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    Conventional MRI features can predict the molecular subtype of adult grade 2-3 intracranial diffuse gliomas. Neuroradiology PURPOSE:Molecular biomarkers are important for classifying intracranial gliomas, prompting research into correlating imaging with genotype ("radiogenomics"). A limitation of the existing radiogenomics literature is the paucity of studies specifically characterizing grade 2-3 gliomas into the three key molecular subtypes. Our study investigated the accuracy of multiple different conventional MRI features for genotype prediction. METHODS:Grade 2-3 gliomas diagnosed between 2007 and 2013 were identified. Two neuroradiologists independently assessed nine conventional MRI features. Features with better inter-observer agreement (κ ≥ 0.6) proceeded to consensus assessment. MRI features were correlated with genotype, classified as IDH-mutant and 1p/19q-codeleted (IDH/1p19q), IDH-mutant and 1p/19q-intact (IDH/1p19q), or IDH-wildtype (IDH). For IDH tumors, additional molecular markers of glioblastoma were noted. RESULTS:One hundred nineteen patients were included. T2-FLAIR mismatch (stratified as > 50%, 25-50%, or < 25%) was the most predictive feature across genotypes (p < 0.001). All 30 tumors with > 50% mismatch were IDH/1p19q, and all seven with 25-50% mismatch. Well-defined margins correlated with IDH/1p19q status on univariate analysis (p < 0.001), but this related to correlation with T2-FLAIR mismatch; there was no longer an association when considering only tumors with < 25% mismatch (p = 0.386). Enhancement (p = 0.001), necrosis (p = 0.002), and hemorrhage (p = 0.027) correlated with IDH status (especially "molecular glioblastoma"). Calcification correlated with IDH/1p19q status (p = 0.003). A simple, step-wise algorithm incorporating these features, when present, correctly predicted genotype with a positive predictive value 91.8%. CONCLUSION:T2-FLAIR mismatch strongly predicts IDH/1p19q even with a lower threshold of ≥ 25% mismatch and outweighs other features. Secondary features include enhancement, necrosis and hemorrhage (predicting IDH, especially "molecular glioblastoma"), and calcification (predicting IDH/1p19q). 10.1007/s00234-022-02975-0
    The prognostic value of the preoperative inflammatory index on the survival of glioblastoma patients. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology OBJECTIVES:The growth and development of tumors are closely related to the initiation and amplification of the inflammatory response. Various inflammatory biomarkers had attained growing attention for nearly two decades and were discovered strongly associated with cancer patients' prognosis, indicating that systemic inflammatory response is possibly essential to cancer progression. However, little was known about the sensitive biomarkers associated with the detection, persistence, treatment, and prognosis of GBM. Hence, the retrospective research endeavored to evaluate the prognostic value of preoperative inflammatory biomarkers in patients with GBM who initially received standardized treatment. METHODS:The 232 glioblastoma patients eligible who were admitted to Qilu Hospitals in Shandong Province from January 2014 to January 2018 were collected for this analysis. Inflammatory markers, including the systemic immune-inflammation index (SII), systemic immune response index (SIRI), neutrophil-lymphocyte ratio (NLR), platelet-lymphocyte ratio (PLR), monocyte-lymphocyte ratio (MLR), and albumin/globulin ratio (AGR), were designed. Progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan-Meier method, and we calculated the area under the ROC curve to determine the AUC value. Besides, we used the Cox proportional hazard model to estimate the relationship between variables and PFS and OS. The statistical differences between variables and PFS and OS were tested through the log-rank test. What is more, the LR method was used to perform Cox multiple regression analysis. The results were represented by hazard ratio (HR), 95% CI, any 2-tailed P < 0.01 was accepted as statistically different. RESULTS:The multivariate Cox proportional hazard model presented that SII ≥ 659.1 was an independent risk factor affecting OS (HR = 2.238, 95% CI = 1.471-3.406, P < 0.001) and postoperative PFS (HR = 2.000, 95% CI = 1.472-2.716, P < 0.001) in GBM patients. The 1-, 3-, and 5-year OS of the SII < 659.1 group was 70.8%, 26.9%, and 14.1%, respectively, while the 1- and 3-year OS of the SII ≥ 659.1 group was 37.5% and 11.5% (P < 0.001). The 1-, 3-, and 5-year PFS of the SII < 659.1 group was 36.3%, 19.6%, and 13%, respectively, while the 1-year PFS of the SII ≥ 659.1 group was 11.3% (P < 0.001). Results of patients' clinical and pathological characteristics paraded that in comparison to the lower SII group, the higher SII group had significantly inferior Karnofsky Performance Scale (KPS) scores (P < 0.001) and more frequent cystic changes of the tumors (P < 0.001), whereas the values of SIRI, NLR, PLR, MLR, and AGR were low. CONCLUSIONS:SII is an independent inflammatory indicator for predicting the prognosis of GBM patients after receiving initially standardized treatments. 10.1007/s10072-022-06158-w
    Hypoxia Promotes Glioma Stem Cell Proliferation by Enhancing the 14-3-3 Expression via the PIK Pathway. Journal of immunology research Glioma is a serious fatal type of cancer with the shorter median survival period and poor quality of living. The overall 5-year survival rate remains low due to high recurrence rates. Glioma stem cells (GSCs) play the important roles in the development of gliomas. Examination of the numerous biomarkers or cancer-associated genes involved in the development or prevention of glioma may therefore serve the discovery of novel strategies to treat patients with glioma. Hypoxia induced by using CoCl application and 14-3-3 protein knockdown by specific small interfering RNA transfection were performed in GSCs both in vitro and in vivo to observe their role in glioma progression and metastasis occurrence by using western blot analysis and MTT assay. The results demonstrated that CoCl application enhanced the 14-3-3 protein expression and mRNA levels via the PIK pathway in GSCs. Furthermore, hypoxia promoted GSC cell proliferation and activated the expression of proliferating cell nuclear antigen, which was inhibited following 14-3-3 knockdown. In addition, tumor growth in mice was enhanced by CoCl application but reversed following 14-3-3 knockdown, which also enhanced GSC cell apoptosis. In conclusion, the present study demonstrated that hypoxia promoted glioma growth both in vitro and in vivo by increasing the 14-3-3 expression via the PIK signaling pathway. 14-3-3 and HIF-1 may therefore be considered as the potential therapeutic target to treat patients with glioma. 10.1155/2022/5799776
    Survival Prediction After Neurosurgical Resection of Brain Metastases: A Machine Learning Approach. Neurosurgery BACKGROUND:Current prognostic models for brain metastases (BMs) have been constructed and validated almost entirely with data from patients receiving up-front radiotherapy, leaving uncertainty about surgical patients. OBJECTIVE:To build and validate a model predicting 6-month survival after BM resection using different machine learning algorithms. METHODS:An institutional database of 1062 patients who underwent resection for BM was split into an 80:20 training and testing set. Seven different machine learning algorithms were trained and assessed for performance; an established prognostic model for patients with BM undergoing radiotherapy, the diagnosis-specific graded prognostic assessment, was also evaluated. Model performance was assessed using area under the curve (AUC) and calibration. RESULTS:The logistic regression showed the best performance with an AUC of 0.71 in the hold-out test set, a calibration slope of 0.76, and a calibration intercept of 0.03. The diagnosis-specific graded prognostic assessment had an AUC of 0.66. Patients were stratified into regular-risk, high-risk and very high-risk groups for death at 6 months; these strata strongly predicted both 6-month and longitudinal overall survival (P < .0005). The model was implemented into a web application that can be accessed through http://brainmets.morethanml.com. CONCLUSION:We developed and internally validated a prediction model that accurately predicts 6-month survival after neurosurgical resection for BM and allows for meaningful risk stratification. Future efforts should focus on external validation of our model. 10.1227/neu.0000000000002037
    A comprehensive profiling of the immune microenvironment of breast cancer brain metastases. Neuro-oncology BACKGROUND:Despite potential clinical implications, the complexity of breast cancer (BC) brain metastases (BM) immune microenvironment is poorly understood. Through multiplex immunofluorescence, we here describe the main features of BCBM immune microenvironment (density and spatial distribution) and evaluate its prognostic impact. METHODS:60 BCBM from patients undergoing neurosurgery at three institutions (2003-2018) was comprehensively assessed using two multiplex immunofluorescence panels (CD4, CD8, Granzyme B, FoxP3, CD68, pan-cytokeratin, DAPI; CD3, PD-1, PD-L1, LAG-3, TIM-3, CD163, pan-cytokeratin, DAPI). The prognostic impact of immune subpopulations and cell-to-cell spatial interactions was evaluated. RESULTS:Subtype-related differences in BCBM immune microenvironment and its prognostic impact were observed. While in HR-/HER2- BM and HER2+ BM, higher densities of intra-tumoral CD8+ lymphocytes were associated with significantly longer OS (HR 0.16 and 0.20, respectively), in HR+/HER2- BCBMs a higher CD4+FoxP3+/CD8+ cell ratio in the stroma was associated with worse OS (HR 5.4). Moreover, a higher density of intra-tumoral CD163+ M2-polarized microglia/macrophages in BCBMs was significantly associated with worse OS in HR-/HER2- and HR+/HER2- BCBMs (HR 6.56 and 4.68, respectively), but not in HER2+ BCBMs. In HER2+ BCBMs, multiplex immunofluorescence highlighted a negative prognostic role of PD-1/PD-L1 interaction: patients with a higher percentage of PD-L1+ cells spatially interacting with (within a 20 µm radius) PD-1+ cells presented a significantly worse OS (HR 4.60). CONCLUSIONS:Our results highlight subtype-related differences in BCBM immune microenvironment and identify two potential therapeutic targets, M2 microglia/macrophage polarization in HER2- and PD-1/PD-L1 interaction in HER2+ BCBMs, which warrant future exploration in clinical trials. 10.1093/neuonc/noac136
    GLI1 is involved in HIF-1α-induced migration, invasion, and epithelial-mesenchymal transition in glioma cells. Folia histochemica et cytobiologica INTRODUCTION:Glioma is characterized by hypoxia that activates the hypoxia inducible factor (HIF) pathway and controls a myriad of genes that drive cancer progression. HIF-1α promotes GLI1 transferring to the nucleus by activating the hedgehog pathway under hypoxic conditions. However, their mechanisms in glioma cells under hypoxia remain unknown. MATERIAL AND METHODS:Human glioma cell lines (LN229 and LN18) were transfected with HIF-1α or GLI1-specific short hairpin RNAs (shRNAs) and cultured under normoxic or hypoxic conditions. The protein levels of HIF-1α, GLI1, and epithelial-mesenchymal transition (EMT) markers including E-cadherin and vimentin were measured by Western blot analysis. RT-qPCR analysis was performed for the detection of HIF-1α and GLI1 mRNA expression. Cell migratory and invasive capacities were evaluated by wound healing and Transwell assays, respectively. RESULTS:Hypoxia blocked the breakdown of the HIF-1α protein and upregulated GLI1 expression in glioma cells. Downregulation of HIF-1α expression inhibited hypoxia-induced cell migration and invasion, as well as reversed the effects of hypoxia on GLI1, E-cadherin, and vimentin expression in LN229 and LN18 cells. Depletion of GLI1 inhibited glioma cell migration and invasion induced by hypoxia. Silenced GLI1 did not affect HIF-1α expression but completely offset hypoxia-regulated expression of E-cadherin and vimentin in glioma cells. CONCLUSIONS:GLI1 is involved in HIF-1α-induced migration, invasion, and EMT in glioma cells, thus revealing a novel molecular mechanism for glioma research. 10.5603/FHC.a2022.0014
    Multi-institutional study of the frequency, genomic landscape and outcome of IDH-mutant glioma in paediatrics. Neuro-oncology BACKGROUND:The incidence and biology of IDH1/2 mutations in pediatric gliomas are unclear. Notably, current treatment approaches by pediatric and adult providers vary significantly. We describe the frequency and clinical outcomes of IDH1/2-mutant gliomas in pediatrics. METHODS:We performed a multi-institutional analysis of the frequency of pediatric IDH1/2-mutant gliomas, identified by next-generation sequencing (NGS). In parallel, we retrospectively reviewed pediatric IDH1/2-mutant gliomas, analyzing clinico-genomic features, treatment approaches, and outcomes. RESULTS INCIDENCE:Among 851 patients with pediatric glioma who underwent NGS, we identified 78 with IDH1/2 mutations. Among patients 0-9 and 10-21 years old, 2/378 (0.5%) and 76/473 (16.1%) had IDH1/2-mutant tumors, respectively. Frequency of IDH mutations was similar between low- (52/570, 9.1%) and high-grade glioma (25/277, 9.0%). Four tumors were graded as intermediate histologically, with one IDH1 mutation. OUTCOME:Seventy-six patients with IDH1/2-mutant glioma had outcome data available. Eighty-four percent of patients with low-grade glioma were managed observantly without additional therapy. For low-grade astrocytoma, 5-year progression-free survival (PFS) was 42.9% (95%CI:20.3-63.8) and, despite excellent short-term overall survival (OS), numerous disease-related deaths after year 10 were reported. Patients with high-grade astrocytoma had a 5-year PFS/OS of 36.8% (95%CI:8.8-66.4) and 84% (95%CI:50.1-95.6), respectively. Patients with oligodendroglioma had excellent OS. CONCLUSIONS:A subset of pediatric gliomas are driven by IDH1/2 mutations, with a higher rate among adolescents. The majority of patients underwent upfront observant management without adjuvant therapy. Findings suggest that the natural history of pediatric IDH1/2-mutant glioma may be similar to that of adults, though additional studies are needed. 10.1093/neuonc/noac132
    Deep Brain Stimulation for Tremor: Direct Targeting of a Novel Imaging Biomarker. Annals of neurology 10.1002/ana.26422
    DNA Methylation subclass Receptor Tyrosine Kinase II (RTK II) is predictive for seizure development in glioblastoma patients. Neuro-oncology BACKGROUND:Seizures can present at any time before or after the diagnosis of a glioma. Roughly, 25-30 % of glioblastoma (GBM) patients initially present with seizures, and an additional 30 % develop seizures during the course of the disease. Early studies failed to show an effect of general administration of anti-epileptic drugs for glioblastoma patients, since they were unable to stratify patients into high- or low-risk seizure groups. METHODS:111 patients, who underwent surgery for a GBM, were included. Genome-wide DNA methylation profiling was performed, before methylation subclasses and copy number changes inferred from methylation data were correlated with clinical characteristics. Independently, global gene expression was analyzed in GBM methylation subclasses from TCGA datasets (n=68). RESULTS:Receptor tyrosine Kinase (RTK) II GBM showed a significantly higher incidence of seizures than RTK I and mesenchymal (MES) GBM (p<0.01). Accordingly, RNA expression datasets revealed an upregulation of genes involved in neurotransmitter synapses and vesicle transport in RTK II glioblastomas. In a multivariate analysis, temporal location (p=0.02, OR 5.69) and RTK II (p=0.03, OR 5.01) were most predictive for preoperative seizures. During postoperative follow-up, only RTK II remained significantly associated with the development of seizures (p<0.01, OR 8.23). Consequently, the need for antiepileptic medication and its increase due to treatment failure was highly associated with the RTK II methylation subclass (p<0.01). CONCLUSION:Our study shows a strong correlation of RTK II glioblastomas with preoperative and long-term seizures. These results underline the benefit of molecular glioblastoma profiling with important implications for postoperative seizure control. 10.1093/neuonc/noac108
    Systematic discovery of mutation-directed neo-protein-protein interactions in cancer. Cell Comprehensive sequencing of patient tumors reveals genomic mutations across tumor types that enable tumorigenesis and progression. A subset of oncogenic driver mutations results in neomorphic activity where the mutant protein mediates functions not engaged by the parental molecule. Here, we identify prevalent variant-enabled neomorph-protein-protein interactions (neoPPI) with a quantitative high-throughput differential screening (qHT-dS) platform. The coupling of highly sensitive BRET biosensors with miniaturized coexpression in an ultra-HTS format allows large-scale monitoring of the interactions of wild-type and mutant variant counterparts with a library of cancer-associated proteins in live cells. The screening of 17,792 interactions with 2,172,864 data points revealed a landscape of gain of interactions encompassing both oncogenic and tumor suppressor mutations. For example, the recurrent BRAF V600E lesion mediates KEAP1 neoPPI, rewiring a BRAF/KEAP1 signaling axis and creating collateral vulnerability to NQO1 substrates, offering a combination therapeutic strategy. Thus, cancer genomic alterations can create neo-interactions, informing variant-directed therapeutic approaches for precision medicine. 10.1016/j.cell.2022.04.014
    The oncogenic role of tubulin alpha-1c chain in human tumours. BMC cancer Tubulin alpha-1c chain (TUBA1C), a subtype of α-tubulin, has been shown to be involved in cell proliferation and cell cycle progression in several cancers and to influence cancer development and prognosis. However, a pancancer analysis of TUBA1C to reveal its immunological and prognostic roles has not been performed. In this study, we first downloaded raw data on TUBA1C expression in cancers from The Cancer Genome Atlas (TCGA) database and multiple other databases and analysed these data with R software to investigate the prognostic and immunological value of TUBA1C in cancers. Immunohistochemical analysis was performed in gliomas to further validate our findings. Overall, TUBA1C was overexpressed in most cancers, and overexpression of TUBA1C was linked to poor prognosis and higher tumour grade in patients. In addition, TUBA1C expression was associated with tumour mutation burden (TMB), microsatellite instability (MSI), the tumour microenvironment (TME) and the infiltration of immune cells. TUBA1C was also coexpressed with most immune-related genes and influenced immune-related pathways. Immunohistochemical analysis showed that TUBA1C expression was highest in glioblastoma (GBM) tissues, second highest in low-grade glioma (LGG) tissues and lowest in normal tissues. Our study indicated that TUBA1C might be a biomarker for predicting the immune status and prognosis of cancers, offering new ideas for cancer treatment. 10.1186/s12885-022-09595-0
    A Novel Risk Score Model Based on Eleven Extracellular Matrix-Related Genes for Predicting Overall Survival of Glioma Patients. Journal of oncology Gliomas are the most common lethal primary brain tumors with variable survival outcomes for patients. The extracellular matrix (ECM) is linked with clinical prognosis of glioma patients, but it is not commonly used as a clinical indicator. Herein, we investigated changes in ECM-related genes (ECMRGs) via analyzing the transcriptional data of 938 gliomas from TCGA and CGGA datasets. Based on least absolute shrinkage and selection operator (LASSO) Cox regression analysis, a 11-ECMRG signature that is strongly linked with overall survival (OS) in glioma patients was identified. This signature was characterized by high-risk and low-risk score patterns. We found that the patients in the high-risk group are significantly linked with malignant molecular features and worse outcomes. Univariate and multivariate Cox regression analyses suggested that the signature is an independent indicator for glioma prognosis. The prediction accuracy of the signature was verified through time-dependent receiver operating characteristic (ROC) curves and calibration plots. Further bioinformatics analyses implied that the ECMRG signature is strongly associated with the activation of multiple oncogenic and metabolic pathways and immunosuppressive tumor microenvironment in gliomas. In addition, we confirmed that the high-risk score is an indicator for a therapy-resistant phenotype. In addition to bioinformatics analyses, we functionally verified the oncogenic role of bone morphogenetic protein 1 (BMP1) in gliomas . 10.1155/2022/4966820
    Single-Cell Sequencing Analysis Based on Public Databases for Constructing a Metastasis-Related Prognostic Model for Gastric Cancer. Applied bionics and biomechanics Background:Although incidences of gastric cancer have decreased in recent years, the disease remains a significant danger to human health. Lack of early symptoms often leads to delayed diagnosis of gastric cancer, so that many patients miss the opportunity for surgery. Treatment for advanced gastric cancer is often limited. Immunotherapy, targeted therapy, and the mRNA vaccine have all emerged as potentially viable treatments for advanced gastric cancer. However, our understanding of the immune microenvironment of gastric cancer is far from sufficient; now is the time to explore this microenvironment. Methods:In our study, using TCGA dataset and the GEO dataset GSE62254, we performed in-depth transcriptome and single-cell sequencing analyses based on public databases. We analyzed differential gene expressions of immune cells in metastatic and nonmetastatic gastric cancer and constructed a prognostic model of gastric cancer patients based on these differential gene expressions. We also screened candidate vaccine genes for gastric cancer. Results:This prognostic model can accurately predict the prognosis of gastric cancer patients by dividing them into high-risk and low-risk groups. In addition to this, we identified a candidate vaccine gene for gastric cancer: PTPN6. Conclusions:Our study could provide new ideas for the treatment of gastric cancer. 10.1155/2022/7061263
    The Comprehensive Analysis Identified an Autophagy Signature for the Prognosis and the Immunotherapy Efficiency Prediction in Lung Adenocarcinoma. Frontiers in immunology Background:Lung adenocarcinoma (LUAD) is a fatal malignancy in the world. Growing evidence demonstrated that autophagy-related genes regulated the immune cell infiltration and correlated with the prognosis of LUAD. However, the autophagy-based signature that can predict the prognosis and the efficiency of checkpoint immunotherapy in LUAD patients is yet to be discovered. Methods:We used conventional autophagy-related genes to screen candidates for signature construction in TCGA cohort and 9 GEO datasets (tumor samples, n=2181; normal samples, n=419). An autophagy-based signature was constructed, its correlation with the prognosis and the immune infiltration of LUAD patients was explored. The prognostic value of the autophagy-based signature was validated in an independent cohort with 70 LUAD patients. Single-cell sequencing data was used to further characterize the various immunological patterns in tumors with different signature levels. Moreover, the predictive value of autophagy-based signature in PD-1 immunotherapy was explored in the IMvigor210 dataset. At last, the protective role of DRAM1 in LUAD was validated by experiments. Results:After screening autophagy-related gene candidates, a signature composed by CCR2, ITGB1, and DRAM1 was established with the ATscore in each sample. Further analyses showed that the ATscore was significantly associated with immune cell infiltration and low ATscore indicated poor prognosis. Meanwhile, the prognostic value of ATscore was validated in our independent LUAD cohort. GSEA analyses and single-cell sequencing analyses revealed that ATscore was associated with the immunological status of LUAD tumors, and ATscore could predict the efficacy of PD-1 immunotherapy. Moreover, experiments demonstrated that the inhibition of DRAM1 suppressed the proliferation and migration capacity of LUAD cells. Conclusion:Our study identified a new autophagy-based signature that can predict the prognosis of LUAD patients, and this ATscore has potential applicative value in the checkpoint therapy efficiency prediction. 10.3389/fimmu.2022.749241
    A Rare Presentation of Primary Central Nervous System Lymphoma in an Immunocompetent Patient. Cureus Primary central nervous system lymphoma (PCNSL) is a rare non-Hodgkin's lymphoma (NHL) that can develop in the brain, spinal cord, leptomeninges, and vitreoretinal space. The majority of cases are diffuse large B-cell lymphomas. Risk factors include immune dysfunction, prior Epstein-Barr viral infection, HIV, and a family history of non-Hodgkin's lymphoma. Although the majority of the patients are immunocompromised, PCNSL is still seen in immunocompetent patients. PCNSL has a poor prognosis and a high relapse rate despite its radiosensitive and chemosensitive nature. It is important to recognize and diagnose PCNSL early to improve outcomes. We present a case of PCNSL in an immunocompetent adult with no previously known risk factors. We present a case of a 66-year-old male who presented with a 1.5-week history of right-sided headache and left-sided weakness. After being admitted for further evaluation, he underwent multiple laboratory tests and imaging studies. The CT head indicated ill-defined hypodensities in the pons and left cerebellum. CTA revealed a 1.5 cm outpouching along the medial aspect of the distal left cervical internal carotid artery at the C1-C2 level concerning a pseudoaneurysm. Neurology was consulted, and an MRI of the brain revealed equivocal brain lesions. Neurosurgery was consulted, and the patient underwent an open brain biopsy, which revealed a high likelihood of primary CNS lymphoma based on intraoperative pathology findings. CSF analysis revealed an elevated percentage of lymphocytes, including the presence of atypical lymphocytes as well as elevated oligoclonal bands. Subsequent pathology results confirmed PCNSL. The oncology service was consulted, and the patient was started on corticosteroids and methotrexate for chemotherapy as well as leucovorin. This case represents a rare presentation of PCNSL in which the patient had no known history to support an immunocompromised state. Imaging findings, in this case, were also atypical for a primary CNS lesion as they were mostly equivocal. Furthermore, imaging findings showed diffuse CNS disease rather than an obvious primary lesion as typically demonstrated in the literature. In this case, the open brain biopsy was pivotal in making a timely diagnosis and beginning disease-modifying therapy as early as possible. This case demonstrates the imperative need for clinicians to be aware of varying presentations of PCNSL and possibly consider pursuing a definitive diagnosis with biopsy when the differential includes PCNSL but remains broad after advanced imaging. 10.7759/cureus.23858
    Knockdown of NUSAP1 inhibits cell proliferation and invasion through downregulation of TOP2A in human glioblastoma. Cell cycle (Georgetown, Tex.) Nucleolar and spindle associated protein 1 (NUSAP1), an indispensable mitotic regulator, has been reported to be involved in the development, progression, and metastasis of several types of cancer. Here, we investigated the expression and biological function of NUSAP1 in human glioblastoma (GBM), an aggressive brain tumor type with largely ineffective treatment options. Analysis of the molecular data in CGGA, TCGA and Rembrandt datasets demonstrated that NUSAP1 was significantly upregulated in GBM relative to low grade gliomas and non-neoplastic brain tissue samples. Kaplan-Meier analysis indicated that patients with tumors showing high NUSAP1 expression exhibited significantly poorer survival in both CGGA (P = 0.002) and Rembrandt cohorts (P = 0.017). Analysis of RNA sequencing data from P3-cells with stable knockdown of NUSAP1 revealed topoisomerase 2A (TOP2A) as a possible molecule downregulated by the loss of NUSAP1. Molecular analysis of the CGGA data revealed a strong correlation between NUSAP1 and TOP2A expression in primary gliomas and recurrent gliomas samples. SiRNA knockdown of either NUSAP1 or TOP2A in U251, T98 and GBM derived patient P3 cells inhibited GBM cell proliferation and invasion, and induced cell apoptosis. Finally, stable knockdown of NUSAP1 with shRNA led to decreased tumor growth in an orthotopic xenograft model of GBM in mice. Taken together, NUSAP1 gene silencing induced apoptosis possibly through the downregulation of the candidate downstream molecule TOP2A. Interference with the expression of NUSAP1 might therefore inhibit malignant progression in GBM, and NUSAP1 might thus serve as a promising molecular target for GBM treatment. 10.1080/15384101.2022.2074199
    Single-cell profiling of human dura and meningioma reveals cellular meningeal landscape and insights into meningioma immune response. Genome medicine BACKGROUND:Recent investigations of the meninges have highlighted the importance of the dura layer in central nervous system immune surveillance beyond a purely structural role. However, our understanding of the meninges largely stems from the use of pre-clinical models rather than human samples. METHODS:Single-cell RNA sequencing of seven non-tumor-associated human dura samples and six primary meningioma tumor samples (4 matched and 2 non-matched) was performed. Cell type identities, gene expression profiles, and T cell receptor expression were analyzed. Copy number variant (CNV) analysis was performed to identify putative tumor cells and analyze intratumoral CNV heterogeneity. Immunohistochemistry and imaging mass cytometry was performed on selected samples to validate protein expression and reveal spatial localization of select protein markers. RESULTS:In this study, we use single-cell RNA sequencing to perform the first characterization of both non-tumor-associated human dura and primary meningioma samples. First, we reveal a complex immune microenvironment in human dura that is transcriptionally distinct from that of meningioma. In addition, we characterize a functionally diverse and heterogenous landscape of non-immune cells including endothelial cells and fibroblasts. Through imaging mass cytometry, we highlight the spatial relationship among immune cell types and vasculature in non-tumor-associated dura. Utilizing T cell receptor sequencing, we show significant TCR overlap between matched dura and meningioma samples. Finally, we report copy number variant heterogeneity within our meningioma samples. CONCLUSIONS:Our comprehensive investigation of both the immune and non-immune cellular landscapes of human dura and meningioma at single-cell resolution builds upon previously published data in murine models and provides new insight into previously uncharacterized roles of human dura. 10.1186/s13073-022-01051-9
    Natural history of meningiomas: a serial volumetric analysis of 240 tumors. Journal of neurosurgery OBJECTIVE:The management of asymptomatic intracranial meningiomas is controversial. Through the assessment of growth predictors, the authors aimed to create the basis for practicable clinical pathways for the management of these tumors. METHODS:The authors volumetrically analyzed meningiomas radiologically diagnosed at their institution between 2003 and 2015. The primary endpoint was growth of tumor volume. The authors used significant variables from the multivariable regression model to construct a decision tree based on the exhaustive Chi-Square Automatic Interaction Detection (CHAID) algorithm. RESULTS:Of 240 meningiomas, 159 (66.3%) demonstrated growth during a mean observation period of 46.9 months. On multivariable logistic regression analysis, older age (OR 0.979 [95% CI 0.958-1.000], p = 0.048) and presence of calcification (OR 0.442 [95% CI 0.224-0.872], p = 0.019) had a negative predictive value for tumor growth, while T2-signal iso-/hyperintensity (OR 4.415 [95% CI 2.056-9.479], p < 0.001) had a positive predictive value. A decision tree model yielded three growth risk groups based on T2 signal intensity and presence of calcifications. The median tumor volume doubling time (Td) was 185.7 months in the low-risk, 100.1 months in the intermediate-risk, and 51.7 months in the high-risk group (p < 0.001). Whereas 0% of meningiomas in the low- and intermediate-risk groups had a Td of ≤ 12 months, the percentage was 8.9% in the high-risk group (p = 0.021). CONCLUSIONS:Most meningiomas demonstrated growth during follow-up. The absence of calcifications and iso-/hyperintensity on T2-weighted imaging offer a practical way of stratifying meningiomas as low, intermediate, or high risk. Small tumors in the low- or intermediate-risk categories can be monitored with longer follow-up intervals. 10.3171/2022.3.JNS212626
    Risk stratification of H3 K27M-mutant diffuse midline gliomas based on anatomical locations: an integrated systematic review of individual participant data. Journal of neurosurgery. Pediatrics OBJECTIVE:The prognostic significance and genetic characteristics of H3 K27M-mutant diffuse midline gliomas (DMGs) in different anatomical locations requires further clarification. In this study, the authors integrated published data to investigate the differences between brainstem, thalamic, and spinal cord tumors. METHODS:PubMed and Web of Science databases were used to search for eligible articles. Studies were included if they provided individual patient data of H3 K27M-mutant DMGs with available tumor locations. Hazard ratios (HRs) and 95% confidence intervals (CIs) were computed to investigate the survival of each subgroup. RESULTS:Eight hundred four tumors were identified, including 467, 228, and 109 in the brainstem, thalamus, and spine, respectively. Brainstem tumors were primarily observed in young children, while patients with thalamic and spinal cord tumors afflicted older patients. The Ki-67 labeling index was highest in brainstem tumors. Compared to patients with brainstem tumors, those with thalamic (HR 0.573, 95% CI 0.463-0.709; p < 0.001) and spinal cord lesions (HR 0.460, 95% CI 0.341-0.621; p < 0.001) had a significantly better survival. When patients were stratified by age groups, superior overall survival (OS) of thalamic tumors was observed in comparison to brainstem tumors in young children and adolescents, whereas adult tumors had uniform OS regardless of anatomical sites. Genetically, mutations in HIST1H3B/C (H3.1) and ACVR1 genes were mostly detected in brainstem tumors, whereas spinal cord tumors were characterized by a higher incidence of mutations in the TERT promoter. CONCLUSIONS:This study demonstrated that H3 K27M-mutant DMGs have distinct clinical characteristics, prognoses, and molecular profiles in different anatomical locations. 10.3171/2022.3.PEDS2250
    Meningioma DNA methylation groups identify biological drivers and therapeutic vulnerabilities. Nature genetics Meningiomas are the most common primary intracranial tumors. There are no effective medical therapies for meningioma patients, and new treatments have been encumbered by limited understanding of meningioma biology. Here, we use DNA methylation profiling on 565 meningiomas integrated with genetic, transcriptomic, biochemical, proteomic and single-cell approaches to show meningiomas are composed of three DNA methylation groups with distinct clinical outcomes, biological drivers and therapeutic vulnerabilities. Merlin-intact meningiomas (34%) have the best outcomes and are distinguished by NF2/Merlin regulation of susceptibility to cytotoxic therapy. Immune-enriched meningiomas (38%) have intermediate outcomes and are distinguished by immune infiltration, HLA expression and lymphatic vessels. Hypermitotic meningiomas (28%) have the worst outcomes and are distinguished by convergent genetic and epigenetic mechanisms driving the cell cycle and resistance to cytotoxic therapy. To translate these findings into clinical practice, we show cytostatic cell cycle inhibitors attenuate meningioma growth in cell culture, organoids, xenografts and patients. 10.1038/s41588-022-01061-8
    Circulating Tumor DNA in Adults With Glioma: A Systematic Review and Meta-Analysis of Biomarker Performance. Neurosurgery BACKGROUND:Circulating tumor DNA (ctDNA) has emerged as a promising noninvasive biomarker to capture tumor genetics in patients with brain tumors. Research into its clinical utility, however, has not been standardized because the sensitivity and specificity of ctDNA remain undefined. OBJECTIVE:To (1) review the primary literature about ctDNA in adults with glioma to compare the sensitivity and specificity of ctDNA in the cerebrospinal fluid vs the plasma and (2) to evaluate the effect of tumor grade on detection of ctDNA. METHODS:PRISMA-guided systematic review and meta-analysis was performed using published studies that assessed ctDNA in either plasma or cerebrospinal fluid among adult patients with confirmed glioma. Summary receiver operating characteristic curves were generated using the Rücker-Schumacher method, and area under the curve (AUC) was calculated. RESULTS:Meta-analysis revealed improved biomarker performance for CSF (AUC = 0.947) vs plasma (AUC = 0.741) ctDNA, although this did not reach statistical significance (P = .141). Qualitative analysis revealed greater sensitivities among single-allele PCR and small, targeted next-generation sequencing panels compared with broader panels. It additionally demonstrated higher sensitivity of ctDNA detection in high-grade vs low-grade gliomas, although these analyses were limited by a lack of specificity reporting in many studies. CONCLUSION:ctDNA seems to be a highly sensitive and specific noninvasive biomarker among adults with gliomas. To maximize its performance, CSF should be studied with targeted genetic analysis platforms, particularly in high-grade gliomas. Further studies on ctDNA are needed to define its clinical utility in diagnosis, prognostication, glioblastoma pseudoprogression, and other scenarios wherein neoadjuvant therapies may be considered. 10.1227/neu.0000000000001982
    XPA Enhances Temozolomide Resistance of Glioblastoma Cells by Promoting Nucleotide Excision Repair. Cell transplantation Glioblastoma is the most frequent, as well as aggressive kind of high-grade malignant glioma. Chemoresistance is posing a significant clinical barrier to the efficacy of temozolomide-based glioblastoma treatment. By suppressing xeroderma pigmentosum group A (XPA), a pivotal DNA damage recognition protein implicated in nucleotide excision repair (NER), we devised a novel method to enhance glioblastoma therapy and alleviate temozolomide resistance. On the basis of preliminary assessment, we found that XPA dramatically increased in glioblastoma compared with normal cells and contributed to temozolomide resistance. By constructing XPA stably knockdown cells, we illustrate that XPA protects glioma cells from temozolomide-triggered reproductive cell death, apoptosis, as well as DNA repair. Besides, XPA silencing remarkably enhances temozolomide efficacy . This study revealed a crucial function of XPA-dependent NER in the resistance of glioma cells to temozolomide. 10.1177/09636897221092778
    Deep Learning for Prediction of Progression and Recurrence in Nonfunctioning Pituitary Macroadenomas: Combination of Clinical and MRI Features. Frontiers in oncology Objectives:A subset of non-functioning pituitary macroadenomas (NFMAs) may exhibit early progression/recurrence (P/R) after tumor resection. The purpose of this study was to apply deep learning (DL) algorithms for prediction of P/R in NFMAs. Methods:From June 2009 to December 2019, 78 patients diagnosed with pathologically confirmed NFMAs, and who had undergone complete preoperative MRI and postoperative MRI follow-up for more than one year, were included. DL classifiers including multi-layer perceptron (MLP) and convolutional neural network (CNN) were used to build predictive models. Categorical and continuous clinical data were fed into the MLP model, and images of preoperative MRI (T2WI and contrast enhanced T1WI) were analyzed by the CNN model. MLP, CNN and multimodal CNN-MLP architectures were performed to predict P/R in NFMAs. Results:Forty-two (42/78, 53.8%) patients exhibited P/R after surgery. The median follow-up time was 42 months, and the median time to P/R was 25 months. As compared with CNN using MRI (accuracy 83%, precision 87%, and AUC 0.84) or MLP using clinical data (accuracy 73%, precision 73%, and AUC 0.73) alone, the multimodal CNN-MLP model using both clinical and MRI features showed the best performance for prediction of P/R in NFMAs, with accuracy 83%, precision 90%, and AUC 0.85. Conclusions:DL architecture incorporating clinical and MRI features performs well to predict P/R in NFMAs. Pending more studies to support the findings, the results of this study may provide valuable information for NFMAs treatment planning. 10.3389/fonc.2022.813806
    An Update on Neurosurgical Management of Primary CNS Lymphoma in Immunocompetent Patients. Frontiers in oncology Primary central nervous system lymphomas (PCNSL) are rare CNS tumors that harbor a conspicuously longer diagnostic delay compared to other malignant brain tumors. The gold standard for diagnosis is stereotactic biopsy to acquire tissue for histopathological analysis and therefore neurosurgery plays a central role when reducing the diagnostic period is mandated. However, histopathological diagnosis could be complicated if the patient was preoperatively exposed to corticosteroids. Besides the histopathological result, diagnosis of a PCNSL also requires full diagnostic workup to exclude cerebral metastatic disease of a systemic lymphoma. Most reviews of PCNSL discuss recent advancements in systemic treatment options from an (neuro-)oncologic viewpoint, whereas our intention was to discuss the optimization of the diagnostic period and therefore describe current standards of imaging, summarizing the diagnostic workup, discussing the surgical workup and future diagnostic prospects as well as the influence of preoperative corticosteroid therapy to reduce the diagnostic delay of PCNSL patients. 10.3389/fonc.2022.884724
    FBXW7 and the Hallmarks of Cancer: Underlying Mechanisms and Prospective Strategies. Frontiers in oncology FBXW7, a member of the F-box protein family within the ubiquitin-proteasome system, performs an indispensable role in orchestrating cellular processes through ubiquitination and degradation of its substrates, such as c-MYC, mTOR, MCL-1, Notch, and cyclin E. Mainly functioning as a tumor suppressor, inactivation of FBXW7 induces the aberrations of its downstream pathway, resulting in the occurrence of diseases especially tumorigenesis. Here, we decipher the relationship between FBXW7 and the hallmarks of cancer and discuss the underlying mechanisms. Considering the interplay of cancer hallmarks, we propose several prospective strategies for circumventing the deficits of therapeutic resistance and complete cure of cancer patients. 10.3389/fonc.2022.880077
    A Nicotinamide Phosphoribosyltransferase Inhibitor, FK866, Suppresses the Growth of Anaplastic Meningiomas and Inhibits Immune Checkpoint Expression by Regulating STAT1. Frontiers in oncology Anaplastic meningioma is classified as a World Health Organization (WHO) grade III tumor and shows a strong tendency to recur. Although the incidence of anaplastic meningioma is low, the high rate of recurrence and death still makes treatment a challenge. A proteomics analysis was performed to investigate the differentially expressed proteins between anaplastic meningiomas and fibrous meningiomas by micro-LC-MS/MS. The key metabolic enzyme nicotinamide phosphoribosyltransferase (NAMPT) showed upregulated expression in anaplastic meningiomas. However, targeting NAMPT to treat anaplastic meningiomas has not been reported. , NAMPT inhibitor -FK866 reduced the viability of anaplastic meningiomas by inducing cell cycle arrest at the G2/M phase. Intriguingly, the NAMPT inhibitor -FK866 decreased the protein expression of immune checkpoints PD-L1 and B7-H3 by down-regulating the STAT1 and p-STAT1 expression . Furthermore, FK866 suppressed the growth of anaplastic meningiomas in an xenograft model. The expression of Ki-67 and immune checkpoint proteins (PD-L1 and B7-H3) showed significant differences between the group treated with FK866 and the control group treated with DMSO. In conclusion, the expression of NAMPT, which plays a crucial role in energy metabolism, was upregulated in anaplastic meningiomas. The NAMPT inhibitor -FK866 significantly suppressed the growth of anaplastic meningiomas and . More strikingly, FK866 potently inhibited immune checkpoint protein (PD-L1 and B7-H3) expression by regulating STAT1 and . Our results demonstrated that NAMPT inhibitors could potentially be an effective treatment method for patients suffering from anaplastic meningiomas. 10.3389/fonc.2022.836257
    WZY-321 triggers glioma cell apoptosis via XAF1 up-regulation caused by MTM-mediated miR-873 down-regulation. Journal of Cancer Gliomas account for the majority of primary malignant brain tumors around the world and are highly aggressive. Evodiamine is one of the main effective components of Evodia rutaecarpa, which can inhibit proliferation and promote apoptosis of tumor cells including glioma cells. The derivative of Evodiamine named WZY-321 was successfully developed, and exhibited significant cytotoxicity and could efficiently induce glioma cell apoptosis; however, the mechanism of WZY-321-induced glioma cell apoptosis is not clear. Our current studies showed that WZY-321 increased X-linked inhibitor of apoptosis-associated factor 1 (XAF1) expression in glioma cells, and up-regulated XAF1 resulted in glioma cell apoptosis. Moreover, WZY-321 treatment decreased miR-873 expression and increased lncRNA MTM expression in glioma cells, and down-regulated miR-873 or up-regulated MTM lead to glioma cell apoptosis. Mechanically, WZY-321 up-regulated XAF1 gene expression via MTM-decreased miR-873 expression, that bound to XAF1 3' UTR and decreased XAF1 mRNA levels. Taken together, these data indicate that WZY-321 triggers glioma cell apoptosis via XAF1 up-regulation caused by MTM-mediated miR-873 down-regulation. 10.7150/jca.68775
    Prostate-Specific Membrane Antigen as Target for Neuroimaging of Central Nervous System Tumors. Molecular imaging Introduction:Positron emission tomography (PET) imaging with prostate-specific membrane antigen- (PSMA-) binding tracers has been found incidentally to demonstrate uptake in CNS tumors. Following the encouraging findings of several such case reports, there is a growing interest in the potential application of PSMA-targeted PET imaging for diagnostics, theranostics, and monitoring of CNS tumors. This is a systematic literature review on PSMA-binding tracers in CNS tumors. Methods:A PubMed search was conducted, including preclinical and clinical reports. One hundred and twelve records were identified, and after screening, 56 were included in the final report. Results:Tissue studies demonstrated PSMA expression in tumor vascular endothelial cells, without expression in normal brain tissue, though the extent and intensity of staining varied by anti-PSMA antibody and methodology. Most included studies reported on gliomas, which showed strong PSMA ligand uptake and more favorable tumor to background ratios than other PET tracers. There are also case reports demonstrating PSMA ligand uptake in prostate cancer brain metastases, nonprostate cancer brain metastases, and meningiomas. We also review the properties of the various PSMA-binding radiotracers available. Therapeutic and theranostic applications of PSMA-binding tracers have been studied, including labeled alpha- and beta-ray emitting isotopes, as well as PSMA targeting in directing MRI-guided focused ultrasound. Conclusions:There is a potential application for PSMA-targeted PET in neuro-oncology as a combination of diagnostic and therapeutic use, as a theranostic modality for managing CNS tumors. Further research is needed regarding the mechanism(s) of PSMA expression in CNS tumors and its differential performance by tumor type. 10.1155/2022/5358545
    Body Mass Index Has a Nonlinear Association With Postoperative 30-Day Mortality in Patients Undergoing Craniotomy for Tumors in Men: An Analysis of Data From the ACS NSQIP Database. Frontiers in endocrinology Background:The association between body mass index (BMI) and mortality is controversial. Thus, the purpose of our research was to survey the association between BMI and postoperative 30-day mortality in brain tumor patients undergoing craniotomy. Methods:This study analyzed data collected in a multicenter, cross-sectional study that consecutively and nonselectively collected data from a total of 18,642 patients undergoing craniotomy for tumors in the ACS NSQIP from 2012 to 2015. We constructed three linear and non-linear binomial logistic models (the inflection point was set at 18.5) to evaluate the association between BMI and postoperative 30-day mortality, respectively. We also conducted subgroup analyses. Additionally, we compared non-linear models with vs. without interaction with sex. Results:A total of 17,713 patients were included in this analysis. Of these, 47.38% were male. The postoperative 30-day mortality of the included cases was 2.39% (423/17,713), and the mean BMI was 28.41 ± 6.05 kg/m. The linear logistic models suggested that after adjusting for the covariates, BMI was not associated with postoperative 30-day mortality (OR=0.999; 95% CI: 0.981, 1.017). The non-linear binomial logistic models suggested a nonlinear relationship between BMI and postoperative 30-day mortality. When BMI was < 18.5, we observed a stronger negative association between them after adjusting for covariates; the OR and 95% CI were 0.719, 0.576-0.896. When BMI was > 18.5, the relationship between them was not significant. We also found that a one-unit decrease in BMI for male patients with BMI < 18.5 kg/m was related to a 34.6% increase in the risk of postoperative 30-day mortality (OR=0.654, 95% CI (0.472, 0.907). There was no significant association between them in male patients with BMI > 18.5 kg/m or female patients. Conclusions:This study demonstrates a non-linear relationship between BMI and the risk of postoperative death. Preoperative underweight (BMI < 18.5 kg/m) would increase the risk of postoperative death in male patients (> 18 years old) undergoing craniotomy for brain tumors. Appropriate nutritional management prior to craniotomy for brain tumors may reduce the risk of postoperative 30-day mortality in underweight men. 10.3389/fendo.2022.868968
    Alterations in 3D chromatin organization contribute to tumorigenesis of -amplified glioblastoma. Computational and structural biotechnology journal Background: amplification and/or mutation are found in more than half of the cases with glioblastoma. Yet, the role of chromatin interactions and its regulation of gene expression in -amplified glioblastoma remains unclear. Methods:In this study, we explored alterations in 3D chromatin organization of amplified glioblastoma and its subsequent impact by performing a comparative analysis of Hi-C, RNA-seq, and whole-genome sequencing (WGS) on -amplified glioblastoma-derived A172 and normal astrocytes (HA1800 cell line). Results:A172 cells showed an elevated chromatin relaxation, and unexpected entanglement of chromosome regions. A genome-wide landscape of switched compartments and differentially expressed genes between HA1800 and A172 cell lines demonstrated that compartment activation reshaped chromatin accessibility and activated tumorigenesis-related genes. Topological associating domain (TAD) analysis revealed that altered TAD domains in A172 also contribute to oncogene activation and tumor repressor deactivation. Interestingly, glioblastoma-derived A172 cells showed a different chromatin loop contact propensity. Genes in tumorigenesis-associated signaling pathways were significantly enriched at the anchor loci of altered chromatin loops. Oncogene activation and tumor repressor deactivation were associated with chromatin loop alteration. Structure variations (SVs) had a dramatic impact on the chromatin conformation of amplified glioblastoma-derived tumor cells. Moreover, our results revealed that 7p11.2 duplication activated expression in -amplified glioblastoma via neo-TAD formation and novel enhancer-promoter interaction emergence between and . Conclusions:The disordered 3D genomic map and multi-omics data of amplified glioblastoma provide a resource for future interrogation of the relationship between chromatin interactions and transcriptome in tumorigenesis. 10.1016/j.csbj.2022.04.007
    Characteristics of Anaplastic Oligodendrogliomas Short-Term Survivors: A POLA Network Study. The oncologist BACKGROUND:Anaplastic oligodendrogliomas IDH-mutant and 1p/19q codeleted (AO) occasionally have a poor outcome. Herein we aimed at analyzing their characteristics. METHODS:We retrospectively analyzed the characteristics of 44 AO patients with a cancer-specific survival <5 years (short-term survivors, STS) and compared them with those of 146 AO patients with a survival ≥5 years (classical survivors, CS) included in the POLA network. RESULTS:Compared to CS, STS were older (P = .0001), less frequently presented with isolated seizures (P < .0001), more frequently presented with cognitive dysfunction (P < .0001), had larger tumors (P = .= .003), a higher proliferative index (P = .= .0003), and a higher number of chromosomal arm abnormalities (P = .= .02). Regarding treatment, STS less frequently underwent a surgical resection than CS (P = .= .0001) and were more frequently treated with chemotherapy alone (P = .= .009) or with radiotherapy plus temozolomide (P = .= .05). Characteristics independently associated with STS in multivariate analysis were cognitive dysfunction, a number of mitosis > 8, and the absence of tumor resection. Based on cognitive dysfunction, type of surgery, and number of mitosis, patients could be classified into groups of standard (18%) and high (62%) risk of <5 year survival. CONCLUSION:The present study suggests that although STS poor outcome appears to largely result from a more advanced disease at diagnosis, surgical resection may be particularly important in this population. 10.1093/oncolo/oyac023
    Emerging Systemic Treatment Perspectives on Brain Metastases: Moving Toward a Better Outlook for Patients. American Society of Clinical Oncology educational book. American Society of Clinical Oncology. Annual Meeting The diagnosis of brain metastases has historically been a dreaded, end-stage complication of systemic disease. Additionally, with the increasing effectiveness of systemic therapies that prolong life expectancy and improved imaging tools, the incidence of intracranial progression is becoming more common. Within this context, there has been increasing attention directed at understanding the molecular underpinnings of intracranial progression. Exploring the unique features of brain metastases compared with their extracranial counterparts to identify aberrant signaling pathways, which can be targeted pharmacologically, may help lead to new treatments for this patient population. Additionally, critical discoveries outside the sphere of the central nervous system are increasingly being applied to brain metastases with the emergence of immune checkpoint inhibition, becoming a prevalent treatment option for patients with brain metastases across multiple histologies. As novel treatment strategies are considered, they require thoughtful incorporation of agents that can cross the blood-brain barrier and can synergize with pre-existing agents through rational combinations. Lastly, as clinicians and scientists continue to understand key molecular features of these tumors, they will continue to influence the treatment algorithms that are developing for the management of these patients. Due to the complexity of treatment decisions for patients with brain metastases, an emerging tool is the utilization of multidisciplinary brain metastasis tumor boards to ensure optimal treatment decisions are made and that patients are provided access to applicable clinical trials. Looking to the future, the collective effort to understand the various tumor-intrinsic and tumor-extrinsic factors that promote central nervous system seeding and propagation will have the potential to change the clinical trajectory for these patients. 10.1200/EDBK_352320
    Clinical Reasoning: A 67-Year-Old Woman With Abdominal Pain, Constipation, and Urinary Retention. Neurology Meningeal melanocytomas are an extremely rare, pigmented tumors of the central nervous system (CNS). They generally carry a favorable prognosis, although recurrence and transformation into the more aggressive malignant melanoma has been reported. We present a case of a patient who reported constipation and abdominal pain around the umbilicus, which progressed into cord compression with lower extremity weakness and gait instability. Spinal magnetic resonance imaging (MRI) revealed a tumor at the level of T11, and she underwent gross total resection of the mass. Pathology demonstrated a meningeal melanocytoma with intermediate features. She received post-operative radiation therapy and had stable disease for three years, at which time she developed new weakness and drop metastases. This case represents a rare presentation of a rare disease, in which a spinal cord tumor presented with constipation and abdominal distress. Intradural-extramedullary tumors of the thoracic spine are most commonly nerve sheath tumors or meningiomas, but rare entities such as melanocytomas can present in this location; even more rarely, these tumors can have an aggressive course with delayed recurrence. 10.1212/WNL.0000000000200748
    The identification of miRNA and mRNA expression profiles associated with pediatric atypical teratoid/rhabdoid tumor. BMC cancer BACKGROUND:Atypical teratoid/rhabdoid tumor (AT/RT) is a malignant pediatric tumor of the central nervous system (CNS) with high recurrence and low survival rates that is often misdiagnosed. MicroRNAs (miRNAs) are involved in the tumorigenesis of numerous pediatric cancers, but their roles in AT/RT remain unclear. METHODS:In this study, we used miRNA sequencing and gene expression microarrays from patient tissue to study both the miRNAome and transcriptome traits of AT/RT. RESULTS:Our findings demonstrate that 5 miRNAs were up-regulated, 16 miRNAs were down-regulated, 179 mRNAs were up-regulated and 402 mRNAs were down-regulated in AT/RT. qPCR revealed that hsa-miR-17-5p and MAP7 mRNA were the most significantly differentially expressed miRNA and mRNA in AT/RT tissues. Furthermore, the results from analyses using the miRTarBase database identified MAP7 mRNA as a target gene of hsa-miR-17-5p. CONCLUSIONS:Our findings suggest that the dysregulation of hsa-miR-17-5p may be a pivotal event in AT/RT and miRNAs that may represent potential therapeutic targets and diagnostic biomarkers. 10.1186/s12885-022-09549-6
    The role of mitochondria-targeting miRNAs in intracerebral hemorrhage. Current neuropharmacology Non-traumatic intracerebral hemorrhage (ICH) is the most common type of hemorrhagic stroke, most often occurring between the ages of 45 and 60. Arterial hypertension (AH) is most often the cause of ICH, followed by atherosclerosis, blood diseases, inflammatory changes in cerebral vessels, intoxication and vitamin deficiencies. Cerebral hemorrhage can occur by diapedesis or as a result of a ruptured vessel. AH is difficult to treat; requires surgery and can lead to disability or death. One of the important directions in the study of the pathogenesis of ICH is mitochondrial dysfunction and its regulation. The key role of mitochondrial dysfunction in AH and atherosclerosis, as well as in the development of brain damage after hemorrhage, has been acknowledged. MicroRNAs (miRNAs) are a class of non-coding RNAs (about 18-22 nucleotides) that regulate a variety of biological processes including cell differentiation, proliferation, apoptosis, etc., primarily through gene repression. There is growing evidence to support dysregulated miRNAs in various cardiovascular diseases, including ICH. Further, the realization of miRNAs within mitochondrial compartment has challenged the traditional knowledge of signaling pathways involved in the regulatory network of cardiovascular diseases. However, the role of miRNAs in mitochondrial dysfunction for ICH is still under-appreciated, with comparatively much lesser studies and investigations reported, than those in other cardiovascular diseases. In this review, we summarize the up-to-date findings on the published role miRNAs in mitochondrial function for ICH, and the potential use of miRNAs in clinical settings, such as potential therapeutic targets and non-invasive diagnostic/prognostic biomarker tools. 10.2174/1570159X20666220507021445
    A novel mouse model of diffuse midline glioma initiated in neonatal oligodendrocyte progenitor cells highlights cell-of-origin dependent effects of H3K27M. Glia Diffuse midline glioma (DMG) is a type of lethal brain tumor that develops mainly in children. The majority of DMG harbor the K27M mutation in histone H3. Oligodendrocyte progenitor cells (OPCs) in the brainstem are candidate cells-of-origin for DMG, yet there is no genetically engineered mouse model of DMG initiated in OPCs. Here, we used the RCAS/Tv-a avian retroviral system to generate DMG in Olig2-expressing progenitors and Nestin-expressing progenitors in the neonatal mouse brainstem. PDGF-A or PDGF-B overexpression, along with p53 deletion, resulted in gliomas in both models. Exogenous overexpression of H3.3K27M had a significant effect on tumor latency and tumor cell proliferation when compared with H3.3WT in Nestin+ cells but not in Olig2+ cells. Further, the fraction of H3.3K27M-positive cells was significantly lower in DMGs initiated in Olig2+ cells relative to Nestin+ cells, both in PDGF-A and PDGF-B-driven models, suggesting that the requirement for H3.3K27M is reduced when tumorigenesis is initiated in Olig2+ cells. RNA-sequencing analysis revealed that the differentially expressed genes in H3.3K27M tumors were non-overlapping between Olig2;PDGF-B, Olig2;PDGF-A, and Nestin;PDGF-A models. GSEA analysis of PDGFA tumors confirmed that the transcriptomal effects of H3.3K27M are cell-of-origin dependent with H3.3K27M promoting epithelial-to-mesenchymal transition (EMT) and angiogenesis when Olig2 marks the cell-of-origin and inhibiting EMT and angiogenesis when Nestin marks the cell-of-origin. We did observe some overlap with H3.3K27M promoting negative enrichment of TNFA_Signaling_Via_NFKB in both models. Our study suggests that the tumorigenic effects of H3.3K27M are cell-of-origin dependent, with H3.3K27M being more oncogenic in Nestin+ cells than Olig2+ cells. 10.1002/glia.24189