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Neurologia Medico-chirurgica Sep 2022Rapid technological advances in molecular biology, including next-generation sequencing, have identified key genetic alterations in central nervous system (CNS) tumors....
Rapid technological advances in molecular biology, including next-generation sequencing, have identified key genetic alterations in central nervous system (CNS) tumors. Accordingly, the fifth edition of the World Health Organization (WHO) CNS tumor classification was published in 2021. We analyzed 303 patients with diffuse glioma using an amplicon-based glioma-tailored gene panel for detecting 1p/19q codeletion and driver gene mutations such as IDH1/2, TERTp, EGFR, and CDKN2A/B on a single platform. Within glioblastomas (GBMs), the most commonly mutated genes were TERTp, TP53, PTEN, NF1, and PDGFRA, which was the most frequently mutated tyrosine kinase receptor in GBM, followed by EGFR. The genes that most commonly showed evidence of loss were PTEN, CDKN2A/B, and RB1, whereas the genes that most commonly showed evidence of gain/amplification were EGFR, PDGFRA, and CDK4. In 22 grade III oligodendroglial tumors, 3 (14%) patients had CDKN2A/B homozygous deletion, and 4 (18%) patients had ARID1A mutation. In grade III oligodendroglial tumors, an ARID1A mutation was associated with worse progression-free survival. Reclassification based on the WHO 2021 classification resulted in 62.5% of grade II/III isocitrate dehydrogenase (IDH) -wildtype astrocytomas being classified as IDH-wildtype GBM and 37.5% as not elsewhere classified. In summary, our glioma-tailored gene panel was applicable for molecular diagnosis in the WHO 2021 classification. In addition, we successfully reclassified the 303 diffuse glioma cases based on the WHO 2021 classification and clarified the genetic profile of diffuse gliomas in the Japanese population.
Topics: Astrocytoma; Brain Neoplasms; ErbB Receptors; Genetic Profile; Glioma; Homozygote; Humans; Isocitrate Dehydrogenase; Japan; Molecular Biology; Mutation; Prognosis; Sequence Deletion
PubMed: 36031351
DOI: 10.2176/jns-nmc.2022-0103 -
Journal of Neuropathology and... Jan 2023Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and...
Multifocal demyelinating leukoencephalopathy and oligodendroglial lineage cell loss with immune effector cell-associated neurotoxicity syndrome (ICANS) following CD19 CAR T-cell therapy for mantle cell lymphoma.
Immune effector cell-associated neurotoxicity syndrome (ICANS) is a prevalent condition seen after treatment with chimeric antigen receptor T-cell (CAR T) therapy and other cancer cell therapies. The underlying pathophysiology and neuropathology of the clinical syndrome are incompletely understood due to the limited availability of brain tissue evaluation from patient cases, and a lack of high-fidelity preclinical animal models for translational research. Here, we present the cellular and tissue neuropathologic analysis of a patient who experienced grade 4 ICANS after treatment with anti-CD19 CAR T therapy for mantle cell lymphoma. Our pathologic evaluation reveals a pattern of multifocal demyelinating leukoencephalopathy associated with a clinical course of severe ICANS. A focused analysis of glial subtypes further suggests region-specific oligodendrocyte lineage cell loss as a potential cellular and pathophysiologic correlate in severe ICANS. We propose a framework for the continuum of neuropathologic changes thus far reported across ICANS cases. Future elucidation of the mechanistic processes underlying ICANS will be critical in minimizing neurotoxicity following CAR T-cell and related immunotherapy treatments across oncologic and autoimmune diseases.
Topics: Animals; Lymphoma, Mantle-Cell; Immunotherapy, Adoptive; Receptors, Chimeric Antigen; Neurotoxicity Syndromes; Leukoencephalopathy, Progressive Multifocal; Adaptor Proteins, Signal Transducing
PubMed: 36592076
DOI: 10.1093/jnen/nlac121 -
Frontiers in Veterinary Science 2021A 2-year-old cat was presented with progressive ataxia. Despite treatment the animal died. Pathomorphological examination revealed a widespread leptomeningeal mass at...
A 2-year-old cat was presented with progressive ataxia. Despite treatment the animal died. Pathomorphological examination revealed a widespread leptomeningeal mass at all levels of the central nervous system accentuated on the cervical spinal cord and the medulla oblongata without presence of a primary intraaxial tumor. The neoplasm was mainly composed of round, uninucleate cells with hyperchromatic nuclei, which were immunopositive for OLIG2, doublecortin, MAP2, synaptophysin, and vimentin, indicating components of both oligodendroglial and neuronal differentiation. Ki-67 immunohistochemistry indicated a high proliferation activity of the neoplasm. Few GFAP positive and Iba-1 positive cells were interpreted as reactive astrocytes and macrophages or microglia, respectively. The tumor was immunonegative for CD3, CD20, PAX5, MUM1, pan-cytokeratin, S100, NSE, p75, NeuN and periaxin. These findings led to the diagnosis of primary diffuse leptomeningeal oligodendrogliomatosis. This is the first reported case of this entity in a young cat, which should be considered as a differential diagnosis for diffuse subarachnoidal round cell infiltrates.
PubMed: 34977226
DOI: 10.3389/fvets.2021.795126 -
Neuro-oncology Sep 2019Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of...
BACKGROUND
Chromosomal instability is associated with earlier progression in isocitrate dehydrogenase (IDH)-mutated astrocytomas. Here we evaluated the prognostic significance of polysomy in gliomas tested for 1p/19q status.
METHODS
We analyzed 412 histologic oligodendroglial tumors with use of 1p/19q testing at 8 institutions from 1996 to 2013; fluorescence in situ hybridization (FISH) for 1p/19q was performed. Polysomy was defined as more than two 1q and 19p signals in cells. Tumors were divided into groups on the basis of their 1p/19q status and polysomy and were compared for progression-free survival (PFS) and overall survival (OS).
RESULTS
In our cohort, 333 tumors (81%) had 1p/19q loss; of these, 195 (59%) had concurrent polysomy and 138 (41%) lacked polysomy, 79 (19%) had 1p/19q maintenance; of these, 30 (38%) had concurrent polysomy and 49 (62%) lacked polysomy. In agreement with prior studies, the group with 1p/19q loss had significantly better PFS and OS than did the group with 1p/19q maintenance (P < 0.0001 each). Patients with 1p/19q loss and polysomy showed significantly shorter PFS survival than patients with 1p/19q codeletion only (P < 0.0001), but longer PFS and OS than patients with 1p/19q maintenance (P < 0.01 and P < 0.0001). There was no difference in survival between tumors with >30% polysomic cells and those with <30% polysomic cells. Polysomy had no prognostic significance on PFS or OS in patients with 1p/19q maintenance.
CONCLUSIONS
The presence of polysomy in oligodendroglial tumors with codeletion of 1p/19q predicts early recurrence and short survival in patients with 1p/19q codeleted tumors.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Aneuploidy; Brain Neoplasms; Chemotherapy, Adjuvant; Child; Chromosomal Instability; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Female; Humans; In Situ Hybridization, Fluorescence; Isocitrate Dehydrogenase; Male; Middle Aged; Neoadjuvant Therapy; Neurosurgical Procedures; Oligodendroglioma; Prognosis; Progression-Free Survival; Radiotherapy, Adjuvant; Survival Rate; Young Adult
PubMed: 31140557
DOI: 10.1093/neuonc/noz098 -
Brain Pathology (Zurich, Switzerland) Jan 2024The tumor showed extensive microcalcifications and cells with oval, nuclei and a clear perinuclear halo (A), positive immunostaining for OLIG-2 (B), GFAP (C), and CD34...
The tumor showed extensive microcalcifications and cells with oval, nuclei and a clear perinuclear halo (A), positive immunostaining for OLIG-2 (B), GFAP (C), and CD34 (D), and intermingled Neu-N-positive neurons (E). FISH revealed multiple signals for the centromere of chromosome 7 (gains) (green probe) and the EGFR locus (red probe) (F, left), and a single signal for the centromere of chromosome 10 (loss) (F, right).
Topics: Humans; Brain Neoplasms; Microtubule-Associated Proteins; Glioma; Oligodendroglia; Calcinosis
PubMed: 37409721
DOI: 10.1111/bpa.13187 -
Acta Neuropathologica Communications May 2021Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH)1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis...
Oligodendrogliomas are defined by mutation in isocitrate dehydrogenase (NADP(+)) (IDH)1/2 genes and chromosome 1p/19q codeletion. World Health Organisation diagnosis endorses testing for 1p/19q codeletion to distinguish IDH mutant (Mut) oligodendrogliomas from astrocytomas because these gliomas require different treatments and they have different outcomes. Several methods have been used to identify 1p/19q status; however, these techniques are not routinely available and require substantial infrastructure investment. Two recent studies reported reduced immunostaining for trimethylation at lysine 27 on histone H3 (H3K27me3) in IDH Mut 1p/19q codeleted oligodendroglioma. However, the specificity of H3K27me3 immunostaining in this setting is controversial. Therefore, we developed an easy-to-implement immunohistochemical surrogate for IDH Mut glioma subclassification and evaluated a validated adult glioma cohort. We screened 145 adult glioma cases, consisting of 45 IDH Mut and 1p/19q codeleted oligodendrogliomas, 30 IDH Mut astrocytomas, 16 IDH wild-type (Wt) astrocytomas, and 54 IDH Wt glioblastomas (GBMs). We compared immunostaining with DNA sequencing and fluorescent in situ hybridization analysis and assessed differences in H3K27me3 staining between oligodendroglial and astrocytic lineages and between IDH1-R132H and non-canonical (non-R132H) IDH1/2 Mut oligodendroglioma. A loss of H3K27me3 was observed in 36/40 (90%) of IDH1-R132H Mut oligodendroglioma. In contrast, loss of H3K27me3 was never seen in IDH1-R132L or IDH2-mutated 1p/19q codeleted oligodendrogliomas. IDH Mut astrocytoma, IDH Wt astrocytoma and GBM showed preserved nuclear staining in 87%, 94%, and 91% of cases, respectively. A high recursive partitioning model predicted probability score (0.9835) indicated that the loss of H3K27me3 is frequent to IDH1-R132H Mut oligodendroglioma. Our results demonstrate H3K27me3 immunohistochemical evaluation to be a cost-effective and reliable method for defining 1p/19q codeletion along with IDH1-R132H and ATRX immunostaining, even in the absence of 1p/19q testing.
Topics: Adult; Aged; Aged, 80 and over; Chromosome Deletion; Chromosomes, Human, Pair 1; Chromosomes, Human, Pair 19; Cohort Studies; Female; Humans; Isocitrate Dehydrogenase; Japan; Male; Middle Aged; Mutation; Oligodendroglioma; Young Adult
PubMed: 34020723
DOI: 10.1186/s40478-021-01194-7 -
Epidemiology of brain tumors in the United Arab Emirates: a National Registry Cross-sectional Study.BMC Neurology Aug 2020Cancer is the third leading cause of death in the United Arab Emirates (UAE); brain cancer ranks 10th among the cancers, with 2.9% of the primary cancers originating...
BACKGROUND
Cancer is the third leading cause of death in the United Arab Emirates (UAE); brain cancer ranks 10th among the cancers, with 2.9% of the primary cancers originating from the nervous system. The epidemiology of brain cancers has not been explored. The unique population dynamics of UAE make it a fertile ground for analyzing the epidemiology of brain cancer. In this study, we aim to look at the frequency patterns and distribution of malignant primary brain tumors in the UAE.
METHODS
A cross sectional study was carried out using data obtained from the Tawam Hospital Cancer Registry for the years 1984-2017. The sample size included 756 diagnosed cases of malignant primary brain tumors in the UAE. Using SPSS and Excel software, frequencies, mean ages, histological type frequencies, average annual crude incidence rates and average annual age adjusted incidence rates were analyzed.
RESULTS
The expatriate population had higher percentage of brain tumors (72%) than the locals. The mean age at diagnosis was 33.48 years (± 21.14 years) with a male to female ratio of 1.69. Diffuse astrocytic and oligodendroglial tumors were the most commonly diagnosed tumors overall. Older adults had more cases of lymphoma while embryonal and ependymal tumors were most commonly seen in younger age groups. The overall average annual crude incidence rate for 2013-2016 for all primary brain tumors was 0.56 per 100,000 population.
CONCLUSION
This is the first cancer registry study in the UAE that describes histological types of primary brain tumors based on the WHO 2016 classification of brain tumors and highlights their incidence rates. Through this study, several patterns of incidence trends for brain tumors in the UAE, according to histological types, sex and age groups have been recognized. Comparative studies would help identify the influence of potential changes in lifestyle, environmental or occupational risk factors on primary brain tumors.
Topics: Adolescent; Adult; Brain Neoplasms; Child; Cross-Sectional Studies; Female; Humans; Male; Middle Aged; Registries; United Arab Emirates; Young Adult
PubMed: 32795357
DOI: 10.1186/s12883-020-01869-z -
Archives of Pathology & Laboratory... May 2022Integration of molecular data into glioma classification supports diagnostic, prognostic, and therapeutic decision-making; however, testing practices for these...
CONTEXT.—
Integration of molecular data into glioma classification supports diagnostic, prognostic, and therapeutic decision-making; however, testing practices for these informative biomarkers in clinical laboratories remain unclear.
OBJECTIVE.—
To examine the prevalence of molecular testing for clinically relevant biomarkers in adult and pediatric gliomas through review of a College of American Pathologists proficiency testing survey prior to the release of the 2021 World Health Organization Classification of Central Nervous System Tumors.
DESIGN.—
College of American Pathologists proficiency testing 2020 survey results from 96 laboratories performing molecular testing for diffuse gliomas were used to determine the use of testing for molecular biomarkers in gliomas.
RESULTS.—
The data provide perspective into the testing practices for diffuse gliomas from a broad group of clinical laboratories in 2020. More than 98% of participating laboratories perform testing for glioma biomarkers recognized as diagnostic for specific subtypes, including IDH. More than 60% of laboratories also use molecular markers to differentiate between astrocytic and oligodendroglial lineage tumors, with some laboratories providing more comprehensive analyses, including prognostic biomarkers, such as CDKN2A/B homozygous deletions. Almost all laboratories test for MGMT promoter methylation to identify patients with an increased likelihood of responding to temozolomide.
CONCLUSIONS.—
These findings highlight the state of molecular testing in 2020 for the diagnosis and classification of diffuse gliomas at large academic medical centers. The findings show that comprehensive molecular testing is not universal across clinical laboratories and highlight the gaps between laboratory practices in 2020 and the recommendations in the 2021 World Health Organization Classification of Central Nervous System Tumors.
Topics: Adult; Humans; Child; Brain Neoplasms; Mutation; Glioma; Central Nervous System Neoplasms; Clinical Laboratory Techniques; World Health Organization
PubMed: 35878398
DOI: 10.5858/arpa.2021-0431-CP -
Redox Biology Feb 2022Redox regulation of specific cysteines via oxidoreductases of the thioredoxin family is increasingly being recognized as an important signaling pathway. Here, we...
Redox regulation of specific cysteines via oxidoreductases of the thioredoxin family is increasingly being recognized as an important signaling pathway. Here, we demonstrate that the cytosolic isoform of the vertebrate-specific oxidoreductase Glutaredoxin 2 (Grx2c) regulates the redox state of the transcription factor SP-1 and thereby its binding affinity to both the promoter and an enhancer region of the CSPG4 gene encoding chondroitin sulfate proteoglycan nerve/glial antigen 2 (NG2). This leads to an increased number of NG2 glia during in vitro oligodendroglial differentiation and promotes migration of these wound healing cells. On the other hand, we found that the same mechanism also leads to increased invasion of glioma tumor cells. Using in vitro (human cell lines), ex vivo (mouse primary cells), and in vivo models (zebrafish), as well as glioblastoma patient tissue samples we provide experimental data highlighting the Yin and Yang of redox signaling in the central nervous system and the enzymatic Taoism of Grx2c.
Topics: Animals; Chondroitin Sulfate Proteoglycans; Glioma; Glutaredoxins; Humans; Membrane Proteins; Mice; Neuroglia; Religious Philosophies; Wound Healing; Zebrafish
PubMed: 34952462
DOI: 10.1016/j.redox.2021.102221 -
Sensors (Basel, Switzerland) May 2021Diffuse gliomas are the most common primary brain tumors and they vary considerably in their morphology, location, genetic alterations, and response to therapy. In 2016,...
Diffuse gliomas are the most common primary brain tumors and they vary considerably in their morphology, location, genetic alterations, and response to therapy. In 2016, the World Health Organization (WHO) provided new guidelines for making an integrated diagnosis that incorporates both morphologic and molecular features to diffuse gliomas. In this study, we demonstrate how deep learning approaches can be used for an automatic classification of glioma subtypes and grading using whole-slide images that were obtained from routine clinical practice. A deep transfer learning method using the ResNet50V2 model was trained to classify subtypes and grades of diffuse gliomas according to the WHO's new 2016 classification. The balanced accuracy of the diffuse glioma subtype classification model with majority voting was 0.8727. These results highlight an emerging role of deep learning in the future practice of pathologic diagnosis.
Topics: Brain Neoplasms; Glioma; Humans; Machine Learning; Mutation; World Health Organization
PubMed: 34067934
DOI: 10.3390/s21103500