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The 2016 and 2021 World Health Organization (WHO) 2021 Classification of Central Nervous System (CNS) tumors have resulted in a major improvement of the classification of IDH-mutant gliomas. With more effective treatments many patients experience prolonged survival . However, treatment guidelines are often still based on information from historical series comprising both patients with IDHwt and IDH mutant tumors. They provide recommendations for radiotherapy and chemotherapy for so-called high-risk patients, usually based on residual tumor after surgery and age over 40. More up-to-date studies give a better insight into clinical, radiological and molecular factors associated with outcome of patients with IDH-mutant glioma. These insights should be used today for risk stratification and for treatment decisions. In many patients with an IDH-mutant grade 2 and grade 3 glioma, if carefully monitored postponing radiotherapy and chemotherapy is safe, and will not jeopardize overall outcome of patients. With the INDIGO trial showing patient benefit from the IDH inhibitor vorasidenib, there is a sizable population in which it seems reasonable to try this class of agents before recommending radio-chemotherapy with its delayed adverse event profile affecting quality of survival. Ongoing trials should help to further identify the patients that are benefiting from this treatment.
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Macrophages and microglia are professional phagocytes that sense and migrate toward "eat-me" signals. The role of phagocytic cells is to maintain homeostasis by engulfing senescent or apoptotic cells, debris, and abnormally aggregated macromolecules. Usually, dying cells send out "find-me" signals, facilitating the recruitment of phagocytes. Healthy cells can also promote or inhibit the phagocytosis phenomenon of macrophages and microglia by tuning the balance between "eat-me" and "don't-eat-me" signals at different stages in their lifespan, while the "don't-eat-me" signals are often hijacked by tumor cells as a mechanism of immune evasion. Using a combination of bioinformatic analysis and spatial profiling, we delineate the balance of the "don't-eat-me" CD47/SIRPα and "eat-me" CALR/STC1 ligand-receptor interactions to guide therapeutic strategies that are being developed for glioblastoma sequestered in the central nervous system (CNS).
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Antígeno CD47 , Calreticulina , Glioblastoma , Fagócitos , Fagocitose , Humanos , Glioblastoma/patologia , Glioblastoma/terapia , Glioblastoma/metabolismo , Antígeno CD47/metabolismo , Fagócitos/metabolismo , Calreticulina/metabolismo , Receptores Imunológicos/metabolismo , Macrófagos/metabolismo , Macrófagos/imunologia , Microglia/metabolismo , Microglia/patologia , Morte Celular , Animais , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/terapia , Antígenos de DiferenciaçãoRESUMO
Meningioma classification and treatment have evolved over the past eight decades. Since Bailey, Cushing, and Eisenhart's description of meningiomas in the 1920s and 1930s, there have been continual advances in clinical stratification by histopathology, radiography and, most recently, molecular profiling, to improve prognostication and predict response to therapy. Precise and accurate classification is essential to optimizing management for patients with meningioma, which involves surveillance imaging, surgery, primary or adjuvant radiotherapy, and consideration for clinical trials. Currently, the World Health Organization (WHO) grade, extent of resection (EOR), and patient characteristics are used to guide management. While these have demonstrated reliability, a substantial number of seemingly benign lesions recur, suggesting opportunities for improvement of risk stratification. Furthermore, the role of adjuvant radiotherapy for grade 1 and 2 meningioma remains controversial. Over the last decade, numerous studies investigating the molecular drivers of clinical aggressiveness have been reported, with the identification of molecular markers that carry clinical implications as well as biomarkers of radiotherapy response. Here, we review the historical context of current practices, highlight recent molecular discoveries, and discuss the challenges of translating these findings into clinical practice.
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Meningeal solitary fibrous tumors (SFT) are rare and have a high frequency of local recurrence and distant metastasis. In a cohort of 126 patients (57 female, 69 male; mean age at surgery 53.0 years) with pathologically confirmed meningeal SFTs with extended clinical follow-up (median 9.9 years; range 15 days-43 years), we performed extensive molecular characterization including genome-wide DNA methylation profiling (n = 80) and targeted TERT promoter mutation testing (n = 98). Associations were examined with NAB2::STAT6 fusion status (n = 101 cases; 51 = ex5-7::ex16-17, 26 = ex4::ex2-3; 12 = ex2-3::exANY/other and 12 = no fusion) and placed in the context of 2021 Central Nervous System (CNS) WHO grade. NAB2::STAT6 fusion breakpoints (fusion type) were significantly associated with metastasis-free survival (MFS) (p = 0.03) and, on multivariate analysis, disease-specific survival (DSS) when adjusting for CNS WHO grade (p = 0.03). DNA methylation profiling revealed three distinct clusters: Cluster 1 (n = 38), Cluster 2 (n = 22), and Cluster 3 (n = 20). Methylation clusters were significantly associated with fusion type (p < 0.001), with Cluster 2 harboring ex4::ex2-3 fusion in 16 (of 20; 80.0%), nearly all TERT promoter mutations (7 of 8; 87.5%), and predominantly an "SFT" histologic phenotype (15 of 22; 68.2%). Clusters 1 and 3 were less distinct, both dominated by tumors having ex5-7::ex16-17 fusion (respectively, 25 of 33; 75.8%, and 12 of 18; 66.7%) and with variable histological phenotypes. Methylation clusters were significantly associated with MFS (p = 0.027), but not overall survival (OS). In summary, NAB2::STAT6 fusion type was significantly associated with MFS and DSS, suggesting that tumors with an ex5::ex16-17 fusion may have inferior patient outcomes. Methylation clusters were significantly associated with fusion type, TERT promoter mutation status, histologic phenotype, and MFS.
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Nearly all glioblastoma (GBM) patients relapse following standard treatment and eventually succumb to disease. While large-scale, integrated multiomic studies have tremendously advanced the understanding of primary GBM at the cellular and molecular level, the posttherapeutic trajectory and biological properties of recurrent GBM remain poorly understood. This knowledge gap was addressed in a recent Cancer Cell article in which Kim and colleagues report on a highly integrative proteogenomic analysis performed on 123 matched primary and recurrent GBMs that uncovered a dramatic evolutionary shift from a proliferative state at initial diagnosis to the activation of neuronal and synaptogenic pathways at recurrence following therapy. Neuronal transition was characterized by posttranslational activation of WNT/PCP signaling and BRAF kinase, while many canonical oncogenic pathways, and EGFR in particular, were downregulated. Parallel multiomics analyses of patient-derived xenograft (PDX) models corroborated this evolutionary trajectory, allowing in vivo experiments for translational significance. Notably, targeting BRAF kinase disrupted both the neuronal transition and migration capabilities of recurrent gliomas, which were key characteristics of posttreatment progression. Furthermore, combining BRAF inhibitor vemurafenib with temozolomide prolonged survival in PDX models. Overall, the results reveal novel biological mechanisms of GBM evolution and therapy resistance, and suggest promising therapeutic intervention.
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Neoplasias Encefálicas , Glioblastoma , Proteogenômica , Humanos , Glioblastoma/genética , Glioblastoma/patologia , Glioblastoma/tratamento farmacológico , Glioblastoma/metabolismo , Proteogenômica/métodos , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/tratamento farmacológico , Neoplasias Encefálicas/patologia , Neoplasias Encefálicas/metabolismo , Animais , Proteínas Proto-Oncogênicas B-raf/genética , Proteínas Proto-Oncogênicas B-raf/antagonistas & inibidores , Proteínas Proto-Oncogênicas B-raf/metabolismo , Recidiva Local de Neoplasia/patologia , Recidiva Local de Neoplasia/genética , Recidiva Local de Neoplasia/tratamento farmacológico , Camundongos , Temozolomida/farmacologiaRESUMO
Glioblastoma (GBM) is a malignancy dominated by the infiltration of tumor-associated myeloid cells (TAMCs). Examination of TAMC metabolic phenotypes in mouse models and patients with GBM identified the de novo creatine metabolic pathway as a hallmark of TAMCs. Multi-omics analyses revealed that TAMCs surround the hypoxic peri-necrotic regions of GBM and express the creatine metabolic enzyme glycine amidinotransferase (GATM). Conversely, GBM cells located within these same regions are uniquely specific in expressing the creatine transporter (SLC6A8). We hypothesized that TAMCs provide creatine to tumors, promoting GBM progression. Isotopic tracing demonstrated that TAMC-secreted creatine is taken up by tumor cells. Creatine supplementation protected tumors from hypoxia-induced stress, which was abrogated with genetic ablation or pharmacologic inhibition of SLC6A8. Lastly, inhibition of creatine transport using the clinically relevant compound, RGX-202-01, blunted tumor growth and enhanced radiation therapy in vivo. This work highlights that myeloid-to-tumor transfer of creatine promotes tumor growth in the hypoxic niche.
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Glioblastoma , Camundongos , Animais , Humanos , Glioblastoma/metabolismo , Creatina , Hipóxia/metabolismo , Células Mieloides/metabolismo , Células Progenitoras Mieloides , Linhagem Celular TumoralRESUMO
The ubiquitin-specific peptidase Ataxin-3 (ATXN3) has emerged as a potential oncogene in a variety of human cancers. However, the molecular mechanisms underlying how ATXN3 achieves its tumorigenic functions remain largely undefined. Herein, we report that targeted deletion of the ATXN3 gene in cancer cells by the CRISPR-Cas9 system resulted in decreased protein expression of Yes-associated protein 1 (YAP1) without altering its mRNA transcription. Interestingly, genetic ATXN3 suppression selectively inhibited the expression levels of YAP1 target genes including the connective tissue growth factor (Ctgf) and cysteine-rich angiogenic inducer 61 (Cyr61), both of which have important functions in cell adhesion, migration, proliferation and angiogenesis. Consequently, ATXN3 suppression resulted in reduced cancer cell growth and migration, which can also be largely rescued by YAP1 reconstitution. At the molecular level, ATNX3 interacts with the WW domains of YAP1 to protect YAP1 from ubiquitination-mediated degradation. Immunohistology analysis revealed a strong positive correlation between ATXN3 and YAP1 protein expression in human breast and pancreatic cancers. Collectively, our study defines ATXN3 as a previously unknown YAP1 deubiquitinase in tumorigenesis and provides a rationale for ATXN3 targeting in antitumor chemotherapy.
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Gliomas harboring oncogenic ROS1 alterations are uncommon and primarily described in infants. Our goal was to characterize the clinicopathological features and molecular signatures of the full spectrum of ROS1 fusion-positive gliomas across all age groups. Through a retrospective multi-institutional collaboration, we report a collection of unpublished ROS1 fusion gliomas along with the characterization and meta-analysis of new and published cases. A cohort of 32 new and 58 published cases was divided into the following 3 age groups: 19 infants, 40 pediatric patients, and 31 adults with gliomas. Tumors in infants and adults showed uniformly high-grade morphology; however, tumors in pediatric patients exhibited diverse histologic features. The GOPC::ROS1 fusion was prevalent (61/79, 77%) across all age groups, and 10 other partner genes were identified. Adult tumors showed recurrent genomic alterations characteristic of IDH wild-type glioblastoma, including the +7/-10/CDKN2A deletion; amplification of CDK4, MDM2, and PDGFRA genes; and mutations involving TERTp, TP53, PIK3R1, PIK3CA, PTEN, and NF1 genes. Infant tumors showed few genomic alterations, whereas pediatric tumors showed moderate genomic complexity. The outcomes were significantly poorer in adult patients. Although not statistically significant, tumors in infant and pediatric patients with high-grade histology and in hemispheric locations appeared more aggressive than tumors with lower grade histology or those in nonhemispheric locations. In conclusion, this study is the largest to date to characterize the clinicopathological and molecular signatures of ROS1 fusion-positive gliomas from infant, pediatric, and adult patients. We conclude that ROS1 likely acts as a driver in infant and pediatric gliomas and as a driver or codriver in adult gliomas. Integrated comprehensive clinical testing might be helpful in identifying such patients for possible targeted therapy.
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Neoplasias Encefálicas , Glioblastoma , Glioma , Humanos , Criança , Adulto , Lactente , Adulto Jovem , Proteínas Tirosina Quinases/genética , Estudos Retrospectivos , Proteínas Proto-Oncogênicas/genética , Glioma/genética , Glioma/patologia , Glioblastoma/genética , Mutação , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/patologiaRESUMO
BACKGROUND: Animal models representing different molecular subtypes of glioblastoma multiforme (GBM) is desired for developing new therapies. SVV-001 is an oncolytic virus selectively targeting cancer cells. It's capacity of passing through the blood brain barrier makes is an attractive novel approach for GBM. MATERIALS AND METHODS: 23 patient tumor samples were implanted into the brains of NOD/SCID mice (1 × 105 cells/mouse). Tumor histology, gene expression (RNAseq), and growth rate of the developed patient-derived orthotopic xenograft (PDOX) models were compared with the originating patient tumors during serial subtransplantations. Anti-tumor activities of SVV-001 were examined in vivo; and therapeutic efficacy validated in vivo via single i.v. injection (1 × 1011 viral particle) with or without fractionated (2 Gy/day x 5 days) radiation followed by analysis of animal survival times, viral infection, and DNA damage. RESULTS: PDOX formation was confirmed in 17/23 (73.9%) GBMs while maintaining key histopathological features and diffuse invasion of the patient tumors. Using differentially expressed genes, we subclassified PDOX models into proneural, classic and mesenchymal groups. Animal survival times were inversely correlated with the implanted tumor cells. SVV-001 was active in vitro by killing primary monolayer culture (4/13 models), 3D neurospheres (7/13 models) and glioma stem cells. In 2/2 models, SVV-001 infected PDOX cells in vivo without harming normal brain cells and significantly prolonged survival times in 2/2 models. When combined with radiation, SVV-001 enhanced DNA damages and further prolonged animal survival times. CONCLUSION: A panel of 17 clinically relevant and molecularly annotated PDOX modes of GBM is developed, and SVV-001 exhibited strong anti-tumor activities in vitro and in vivo.
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Neoplasias Encefálicas , Glioblastoma , Terapia Viral Oncolítica , Vírus Oncolíticos , Humanos , Animais , Camundongos , Glioblastoma/radioterapia , Glioblastoma/metabolismo , Neoplasias Encefálicas/radioterapia , Neoplasias Encefálicas/metabolismo , Ensaios Antitumorais Modelo de Xenoenxerto , Camundongos Endogâmicos NOD , Camundongos SCID , Modelos Animais de Doenças , Linhagem Celular TumoralRESUMO
Materials & methods: We recently reported the largest trial of breast cancer patients with HER2 positive leptomeningeal metastases (LM) treated with trastuzumab. An additional treatment indication was explored as part of a single institution retrospective case series of HER2 positive esophageal adenocarcinoma LM (n = 2). Results: One patient received intrathecal trastuzumab (80 mg twice weekly) as part of their treatment regimen with durable long-term response and clearance of circulating tumor cells in the cerebral spinal fluid. The other patient demonstrated rapid progression and death as previously described in the literature. Conclusion: Intrathecal trastuzumab is a well-tolerated and reasonable therapeutic option worthy of further exploration for patients with HER2 positive esophageal carcinoma LM. An associative, but not a causal relationship, can be made regarding therapeutic intervention.
Cancer of the esophagus, the tube that connects the mouth to the stomach, tends to be aggressive. Very rarely, this cancer can spread to the lining that surrounds your brain, called the leptomeninges. Previous reports of patients who have experienced this specific spreading pattern of esophageal cancer to the leptomeninges are quite grim, with patients experiencing rapid decline and death within weeks to months. However, we write with two cases of esophageal cancer with this leptomeningeal spreading pattern, one of which involves a patient treated with a medication known as trastuzumab. As part of his long and complex course of treatment, this patient was given trastuzumab through a tube traveling directly to the area of the leptomeninges. This patient, now almost 2 years out from his initial diagnosis, has responded well to the treatment. As such, we believe that this specific treatment regimen as well as the ways in which our clinical team tracked this patient's response to medications are worth exploring further.
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Neoplasias da Mama , Carcinoma , Carcinomatose Meníngea , Humanos , Feminino , Estudos Retrospectivos , Receptor ErbB-2/uso terapêutico , Trastuzumab/efeitos adversos , Neoplasias da Mama/patologia , Carcinomatose Meníngea/tratamento farmacológico , Protocolos de Quimioterapia Combinada Antineoplásica/uso terapêuticoRESUMO
Background: Pediatric high-grade gliomas (pHGGs) are aggressive pediatric CNS tumors and an important subset are characterized by mutations in H3F3A, the gene that encodes Histone H3.3 (H3.3). Substitution of Glycine at position 34 of H3.3 with either Arginine or Valine (H3.3G34R/V), was recently described and characterized in a large cohort of pHGG samples as occurring in 5-20% of pHGGs. Attempts to study the mechanism of H3.3G34R have proven difficult due to the lack of knowledge regarding the cell-of-origin and the requirement for co-occurring mutations for model development. We sought to develop a biologically relevant animal model of pHGG to probe the downstream effects of the H3.3G34R mutation in the context of vital co-occurring mutations. Methods: We developed a genetically engineered mouse model (GEMM) that incorporates PDGF-A activation, TP53 loss and the H3.3G34R mutation both in the presence and loss of Alpha thalassemia/mental retardation syndrome X-linked (ATRX), which is commonly mutated in H3.3G34 mutant pHGGs. Results: We demonstrated that ATRX loss significantly increases tumor latency in the absence of H3.3G34R and inhibits ependymal differentiation in the presence of H3.3G34R. Transcriptomic analysis revealed that ATRX loss in the context of H3.3G34R upregulates Hoxa cluster genes. We also found that the H3.3G34R overexpression leads to enrichment of neuronal markers but only in the context of ATRX loss. Conclusions: This study proposes a mechanism in which ATRX loss is the major contributor to many key transcriptomic changes in H3.3G34R pHGGs. Accession number: GSE197988.
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BACKGROUND AIMS: Chimeric antigen receptor (CAR) T cells have demonstrated remarkable efficacy against hematological malignancies; however, they have not experienced the same success against solid tumors such as glioblastoma (GBM). There is a growing need for high-throughput functional screening platforms to measure CAR T-cell potency against solid tumor cells. METHODS: We used real-time, label-free cellular impedance sensing to evaluate the potency of anti-disialoganglioside (GD2) targeting CAR T-cell products against GD2+ patient-derived GBM stem cells over a period of 2 days and 7 days in vitro. We compared CAR T products using two different modes of gene transfer: retroviral transduction and virus-free CRISPR-editing. Endpoint flow cytometry, cytokine analysis and metabolomics data were acquired and integrated to create a predictive model of CAR T-cell potency. RESULTS: Results indicated faster cytolysis by virus-free CRISPR-edited CAR T cells compared with retrovirally transduced CAR T cells, accompanied by increased inflammatory cytokine release, CD8+ CAR T-cell presence in co-culture conditions and CAR T-cell infiltration into three-dimensional GBM spheroids. Computational modeling identified increased tumor necrosis factor α concentrations with decreased glutamine, lactate and formate as being most predictive of short-term (2 days) and long-term (7 days) CAR T cell potency against GBM stem cells. CONCLUSIONS: These studies establish impedance sensing as a high-throughput, label-free assay for preclinical potency testing of CAR T cells against solid tumors.
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Glioblastoma , Receptores de Antígenos Quiméricos , Humanos , Receptores de Antígenos Quiméricos/genética , Linfócitos T CD8-Positivos , Anticorpos , Citocinas , Imunoterapia Adotiva/métodos , Receptores de Antígenos de Linfócitos TRESUMO
Immune checkpoint blockade (ICB) has revolutionized modern cancer therapy, arousing great interest in the neuro-oncology community. While several reports show that subsets of patients with glioma exhibit durable responses to immunotherapy, the efficacy of this treatment has not been observed for unselected patient populations, preventing its broad clinical implementation for gliomas and glioblastoma (GBM). To exploit the maximum therapeutic potential of ICB for patients with glioma, understanding the different aspects of glioma-related tumor immune responses is of critical importance. In this Review, we discuss contributing factors that distinguish subsets of patients with glioma who may benefit from ICB. Specifically, we discuss (a) the complex interaction between the tumor immune microenvironment and glioma cells as a potential influence on immunotherapy responses; (b) promising biomarkers for responses to immune checkpoint inhibitors; and (c) the potential contributions of peripheral immune cells to therapeutic responses.
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Glioblastoma , Glioma , Humanos , Glioblastoma/tratamento farmacológico , Inibidores de Checkpoint Imunológico/farmacologia , Inibidores de Checkpoint Imunológico/uso terapêutico , Medicina de Precisão , Imunoterapia , Microambiente TumoralRESUMO
BACKGROUND: Molecularly-defined diffuse glioma types-including IDH-wildtype glioblastoma, IDH-mutant astrocytoma, IDH-mutant 1p/19q-codeleted oligodendroglioma, and H3 K27M-mutant diffuse midline glioma-were incorporated into U.S. cancer registry reporting for individuals with brain tumors beginning in 2018. We leveraged these new data to estimate the national-level overall survival (OS) patterns associated with glioma integrated diagnoses. METHODS: Individuals diagnosed with diffuse gliomas in 2018 and had brain molecular marker data were identified within the U.S. National Cancer Database. OS was estimated using Kaplan-Meier methods and stratified by WHO CNS grade, age, sex, tumor size, treatment, extent of resection, and MGMT promoter methylation. Additionally, the effects of WHO CNS grade were examined among individuals with IDH-wildtype astrocytic gliomas. RESULTS: 8651 individuals were identified. One-year OS was 53.7% for WHO grade 4 IDH-wildtype glioblastomas; 98.0%, 92.4%, and 76.3% for WHO grade 2, 3, and 4 IDH-mutant astrocytomas, respectively; 97.9% and 94.4% for WHO grade 2 and 3 IDH-mutant 1p/19q-codeleted oligodendrogliomas, respectively; and 55.9% for H3 K27M-mutant diffuse midline gliomas. Among IDH-wildtype glioblastomas, median OS was 17.1 months and 12.4 months for methylated and unmethylated MGMT promoters. Additionally, IDH-wildtype diffuse astrocytic gliomas reported as WHO grade 2 or 3 demonstrated longer OS compared to grade 4 tumors (both Pâ <â .001). CONCLUSIONS: Our findings provide the initial national OS estimates for molecularly-defined diffuse gliomas in the United States and illustrate the importance of incorporating such data into cancer registry reporting.
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Astrocitoma , Neoplasias Encefálicas , Glioblastoma , Glioma , Oligodendroglioma , Humanos , Prognóstico , Mutação , Glioma/patologia , Neoplasias Encefálicas/patologia , Isocitrato Desidrogenase/genéticaRESUMO
Diffuse intrinsic pontine glioma (DIPG) is an aggressive incurable brainstem tumor that targets young children. Complete resection is not possible, and chemotherapy and radiotherapy are currently only palliative. This study aimed to identify potential therapeutic agents using a computational pipeline to perform an in silico screen for novel drugs. We then tested the identified drugs against a panel of patient-derived DIPG cell lines. Using a systematic computational approach with publicly available databases of gene signature in DIPG patients and cancer cell lines treated with a library of clinically available drugs, we identified drug hits with the ability to reverse a DIPG gene signature to one that matches normal tissue background. The biological and molecular effects of drug treatment was analyzed by cell viability assay and RNA sequence. In vivo DIPG mouse model survival studies were also conducted. As a result, two of three identified drugs showed potency against the DIPG cell lines Triptolide and mycophenolate mofetil (MMF) demonstrated significant inhibition of cell viability in DIPG cell lines. Guanosine rescued reduced cell viability induced by MMF. In vivo, MMF treatment significantly inhibited tumor growth in subcutaneous xenograft mice models. In conclusion, we identified clinically available drugs with the ability to reverse DIPG gene signatures and anti-DIPG activity in vitro and in vivo. This novel approach can repurpose drugs and significantly decrease the cost and time normally required in drug discovery.
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Astrocitoma , Neoplasias do Tronco Encefálico , Glioma Pontino Intrínseco Difuso , Glioma , Humanos , Camundongos , Animais , Glioma Pontino Intrínseco Difuso/tratamento farmacológico , Glioma Pontino Intrínseco Difuso/genética , Ácido Micofenólico/uso terapêutico , Glioma/tratamento farmacológico , Glioma/genética , Glioma/metabolismo , Neoplasias do Tronco Encefálico/tratamento farmacológico , Neoplasias do Tronco Encefálico/genética , Neoplasias do Tronco Encefálico/patologia , Expressão Gênica , Guanosina/uso terapêuticoRESUMO
PURPOSE OF REVIEW: The recently published WHO Classification of Tumours, Central Nervous System Tumours, Fifth Edition (WHO CNS-5) introduces substantial clinically relevant changes based on improved understanding of the molecular underpinnings of brain tumor types as biological entities. This review highlights pertinent changes for practicing neurologists. RECENT FINDINGS: Diffuse gliomas are now divided into adult and pediatric types. Adult types are greatly simplified, being classified into three groups based on IDH and 1p/19q status, with molecular grading criteria now included. Pediatric types are divided into low-grade or high-grade and further classified based on molecular features corresponding to clinical behavior. While still recognizing previous morphological subtypes, meningioma is now a single tumor type, with greatly advanced correlations between molecular alterations, locations, morphologic subtypes, and grades. For the first time, ependymomas are classified based on integration of anatomical location, histopathology, and molecular alterations. Importantly, WHO CNS-5 includes a number of new tumor types that have similar clinicopathologic features and are grouped together by their distinctive molecular characteristics. SUMMARY: The classification of CNS tumors according to objective, reproducible molecular genetic alterations, provides greater opportunity for neurologists to offer individualized treatment options, enroll homogenous patient populations into clinical trials, and ultimately discover novel therapeutics.
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Neoplasias Encefálicas , Neoplasias do Sistema Nervoso Central , Glioma , Adulto , Humanos , Criança , Neurologistas , Organização Mundial da Saúde , Neoplasias do Sistema Nervoso Central/genética , MutaçãoRESUMO
Objective.In the era of precision medicine, human tumor atlas-oriented studies have been significantly facilitated by high-resolution, multi-modal tissue based microscopic pathology image analytics. To better support such tissue-based investigations, we have developed Digital Pathology Laboratory (DPLab), a publicly available web-based platform, to assist biomedical research groups, non-technical end users, and clinicians for pathology whole-slide image visualization, annotation, analysis, and sharing via web browsers.Approach.A major advancement of this work is the easy-to-follow methods to reconstruct three-dimension (3D) tissue image volumes by registering two-dimension (2D) whole-slide pathology images of serial tissue sections stained by hematoxylin and eosin (H&E), and immunohistochemistry (IHC). The integration of these serial slides stained by different methods provides cellular phenotype and pathophysiologic states in the context of a 3D tissue micro-environment. DPLab is hosted on a publicly accessible server and connected to a backend computational cluster for intensive image analysis computations, with results visualized, downloaded, and shared via a web interface.Main results.Equipped with an analysis toolbox of numerous image processing algorithms, DPLab supports continued integration of community-contributed algorithms and presents an effective solution to improve the accessibility and dissemination of image analysis algorithms by research communities.Significance.DPLab represents the first step in making next generation tissue investigation tools widely available to the research community, enabling and facilitating discovery of clinically relevant disease mechanisms in a digital 3D tissue space.
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Processamento de Imagem Assistida por Computador , Software , Humanos , Processamento de Imagem Assistida por Computador/métodos , Algoritmos , Computadores , InternetRESUMO
Glioma stem cells (GSCs) are thought to drive growth and therapy resistance in glioblastoma (GBM) by "hijacking" at least a subset of signaling pathways active in normal neural stem cells (NSCs). Though the origins of GSCs still remain elusive, uncovering the mechanisms of self-renewing division and cell differentiation in normal NSCs has shed light on their dysfunction in GSCs. However, the distinction between self-renewing division pathways utilized by NSC and GSC becomes critical when considering options for therapeutically targeting signaling pathways that are specifically active or altered in GSCs. It is well-established that cyclin-dependent kinases (CDKs) regulate the cell cycle, yet more recent studies have shown that CDKs also play important roles in the regulation of neuronal survival, metabolism, differentiation, and self-renewal. The intimate relationship between cell cycle regulation and the cellular programs that determine self-renewing division versus cell differentiation is only beginning to be understood, yet seems to suggest potential differential vulnerabilities in GSCs. In this timely review, we focus on the role of CDKs in regulating the self-renewal properties of normal NSCs and GSCs, highlighting novel opportunities to therapeutically target self-renewing signaling pathways specifically in GBM.