Psychosurgery? Pediatr Neurosurg 2023; 58:80-88. [PMID: 36787706 PMCID: PMC10233708 DOI: 10.1159/000529683] [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: 10/03/2022] [Accepted: 02/08/2023] [Indexed: 02/16/2023]
Abstract
INTRODUCTION Resection of brain lesions associated with refractory epilepsy to achieve seizure control is well accepted. However, concurrent behavioral effects of these lesions such as changes in mood, personality, and cognition and the effects of surgery on behavior have not been well characterized. We describe 5 such children with epileptogenic lesions and significant behavioral abnormalities which improved after surgery. CASE DESCRIPTIONS Five children (ages 3-14 years) with major behavioral abnormalities and lesional epilepsy were identified and treated at our center. Behavioral problems included academic impairment, impulsivity, self-injurious behavior, and decreased social interaction with diagnoses of ADHD, oppositional defiant disorder, and autism. Pre-operative neuropsychiatric testing was performed in 4/5 patients and revealed low-average cognitive and intellectual abilities for their age, attentional difficulties, and poor memory. Lesions were located in the temporal (2 gangliogliomas, 1 JPA, 1 cavernoma) and parietal (1 DNET) lobes. Gross total resection was achieved in all cases. At mean 1-year follow-up, seizure freedom (Engel 1a in 3 patients, Engel 1c in 2 patients) and significant behavioral improvements (academic performance, attention, socialization, and aggression) were achieved in all. Two patients manifested violence pre-operatively; one had extreme behavior with violence toward teachers and peers despite low seizure burden. Since surgery, his behavior has normalized. CONCLUSION We identified 5 patients with severe behavioral disorders in the setting of lesional epilepsy, all of whom demonstrated improvement after surgery. The degree of behavioral abnormality was disproportionate to epilepsy severity, suggesting a more complicated mechanism by which lesional epilepsy impacts behavior. We propose a novel paradigm in which lesionectomy may offer behavioral benefit even when seizures are not refractory. Thus, behavioral improvement may be an important novel goal for neurosurgical resection in children with epileptic brain lesions.
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Affiliation(s)
- Huy Dang
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA,
| | - Abdul Basit Khan
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA
| | - Nisha Gadgil
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA
- Division of Pediatric Neurosurgery, Department of Surgery, Texas Children's Hospital, Houston, Texas, USA
| | - Himanshu Sharma
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA
| | - Cristina Trandafir
- Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
- Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA
| | - Fatema Malbari
- Department of Neurology, Baylor College of Medicine, Houston, Texas, USA
- Division of Neurology and Developmental Neuroscience, Department of Pediatrics, Texas Children's Hospital, Houston, Texas, USA
| | - Howard L Weiner
- Department of Neurosurgery, Baylor College of Medicine, Houston, Texas, USA
- Division of Pediatric Neurosurgery, Department of Surgery, Texas Children's Hospital, Houston, Texas, USA
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11
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Estevez-Ordonez D, Gary SE, Atchley TJ, Maleknia PD, George JA, Laskay NMB, Gross EG, Devulapalli RK, Johnston JM. Immunotherapy for Pediatric Brain and Spine Tumors: Current State and Future Directions. Pediatr Neurosurg 2022; 58:313-336. [PMID: 36549282 PMCID: PMC10233708 DOI: 10.1159/000528792] [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: 07/29/2022] [Accepted: 12/15/2022] [Indexed: 12/24/2022]
Abstract
BACKGROUND Brain tumors are the most common solid tumors and the leading cause of cancer-related deaths in children. Incidence in the USA has been on the rise for the last 2 decades. While therapeutic advances in diagnosis and treatment have improved survival and quality of life in many children, prognosis remains poor and current treatments have significant long-term sequelae. SUMMARY There is a substantial need for the development of new therapeutic approaches, and since the introduction of immunotherapy by immune checkpoint inhibitors, there has been an exponential increase in clinical trials to adopt these and other immunotherapy approaches in children with brain tumors. In this review, we summarize the current immunotherapy landscape for various pediatric brain tumor types including choroid plexus tumors, embryonal tumors (medulloblastoma, AT/RT, PNETs), ependymoma, germ cell tumors, gliomas, glioneuronal and neuronal tumors, and mesenchymal tumors. We discuss the latest clinical trials and noteworthy preclinical studies to treat these pediatric brain tumors using checkpoint inhibitors, cellular therapies (CAR-T, NK, T cell), oncolytic virotherapy, radioimmunotherapy, tumor vaccines, immunomodulators, and other targeted therapies. KEY MESSAGES The current landscape for immunotherapy in pediatric brain tumors is still emerging, but results in certain tumors have been promising. In the age of targeted therapy, genetic tumor profiling, and many ongoing clinical trials, immunotherapy will likely become an increasingly effective tool in the neuro-oncologist armamentarium.
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Affiliation(s)
- Dagoberto Estevez-Ordonez
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA,
- Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, Alabama, USA,
| | - Sam E Gary
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Travis J Atchley
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, Alabama, USA
| | - Pedram D Maleknia
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Jordan A George
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Nicholas M B Laskay
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, Alabama, USA
| | - Evan G Gross
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Rishi K Devulapalli
- Heersink School of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - James M Johnston
- Department of Neurosurgery, University of Alabama at Birmingham, Birmingham, Alabama, USA
- Division of Pediatric Neurosurgery, Children's of Alabama, Birmingham, Alabama, USA
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12
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Cao L, Tian S, Ma W, Ni Z, Tian G, Zhao Y, Wang Q, Xu Z, Wang J, Liang Z, Zhao H, Yang L, Wang B, Ma J. The tentative application of en bloc concept in the pediatric brain tumor: Experience from a large pediatric center in china. Front Oncol 2022; 12:1018380. [PMID: 36439432 PMCID: PMC9697186 DOI: 10.3389/fonc.2022.1018380] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Accepted: 10/20/2022] [Indexed: 11/12/2022] Open
Abstract
Background Children are more susceptible to the higher rate of massive blood transfusion because of the less allowable blood loss and lower intraoperative tolerance to blood loss during the resection of brain tumors. The surgical concept of en bloc resection, which is widely used in other tumors, may contribute to the improvement of brain tumor resection. However, there is still a lack of comprehensive research on its application in pediatric brain tumors. Objective The aim of this study is to investigate the outcomes of the en bloc concept and the factors associated with the application of the en bloc concept in pediatric brain tumors. Methods According to the surgical concept involved, the patients were divided into three subgroups: complete en bloc concept, partial en bloc concept, and piecemeal concept. The matching comparison (complete and partial en bloc concept groups vs. piecemeal concept group) was conducted to investigate the effect of the en bloc concept on the outcomes. Then, the patient data from January 2018, when the en bloc concept was routinely integrated into the brain tumor surgery in our medical center, were reviewed and analyzed to find out the predictors associated with the application of en bloc concept. Results In the en bloc group, the perioperative parameters, such as hospital stay (p = 0.001), pediatric intensive care unit (PICU) stay (p = 0.003), total blood loss (p = 0.015), transfusion rate (p = 0.005), and complication rate (p = 0.039), were all significantly improved. The multinomial logistic regression analysis showed that tumor volume, bottom vessel, and imaging features, such as encasing nerve or pass-by vessel, finger-like attachment, ratio of “limited line”, and ratio of “clear line”, were independent predictors for the application of the en bloc concept in our medical center. Conclusion This study supports the application of complete and partial en bloc concept in the pediatric brain tumor surgery based on the preoperative evaluation of imaging features, and compared with the piecemeal concept, the en bloc concept can improve the short outcomes without significant increases in the neurological complications. Large-series and additional supportive pieces of evidence are still warranted.
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Affiliation(s)
- Liangliang Cao
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuaiwei Tian
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Wenkun Ma
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhouwen Ni
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Gang Tian
- Department of Epidemiology and Medical Statistics, Xiangya School of Public Health, Central South University, Changsha, Hunan, China
| | - Yang Zhao
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Qinhua Wang
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhen Xu
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Jiajia Wang
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Zhuangzhuang Liang
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Heng Zhao
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Lingrui Yang
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Baocheng Wang
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Ma, ; Baocheng Wang,
| | - Jie Ma
- Department of Pediatric Neurosurgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, China
- *Correspondence: Jie Ma, ; Baocheng Wang,
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13
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Role of Circular RNA in Brain Tumor Development. Cells 2022; 11:cells11142130. [PMID: 35883576 PMCID: PMC9315629 DOI: 10.3390/cells11142130] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2022] [Revised: 07/04/2022] [Accepted: 07/04/2022] [Indexed: 11/20/2022] Open
Abstract
Central nervous system tumors are a leading cause of cancer-related death in children and adults, with medulloblastoma (MB) and glioblastoma (GBM) being the most prevalent malignant brain tumors, respectively. Despite tremendous breakthroughs in neurosurgery, radiation, and chemotherapeutic techniques, cell heterogeneity and various genetic mutations impacting cell cycle control, cell proliferation, apoptosis, and cell invasion result in unwanted resistance to treatment approaches, with a 5-year survival rate of 70–80% for medulloblastoma, and the median survival time for patients with glioblastoma is only 15 months. Developing new medicines and utilizing combination medications may be viewed as excellent techniques for battling MB and GBM. Circular RNAs (circRNAs) can affect cancer-developing processes such as cell proliferation, cell apoptosis, invasion, and chemoresistance in this regard. As a result, several compounds have been introduced as prospective therapeutic targets in the fight against MB and GBM. The current study aims to elucidate the fundamental molecular and cellular mechanisms underlying the pathogenesis of GBM in conjunction with circRNAs. Several mechanisms were examined in detail, including PI3K/Akt/mTOR signaling, Wnt/-catenin signaling, angiogenic processes, and metastatic pathways, in order to provide a comprehensive knowledge of the involvement of circRNAs in the pathophysiology of MB and GBM.
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14
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Affiliation(s)
- Alan R Cohen
- From the Department of Neurosurgery, Johns Hopkins University School of Medicine, Baltimore
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15
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Greco E, Cortez GM, Monteiro A, Granja M, Garrity K, Han S, Beier A, Ranalli N, Hanel RA, Aldana PR. Combined Neuroendoscopic Techniques in the Management of Pediatric Brain and Skull Base Tumors: A Single-Institutional Case Series. World Neurosurg 2022; 164:e134-e142. [PMID: 35439619 DOI: 10.1016/j.wneu.2022.04.045] [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: 03/07/2022] [Revised: 04/08/2022] [Accepted: 04/09/2022] [Indexed: 10/18/2022]
Abstract
BACKGROUND Central nervous system tumors encompass the leading cause of cancer-related death in the pediatric population. Neuroendoscopic techniques have been optimized over the years, becoming an important tool for the management of brain tumors. Our study aims to review the indications for neuroendoscopic procedures and the feasibility of combined interventions. METHODS This is a single-center, self-adjudicated, retrospective experience. Inclusion criteria consisted of pediatric patients (≤18 years old) who underwent management of brain tumor or related diseases with the employment of neuroendoscopy. RESULTS A total of 47 patients undergoing 51 procedures met inclusion criteria. The mean age was 9.8 ± 4.6 years, and the majority were female (55.3%). Common indications for endoscopic intervention were hydrocephalus management (n = 24; 16 endoscopic third ventriculostomies and 9 septostomies), tumor biopsy (n = 19), cyst fenestration (n = 16), and tumor resection (n = 9). In one third of the cases, combined interventions occurred during a single operative session. Hydrocephalus was successfully managed in 74.4% of cases; tumor biopsy confirmed the diagnosis in 95.8% of cases, and gross total resection was achieved in 88.9% of cases. Cyst fenestration required reintervention in 3 cases: one case associated with initial cyst enlargement and 2 cases with the development of new tumor cysts separated from the originally fenestrated cyst. The overall complication rate was 6.3%, with only one major safety event, which was successfully managed. CONCLUSIONS Neuroendoscopy is an important minimally invasive tool for diagnosing and treating pediatric patients with brain tumors, permitting to address multiple problems in a single surgery.
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Affiliation(s)
- Elena Greco
- Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA; San Paolo Medical School, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy
| | - Gustavo M Cortez
- Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA; Research Department, Jacksonville University, Jacksonville, Florida, USA
| | - Andre Monteiro
- Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA
| | - Manuel Granja
- Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA
| | - Kelsey Garrity
- Department of Neurosurgery, University of Florida College of Medicine, Jacksonville, Florida, USA
| | - Sabrina Han
- Department of Neurosurgery, University of Florida College of Medicine, Jacksonville, Florida, USA
| | - Alexandra Beier
- Department of Neurosurgery, University of Florida College of Medicine, Jacksonville, Florida, USA
| | - Nathan Ranalli
- Department of Neurosurgery, University of Florida College of Medicine, Jacksonville, Florida, USA
| | - Ricardo A Hanel
- Lyerly Neurosurgery, Baptist Neurological Institute, Jacksonville, Florida, USA
| | - Philipp R Aldana
- Department of Neurosurgery, University of Florida College of Medicine, Jacksonville, Florida, USA.
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16
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Lutz K, Jünger ST, Messing-Jünger M. Essential Management of Pediatric Brain Tumors. CHILDREN 2022; 9:children9040498. [PMID: 35455542 PMCID: PMC9031600 DOI: 10.3390/children9040498] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 02/02/2023]
Abstract
Brain tumors are the most common solid tumors in children and are associated with high mortality. The most common childhood brain tumors are grouped as low-grade gliomas (LGG), high grade gliomas (HGG), ependymomas, and embryonal tumors, according to the World Health Organization (WHO). Advances in molecular genetics have led to a shift from pure histopathological diagnosis to integrated diagnosis. For the first time, these new criteria were included in the WHO classification published in 2016 and has been further updated in the 2021 edition. Integrated diagnosis is based on molecular genomic similarities of the tumor subclasses, and it can better explain the differences in clinical courses of previously histopathologically identical entities. Important advances have also been made in pediatric neuro-oncology. A growing understanding of the molecular-genetic background of tumorigenesis has improved the diagnostic accuracy. Re-stratification of treatment protocols and the development of targeted therapies will significantly affect overall survival and quality of life. For some pediatric tumors, these advances have significantly improved therapeutic management and prognosis in certain tumor subgroups. Some therapeutic approaches also have serious long-term consequences. Therefore, optimized treatments are greatly needed. Here, we discuss the importance of multidisciplinary collaboration and the role of (pediatric) neurosurgery by briefly describing the most common childhood brain tumors and their currently recognized molecular subgroups.
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Affiliation(s)
- Katharina Lutz
- Neurosurgery Department, Inselspital, 3010 Bern, Switzerland
- Pediatric Neurosurgery, Asklepios Children’s Hospital, 53757 Sankt Augustin, Germany;
- Correspondence:
| | - Stephanie T. Jünger
- Center for Neurosurgery, Department of General Neurosurgery, Faculty of Medicine and University Hospital Cologne, University of Cologne, 50937 Cologne, Germany;
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17
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Daetwyler E, Bargetzi M, Otth M, Scheinemann K. Late effects of high-dose methotrexate treatment in childhood cancer survivors-a systematic review. BMC Cancer 2022; 22:267. [PMID: 35287628 PMCID: PMC8919635 DOI: 10.1186/s12885-021-09145-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 12/23/2021] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND High-dose methotrexate (HD-MTX) is used in the treatment of different childhood cancers, including leukemia, the most common cancer type and is commonly defined as an intravenous dose of at least 1 g/m2 body surface area per application. A systematic review on late effects on different organs due to HD-MTX is lacking. METHOD We conducted a systematic literature search in PubMed, including studies published in English or German between 1985 and 2020. The population of each study had to consist of at least 75% childhood cancer survivors (CCSs) who had completed the cancer treatment at least twelve months before late effects were assessed and who had received HD-MTX. The literature search was not restricted to specific cancer diagnosis or organ systems at risk for late effects. We excluded case reports, case series, commentaries, editorial letters, poster abstracts, narrative reviews and studies only reporting prevalence of late effects. We followed PRISMA guidelines, assessed the quality of the eligible studies according to GRADE criteria and registered the protocol on PROSPERO (ID: CRD42020212262). RESULTS We included 15 out of 1731 identified studies. Most studies included CCSs diagnosed with acute lymphoblastic leukemia (n = 12). The included studies investigated late effects of HD-MTX on central nervous system (n = 10), renal (n = 2) and bone health (n = 3). Nine studies showed adverse outcomes in neuropsychological testing in exposed compared to non-exposed CCSs, healthy controls or reference values. No study revealed lower bone density or worse renal function in exposed CCSs. As a limitation, the overall quality of the studies per organ system was low to very low, mainly due to selection bias, missing adjustment for important confounders and low precision. CONCLUSIONS CCSs treated with HD-MTX might benefit from neuropsychological testing, to intervene early in case of abnormal results. Methodological shortcomings and heterogeneity of the tests used made it impossible to determine the most appropriate test. Based on the few studies on renal function and bone health, regular screening for dysfunction seems not to be justified. Only screening for neurocognitive late effects is warranted in CCSs treated with HD-MTX.
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Affiliation(s)
- Eveline Daetwyler
- Department of Medical Oncology, University Hospital Basel, Basel, Switzerland.,Faculty of Medicine, University of Basel, Basel, Switzerland
| | - Mario Bargetzi
- Faculty of Medicine, University of Basel, Basel, Switzerland.,Division of Hematology/Oncology, University Medical Clinic, Kantonsspital Aarau, Aarau, Switzerland
| | - Maria Otth
- Division of Hematology-Oncology, Department of Pediatrics, Kantonsspital Aarau AG, Tellstrasse 25, CH-5001, Aarau, Switzerland. .,Department of Oncology, Hematology, Immunology, Stem Cell Transplantation and Somatic Gene Therapy, University Children's Hospital Zurich - Eleonore Foundation, Zurich, Switzerland.
| | - Katrin Scheinemann
- Faculty of Medicine, University of Basel, Basel, Switzerland.,Division of Hematology-Oncology, Department of Pediatrics, Kantonsspital Aarau AG, Tellstrasse 25, CH-5001, Aarau, Switzerland.,Department of Pediatrics, McMaster Children's Hospital and McMaster University, Hamilton, Canada
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18
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Lamba N, Groves A, Torre M, Yeo KK, Iorgulescu JB. The epidemiology of primary and metastatic brain tumors in infancy through childhood. J Neurooncol 2022; 156:419-429. [PMID: 35037155 DOI: 10.1007/s11060-021-03927-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2021] [Accepted: 12/08/2021] [Indexed: 12/11/2022]
Abstract
PURPOSE To evaluate the epidemiology of primary and metastatic pediatric brain tumors in the United States according to the WHO CNS 4th and 5th editions classifications. METHODS Pediatric patients (age ≤ 14) presenting between 2004 and 2017 with a brain tumor were identified in the National Cancer Database and categorized by NICHD age stages. Patients' age, sex, race/ethnicity, overall survival, and tumor characteristics were evaluated according to WHO CNS 4th and 5th editions. RESULTS 23,978 pediatric brain tumor patients were identified. Overall, other (i.e. circumscribed) astrocytic gliomas (21%), diffuse astrocytic/oligodendroglial gliomas (21%; 64% of which were midline), and embryonal tumors (16%) predominated. A minority of brain tumors were of ependymal (6%), glioneuronal & neuronal (6%), germ cell tumor (GCT; 4%), mesenchymal non-meningothelial (2%), cranial nerve (2%), choroid plexus (2%), meningioma (2%), pineal (1%), and hematolymphoid (0.4%) types. GCTs were more likely in patients of Asian/Pacific Islander race/ethnicity. Brain metastases were exceedingly rare, accounting for 1.4% overall, with the most common primary tumor being neuroblastoma (61%) and non-CNS sarcoma (16%). Brain metastatic, choroid plexus, and embryonal tumors peaked during infancy and toddlerhood; whereas diffuse gliomas peaked in middle-late childhood. GCTs and glioneuronal & neuronal tumors uniquely displayed bimodal distributions, with elevated prevalence in both infancy and middle-to-late childhood. CONCLUSION We systematically described the epidemiology of pediatric brain tumors in the context of contemporary classification schema, thereby validating our current understanding and providing key insights.
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Affiliation(s)
- Nayan Lamba
- Department of Radiation Oncology, Harvard Medical School, Boston, MA, United States of America
| | - Andrew Groves
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, United States of America
| | - Matthew Torre
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, United States of America
| | - Kee Kiat Yeo
- Department of Pediatric Oncology, Dana-Farber/Boston Children's Cancer and Blood Disorders Center, Boston, MA, United States of America
| | - J Bryan Iorgulescu
- Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis St., Boston, MA, 02115, United States of America.
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Guido C, Baldari C, Maiorano G, Mastronuzzi A, Carai A, Quintarelli C, De Angelis B, Cortese B, Gigli G, Palamà IE. Nanoparticles for Diagnosis and Target Therapy in Pediatric Brain Cancers. Diagnostics (Basel) 2022; 12:diagnostics12010173. [PMID: 35054340 PMCID: PMC8774904 DOI: 10.3390/diagnostics12010173] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2021] [Revised: 01/04/2022] [Accepted: 01/07/2022] [Indexed: 02/04/2023] Open
Abstract
Pediatric brain tumors represent the most common types of childhood cancer and novel diagnostic and therapeutic solutions are urgently needed. The gold standard treatment option for brain cancers in children, as in adults, is tumor resection followed by radio- and chemotherapy, but with discouraging therapeutic results. In particular, the last two treatments are often associated to significant neurotoxicity in the developing brain of a child, with resulting disabilities such as cognitive problems, neuroendocrine, and neurosensory dysfunctions/deficits. Nanoparticles have been increasingly and thoroughly investigated as they show great promises as diagnostic tools and vectors for gene/drug therapy for pediatric brain cancer due to their ability to cross the blood–brain barrier. In this review we will discuss the developments of nanoparticle-based strategies as novel precision nanomedicine tools for diagnosis and therapy in pediatric brain cancers, with a particular focus on targeting strategies to overcome the main physiological obstacles that are represented by blood–brain barrier.
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Affiliation(s)
- Clara Guido
- Department of Mathematics and Physics, University of Salento, Monteroni Street, 73100 Lecce, Italy; (C.G.); (C.B.); (G.G.)
| | - Clara Baldari
- Department of Mathematics and Physics, University of Salento, Monteroni Street, 73100 Lecce, Italy; (C.G.); (C.B.); (G.G.)
| | - Gabriele Maiorano
- Nanotechnology Institute, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy;
| | - Angela Mastronuzzi
- Neuro-Oncology Unit, Department of Onco-Haematology, Cell Therapy, Gene Therapy and Haemopoietic Transplant, IRCCS Bambino Gesù Children’s Hospital, 00165 Rome, Italy;
| | - Andrea Carai
- Neurosurgery Unit, Department of Neurosciences, IRCCS Bambino Gesù Children’s Hospital, 00165 Rome, Italy;
| | - Concetta Quintarelli
- Department Onco-Haematology, and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, 00165 Rome, Italy; (C.Q.); (B.D.A.)
- Department of Clinical Medicine and Surgery, University of Naples Federico II, 80138 Naples, Italy
| | - Biagio De Angelis
- Department Onco-Haematology, and Cell and Gene Therapy, IRCCS Bambino Gesù Children’s Hospital, 00165 Rome, Italy; (C.Q.); (B.D.A.)
| | - Barbara Cortese
- Nanotechnology Institute, CNR-NANOTEC, c/o La Sapienza University, Piazzale A. Moro, 00165 Rome, Italy;
| | - Giuseppe Gigli
- Department of Mathematics and Physics, University of Salento, Monteroni Street, 73100 Lecce, Italy; (C.G.); (C.B.); (G.G.)
- Nanotechnology Institute, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy;
| | - Ilaria Elena Palamà
- Nanotechnology Institute, CNR-NANOTEC, Monteroni Street, 73100 Lecce, Italy;
- Correspondence:
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20
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Elbaroody M, Abdullah A. Primary intracranial Ewing’s sarcoma/peripheral primitive neuroectodermal tumor in pediatric age group: A comprehensive review of literature. J Pediatr Neurosci 2022. [DOI: 10.4103/jpn.jpn_198_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/04/2022] Open
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21
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Sommonte F, Arduino I, Racaniello GF, Lopalco A, Lopedota AA, Denora N. The Complexity of the Blood-Brain Barrier and the Concept of Age-Related Brain Targeting: Challenges and Potential of Novel Solid Lipid-Based Formulations. J Pharm Sci 2021; 111:577-592. [PMID: 34469749 DOI: 10.1016/j.xphs.2021.08.029] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2021] [Revised: 08/26/2021] [Accepted: 08/27/2021] [Indexed: 11/17/2022]
Abstract
Diseases that affect the Central Nervous System (CNS) are one of the most exciting challenges of recent years, as they are ubiquitous and affect all ages. Although these disorders show different etiologies, all treatments share the same difficulty represented by the Blood-Brain Barrier (BBB). This barrier acts as a protective system of the delicate cerebral microenvironment, isolating it and making extremely arduous delivering drugs to the brain. To overtake the obstacles provided by the BBB it is essential to explore the changes that affect it, to understand how to exploit these findings in the study and design of innovative brain targeted formulations. Interestingly, the concept of age-related targeting could prove to be a winning choice, as it allows to consider the type of treatment according to the different needs and peculiarities depending on the disease and the age of onset. In this review was considered the prospective contribution of lipid-based formulations, namely Solid Lipid Nanoparticles (SLNs) and Nanostructured Lipid Carriers (NLCs), which have been highlighted as able to overcome some limitations of other innovative approaches, thus representing a promising strategy for the non-invasive specific treatment of CNS-related diseases.
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Affiliation(s)
- Federica Sommonte
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy
| | - Ilaria Arduino
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy
| | | | - Antonio Lopalco
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy
| | - Angela Assunta Lopedota
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy
| | - Nunzio Denora
- Department of Pharmacy - Pharmaceutical Sciences, University of Bari "Aldo Moro", 4 Orabona St., 70125, Bari, Italy.
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22
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An Insight into Pathophysiological Features and Therapeutic Advances on Ependymoma. Cancers (Basel) 2021; 13:cancers13133221. [PMID: 34203272 PMCID: PMC8269186 DOI: 10.3390/cancers13133221] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Revised: 06/21/2021] [Accepted: 06/23/2021] [Indexed: 12/21/2022] Open
Abstract
Simple Summary Although biological information and the molecular classification of ependymoma have been studied, the treatment systems for ependymoma are still insufficient. In addition, because the disease occurs infrequently, it is difficult to obtain sufficient data to conduct large-scale or randomized clinical trials. Therefore, this study is intended to emphasize the importance of understanding its pathological characteristics and prognosis as well as developing treatments for ependymoma through multilateral studies. Abstract Glial cells comprise the non-sensory parts of the central nervous system as well as the peripheral nervous system. Glial cells, also known as neuroglia, constitute a significant portion of the mammalian nervous system and can be viewed simply as a matrix of neural cells. Despite being the “Nervenkitt” or “glue of the nerves”, they aptly serve multiple roles, including neuron repair, myelin sheath formation, and cerebrospinal fluid circulation. Ependymal cells are one of four kinds of glial cells that exert distinct functions. Tumorigenesis of a glial cell is termed a glioma, and in the case of an ependymal cell, it is called an ependymoma. Among the various gliomas, an ependymoma in children is one of the more challenging brain tumors to cure. Children are afflicted more severely by ependymal tumors than adults. It has appeared from several surveys that ependymoma comprises approximately six to ten percent of all tumors in children. Presently, the surgical removal of the tumor is considered a standard treatment for ependymomas. It has been conspicuously evident that a combination of irradiation therapy and surgery is much more efficacious in treating ependymomas. The main purpose of this review is to present the importance of both a deep understanding and ongoing research into histopathological features and prognoses of ependymomas to ensure that effective diagnostic methods and treatments can be developed.
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23
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Sharafeddine H, Hamideh D, Morsi RZ, Najjar MW. Surgical techniques in the management of supratentorial pediatric brain tumors: 10 years' experience at a tertiary care center in the Middle East. Surg Neurol Int 2021; 12:269. [PMID: 34221600 PMCID: PMC8247713 DOI: 10.25259/sni_205_2021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2021] [Accepted: 05/25/2021] [Indexed: 12/21/2022] Open
Abstract
Background: The goal of this retrospective study is to present the first epidemiological data on pediatric supratentorial central nervous system (CNS) tumors in Lebanon and to review the various surgical management strategies used. Methods: We conducted a retrospective case series of all pediatric patients who presented with a supratentorial CNS tumor and underwent surgery at our institution between 2006 and 2016. We collected and analyzed demographic characteristics, tumor location, clinical manifestations, histopathology, and surgical management strategies and outcome, and discussed them after dividing the tumors as per location and in view of published literature. Results: Ninety-nine children were studied with a male-to-female ratio of 2.3:1 and a mean age of 8.5 years. The most common location was convexity (44%) and included low-grade and high-grade glial tumors, along with other miscellaneous lesions. The next location was sellar/diencephalic (34%), including craniopharyngiomas, hypothalamic/optic pathway/thalamic gliomas, hamartomas, and pituitary/Rathke’s cyst, where there was notable use of endoscopic techniques (21%). Tumors in the pineal region (13%) were tectal gliomas, germ cell tumors, and pineoblastomas and were mostly treated endoscopically. The last group was lateral intraventricular tumors (8%) and was mostly choroid plexus lesions and ependymomas. Overall, the surgical objective was achieved in 95% with mild/moderate complications in 17%. Conclusion: A variety of pathologies may affect the pediatric population in the supratentorial region. Different surgical strategies, including microsurgical and endoscopic techniques, may be employed to remove, debulk, or biopsy these tumors depending on their location, suspected diagnosis, prognosis, and the need for treatment of possible associated hydrocephalus.
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Affiliation(s)
- Hiba Sharafeddine
- Department of Surgery-Neurosurgery, American University of Beirut, United States
| | - Dima Hamideh
- Department of Pediatrics, Children Cancer Institute, American University of Beirut, Beirut, Lebanon, United States
| | - Rami Z Morsi
- Department of Neurology, University of Chicago, Chicago, IL, United States
| | - Marwan W Najjar
- Department of Surgery-Neurosurgery, American University of Beirut, United States
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24
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Hossain MJ, Xiao W, Tayeb M, Khan S. Epidemiology and prognostic factors of pediatric brain tumor survival in the US: Evidence from four decades of population data. Cancer Epidemiol 2021; 72:101942. [PMID: 33946020 DOI: 10.1016/j.canep.2021.101942] [Citation(s) in RCA: 26] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 03/28/2021] [Accepted: 04/17/2021] [Indexed: 11/30/2022]
Abstract
Brain tumors, a group of heterogeneous diseases, are the second most common cancer and the leading cause of cancer-related deaths in children. Insight into the prognosis of pediatric brain tumor survival has led to improved outcomes and could be further advanced through precision in prognosis. We analyzed the United States SEER population-based dataset of 15,723 pediatric brain tumor patients diagnosed and followed between 1975 and 2016 using a stratified Cox proportional hazards model. Mortality risk declined with increased age at diagnosis, the adjusted hazard ratio (aHR) (95 % confidence interval) was 0.60 (0.55, 0.67) and 0.47 (0.42, 0.52) for ages at diagnosis 1-10 years and 10-19 years, respectively, when compared with infants. Non-Hispanic Caucasian patients showed a lower risk of mortality than non-Hispanic African Americans (1.21 (1.11, 1.32)) and Hispanics (1.21 (1.11, 1.32)). Primary tumor sites, grades, and histology showed substantial heterogeneity in mortality risk. Brainstem (2.62 (2.41, 2.85)) and Cerebrum (1.63 (1.46, 1.81)) had an elevated risk of mortality than lobes. Similarly, Grade II (1.32 (1.07, 1.62)), Grade III (3.39 (2.74, 4.19)), and Grade IV (2.18 (1.80, 2.64)) showed an inflated risk of mortality than Grade I. Compared to low-grade glioma, high-grade glioma (7.92 (7.09, 8.85)), Primitive neuroectodermal tumors (4.72 (4.15, 5.37)), Medulloblastoma (3.11 (2.79, 3.47)), and Ependymal-tumors (2.20 (1.95, 2.48)) had increased risk of mortality. County-level poverty and geographic region showed substantial variation in survival. This large population-based comprehensive study confirmed identified prognostic factors of pediatric brain tumor survival and provided estimates as epidemiologic evidence with greater generalization.
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Affiliation(s)
- Md Jobayer Hossain
- Biostatistics Program, Biomedical Research, A. I. DuPont Hospital for Children, Nemours Children's Health System, Wilmington, DE, 19803, United States; Department of Applied Economics and Statistics, University of Delaware, Newark, DE, 19716, United States.
| | - Wendi Xiao
- Biostatistics Program, Biomedical Research, A. I. DuPont Hospital for Children, Nemours Children's Health System, Wilmington, DE, 19803, United States
| | - Maliha Tayeb
- Department of Biology, University of Pittsburgh, Pittsburgh, PA, 15260, United States
| | - Saira Khan
- Program of Epidemiology, College of Health Sciences, University of Delaware, 100 Discovery Blvd, Newark, DE, 19713, United States
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25
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Peng J, Zhou H, Tang O, Chang K, Wang P, Zeng X, Shen Q, Wu J, Xiao Y, Patel SH, Hu C, Jin K, Xiao B, Boxerman J, Gao X, Wen PY, Bai HX, Huang RY, Yang L. Evaluation of RAPNO criteria in medulloblastoma and other leptomeningeal seeding tumors using MRI and clinical data. Neuro Oncol 2021; 22:1536-1544. [PMID: 32215549 DOI: 10.1093/neuonc/noaa072] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022] Open
Abstract
BACKGROUND Although the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group has made recommendations for response assessment in patients with medulloblastoma (MBL) and leptomeningeal seeding tumors, these criteria have yet to be evaluated. METHODS We examined MR imaging and clinical data in a multicenter retrospective cohort of 269 patients with MBL diagnoses, high grade glioma, embryonal tumor, germ cell tumor, or choroid plexus papilloma. Interobserver agreement, objective response (OR) rates, and progression-free survival (PFS) were calculated. Landmark analyses were performed for OR and progression status at 0.5, 1.0, and 1.5 years after treatment initiation. Cox proportional hazards models were used to determine the associations between OR and progression with overall survival (OS). Subgroup analyses based on tumor subgroup and treatment modality were performed. RESULTS The median follow-up time was 4.0 years. In all patients, the OR rate was .0.565 (95% CI: 0.505-0.625) by RAPNO. The interobserver agreement of OR determination between 2 raters (a neuroradiologist and a neuro-oncologist) for the RAPNO criteria in all patients was 83.8% (k statistic = 0.815; P < 0.001). At 0.5-, 1.0-, and 1.5-year landmarks, both OR status and PFS determined by RAPNO were predictive of OS (hazard ratios [HRs] for 1-year landmark: OR HR = 0.079, P < 0.001; PFS HR = 10.192, P < 0.001). In subgroup analysis, OR status and PFS were predictive of OS for all tumor subtypes and treatment modalities. CONCLUSION RAPNO criteria showed excellent consistency in the treatment response evaluation of MBL and other leptomeningeal seeding tumors. OR and PFS determined by RAPNO criteria correlated with OS.
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Affiliation(s)
- Jian Peng
- Department of Neurology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Hao Zhou
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Oliver Tang
- Warren Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Ken Chang
- Department of Radiology, Athinoula A. Martinos Center for Biomedical Imaging, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - Panpan Wang
- Department of Neurology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiaowei Zeng
- Department of Neurology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Qin Shen
- Department of Radiology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jing Wu
- Department of Radiology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Yanhe Xiao
- Department of Neurology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Sohil H Patel
- Department of Radiology and Medical Imaging, University of Virginia Health System, Charlottesville, Virginia, USA
| | - Chongyu Hu
- Department of Neurology, Hunan Provincial People's Hospital, Changsha, Hunan, China
| | - Ke Jin
- Department of Radiology, Hunan Children's Hospital, Changsha, Hunan, China
| | - Bo Xiao
- Department of Neurology, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Jerrold Boxerman
- Department of Diagnostic Imaging, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island, USA
| | - Xiaoping Gao
- Department of Neurology, Hunan Provincial People's Hospital, Changsha, Hunan, China
| | - Patrick Y Wen
- Center for Neuro-Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, USA
| | - Harrison X Bai
- Department of Diagnostic Imaging, Rhode Island Hospital and Alpert Medical School of Brown University, Providence, Rhode Island, USA.,Department of Radiology, Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Raymond Y Huang
- Department of Radiology, Brigham and Women's Hospital, Boston, Massachusetts, USA
| | - Li Yang
- Department of Neurology, Second Xiangya Hospital of Central South University, Changsha, Hunan, China
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26
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Badodi S, Pomella N, Zhang X, Rosser G, Whittingham J, Niklison-Chirou MV, Lim YM, Brandner S, Morrison G, Pollard SM, Bennett CD, Clifford SC, Peet A, Basson MA, Marino S. Inositol treatment inhibits medulloblastoma through suppression of epigenetic-driven metabolic adaptation. Nat Commun 2021; 12:2148. [PMID: 33846320 PMCID: PMC8042111 DOI: 10.1038/s41467-021-22379-7] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2020] [Accepted: 03/12/2021] [Indexed: 12/11/2022] Open
Abstract
Deregulation of chromatin modifiers plays an essential role in the pathogenesis of medulloblastoma, the most common paediatric malignant brain tumour. Here, we identify a BMI1-dependent sensitivity to deregulation of inositol metabolism in a proportion of medulloblastoma. We demonstrate mTOR pathway activation and metabolic adaptation specifically in medulloblastoma of the molecular subgroup G4 characterised by a BMI1High;CHD7Low signature and show this can be counteracted by IP6 treatment. Finally, we demonstrate that IP6 synergises with cisplatin to enhance its cytotoxicity in vitro and extends survival in a pre-clinical BMI1High;CHD7Low xenograft model.
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Affiliation(s)
- Sara Badodi
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Nicola Pomella
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Xinyu Zhang
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - Gabriel Rosser
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
| | - John Whittingham
- Centre for Craniofacial and Regenerative Biology, King's College London, London, UK
| | - Maria Victoria Niklison-Chirou
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
- Centre for Therapeutic Innovation (CTI-Bath), Department of Pharmacy & Pharmacology, University of Bath, Bath, UK
| | - Yau Mun Lim
- UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
| | - Sebastian Brandner
- UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, University College London Hospitals NHS Foundation Trust, London, UK
| | - Gillian Morrison
- Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK
| | - Steven M Pollard
- Centre for Regenerative Medicine & Cancer Research UK Edinburgh Centre, The University of Edinburgh, Edinburgh, UK
| | - Christopher D Bennett
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Birmingham Women and Children's Hospital, Birmingham, UK
| | - Steven C Clifford
- Newcastle University Centre for Cancer, Wolfson Childhood Cancer Research Centre, Translational and Clinical Research Institute, Newcastle upon Tyne, UK
| | - Andrew Peet
- Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK
- Birmingham Women and Children's Hospital, Birmingham, UK
| | - M Albert Basson
- Centre for Craniofacial and Regenerative Biology, King's College London, London, UK
- MRC Centre for Neurodevelopmental Disorders, King's College London, London, UK
| | - Silvia Marino
- Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
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27
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Upregulated Tripartite Motif 47 Could Facilitate Glioma Cell Proliferation and Metastasis as a Tumorigenesis Promoter. COMPUTATIONAL AND MATHEMATICAL METHODS IN MEDICINE 2021; 2021:5594973. [PMID: 33833824 PMCID: PMC8016597 DOI: 10.1155/2021/5594973] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/06/2021] [Revised: 02/28/2021] [Accepted: 03/05/2021] [Indexed: 01/26/2023]
Abstract
Introduction Tripartite motif 47 (TRIM47) belongs to a category of the TRIM family. It takes part in cancer tumorigenesis, thus demonstrating important functions across numerous carcinomas. Unfortunately, it is still elusive towards TRIM47 expression, characteristic, and biological function in brain gliomas. Methods Public database analysis was applied to analyze TRIM47 expression, and quantitative real-time PCR (qRT-PCR) was applied to detect the expression of TRIM47 in 9 paired tissues of glioma. The Cancer Genome Atlas (TCGA) and the Chinese Glioma Genome Atlas (CGGA) databases were applied to evaluate the overall survival (OS). Gene Ontology (GO) term and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways were applied to analyze differentially expressed gene (DEG) functions. In vitro experiments were performed to validate TRIM47-mediated effects on glioma cell proliferation, migration, and invasion. Results Compared to that in normal tissues, TRIM47 expression was greatly higher in glioma tissues, and its expression level was associated with different grades of glioma. Our data indicated that highly expressed TRIM47 displayed an association with the poor prognosis of glioma patients. Ablating TRIM47 obviously impeded glioma cell invasion and migration. Conclusion TRIM47 could modulate glioma cell proliferation, invasion, and migration. Highly expressed TRIM47 exhibited a correlation with poor prognosis. All data imply that TRIM47 is a probable biomarker for glioma and has the potentiality to become a newly generated target for glioma treatment.
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28
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Massie AM, Ebelhar J, Allen KE, DeGroote NP, Wasilewski-Masker K, Brock KE. Defining and timing of palliative opportunities in children with central nervous system tumors. Neurooncol Pract 2021; 8:451-459. [PMID: 34277023 DOI: 10.1093/nop/npab020] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/23/2022] Open
Abstract
Background Children with brain and central nervous system (CNS) tumors experience substantial challenges to their quality of life during their disease course. These challenges are opportunities for increased subspecialty palliative care (PC) involvement. Palliative opportunities have been defined in the pediatric oncology population, but the frequency, timing, and factors associated with palliative opportunities in pediatric patients with CNS tumors are unknown. Methods A single-institution retrospective review was performed on children ages 0-18 diagnosed with a CNS tumor who died between January 1, 2012 and November 30, 2017. Nine palliative opportunities were defined prior to data collection (progression, relapse, admission for severe symptoms, intensive care admission, bone marrow transplant, phase 1 trial, hospice, do-not-resuscitate (DNR) order). Demographic, disease, treatment, palliative opportunity, and end-of-life data were collected. Opportunities were evaluated over quartiles from diagnosis to death. Results Amongst 101 patients with a median age at death of eight years (interquartile range [IQR] = 8.0, range 0-22), there was a median of seven (IQR = 6) palliative opportunities per patient, which increased closer to death. PC consultation occurred in 34 (33.7%) patients, at a median of 2.2 months before death, and was associated with having a DNR order (P = .0028). Hospice was involved for 72 (71.3%) patients. Conclusion Children with CNS tumors suffered repeated events warranting PC yet received PC support only one-third of the time. Mapping palliative opportunities over the cancer course promotes earlier timing of PC consultation which can decrease suffering and resuscitation attempts at the end-of-life.
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Affiliation(s)
| | - Jonathan Ebelhar
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Emory University, Atlanta, Georgia, USA
| | - Kristen E Allen
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Nicholas P DeGroote
- Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Karen Wasilewski-Masker
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Emory University, Atlanta, Georgia, USA.,Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA
| | - Katharine E Brock
- Department of Pediatrics, Division of Pediatric Hematology/Oncology, Emory University, Atlanta, Georgia, USA.,Aflac Cancer and Blood Disorders Center, Children's Healthcare of Atlanta, Atlanta, Georgia, USA.,Department of Pediatrics, Division of Pediatric Palliative Care, Emory University, Atlanta, Georgia, USA
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29
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Minh Duc N. The diagnostic function of intravoxel incoherent motion for distinguishing between pilocytic astrocytoma and ependymoma. PLoS One 2021; 16:e0247899. [PMID: 33647051 PMCID: PMC7920344 DOI: 10.1371/journal.pone.0247899] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2020] [Accepted: 02/16/2021] [Indexed: 01/03/2023] Open
Abstract
INTRODUCTION Intravoxel incoherent motion (IVIM) imaging concurrently measures diffusion and perfusion parameters and has potential applications for brain tumor classification. However, the effectiveness of IVIM for the differentiation between pilocytic astrocytoma and ependymoma has not been verified. The aim of this study was to determine the potential diagnostic role of IVIM for the distinction between ependymoma and pilocytic astrocytoma. METHODS Between February 2019 and October 2020, 22 children (15 males and 7 females; median age 4 years) with either ependymoma or pilocytic astrocytoma were recruited for this prospective study. IVIM parameters were fitted using 7 b-values (0-1,500 s/mm2), to develop a bi-exponential model. The diffusivity (D), perfusion fraction (f), and pseudo diffusivity (D*) were measured in both tumors and the adjacent normal-appearing parenchyma. These IVIM parameters were compared using the Mann-Whitney U test. Receiver operating characteristic (ROC) curve analysis was employed to assess diagnostic performance. RESULTS The median D values for ependymoma and pilocytic astrocytoma were 0.87 and 1.25 × 10-3 mm2/s (p < 0.05), respectively, whereas the f values were 0.11% and 0.15% (p < 0.05). The ratios of the median D values for ependymoma and pilocytic astrocytoma relative to the median D values for the adjacent, normal-appearing parenchyma were 1.45 and 2.10 (p < 0.05), respectively. ROC curve analysis found that the D value had the best diagnostic performance for the differentiation between pilocytic astrocytoma and ependymoma, with an area under the ROC curve of 1. CONCLUSION IVIM is a beneficial, effective, non-invasive, and endogenous-contrast imaging technique. The D value derived from IVIM was the most essential factor for differentiating ependymoma from pilocytic astrocytoma.
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Affiliation(s)
- Nguyen Minh Duc
- Doctoral Program, Department of Radiology, Hanoi Medical University, Hanoi, Vietnam
- Department of Radiology, Pham Ngoc Thach University of Medicine, Ho Chi Minh City, Vietnam
- Department of Radiology, Children’s Hospital 02, Ho Chi Minh City, Vietnam
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30
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Zhao F, Zhang ZW, Zhang J, Zhang S, Zhang H, Zhao C, Chen Y, Luo L, Tong WM, Li C, Niu Y, Liu P. Loss of 5-Hydroxymethylcytosine as an Epigenetic Signature That Correlates With Poor Outcomes in Patients With Medulloblastoma. Front Oncol 2021; 11:603686. [PMID: 33718152 PMCID: PMC7945595 DOI: 10.3389/fonc.2021.603686] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2020] [Accepted: 01/08/2021] [Indexed: 12/11/2022] Open
Abstract
Medulloblastoma, as the most common malignant brain tumor in children, exhibits highly dysregulated DNA methylation. The novel epigenetic marker—5-hydroxymethylcytosine (5hmC) plays essential role in gene regulation during brain development and in brain tumors. However, the biological and clinical implications of 5hmC in medulloblastoma are still unclear. Here, we detected global 5hmC levels in two independent medulloblastoma patient cohorts (discovery cohort: n = 81; validation cohort: n = 171) using ultra-high performance liquid chromatography-tandem mass spectrometry analysis. Immunohistochemistry was used to identify the cell proliferation and expression of Ten-eleven translocation 1 and 2 (TET1/2). The prognostic impacts of covariates on progression-free survival (PFS) and overall survival (OS) were evaluated using multivariate Cox hazards regression models. We observed that global 5hmC levels were decreased in medulloblastomas compared to normal cerebellums (P < 0.001). Multivariate analysis showed that low global 5hmC levels correlated with poor PFS and OS rates (discovery cohort: PFS: P = 0.003, OS: P = 0.002; validation cohort: PFS: P = 0.0002, OS: P = 0.001). Immunohistochemistry showed an inverse correlation between 5hmC score and Ki-67 index (r = -0.747, P < 0.0001). Moreover, 5hmC score in MB samples was associated with nuclear expression of TET1 (r = -0.419, P = 0.003) and TET2 (r = -0.399, P = 0.005) proteins. Our study demonstrates that loss of 5hmC is an epigenetic biomarker in medulloblastomas. Our results indicate that 5hmC could be a candidate prognostic indicator for improving survival prediction of risk stratification in patients with medulloblastoma.
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Affiliation(s)
- Fu Zhao
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China.,Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Zhi-Wei Zhang
- Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Jing Zhang
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China
| | - Shun Zhang
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China.,Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Heng Zhang
- Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Chi Zhao
- Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University, Beijing, China
| | - Yang Chen
- Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China
| | - Lin Luo
- Department of Pathology, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Wei-Min Tong
- Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Chunde Li
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China.,Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
| | - Yamei Niu
- Department of Pathology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, China.,Neuroscience Center, Chinese Academy of Medical Sciences, Beijing, China
| | - Pinan Liu
- Department of Neurosurgery, Beijing Tian Tan Hospital, Capital Medical University, Beijing, China.,Department of Neural Reconstruction, Beijing Neurosurgical Institute, Capital Medical University, Beijing, China
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Pak‐Yin Liu A, Moreira DC, Sun C, Krull L, Gao Y, Yang B, Zhang C, He K, Yuan X, Chi‐Fung Chan G, Sun X, Ma X, Qaddoumi IA. Challenges and opportunities for managing pediatric central nervous system tumors in China. Pediatr Investig 2020; 4:211-217. [PMID: 33150316 PMCID: PMC7520110 DOI: 10.1002/ped4.12212] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 08/30/2020] [Indexed: 12/21/2022] Open
Abstract
Central nervous system (CNS) tumors represent the most deadly cancer in pediatric age group. In China, thousands of children are diagnosed with CNS tumors every year. Despite the improving socioeconomic status and availability of medical expertise within the country, unique challenges remain for the delivery of pediatric neuro-oncology service. In this review, we discuss the existing hurdles for improving the outcome of children with CNS tumors in China. Need for precise disease burden estimation, lack of intra- and inter-hospital collaborative networks, high probability of treatment abandonment, along with financial toxicities from treatment represent the key challenges that Chinese healthcare providers encounter. The tremendous opportunities for advancing the status of pediatric neuro-oncology care in and beyond the country are explored.
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Affiliation(s)
- Anthony Pak‐Yin Liu
- Department of OncologySt. Jude Children’s Research HospitalMemphisTNUSA
- Department of Paediatrics and Adolescent MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina
| | - Daniel C. Moreira
- Department of OncologySt. Jude Children’s Research HospitalMemphisTNUSA
- Department of Global Pediatric MedicineSt. Jude Children’s Research HospitalMemphisTNUSA
| | - Chenchen Sun
- Department of Global Pediatric MedicineSt. Jude Children’s Research HospitalMemphisTNUSA
| | - Lisa Krull
- Department of Global Pediatric MedicineSt. Jude Children’s Research HospitalMemphisTNUSA
| | - Yijin Gao
- Department of Hematology/OncologyShanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Bo Yang
- Department of NeurosurgeryShanghai Children’s Medical CenterSchool of MedicineShanghai Jiao Tong UniversityShanghaiChina
| | - Chenran Zhang
- Pediatric Neurological Disease CentreXinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Kejun He
- Department of Pediatric Hematology/OncologyXinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Xiaojun Yuan
- Department of Pediatric Hematology/OncologyXinhua HospitalShanghai Jiao Tong University School of MedicineShanghaiChina
| | - Godfrey Chi‐Fung Chan
- Department of Paediatrics and Adolescent MedicineLi Ka Shing Faculty of MedicineThe University of Hong KongHong KongChina
- Department of Paediatrics and Adolescent MedicineHong Kong Children’s HospitalHong KongChina
| | - Xiaofei Sun
- Department of Pediatric OncologyState Key Laboratory of Oncology in South ChinaCollaborative Innovation Center for Cancer MedicineSun Yat‐Sen University Cancer CenterGuangzhouChina
| | - Xiaoli Ma
- Hematology Oncology CenterBeijing Children’s HospitalCapital Medical UniversityBeijingChina
| | - Ibrahim A. Qaddoumi
- Department of OncologySt. Jude Children’s Research HospitalMemphisTNUSA
- Department of Global Pediatric MedicineSt. Jude Children’s Research HospitalMemphisTNUSA
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Valarezo Chuchuca A, Wong-Achi X, Ullauri Torres L. Medulloblastoma during pregnancy: Hormone-mediated association? Report of 2 cases. Neurochirurgie 2020; 67:140-144. [PMID: 32623061 DOI: 10.1016/j.neuchi.2020.04.135] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2020] [Revised: 03/10/2020] [Accepted: 04/05/2020] [Indexed: 11/16/2022]
Abstract
OBJECTIVE To report two rare cases of medulloblastoma in pregnant patients and a review of the literature. MATERIAL AND METHODS Report of patients diagnosed with medulloblastoma during their pregnancies, who were treated with surgery and adjuvant therapy. We also reviewed other cases reported in the literature and the association made with hormonal receptors. RESULTS Brain tumors in coincidence with pregnancy are unusual, and the incidence of medulloblastoma in pregnancy is still rarer. We found 8 cases of medulloblastomas diagnosed during pregnancy. Reports suggest that hormonal changes and increases in the levels of growth factors and angiogenic factors during pregnancy influence the rate of growth of brain tumors (not only medulloblastomas but also meningiomas or glial tumors). CONCLUSIONS The uniqueness of these cases is their rarity. The symptoms are usually masked by the symptoms of pregnancy. At present, there is still little evidence regarding the pathogenesis and treatment of medulloblastoma in pregnancy.
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Affiliation(s)
- A Valarezo Chuchuca
- Deparment of Neurosurgery, National Oncologic Institute "Dr. Juan Tanca Marengo" ION-SOLCA, 090505 Guayaquil, Ecuador
| | - X Wong-Achi
- Universidad Espíritu Santo, 092301 Samborondón, Ecuador.
| | - L Ullauri Torres
- Deparment of Neurosurgery, National Oncologic Institute "Dr. Juan Tanca Marengo" ION-SOLCA, 090505 Guayaquil, Ecuador
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Wallace D, Taylor DR, Pan H, Hwang S, Lucas JT, Klimo P, Upadhyaya SA, Boop FA. Treatment-related calvarial lesions in pediatric brain tumor survivors. Pediatr Blood Cancer 2020; 67:e28189. [PMID: 32286018 PMCID: PMC8674206 DOI: 10.1002/pbc.28189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/20/2019] [Revised: 12/12/2019] [Accepted: 12/23/2019] [Indexed: 11/08/2022]
Abstract
BACKGROUND Despite improved survival, many pediatric brain tumor survivors receiving radiation therapy (RT) experience late effects. PROCEDURE To study calvarial lesions in this population, we retrospectively reviewed records of patients undergoing neurosurgical evaluation for calvarial bone lesions detected in posttreatment follow-up imaging at St. Jude Children's Research Hospital. Primary tumor diagnosis, treatment, imaging, surgical intervention, and histopathology from patients with radiographic evidence of lesions followed for ≥2 years post-RT were studied. RESULTS For 17 patients with 18 index lesions, median time to lesion manifestation was 2.34 years. Medulloblastoma patients developed lesions at a shorter interval from RT than ependymoma patients (P = .05). Twelve of 14 lesions requiring surgery were benign fibro-osseous or sclerotic. Two malignant lesions distinct from the primary tumor had genetic predisposition to malignancy. CONCLUSION Most calvarial lesions arising post-RT are benign and fibro-osseous. Serial imaging is recommended, and high index of suspicion for malignant lesions is warranted for patients genetically predisposed to cancer.
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Affiliation(s)
- David Wallace
- University of Tennessee Health Science Center, College of Medicine, Memphis, Tennessee
| | - Douglas R. Taylor
- Department of Neurosurgery, LeBonheur Children’s Hospital, Memphis, Tennessee
| | - Haitao Pan
- Department of Biostatistics, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Scott Hwang
- Department of Diagnostic Imaging, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - John T. Lucas
- Department of Radiation Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Paul Klimo
- Department of Neurosurgery, LeBonheur Children’s Hospital, Memphis, Tennessee,Department of Surgery, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Santhosh A. Upadhyaya
- Department of Oncology, Division of Neuro-Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee
| | - Frederick A. Boop
- Department of Neurosurgery, LeBonheur Children’s Hospital, Memphis, Tennessee,Department of Surgery, St. Jude Children’s Research Hospital, Memphis, Tennessee
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Wang H, Long-Boyle J, Winger BA, Nicolaides T, Mueller S, Prados M, Ivaturi V. Population Pharmacokinetics of Vemurafenib in Children With Recurrent/Refractory BRAF Gene V600E-Mutant Astrocytomas. J Clin Pharmacol 2020; 60:1209-1219. [PMID: 32476174 DOI: 10.1002/jcph.1617] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2019] [Accepted: 03/12/2020] [Indexed: 02/03/2023]
Abstract
Vemurafenib (Zelboraf) is an orally available BRAFV600E inhibitor approved for the treatment of unresectable or metastatic BRAFV600E -mutant melanoma. The primary objective of this work was to characterize the pharmacokinetics (PK) of vemurafenib in pediatric patients with recurrent/refractory astrocytomas harboring the BRAFV600E mutation. The study was also designed to evaluate the feasibility of replacing whole vemurafenib tablets with crushed tablets in young children unable to swallow tablets. Twenty-five pediatric patients (median age, 8.8 years; range, 3.3-19.2) with recurrent/refractory BRAFV600E -mutant astrocytomas received whole (n = 19) or crushed (n = 6) vemurafenib tablets twice daily. Plasma samples were collected on days 1, 15, and 22 in cycle 1 of vemurafenib treatment. Descriptive PK analyses demonstrated significant variability (approximately 6-fold) in drug exposure. A 1-compartment model with first-order absorption and elimination was developed by adjusting the vemurafenib PK model previously validated in adults with mutant BRAFV600E melanoma. After inclusion of allometric scaling on total body weight, the model adequately described the PK of vemurafenib in children between a wide age range of 3 to 19 years old. In the crushed-tablet cohort, relative bioavailability was approximately 96% (95% confidence interval, 49%-142%) compared to that seen in pediatric patients receiving whole tablets based on the preliminary comparison analysis results. Moderate intrapatient variability (48%) of vemurafenib clearance was observed. There was significant correlation (R2 = 0.83) between area under the plasma concentration-time curve and trough concentration at steady state. These results will help increase the number of pediatric patients for whom vemurafenib is accessible and facilitate improved dosing in pediatric patients with recurrent/refractory BRAFV600E astrocytomas.
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Affiliation(s)
- Hechuan Wang
- Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA
| | - Janel Long-Boyle
- Department of Pediatrics, Division of Allergy, Immunology, and Bone Marrow Transplantation, University of California San Francisco, San Francisco, California, USA.,Department of Clinical Pharmacy, University of California San Francisco, San Francisco, California, USA
| | - Beth Apsel Winger
- Department of Pediatric, University of California San Francisco, San Francisco, California, USA
| | | | - Sabine Mueller
- Department of Pediatric, University of California San Francisco, San Francisco, California, USA.,Department of Neurology, University of California San Francisco, San Francisco, California, USA.,Department of Neurosurgery, University of California San Francisco, San Francisco, California, USA
| | - Michael Prados
- Department of Pediatric, University of California San Francisco, San Francisco, California, USA.,Department of Neurology, University of California San Francisco, San Francisco, California, USA
| | - Vijay Ivaturi
- Center for Translational Medicine, School of Pharmacy, University of Maryland, Baltimore, Maryland, USA
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Esa MMM, Mashaly EM, El-Sawaf YF, Dawoud MM. Diagnostic accuracy of apparent diffusion coefficient ratio in distinguishing common pediatric CNS posterior fossa tumors. THE EGYPTIAN JOURNAL OF RADIOLOGY AND NUCLEAR MEDICINE 2020. [DOI: 10.1186/s43055-020-00194-2] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022] Open
Abstract
Abstract
Background
Pilocytic astrocytoma, medulloblastoma, and ependymoma are the most common pediatric CNS tumors seen at posterior cranial fossa and final diagnosis obtained by histopathology after surgical excision. Routine MRI study gives an idea about site and extension of the tumors but provide a little information about type and grade of tumors. ADC ratio had high sensitivity and specificity in differentiation between these tumors as regard type and grade according to tumor cellularity.
Patients and methods
Prospective study conducted on thirty pediatric patients (11 males and 19 females) with CNS posterior fossa masses, their ages ranged from 2 to 17 years (mean age of 8.7 years), conventional MRI, DWI, ADC value, and ADC ratio were done for all patients.
Results
ADC values were significantly different between pilocytic astrocytomas (1.43 ± 0.28 × 10−3) and medulloblastomas (0.71 ± 0. 21 × 10−3) with a P value < 0.001, also there was a significant difference when comparing medulloblastomas (0.71 ± 0.21 × 10−3) with ependymomas (1.04 × 10−3 ± 0.21) with a P value < 0.001. ADC ratio at a cutoff > 1.7 showed significant good power of discrimination of astrocytoma (AUC = 0.85) from ependymoma with 87.5% sensitivity and 93.3% specificity. Similarly, at cutoff ≤ 1.6-> 1.2 was a significant good predictor of ependymoma (AUC = 0.85) with 87.8% sensitivity and 99.5% specificity. While, ADC ratio ≤ 1.2 was significant excellent discriminator of medulloblastoma (AUC = 0.99) with 100% sensitivity and 90% specificity.
Conclusion
ADC ratio is a simple way used in distinguishing juvenile pilocytic astrocytoma, ependymoma, and medulloblastoma, which are the most frequent pediatric posterior fossa tumors. Cutoff ADC ratio of more than 1.7 characteristic of JPA with 87.5% sensitivity and 93.3% specificity, ADC ratio less than 1.1 characteristic of medulloblastoma with 100% sensitivity and 90% specificity. ADC ratios more than 1.1 and less than 1.7 characteristic of ependymoma with 87.8% sensitivity and 99.5% specificity. We recommended ADC ratio as a routine study in evaluation of pediatric CNS posterior fossa tumors.
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Kabir TF, Kunos CA, Villano JL, Chauhan A. Immunotherapy for Medulloblastoma: Current Perspectives. Immunotargets Ther 2020; 9:57-77. [PMID: 32368525 PMCID: PMC7182450 DOI: 10.2147/itt.s198162] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2020] [Accepted: 03/29/2020] [Indexed: 12/11/2022] Open
Abstract
Background Immune-mediated therapies have transformed the treatment of metastatic melanoma and renal, bladder, and both small and non-small cell lung carcinomas. However, immunotherapy is yet to demonstrate dramatic results in brain tumors like medulloblastoma for a variety of reasons. Recent pre-clinical and early phase human trials provide encouraging results that may overcome the challenges of central nervous system (CNS) tumors, which include the intrinsic immunosuppressive properties of these cancers, a lack of antigen targets, antigenic variability, and the immune-restrictive site of the CNS. These studies highlight the growing potential of immunotherapy to treat patients with medulloblastoma, a disease that is a frequent cause of morbidity and mortality to children and young adults. Methods We conducted an inclusive review of the PubMed-indexed literature and studies listed in clinicaltrials.gov using combinations of the keywords medulloblastoma, immunotherapy, CNS tumors, brain tumors, vaccines, oncolytic virus, natural killer, and CAR T to identify trials evaluating immunotherapy in preclinical experiments or in patients with medulloblastoma. Given a limited number of investigations using immunotherapy to treat patients with medulloblastoma, 24 studies were selected for final analysis and manuscript citation. Results This review presents results from pre-clinical studies in medulloblastoma cell lines, animal models, and the limited trials involving human patients. Conclusion From our review, we suggest that cancer vaccines, oncolytic viral therapy, natural killer cells, and CAR T therapy hold promise against the innate immunosuppressive properties of medulloblastoma in order to prolong survival. There is an unmet need for immunotherapy regimens that target overexpressed antigens in medulloblastoma tumors. We advocate for more combination treatment clinical trials using conventional surgical and radiochemotherapy approaches in the near-term clinical development.
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Affiliation(s)
- Tanvir F Kabir
- Department of Internal Medicine, University of Louisville, Louisville, KY, USA
| | - Charles A Kunos
- Cancer Therapy Evaluation Program, National Cancer Institute, Bethesda, MD, USA
| | - John L Villano
- Department of Internal Medicine-Medical Oncology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA
| | - Aman Chauhan
- Department of Internal Medicine-Medical Oncology, Markey Cancer Center, University of Kentucky, Lexington, KY, USA
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Janjua MB, Reddy S, Welch WC, Samdani AF, Ozturk AK, Hwang SW, Price AV, Weprin BE, Swift DM. Thirty-day readmission risk after intracranial tumor resection surgeries in children. J Neurosurg Pediatr 2020; 25:97-105. [PMID: 31675691 DOI: 10.3171/2019.7.peds19272] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2019] [Accepted: 07/29/2019] [Indexed: 11/06/2022]
Abstract
OBJECTIVE The risk of readmission after brain tumor resection among pediatric patients has not been defined. The authors' objective was to evaluate the readmission rates and predictors of readmission after pediatric brain tumor resection. METHODS Nationwide Readmissions Database (NRD) data sets from 2010 to 2014 were searched for unplanned readmissions within 30 days of the discharge date after pediatric brain tumor resection. Patient demographic variables included sex, age, expected payment source (Medicaid or private insurance), and median annual household income. Readmission events for chemotherapy, radiation therapy, or further tumor resection were not included. RESULTS Of 282 patients (12.7%) readmitted within 30 days of the index event, the median time to readmission was 10 days (IQR 5-19 days). The most common reason for readmission was hydrocephalus, which accounted for 19% of readmission events. Other CNS-related complications (24%), surgical site infections or septicemia (14%), seizures (7%), and hematological disorders (7%) accounted for other major readmission events. The median charge for readmission events was $35,431, and the median length of readmission stay was 4 days. In multivariate regression, factors associated with a significant increase in readmission risk included Medicaid as the primary payor, discharge from the index event with home health services, and fluid and electrolyte disorders during the index event. CONCLUSIONS More than 10% of pediatric brain tumor patients have unplanned readmission events within 30 days of discharge after tumor resection. Medicaid patients and those with preoperative or early postoperative fluid and electrolyte disturbances may benefit from early or frequent outpatient visits after tumor resection.
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Affiliation(s)
- M Burhan Janjua
- 1Division of Pediatric Neurosurgery, Department of Neurosurgery, UT Southwestern Medical Center, Dallas, Texas
- 2Department of Neurosurgery, University of Pennsylvania Hospital System, Philadelphia; and
| | - Sumanth Reddy
- 1Division of Pediatric Neurosurgery, Department of Neurosurgery, UT Southwestern Medical Center, Dallas, Texas
| | - William C Welch
- 2Department of Neurosurgery, University of Pennsylvania Hospital System, Philadelphia; and
| | - Amer F Samdani
- 3Department of Neurosurgery, Shriners Hospital for Children, Philadelphia, Pennsylvania
| | - Ali K Ozturk
- 2Department of Neurosurgery, University of Pennsylvania Hospital System, Philadelphia; and
| | - Steven W Hwang
- 3Department of Neurosurgery, Shriners Hospital for Children, Philadelphia, Pennsylvania
| | - Angela V Price
- 1Division of Pediatric Neurosurgery, Department of Neurosurgery, UT Southwestern Medical Center, Dallas, Texas
| | - Bradley E Weprin
- 1Division of Pediatric Neurosurgery, Department of Neurosurgery, UT Southwestern Medical Center, Dallas, Texas
| | - Dale M Swift
- 1Division of Pediatric Neurosurgery, Department of Neurosurgery, UT Southwestern Medical Center, Dallas, Texas
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Xiong A, Spyrou A, Forsberg-Nilsson K. Involvement of Heparan Sulfate and Heparanase in Neural Development and Pathogenesis of Brain Tumors. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1221:365-403. [PMID: 32274718 DOI: 10.1007/978-3-030-34521-1_14] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Brain tumors are aggressive and devastating diseases. The most common type of brain tumor, glioblastoma (GBM), is incurable and has one of the worst five-year survival rates of all human cancers. GBMs are invasive and infiltrate healthy brain tissue, which is one main reason they remain fatal despite resection, since cells that have already migrated away lead to rapid regrowth of the tumor. Curative therapy for medulloblastoma (MB), the most common pediatric brain tumor, has improved, but the outcome is still poor for many patients, and treatment causes long-term complications. Recent advances in the classification of pediatric brain tumors reveal distinct subgroups, allowing more targeted therapy for the most aggressive forms, and sparing children with less malignant tumors the side-effects of massive treatment. Heparan sulfate proteoglycans (HSPGs), main components of the neurogenic niche, interact specifically with a large number of physiologically important molecules and vital roles for HS biosynthesis and degradation in neural stem cell differentiation have been presented. HSPGs are composed of a core protein with attached highly charged, sulfated disaccharide chains. The major enzyme that degrades HS is heparanase (HPSE), an important regulator of extracellular matrix (ECM) remodeling which has been suggested to promote the growth and invasion of other types of tumors. This is of clinical interest because GBM are highly invasive and children with metastatic MB at the time of diagnosis exhibit a worse outcome. Here we review the involvement of HS and HPSE in development of the nervous system and some of its most malignant brain tumors, glioblastoma and medulloblastoma.
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Affiliation(s)
- Anqi Xiong
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
- Department of Medical Biochemistry and Biophysics, Karolinska Insitutet, Stockholm, Sweden
| | - Argyris Spyrou
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden
| | - Karin Forsberg-Nilsson
- Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Uppsala, Sweden.
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Ailion AS, Roberts SR, Crosson B, King TZ. Neuroimaging of the component white matter connections and structures within the cerebellar-frontal pathway in posterior fossa tumor survivors. NEUROIMAGE-CLINICAL 2019; 23:101894. [PMID: 31229941 PMCID: PMC6593203 DOI: 10.1016/j.nicl.2019.101894] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 05/07/2019] [Accepted: 06/08/2019] [Indexed: 12/11/2022]
Abstract
Introduction In posterior fossa tumor survivors, lower white matter integrity (WMI) in the right cerebellar-left frontal pathway has been well documented and appears to be related to proximity to the cerebellum, radiation treatment, as well as time since treatment in both cranial radiation and surgery-only treatment groups. The current study investigated theories of transneural degeneration following cerebellar tumor resection that may underlie or relate to reductions in WMI and regional brain volumes using correlations. We hypothesized a positive relationship between the volume of the right cerebellum and known white matter output pathways, as well as with the volume of structures that receive cerebellar projections along the pathway. Methods Adult survivors of childhood brain tumors were recruited (n = 29; age, M = 22 years, SD = 5; 45% female). Age- and gender-matched controls were also included (n = 29). Participants completed 3 T diffusion-weighted and T1 MPRAGE MRI scans. Brain structure volume relative to intracranial vault served as regional volumetric measures. Fractional anisotropy (FA) and radial diffusivity (RD) served as WMI measures. In the survivor group, partial correlations between WMI and regional volume included controlling for disease severity. Results In posterior fossa tumor survivors, the volumes of the cerebellum, thalamus, and frontal lobe were correlated with WMI of the thalamic-frontal segment of the cerebellar-frontal pathway (r = 0.41–0.49, p < .05). Cerebellar atrophy was correlated with reduced WMI in the cerebellar-rubral segment (FA, r = −0.32 p > .05; RD, r = 0.53, p < .01). In the no-radiation survivor group, the regional volume of each structure along the pathway was associated with WMI in the cerebellar-rubral segment. In the radiation survivor group, significant correlations were found between the regional brain volume of each structure and the thalamic-frontal segment of the pathway. Discussion The results of this multimodal neuroimaging study provide correlational evidence that the mechanism of injury subsequent to brain tumor treatment may be different depending on type of treatment(s). Without radiation, the primary mechanism of injury is cerebellar tumor growth, resection, and hydrocephalus. Therefore, the most proximal connection to that injury (cerebellar-rubral pathway) was correlated with reductions in volume along the pathway. In contrast, the survivor group treated with radiation may have had possible radiation-induced demyelination of the thalamic-frontal portion of the pathway, based on a strong correlation with volume loss in the cerebellum, red nucleus, thalamus, and frontal lobe.
Cerebellar atrophy predicted lower white matter integrity (WMI) in the cerebellar-rubral segment. The no-radiation group showed a correlational pattern that is consistent with possible transneural degeneration. The radiation group showed a correlational pattern consistent with theories of neurodevelopmental vulnerability to radiation-induced demyelination.
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Affiliation(s)
- Alyssa S Ailion
- Department of Psychology, the Neuroscience Institute, Georgia State University, United States of America
| | - Simone Renée Roberts
- Department of Psychology, the Neuroscience Institute, Georgia State University, United States of America; Department of Neurology, Emory University School of Medicine, United States of America; Atlanta VA Center of Excellence for Visual and Neurocognitive Rehabilitation, United States of America
| | - Bruce Crosson
- Department of Psychology, the Neuroscience Institute, Georgia State University, United States of America; Department of Radiology and Imaging Sciences, Emory University School of Medicine, United States of America; Department of Neurology, Emory University School of Medicine, United States of America; Atlanta VA Center of Excellence for Visual and Neurocognitive Rehabilitation, United States of America
| | - Tricia Z King
- Department of Psychology, the Neuroscience Institute, Georgia State University, United States of America.
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Ager BJ, Christensen MT, Burt LM, Poppe MM. The value of high-dose radiotherapy in intracranial ependymoma. Pediatr Blood Cancer 2019; 66:e27697. [PMID: 30865382 DOI: 10.1002/pbc.27697] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2018] [Revised: 02/07/2019] [Accepted: 02/15/2019] [Indexed: 11/07/2022]
Abstract
BACKGROUND We sought to evaluate the impact of adjuvant radiotherapy dose on overall survival (OS) after surgical resection for localized intracranial ependymoma. PROCEDURE The National Cancer Database (NCDB) was queried from 2004 to 2015 for patients of all ages with intracranial WHO grade II to III ependymoma treated with surgery and 4500 to 7000 cGy of adjuvant radiotherapy. Pearson χ2 test and multivariate logistic regression analyses were used to assess clinicodemographic factors and patterns of care. After propensity-score matching, OS was assessed with Kaplan-Meier analyses and doubly robust estimation with multivariate Cox proportional hazards modeling. RESULTS Of the 1153 patients meeting criteria, 529 (46%) received ≤ 5400 cGy and 624 (54%) received > 5400 cGy. At a median follow-up of 54.5 months, an OS benefit was observed for > 5400 cGy in pediatric patients aged 2-18 years (hazard ratio [HR] 0.53; 95% confidence interval [CI] 0.28-0.99, P = 0.047). No OS difference was found between ≤ 5400 cGy and > 5400 cGy in pediatric patients aged < 2 years (P = 0.819) or in adults (P = 0.180). Increasing age, WHO grade III, subtotal resection, and receipt of chemotherapy portended worse OS. Age 2 to 18 years, WHO III grade, supratentorial location, and receipt of chemotherapy were associated with receiving > 5400 cGy. CONCLUSION Adjuvant radiotherapy dose > 5400 cGy was associated with improved OS for children aged 2-18 years with WHO grade II-III intracranial ependymoma. No OS benefit was found with > 5400 cGy in adults or children less than two years of age.
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Affiliation(s)
- Bryan J Ager
- Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | | | - Lindsay M Burt
- Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
| | - Matthew M Poppe
- Department of Radiation Oncology, Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah
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Chel'diev BZ, Kushel' YV, Demin MO. [Radicalness and complications of repeated surgery for malignant neuroepithelial tumors of the posterior cranial fossa in children]. ZHURNAL VOPROSY NEĬROKHIRURGII IMENI N. N. BURDENKO 2019; 82:104-110. [PMID: 30412163 DOI: 10.17116/neiro201882051104] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Treatment of primary malignant neuroepithelial tumors of the posterior cranial fossa (PCF) in childhood includes surgical resection, radiation therapy (RT), and chemotherapy (CT). The radicalness of surgery is one of the most important prognostic factors of survival. Despite the significant advances in treatment, many of these tumors recur. Today, oncologists are increasingly recommending repeated surgery for recurrent malignant neuroepithelial tumors of the PCF to achieve gross total resection (GTR). Patients undergo this surgery after RT and palliative CT, which may increase surgical risks. OBJECTIVE The study objective was to assess the resection extent of recurrent malignant neuroepithelial tumors of the PCF in children as well as the risk and structure of postoperative complications. MATERIAL AND METHODS The prospective study included 50 patients under the age of 18 who underwent surgery for recurrent malignant neuroepithelial tumors of the PCF at the Neurosurgical Institute (NSI) in the period between 2002 and June 2015. Anaplastic ependymomas were present in 37 patients, and medulloblastomas were detected in 13 patients. A total of 58 repeated surgeries were performed. RESULTS GTR was achieved in 53 (91.4%) cases, near total resection (NTR) was achieved in 2 (3.4%) cases, and subtotal resection (STR) was achieved in 3 (5.2%) cases. The mean bed-day after surgery was 12 (4-47) days, and the mean critical care stay was 3.2 (0-23) days. Seven patients required tracheostomy; meningitis developed in 3 patients; liquorrhea occurred in 2 cases. Ventriculoperitoneal shunting was used in 8 (13.8%) cases. One (1.7%) patient died in the early postoperative period. CONCLUSION Our results demonstrate that resection of recurrent malignant neuroepithelial tumors in children can be performed with high radicalness (90%) and acceptable risks.
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Affiliation(s)
| | - Yu V Kushel'
- Burdenko Neurosurgical Institute, Moscow, Russia
| | - M O Demin
- Burdenko Neurosurgical Institute, Moscow, Russia
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Abstract
Medulloblastoma is the most common malignant solid tumor in childhood and the most common embryonal neuroepithelial tumor of the central nervous system. Several morphological variants are recognized: classic medulloblastoma, large cell/anaplastic medulloblastoma, desmoplastic/nodular medulloblastoma, and medulloblastoma with extensive nodularity. Recent advances in transcriptome and methylome profiling of these tumors led to a molecular classification that includes 4 major genetically defined groups. Accordingly, the 2016 revision of the World Health Organization's Classification of Tumors of the Central Nervous System recognizes the following medulloblastoma entities: Wingless (WNT)-activated, Sonic hedgehog (SHH)-activated, Group 3, and Group 4. This transcriptionally driven classification constitutes the basis of new risk stratification schemes applied to current therapeutic clinical trials. Because additional layers of molecular tumor heterogeneities are being progressively unveiled, several clinically relevant subgroups within the 4 major groups have already been identified. The purpose of this article is to review the recent basic science and clinical advances in the understanding of "medulloblastomas," and their diagnostic imaging correlates and the implications of those on current neuroimaging practice.
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Janss AJ, Mazewski C, Patterson B. Guidelines for Treatment and Monitoring of Adult Survivors of Pediatric Brain Tumors. Curr Treat Options Oncol 2019; 20:10. [PMID: 30739214 DOI: 10.1007/s11864-019-0602-0] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/27/2022]
Abstract
OPINION STATEMENT Pathologies of pediatric brain tumors are more varied than those diagnosed in adults and survival outcomes more optimistic. Therapies for pediatric brain tumors are also diverse and treatment options are expanding. The growing number of adult survivors of childhood brain tumors is quite diverse. Medical management of these adults requires understanding the tumor diagnosis and location, the modalities used to treat the tumor, the age of the survivor at the time of diagnosis and treatment, any complications of treatment, and, most importantly, the baseline medical condition and neurological function of each adult survivor. A network of medical, neurological, and mental health providers is critical in the care of a child with a brain tumor. A comparable network should be available to survivors of these tumors since they may transition to adulthood with medical and neurological deficits and can acquire additional late effects of treatments as they age. Optimally, each survivor will have an individualized survivor health plan (SHP) that concisely summarizes the tumor, treatments, potential late effects, and screening that may identify evolving late effects before they impact mental, social or physical functioning. This plan helps patients, families, and the medical team advocate for surveillance aiming to optimize the survivor's quality of life. Failure to support the health and function of these heroic cancer survivors renders the medical advances, the courage, and the struggle that permitted survival meaningless.
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Affiliation(s)
- Anna J Janss
- Neuro-Oncology, Aflac Children's Cancer and Blood Disorders Clinic/Emory Pediatric Institute, 5461 Meridian Mark Road, Suite 400, Atlanta, GA, 30342, USA.
| | - Claire Mazewski
- Neuro-Oncology, Aflac Children's Cancer and Blood Disorders Clinic/Emory Pediatric Institute, 5461 Meridian Mark Road, Suite 400, Atlanta, GA, 30342, USA
| | - Briana Patterson
- Pediatric Endocrinology, Emory Children's Center/Emory Pediatric Institute, 2015 Uppergate Drive, Room 232, Atlanta, GA, 30322, USA
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Deng X, Lin D, Yu L, Xu X, Zhang N, Zhou H, Sheng H, Yin B, Lin F, Xu S, Li D, Fang J, Lu X, Lin J. The role of postoperative radiotherapy in pediatric patients with grade II intracranial ependymomas: a population-based, propensity score-matched study. Cancer Manag Res 2018; 10:5515-5524. [PMID: 30519099 PMCID: PMC6233483 DOI: 10.2147/cmar.s181900] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Purpose The main objectives of this study were to clarify the efficacy of postoperative radiotherapy (PORT) for pediatric intracranial grade II ependymomas (EPNs) and to explore whether various characteristics are associated with different outcomes in patients with and without PORT. Patients and methods Data from patients younger than 18 years diagnosed with grade II intracranial EPNs and treated by surgery, with or without PORT, were obtained from the Surveillance, Epidemiology, and End Results (SEER) database (1973–2013 data set). Propensity score-matched analysis was conducted to balance clinical variables. Patient characteristics were stratified and analyzed. Results In total, data from 632 patients with grade II EPNs treated by cancer-directed surgery with or without PORT were obtained from the SEER database. Multivariable Cox analysis in the matched cohort suggested that undergoing PORT (overall survival [OS], P=0.020; cancer-specific survival [CSS], P=0.031), undergoing gross total resection (GTR; subtotal resection [STR] vs GTR; OS, P<0.001; CSS, P<0.001), and older age (OS, P<0.001; CSS, P<0.001) were the independent predictors of superior prognosis. Stratified analysis demonstrated that patient characteristics, including infratentorial location, younger age, and STR, were associated with benefit from PORT, while the survival advantage was not detected in patients who underwent GTR. Conclusion Propensity score-matched analysis using SEER data indicates survival advantages of PORT. Given the strong prognostic associations with extent of resection and patient age, we recommend PORT for younger patients treated by STR.
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Affiliation(s)
- Xiangyang Deng
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Dongdong Lin
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Lisheng Yu
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Xingxing Xu
- Department of Physiology, School of Basic Medical Sciences, Wenzhou Medical University, Wenzhou, China
| | - Nu Zhang
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Hui Zhou
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Hansong Sheng
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Bo Yin
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Fengchun Lin
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Shangyu Xu
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Dandong Li
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Junhao Fang
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Xiangqi Lu
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
| | - Jian Lin
- Department of Neurosurgery, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China,
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Lv T, Miao YF, Jin K, Han S, Xu TQ, Qiu ZL, Zhang XH. Dysregulated circular RNAs in medulloblastoma regulate proliferation and growth of tumor cells via host genes. Cancer Med 2018; 7:6147-6157. [PMID: 30402980 PMCID: PMC6308054 DOI: 10.1002/cam4.1613] [Citation(s) in RCA: 46] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Revised: 04/18/2018] [Accepted: 05/10/2018] [Indexed: 12/20/2022] Open
Abstract
Circular RNAs (circRNAs) have been demonstrated to be involved in various biological processes. Nevertheless, the function of circRNAs in medulloblastoma (MB) is still unknown. The present study aimed to investigate the expression profiles of circRNAs and related mechanisms for regulating the proliferation and growth of tumor cells in MB. The expression profiles of circRNAs were screened from four normal cerebellum and four MB samples using a HiSeq Sequencer. Bioinformatic analysis was employed to predict the interaction between circRNAs and mRNAs in MB. Subsequently, the expression levels of eight differential circRNAs [circ-SKA3 (hsa_circ_0029696), circ-DTL (hsa_circ_0000179), circ-CRTAM, circ-MAP3K5 (hsa_circ_0006856), circ-RIMS1-1 (hsa_circ_0132250), circ-RIMS1-2 (hsa_circ_0076967), circ-FLT3-1 (hsa_circ_0100165), and circ-FLT3-2 (hsa_circ_0100168)] were validated using quantitative reverse transcription-polymerase chain reaction. Moreover, circ-SKA3 and circ-DTL were silenced using small interfering RNAs and their host genes were overexpressed to investigate their role in the pathogenesis of MB. A total of 33 circRNAs were found to be differentially expressed in MB tissues (fold change ≥ 2.0, FDR <0.05), of which three were upregulated and 30 were downregulated; six circRNAs were experimentally validated successfully. Upregulated circ-SKA3 and circ-DTL promoted the proliferation migration and invasion in vitro by regulating the expression of host genes. This novel study exploited the profiling of circRNAs in MB and demonstrated that circ-SKA3 and circ-DTL were crucial in the tumorigenesis and development of MB and might be considered as novel and potential biomarkers for the diagnosis and new targets for the intervention of MB.
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Affiliation(s)
- Tao Lv
- Department of Neurosurgery, Ren Ji Hospital, Schoolof Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Yi-Feng Miao
- Department of Neurosurgery, Ren Ji Hospital, Schoolof Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Ke Jin
- Department of Neurosurgery, Ren Ji Hospital, Schoolof Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Shuo Han
- Department of Neurosurgery, Ren Ji Hospital, Schoolof Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Tian-Qi Xu
- Department of Neurosurgery, Ren Ji Hospital, Schoolof Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zi-Long Qiu
- Institute of Neuroscience, State Kay Laboratory of Neuroscience, CAS Center for Excellence in Brain Science and Intelligence Technology, Chinese Academy of Sciences, Shanghai, China
| | - Xiao-Hua Zhang
- Department of Neurosurgery, Ren Ji Hospital, Schoolof Medicine, Shanghai Jiao Tong University, Shanghai, China
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Wilke M, Groeschel S, Lorenzen A, Rona S, Schuhmann MU, Ernemann U, Krägeloh‐Mann I. Clinical application of advanced MR methods in children: points to consider. Ann Clin Transl Neurol 2018; 5:1434-1455. [PMID: 30480038 PMCID: PMC6243383 DOI: 10.1002/acn3.658] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 08/10/2018] [Accepted: 08/10/2018] [Indexed: 12/11/2022] Open
Abstract
The application of both functional MRI and diffusion MR tractography prior to a neurosurgical operation is well established in adults, but less so in children, for several reasons. For this review, we have identified several aspects (task design, subject preparation, actual scanning session, data processing, interpretation of results, and decision-making) where pediatric peculiarities should be taken into account. Further, we not only systematically identify common issues, but also provide solutions, based on our experience as well as a review of the pertinent literature. The aim is to provide the clinician as well as the imaging scientist with information that helps to plan, conduct, and interpret such a clinically-indicated exam in a way that maximizes benefit for, and minimizes the burden on the individual child.
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Affiliation(s)
- Marko Wilke
- Department of Pediatric Neurology and Developmental MedicineChildren's HospitalTuebingenGermany
- Children's Hospital and Department of NeuroradiologyExperimental Pediatric NeuroimagingTuebingenGermany
| | - Samuel Groeschel
- Department of Pediatric Neurology and Developmental MedicineChildren's HospitalTuebingenGermany
- Children's Hospital and Department of NeuroradiologyExperimental Pediatric NeuroimagingTuebingenGermany
| | - Anna Lorenzen
- Department of Pediatric Neurology and Developmental MedicineChildren's HospitalTuebingenGermany
- Children's Hospital and Department of NeuroradiologyExperimental Pediatric NeuroimagingTuebingenGermany
| | - Sabine Rona
- Department of NeurosurgeryUniversity HospitalTuebingenGermany
| | | | - Ulrike Ernemann
- Department of Diagnostic and Interventional NeuroradiologyUniversity HospitalUniversity of TübingenTuebingenGermany
| | - Ingeborg Krägeloh‐Mann
- Department of Pediatric Neurology and Developmental MedicineChildren's HospitalTuebingenGermany
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Staglianò S, D'Arco F, Tan AP, Jeelani O, Morana G, Mankad K. Haemostatic material (Surgicel ®) mimicking residual tumour: magnetic resonance imaging findings in operated pediatric neuro-oncology cases. Quant Imaging Med Surg 2018; 8:971-978. [PMID: 30505725 DOI: 10.21037/qims.2018.09.04] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Affiliation(s)
- Serena Staglianò
- Polo scienze delle immagini, di laboratorio ed infettivologiche, Area diagnostica per immagini, Fondazione Policlinico Universitario Agostino Gemelli, Università Cattolica del Sacro Cuore, Largo Francesco Vito 1-00168, Rome, Italy
| | - Felice D'Arco
- Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Ai Peng Tan
- Department of Radiology, National University Health System, Singapore
| | - Owase Jeelani
- Department of Neurosurgery, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
| | - Giovanni Morana
- Neuroradiology Unit, Istituto Giannina Gaslini, Genoa, Italy
| | - Kshitij Mankad
- Department of Radiology, Great Ormond Street Hospital for Children NHS Foundation Trust, London, UK
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Rodríguez-Nogales C, González-Fernández Y, Aldaz A, Couvreur P, Blanco-Prieto MJ. Nanomedicines for Pediatric Cancers. ACS NANO 2018; 12:7482-7496. [PMID: 30071163 DOI: 10.1021/acsnano.8b03684] [Citation(s) in RCA: 57] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/14/2023]
Abstract
Chemotherapy protocols for childhood cancers are still problematic due to the high toxicity associated with chemotherapeutic agents and incorrect dosing regimens extrapolated from adults. Nanotechnology has demonstrated significant ability to reduce toxicity of anticancer compounds. Improvement in the therapeutic index of cytostatic drugs makes this strategy an alternative to common chemotherapy in adults. However, the lack of nanomedicines specifically for pediatric cancer care raises a medical conundrum. This review highlights the current state and progress of nanomedicine in pediatric cancer and discusses the real clinical challenges and opportunities.
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Affiliation(s)
- Carlos Rodríguez-Nogales
- Pharmacy and Pharmaceutical Technology Department , University of Navarra , Pamplona 31008 , Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA) , Pamplona 31008 , Spain
| | | | - Azucena Aldaz
- Department of Pharmacy , Clínica Universidad de Navarra , Pamplona 31008 , Spain
| | - Patrick Couvreur
- Institut Galien Paris-Sud, UMR CNRS 8612, Université Paris-Sud, Université Paris-Saclay, Châtenay-Malabry Cedex 92296 , France
| | - María J Blanco-Prieto
- Pharmacy and Pharmaceutical Technology Department , University of Navarra , Pamplona 31008 , Spain
- Instituto de Investigación Sanitaria de Navarra (IdiSNA) , Pamplona 31008 , Spain
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Zhao C, Chen Q, Li C, Yang J, Li C, Zhou Y, Liao J. The association of NF2 (neurofibromin 2) gene polymorphism and the risk of medulloblastomas. Neurol Sci 2018; 39:1175-1183. [PMID: 29637450 DOI: 10.1007/s10072-018-3327-0] [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: 11/08/2017] [Accepted: 03/13/2018] [Indexed: 02/05/2023]
Abstract
To explore the relationship between NF2 promoter gene mutation and the risk of medulloblastomas (MBs). We collected tissues from 16 MB patients and 7 age-matched non-MB controls. Gene sequencing, qPCR (real-time quantitative polymerase chain reaction), IHC (immunohistochemistry), and WB (Western blot) were used to analyze the changes in the NF2 gene sequence and expression between patients and controls. We found that NF2 promoter gene mutations occurred in MB patients. The NF2 mRNA expression was higher in the controls than in patients (p = 0.03 < 0.05); however, the results of IHC and WB demonstrated that the NF2 protein expression was significantly higher in patients than in the controls (IHC: p = 0.0001; WB: p = 0.01). There was no significant difference in the CRL4 mRNA and protein levels. In addition, NF2 protein was mainly expressed in the nucleus in MB patients, while the NF2 protein was mainly expressed in the cytoplasm in the controls. NF2 promoter mutations exist in MB patients. NF2 mRNA expression was higher in controls than patients; whereas NF2 protein level was higher in patients than in controls.
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Affiliation(s)
- Cailei Zhao
- Department of Biomedical Engineering, Xi'an Jiaotong University, Xi'an, No. 277, Yantaxi Road, Xi'an, 710061, China
- Department of Radiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, No. 277, Yantaxi Road, Xi'an, 710061, China
- Department of Radiology, Shenzhen Children's Hospital, Shenzhen, China
| | - Qian Chen
- Department of Neurosurgery, Shenzhen Children's Hospital, Shenzhen, No. 7019, Yitian Road, Shenzhen, 518038, China.
| | - Chunde Li
- Department of Pediatric Neurosurgery, Beijing Tianan Hospital, China Capital Medical University, Beijing, China.
| | - Jian Yang
- Department of Radiology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, No. 277, Yantaxi Road, Xi'an, 710061, China.
| | - Cong Li
- Department of Neurosurgery, Shenzhen Children's Hospital, Shenzhen, No. 7019, Yitian Road, Shenzhen, 518038, China
| | - Yangyang Zhou
- Department of Radiology, Shenzhen Children's Hospital, Shenzhen, China
| | - Jianxiang Liao
- Department of Neurology, Shenzhen Children's Hospital, Shenzhen, No. 7019, Yitian Road, Shenzhen, 518038, China.
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50
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Estimated IQ Systematically Underestimates Neurocognitive Sequelae in Irradiated Pediatric Brain Tumor Survivors. Int J Radiat Oncol Biol Phys 2018; 101:541-549. [DOI: 10.1016/j.ijrobp.2018.03.012] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/13/2017] [Revised: 03/09/2018] [Accepted: 03/13/2018] [Indexed: 11/19/2022]
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