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Jason C H Chiang, David W Ellison
Advances in our understanding of the biology of paediatric central nervous system (CNS) tumours have encouraged pathologists to use molecular markers alongside histopathological analysis for disease classification or prognostication and treatment stratification. In this article, we review molecular genetic alterations in paediatric CNS tumours, including those in low-grade and high-grade gliomas, ependymomas, and embryonal tumours. Some of these molecular changes with clinicopathological utility have been used for the first time in the most recent edition of the World Health Organization (WHO) classification of CNS tumours to define entities like ependymoma, RELA fusion-positive or diffuse midline glioma, H3 K27M-mutant...
October 4, 2016: Journal of Pathology
Erik Ladomersky, Matthew Genet, Lijie Zhai, Galina Gritsina, Kristen L Lauing, Rishi R Lulla, Jason Fangusaro, Alicia Lenzen, Priya Kumthekar, Jeffrey J Raizer, David C Binder, C David James, Derek A Wainwright
The effective treatment of adult and pediatric malignant glioma is a significant clinical challenge. In adults, glioblastoma (GBM) accounts for the majority of malignant glioma diagnoses with a median survival of 14.6 mo. In children, malignant glioma accounts for 20% of primary CNS tumors with a median survival of less than 1 y. Here, we discuss vaccine treatment for children diagnosed with malignant glioma, through targeting EphA2, IL-13Rα2 and/or histone H3 K27M, while in adults, treatments with RINTEGA, Prophage Series G-100 and dendritic cells are explored...
August 2016: Oncoimmunology
Scott Ryall, Rahul Krishnatry, Anthony Arnoldo, Pawel Buczkowicz, Matthew Mistry, Robert Siddaway, Cino Ling, Sanja Pajovic, Man Yu, Joshua B Rubin, Juliette Hukin, Paul Steinbok, Ute Bartels, Eric Bouffet, Uri Tabori, Cynthia Hawkins
Paediatric brain tumours arising in the thalamus present significant diagnostic and therapeutic challenges to physicians due to their sensitive midline location. As such, genetic analysis for biomarkers to aid in the diagnosis, prognosis and treatment of these tumours is needed. Here, we identified 64 thalamic gliomas with clinical follow-up and characterized targeted genomic alterations using newly optimized droplet digital and NanoString-based assays. The median age at diagnosis was 9.25 years (range, 0...
2016: Acta Neuropathologica Communications
Emeline Tabouret, Anh Tuan Nguyen, Caroline Dehais, Catherine Carpentier, François Ducray, Ahmed Idbaih, Karima Mokhtari, Anne Jouvet, Emmanuelle Uro-Coste, Carole Colin, Olivier Chinot, Hugues Loiseau, Elisabeth Moyal, Claude-Alain Maurage, Marc Polivka, Emmanuèle Lechapt-Zalcman, Christine Desenclos, David Meyronet, Jean-Yves Delattre, Dominique Figarella-Branger
The new WHO classification of diffuse gliomas has been refined and now includes the 1p/19q codeletion, IDH1/2 mutation, and histone H3-K27M mutation. Our objective was to assess the prognostic value of the updated 2016 WHO classification in the French POLA cohort. All cases of high-grade oligodendroglial tumors sent for central pathological review and included into the French nationwide POLA cohort were reclassified according to the updated 4th WHO classification. In total, 1041 patients were included, with a median age at diagnosis of 50...
October 2016: Acta Neuropathologica
Marc Zanello, Mélanie Pages, Arnault Tauziède-Espariat, Raphael Saffroy, Stéphanie Puget, Ludovic Lacroix, Edouard Dezamis, Bertrand Devaux, Fabrice Chrétien, Felipe Andreiuolo, Christian Sainte-Rose, Michel Zerah, Frédéric Dhermain, Sarah Dumont, Guillaume Louvel, Jean-François Meder, Jacques Grill, Christelle Dufour, Johan Pallud, Pascale Varlet
Anaplastic ganglioglioma (AGG) is a rare and malignant variant of ganglioglioma. According to the World Health Organization classification version 2016, their histopathological grading criteria are still ill-defined. The aim of the present study was to assess the clinical, imaging, histopathological, and molecular characteristics and outcomes of AGGs in a large consecutive and retrospective adult and pediatric case series. Eighteen patients with AGGs (13 adults and 5 children) were identified (14 de novo and 4 secondary) from a cohort of 222 gangliogliomas (GG) (8%) treated at our institution between 2000 and 2015...
August 18, 2016: Journal of Neuropathology and Experimental Neurology
Fausto J Rodriguez, M Adelita Vizcaino, Ming-Tseh Lin
Gliomas represent the most common primary intraparenchymal tumors of the central nervous system in adults and children and are a genetic and phenotypic heterogeneous group. Large multi-institutional studies and The Cancer Genome Atlas have provided firm insights into the basic genetic drivers in gliomas. The main molecular biomarkers routinely applied to evaluate diffuse gliomas include MGMT promoter methylation, EGFR alterations (eg, EGFRvIII), IDH1 or IDH2 mutations, and 1p19q co-deletion. Many of these markers have become standard of care for molecular testing and prerequisites for clinical trial enrollment...
September 2016: Journal of Molecular Diagnostics: JMD
Kenichi Ishibashi, Takeshi Inoue, Hiroko Fukushima, Yusuke Watanabe, Yoshiyasu Iwai, Hiroaki Sakamoto, Kai Yamasaki, Jyunichi Hara, Tomoko Shofuda, Daiksuke Kanematsu, Ema Yoshioka, Yonehiro Kanemura
PURPOSE: Histone H3.3 (H3F3A) mutation in the codon for lysine 27 (K27M) has been found as driver mutations in pediatric glioblastoma and has been suggested to play critical roles in the pathogenesis of thalamic gliomas and diffuse intrinsic pontine gliomas. We report a case of thalamic glioma with H3F3A K27M mutation, which was detected in both the primary tumor diagnosed as diffuse astrocytoma obtained during the first surgery and also in the tumor diagnosed as anaplastic astrocytoma obtained at the second surgery...
July 8, 2016: Child's Nervous System: ChNS: Official Journal of the International Society for Pediatric Neurosurgery
Azadeh Ebrahimi, Marco Skardelly, Irina Bonzheim, Ines Ott, Helmut Mühleisen, Franziska Eckert, Ghazaleh Tabatabai, Jens Schittenhelm
Gliomas are the most frequent intraaxial CNS neoplasms with a heterogeneous molecular background. Recent studies on diffuse gliomas have shown frequent alterations in the genes involved in chromatin remodelling pathways such as α-thalassemia/mental-retardation-syndrome-X-linked gene (ATRX). Yet, the reliability of ATRX in predicting isocitrate dehydrogenase (IDH) and H3 histone, family 3A (H3F3A) mutations in gliomas, is unclear.We analysed the ATRX expression status by immunohistochemistry, in a large series of 1064 gliomas and analysed the results in correlation to IDH, H3F3A and loss of heterozygosity (LOH) 1p/19q status in these tumors...
2016: Acta Neuropathologica Communications
Natacha Joyon, Arnault Tauziède-Espariat, Agusti Alentorn, Marine Giry, David Castel, Laurent Capelle, Marc Zanello, Pascale Varlet, Franck Bielle
Here we describe the presence of the mutation p.K27M of H3F3A (H3.3K27M) in two tumors of young patients with classical histopathology of ganglioglioma (grade I WHO 2007) whereas H3.3K27M represents a hallmark of midline High Grade Glioma (HGG). Ganglioglioma grade I is a rare, circumscribed, glioneuronal tumor of the central nervous system (CNS) that occurs most often in young patients, most frequently in the temporal lobe and presents with seizures (1). The neuronal component consists of ganglion cells, abnormally grouped and occasionally binucleated...
May 24, 2016: Neuropathology and Applied Neurobiology
David N Louis, Arie Perry, Guido Reifenberger, Andreas von Deimling, Dominique Figarella-Branger, Webster K Cavenee, Hiroko Ohgaki, Otmar D Wiestler, Paul Kleihues, David W Ellison
The 2016 World Health Organization Classification of Tumors of the Central Nervous System is both a conceptual and practical advance over its 2007 predecessor. For the first time, the WHO classification of CNS tumors uses molecular parameters in addition to histology to define many tumor entities, thus formulating a concept for how CNS tumor diagnoses should be structured in the molecular era. As such, the 2016 CNS WHO presents major restructuring of the diffuse gliomas, medulloblastomas and other embryonal tumors, and incorporates new entities that are defined by both histology and molecular features, including glioblastoma, IDH-wildtype and glioblastoma, IDH-mutant; diffuse midline glioma, H3 K27M-mutant; RELA fusion-positive ependymoma; medulloblastoma, WNT-activated and medulloblastoma, SHH-activated; and embryonal tumour with multilayered rosettes, C19MC-altered...
June 2016: Acta Neuropathologica
M Wiese, F Schill, D Sturm, S Pfister, E Hulleman, S A Johnsen, C M Kramm
BACKGROUND: Glioblastoma multiforme (GBM) and diffuse intrinsic pontine glioma (DIPG) belong to the most aggressive cancers in children with poor prognosis and limited therapeutic options. Therapeutic targeting of epigenetic proteins may offer new treatment options. Preclinical studies identified Enhancer of Zeste Homolog 2 (EZH2) within polycomb repressor complex 2 (PRC2) as a potential epigenetic anti-tumor target in adult GBM cells but similar inhibition studies in pediatric GBM/DIPG were still missing...
April 2016: Klinische Pädiatrie
Hamid Nikbakht, Eshini Panditharatna, Leonie G Mikael, Rui Li, Tenzin Gayden, Matthew Osmond, Cheng-Ying Ho, Madhuri Kambhampati, Eugene I Hwang, Damien Faury, Alan Siu, Simon Papillon-Cavanagh, Denise Bechet, Keith L Ligon, Benjamin Ellezam, Wendy J Ingram, Caedyn Stinson, Andrew S Moore, Katherine E Warren, Jason Karamchandani, Roger J Packer, Nada Jabado, Jacek Majewski, Javad Nazarian
Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from various neuroanatomical structures of whole autopsy brains from nine DIPG patients. Evolutionary reconstruction indicates histone 3 (H3) K27M--including H3.2K27M--mutations potentially arise first and are invariably associated with specific, high-fidelity obligate partners throughout the tumour and its spread, from diagnosis to end-stage disease, suggesting mutual need for tumorigenesis...
2016: Nature Communications
Julia E Neumann, Mario M Dorostkar, Andrey Korshunov, Christian Mawrin, Arend Koch, Armin Giese, Ulrich Schüller
Glioblastomas (GBMs) are malignant brain tumors that can be divided into different molecular subtypes based on genetics, global gene expression, and methylation patterns. Among these subgroups, "IDH" GBMs carry mutations within IDH1 or IDH2 The "K27" and "G34" subgroups are characterized by distinct mutations within Histone 3 (H3). These subtypes can be identified by sequencing methods and are particularly found in younger patients. To determine whether the molecular subtypes correlate with distinct histological features among the diverse histologic patterns of GBM, we performed a blinded assessment of the histology of GBMs of 77 patients ≤30 years old at the time of biopsy...
May 2016: Journal of Neuropathology and Experimental Neurology
Nicholas A Vitanza, Yoon-Jae Cho
PURPOSE OF REVIEW: Central nervous system tumors represent the most common solid tumors in children and are a leading cause of cancer-related fatalities in this age group. Here, we provide an update on insights gained through molecular profiling of the most common malignant childhood brain tumors. RECENT FINDINGS: Genomic profiling studies of medulloblastoma, ependymoma, and diffuse intrinsic pontine glioma (diffuse midline glioma, with H3-K27M mutation), have refined, if not redefined, the diagnostic classification and therapeutic stratification of patients with these tumors...
February 2016: Current Opinion in Pediatrics
David A Solomon, Matthew D Wood, Tarik Tihan, Andrew W Bollen, Nalin Gupta, Joanna J J Phillips, Arie Perry
Somatic mutations of the H3F3A and HIST1H3B genes encoding the histone H3 variants, H3.3 and H3.1, were recently identified in high-grade gliomas arising in the thalamus, pons and spinal cord of children and young adults. However, the complete range of patients and locations in which these tumors arise, as well as the morphologic spectrum and associated genetic alterations remain undefined. Here, we describe a series of 47 diffuse midline gliomas with histone H3-K27M mutation. The 25 male and 22 female patients ranged in age from 2 to 65 years (median = 14)...
September 2016: Brain Pathology
Ergys Subashi, Francisco J Cordero, Kyle G Halvorson, Yi Qi, John C Nouls, Oren J Becher, G Allan Johnson
Pediatric high-grade gliomas (pHGGs) occur with strikingly different frequencies in infratentorial and supratentorial regions. Although histologically these malignancies appear similar, they represent distinct diseases. Recent genomic studies have identified histone K27M H3.3/H3.1 mutations in the majority of brainstem pHGGs; these mutations are rarely encountered in pHGGs that arise in the cerebral cortex. Previous research in brainstem pHGGs suggests a restricted permeability of the blood-brain-barrier (BBB)...
January 2016: Journal of Neuro-oncology
Ganesh M Shankar, Nina Lelic, Corey M Gill, Aaron R Thorner, Paul Van Hummelen, Jeffrey H Wisoff, Jay S Loeffler, Priscilla K Brastianos, John H Shin, Lawrence F Borges, William E Butler, David Zagzag, Rachel I Brody, Ann-Christine Duhaime, Michael D Taylor, Cynthia E Hawkins, David N Louis, Daniel P Cahill, William T Curry, Matthew Meyerson
No abstract text is available yet for this article.
January 2016: Acta Neuropathologica
Rui-Qi Zhang, Zhifeng Shi, Hong Chen, Nellie Yuk-Fei Chung, Zi Yin, Kay Ka-Wai Li, Danny Tat-Ming Chan, Wai Sang Poon, Jinsong Wu, Liangfu Zhou, Aden Ka-Yin Chan, Ying Mao, Ho-Keung Ng
While the predominant elderly and the pediatric glioblastomas have been extensively investigated, young adult glioblastomas were understudied. In this study, we sought to stratify young adult glioblastomas by BRAF, H3F3A and IDH1 mutations and examine the clinical relevance of the biomarkers. In 107 glioblastomas aged from 17 to 35 years, mutually exclusive BRAF-V600E (15%), H3F3A-K27M (15.9%), H3F3A-G34R/V (2.8%) and IDH1-R132H (16.8%) mutations were identified in over half of the cases. EGFR amplification and TERTp mutation were only detected in 3...
January 26, 2016: Oncotarget
David Castel, Cathy Philippe, Raphaël Calmon, Ludivine Le Dret, Nathalène Truffaux, Nathalie Boddaert, Mélanie Pagès, Kathryn R Taylor, Patrick Saulnier, Ludovic Lacroix, Alan Mackay, Chris Jones, Christian Sainte-Rose, Thomas Blauwblomme, Felipe Andreiuolo, Stephanie Puget, Jacques Grill, Pascale Varlet, Marie-Anne Debily
Diffuse intrinsic pontine glioma (DIPG) is the most severe paediatric solid tumour, with no significant therapeutic progress made in the past 50 years. Recent studies suggest that diffuse midline glioma, H3-K27M mutant, may comprise more than one biological entity. The aim of the study was to determine the clinical and biological variables that most impact their prognosis. Ninety-one patients with classically defined DIPG underwent a systematic stereotactic biopsy and were included in this observational retrospective study...
December 2015: Acta Neuropathologica
Ray Zhang, Jing Han, David Daniels, Haojie Huang, Zhiguo Zhang
Diffuse intrinsic pontine glioma (DIPG) is an aggressive pediatric brain tumor with a median survival of 1 year after diagnosis. It has been reported recently that about 80% of DIPG cases and 70% of midline glioblastomas contain a mutation at one allele of the H3F3A gene (encoding histone H3 variant H3.3), replacing the lysine 27 with methionine (K27M). In order to facilitate diagnosis of DIPG patients, a quick and reliable method to identify the H3F3A K27M mutation is needed. Here, we describe a real-time PCR-based procedure involving a mutant-specific primer, a blocker oligonucleotide, and a reverse primer that can differentiate samples with H3F3A K27M mutation from those that do not...
January 2016: Journal of Neuro-oncology
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