PD-L1 regulates tumor proliferation and T-cell function in NF2-associated meningiomas.

INTRODUCTION: Programmed death-ligand 1 (PD-L1) expression is an immune evasion mechanism that has been demonstrated in many tumors and is commonly associated with a poor prognosis. Over the years, anti-PD-L1 agents have gained attention as novel anticancer therapeutics that induce durable tumor regression in numerous malignancies. They may be a new treatment choice for neurofibromatosis type 2 (NF2) patients. AIMS: The aims of this study were to detect the expression of PD-L1 in NF2-associated meningiomas, explore the effect of PD-L1 downregulation on tumor cell characteristics and T-cell functions, and investigate the possible pathways that regulate PD-L1 expression to further dissect the possible mechanism of immune suppression in NF2 tumors and to provide new treatment options for NF2 patients. RESULTS: PD-L1 is heterogeneously expressed in NF2-associated meningiomas. After PD-L1 knockdown in NF2-associated meningioma cells, tumor cell proliferation was significantly inhibited, and the apoptosis rate was elevated. When T cells were cocultured with siPD-L1-transfected NF2-associated meningioma cells, the expression of CD69 on both CD4+ and CD8+ T cells was partly reversed, and the capacity of CD8+ T cells to kill siPD-L1-transfected tumor cells was partly restored. Results also showed that the PI3K-AKT-mTOR pathway regulates PD-L1 expression, and the mTOR inhibitor rapamycin rapidly and persistently suppresses PD-L1 expression. In vivo experimental results suggested that anti-PD-L1 antibody may have a synergetic effect with the mTOR inhibitor in reducing tumor cell proliferation and that reduced PD-L1 expression could contribute to antitumor efficacy. CONCLUSIONS: Targeting PD-L1 could be helpful for restoring the function of tumor-infiltrating lymphocytes and inducing apoptosis to inhibit tumor proliferation in NF2-associated meningiomas. Dissecting the mechanisms of the PD-L1-driven tumorigenesis of NF2-associated meningioma will help to improve our understanding of the mechanisms underlying tumor progression and could facilitate further refinement of current therapies to improve the treatment of NF2 patients.

OH2 oncolytic virus: A novel approach to glioblastoma intervention through direct targeting of tumor cells and augmentation of anti-tumor immune responses.

Glioblastoma (GBM), the deadliest central nervous system cancer, presents a poor prognosis and scant therapeutic options. Our research spotlights OH2, an oncolytic viral therapy derived from herpes simplex virus 2 (HSV-2), which demonstrates substantial antitumor activity and favorable tolerance in GBM. The extraordinary efficacy of OH2 emanates from its unique mechanisms: it selectively targets tumor cells replication, powerfully induces cytotoxic DNA damage stress, and kindles anti-tumor immune responses. Through single-cell RNA sequencing analysis, we discovered that OH2 not only curtails the proliferation of cancer cells and tumor-associated macrophages (TAM)-M2 but also bolsters the infiltration of macrophages, CD4+ and CD8+ T cells. Further investigation into molecular characteristics affecting OH2 sensitivity revealed potential influencers such as TTN, HMCN2 or IRS4 mutations, CDKN2A/B deletion and IDO1 amplification. This study marks the first demonstration of an HSV-2 derived OV's effectiveness against GBM. Significantly, these discoveries have driven the initiation of a phase I/II clinical trial (ClinicalTrials.gov: NCT05235074). This trial is designed to explore the potential of OH2 as a therapeutic option for patients with recurrent central nervous system tumors following surgical intervention.

Function and regulation of miR-186-5p, miR-125b-5p and miR-1260a in chordoma.

BACKGROUND: The function and regulation of miRNAs in progression of chordoma were unclear. METHODS: Five miRNAs were identified by the machine learning method from the miRNA expression array. CCk-8 assay, EDU assay, wound healing migration assay, and trans-well assay were used to reveal the effect of the miRNAs in chordoma cell lines. Moreover, bioinformation analysis and the mRNA expression array between the primary chordomas and recurrent chordomas were used to find the target protein genes of miRNAs. Furthermore, qRT-PCR and luciferase reporter assay were used to verify the result. RESULTS: miR-186-5p, miR-30c-5p, miR-151b, and miR-125b-5p could inhibit proliferation, migration, and invasion of chordoma while miR-1260a enhances proliferation, migration, and invasion of chordoma. Recurrent chordoma has a worse disease-free outcome than the primary chordoma patients. AMOT, NPTX1, RYR3, and P2RX5 were the target protein mRNAs of miR-186-5p; NPTX1 was the target protein mRNAs of miR-125b-5p; and AMOT and TNFSF14 were the target protein mRNAs of miR-1260a. CONCLUSIONS: miR-186-5p, miR-125b-5p, miR-1260a, and their target protein mRNAs including AMOT, NPTX1, RYR3, P2RX5, TNFSF14 may be the basement of chordoma research.

Decoding meningioma heterogeneity and neoplastic cell-macrophage interaction through single-cell transcriptome profiling across pathological grades.

BACKGROUND: Analyzing meningioma of distinct pathological types at the single-cell level can provide new and valuable insights into the specific biological mechanisms of each cellular subpopulation, as well as their vital interplay within the tumor microenvironment. METHODS: We recruited patients diagnosed with four distinct types of meningioma and performed single-cell RNA sequencing on their tumor samples, concurrently analyzing a publicly available dataset for comparison. Next, we separated the cells into discrete clusters and identified their unique identities. Using pseudotime analysis, we demonstrated cellular differentiation and dynamics. To investigate biological function, we employed weighted gene co-expression network analysis, gene regulatory network, and gene set enrichment analysis. Additionally, we conducted cell-cell communication analyses to characterize interactions among different clusters and validated a crucial interaction using multiple immunofluorescence staining. RESULTS: The single-cell transcriptomic profiles for five meningioma of different pathological types demonstrated that neoplastic cells exhibited high inter-sample heterogeneity and diverse biological functions featured by metabolic regulation. A small cluster of neoplastic cells (N5 cluster, < 3%) was most proliferative, indicated by high expression of MKI67 and TOP2A. They were primarily observed in our atypical and transitional meningioma samples and located at the beginning of the pseudotime differentiation branch for neoplastic cells. Macrophages, the most abundant immune cells present, showed two distinct developmental trajectories, one promoting and the other suppressing meningioma growth, with the MIF-CD74 interaction serving as the primary signaling pathway for MIF signals in the tumor environment. Unexpectedly, despite its small cluster size, the N5 cluster demonstrated a significant contribution in this interaction. By staining pathological sections of more samples, we found that this interaction was widely present in different types of meningiomas. CONCLUSIONS: Meningioma neoplastic cells' diverse types cause inter-sample heterogeneity and a wide range of functions. Some proliferative neoplastic cell may educate macrophages, which promotes tumorigenesis possibly through the MIF-CD74 interaction. It provides novel clues for future potential therapeutic avenues.

Unravelling the role of immune cells and FN1 in the recurrence and therapeutic process of skull base chordoma.

BACKGROUND: Skull base chordoma is a rare and aggressive tumour of the bone that has a high likelihood of recurrence. The fundamental differences in single cells between primary and recurrent lesions remain poorly understood, impeding development of effective treatment approaches. METHODS: To obtain an understanding of the differences in single cells between primary and recurrent chordomas, we performed single-cell RNA sequencing and T-cell/B-cell receptor (BCR) sequencing. This allowed us to delineate the differences between the two types of tumour cells, tumour-infiltrating lymphocytes, myeloid cells, fibroblasts and B cells. Copy number variants (CNVs) were detected and compared between the tumour types to assess heterogeneity. Selected samples were subjected to immunohistochemistry to validate protein expression. Fluorescence in situ hybridisation experiments, Transwell assays and xenograft mouse models helped verify the role of fibronectin 1 (FN1) in chordoma. RESULTS: Promoting natural killer (NK) cell and CD8_GZMK T-cell function or inhibiting the transformation of CD8_GZMK T cells to CD8_ZNF683 T cells and promoting the transformation of natural killer T (NKT) cells to NK cells are promising strategies for preventing chordoma recurrence. Additionally, inhibiting the M2-like activity of tumour-associated macrophages (TAMs) could be an effective approach. Antigen-presenting cancer-associated fibroblasts (apCAFs) and dendritic cells (DCs) with high enrichment of the antigen-presenting signature were enriched in primary chordomas. There were fewer plasma cells and BCR clonotypes in recurrent chordomas. Remarkably, FN1 was upregulated, had more CNVs, and was more highly secreted by tumours, macrophages, CD4 T cells, CD8 T cells and fibroblasts in recurrent chordoma than in primary chordoma. Finally, FN1 enhanced the invasion and proliferation of chordomas in vivo and in vitro. CONCLUSION: Our comprehensive picture of the microenvironment of primary and recurrent chordomas provides deep insights into the mechanisms of chordoma recurrence. FN1 is an important target for chordoma therapy.

Postoperative trigeminal neuropathy outcomes following surgery for tumors involving the trigeminal nerve.

OBJECTIVE: To observe the evolution and outcomes of postoperative trigeminal neuropathy following surgery of tumor involving the trigeminal nerve. METHODS: A prospective observational study was conducted between October 2018 and February 2019 involving 25 patients with tumors confirmed to involve the trigeminal nerve during surgery by senior author. Pre- and postoperative trigeminal nerve function status and clinical data were recorded. RESULTS: This study included 18 cases of meningioma and seven of trigeminal schwannoma. Among the meningioma cases, 55.6% of the patients reported facial sensory dysfunction before surgery, 33.3% presented ocular discomfort, and 5.6% had masticatory muscle atrophy. Postoperatively, all patients experienced facial paresthesia, 94.4% complained of eye dryness, and one (5.56%) exhibited keratitis. Additionally, one patient (5.56%) showed new-onset masticatory weakness. During follow-up, 50.0% of patients reported improvement in facial paresthesia, and one (5.56%) experienced deterioration. Eye dryness resolved in 35.3% of patients, and keratitis remission was observed in one patient. However, one patient (5.56%) developed neurotrophic keratitis. Overall, 55.6% of patients displayed mild masticatory weakness without muscle atrophy. In the cases of schwannoma, 28.6% of patients had facial paresthesia before surgery, 42.9% showed ocular discomfort, and one (14.3%) complained of masticatory dysfunction. Postoperatively, 85.7% of patients reported facial paresthesia and eye dryness, with one patient (16.7%) experiencing keratitis. During follow-up, 66.7% of patients demonstrated improvement in facial paresthesia, 28.6% showed eye dryness remission, and one patient (16.7%) recovered from keratitis. However, one patient (16.7%) developed new-onset neurotrophic keratitis. One patient (16.7%) experienced relief of masticatory dysfunction, but 42.9% reported mild deterioration. Another patient (14.3%) had facial anesthesia that had not improved. CONCLUSION: Postoperative trigeminal neuropathy is a common complication with a high incidence rate and poor recovery outcomes after surgery for tumors involving the trigeminal nerve. When trigeminal nerve damage is unavoidable, it is essential to provide a multidisciplinary and careful follow-up, along with active management strategy, to mitigate the more severe effects of postoperative trigeminal neuropathy.

Different clinical and cytogenetic features of primary skull base meningiomas and non-skull base meningiomas.

PURPOSE: To investigate the different clinical and cytogenetic features of skull base meningiomas (SBMs) and non-SBMs (NSBMs). METHODS: We conducted a retrospective study on a series of 316 patients with primary intracranial meningiomas. The t-test and the Chi-square test were used to analyze the differences between 194 SBMs and 122 NSBMs. The Cox analysis was used to determine prognostic factors for tumor recurrence. RESULTS: Compared with NSBMs, on average, the age of patients with SBMs was about 2.88 years younger (p = 0.024); the duration of operation of SBMs was 2.73 h longer (p < 0.001); the duration of hospital stays of patients with SBMs was about 6.76 days longer (p < 0.001); the tumor volume was 7.69 cm3 smaller (p = 0.025); the intraoperative blood loss was 147.61ml more (p = 0.039); the total cost of SBMs was 1.39 times more (p < 0.001); the preoperative KPS, postoperative KPS, and follow-up KPS of patients with SBMs were all respectively lower (p < 0.001); Gross total resection was less achieved (p < 0.001). SBMs (average of 20.80 per sample) had a smaller total number of copy number variations (CNVs) than NSBMs (29.98 per sample) (p = 0.009). Extremely large CNVs (> 5 Mb) were more likely to present in NSBMs (p < 0.001). Cox analysis showed that subtotal resection (p = 0.002) and the total number of CNVs (p = 0.015) were independent risk factors for tumor recurrence. CONCLUSIONS: The clinical and cytogenetic features of SBMs were different from NSBMs. Moreover, the degree of resection and the total number of whole-genome CNVs were independent prognostic factors for tumor recurrence.

Prognostic factors and Doxorubicin involved in malignant progression of meningioma.

Meningioma was the most primary intracranial tumor, but the molecular characteristics and the treatment of malignant meningioma were still unclear. Nine malignant progression-related genes based prognostic signatures were identified by transcriptome analysis between benign meningioma and malignant meningioma. The external dataset GEO136661 and quantitative Real-time Polymerase Chain Reaction were used to verify the prognostic factors. has-miR-3605-5p, hsa-miR-664b-5p, PNRC2, BTBD8, EXTL2, SLFN13, DGKD, NSD2, and BVES were closed with malignant progression. Moreover, Doxorubicin was identified by Connectivity Map website with the differential malignant progression-related genes. CCK-8 assay, Edu assay, wound healing assay, and trans-well experiment were used to reveal that Doxorubicin could inhibit proliferation, migration and invasion of IOMM-Lee Cells.

SERPINF1 Mediates Tumor Progression and Stemness in Glioma.

Serpin family F member 1 (SERPINF1) reportedly plays multiple roles in various tumors; however, its clinical significance and molecular functions in glioma have been largely understudied. In the present study, we analyzed the prognostic value of SERPINF1 in three independent glioma datasets. Next, we explored the molecular functions and transcriptional regulation of SERPINF1 at the single-cell level. Moreover, in vitro experiments were conducted to evaluate the roles of SERPINF1 in the proliferation, invasion, migration, and stemness of glioma cells. Our results showed that a higher expression of SERPINF1 correlated with a poor overall survival rate in glioma patients (hazard ratio: 4.061 in TCGA, 2.017 in CGGA, and 1.675 in GSE16011, p < 0.001). Besides, SERPINF1 knockdown could suppress the proliferation, invasion, and migration of glioma cells in vitro. In addition, SERPINF1 expression was significantly upregulated in glioma stem cells (GSCs) compared to parental glioma cells. Knocking down SERPINF1 impaired the sphere formation of GSC-A172 and GSC-LN18. Bioinformatics analysis revealed that Notch signaling activation was closely associated with high SERPINF1 expression at the single-cell level. Furthermore, STAT1, CREM, and NR2F2 may participate in the transcriptional regulation of SERPINF1 in glioma. Overall, our results suggest that SERPINF1 may be a candidate prognostic predictor and potential therapeutic target for glioma.

PHF6 promotes the progression of endometrial carcinoma by increasing cancer cells growth and decreasing T-cell infiltration.

Uterine corpus endometrial carcinoma (UCEC) is the most common cancer of the female reproductive tract. The overall survival of advanced and recurrent UCEC patients is still unfavourable nowadays. It is urgent to find a predictive biomarker and block tumorgenesis at an early stage. Plant homeodomain finger protein 6 (PHF6) is a key player in epigenetic regulation, and its alterations lead to various diseases, including tumours. Here, we found that PHF6 expression was upregulated in UCEC tissues compared with normal tissues. The UCEC patients with high PHF6 expression had poor survival than UCEC patients with low PHF6 expression. PHF6 mutation occurred in 12% of UCEC patients, and PHF6 mutation predicted favourable clinical outcome in UCEC patients. Depletion of PHF6 effectively inhibited HEC-1-A and KLE cell proliferation in vitro and decreased HEC-1-A cell growth in vivo. Furthermore, high PHF6 level indicated a subtype of UCECs characterized by low immune infiltration, such as CD3+ T-cell infiltration. While knockdown of PHF6 in endometrial carcinoma cells increased T-cell migration by promoting IL32 production and secretion. Taken together, our findings suggested that PHF6 might play an oncogenic role in UCEC patients. Thus, PHF6 could be a potential biomarker in predicting the prognosis of UCEC patients. Depletion of PHF6 may be a novel therapeutic strategy for UCEC patients.

Nomogram for predicting an individual prospective hemorrhage risk in untreated brainstem cavernous malformations.

OBJECTIVE: In this study, the authors aimed to create a nomogram for precisely predicting the 5-year prospective hemorrhage risk in brainstem cavernous malformations (BSCMs). METHODS: Patients with confirmed BSCMs in a single-center prospective observational series from January 2012 to December 2016 were included in the present study for nomogram building and validation. The concordance index (C-index), calibration curves, and decision curve analysis were used to evaluate the predictive accuracy, discriminative ability, and clinical usefulness of the nomogram. Then, a nomogram-based risk stratification model for untreated BSCMs was developed. RESULTS: In total, 600 patients were included in the study; 417 patients who had been enrolled before July 2015 were divided into the training and validation cohorts, and 183 subsequently enrolled patients were used as the external validation cohort. By applying a backward stepwise procedure in the multivariable Cox model, variables, including prior hemorrhage (HR 1.69), hemorrhage on admission (HR 3.33), lesion size > 1.5 cm (HR 1.84), lesion depth (HR 2.35), crossing the axial midpoint (HR 1.94), and developmental venous anomaly (HR 2.62), were incorporated to develop a nomogram. The Harrell C-index values for a 5-year prospective hemorrhage were 0.752 (95% CI 0.687-0.816), 0.801 (95% CI 0.665-0.936), and 0.758 (95% CI 0.674-0.842) in the training, internal validation, and external validation cohorts, respectively. The nomogram performed well in terms of consistency between prediction and actual observation according to the calibration curve. The patients could be classified into three distinct (low, medium, and high) risk groups using the final score of this nomogram. CONCLUSIONS: Independent predictors of the 5-year hemorrhage risk in untreated BSCMs were selected to create the first nomogram for predicting individual prospective hemorrhage. The nomogram was able to stratify patients into different risk groups and assist in clinical decision-making.

Comprehensive Analysis of the Prognostic Value and Molecular Function of CRNDE in Glioma at Bulk and Single-Cell Levels.

Colorectal neoplasia differentially expressed (CRNDE) is an oncogenic long noncoding RNA (lncRNA) overexpressed in diverse malignancies. Here, we comprehensively analyze the prognostic value and molecular function of CRNDE in glioma. Bulk RNA-sequencing data from The Cancer Genome Atlas (TCGA) and Chinese Glioma Genome Atlas (CGGA), and single-cell RNA-sequencing data from the Tumor Immune Single-Cell Hub (TISCH) were analyzed. Kaplan-Meier survival analysis was applied to verify the prognostic value of CRNDE. Then, a nomogram based on multivariate Cox regression was established for individualized survival prediction. Subsequently, the expression characteristic and biological function of CRNDE were analyzed at the single-cell level. Lastly, the effects of CRNDE on the proliferation and invasion of glioma cell were explored in vitro. We discovered that CRNDE was a powerful marker for risk stratification of glioma patients. Regardless of the status of IDH and 1p/19q, CRNDE could effectively stratify patients' prognosis. The nomogram that incorporated the CRNDE expression was proved to be a reliable tool for survival prediction. In addition, epithelial-mesenchymal transition may be the most important biological process regulated by CRNDE, which was identified at both the bulk and single-cell levels. Moreover, CRNDE knockdown significantly inhibited the proliferation and invasion of glioma cell. Overall, CRNDE is a vital oncogene and may be a valuable supplement to improve the clinical stratification of glioma.

Landscape of the oncogenic role of fatty acid synthase in human tumors.

BACKGROUND: Identifying a unique and common regulatory pathway that drives tumorigenesis in cancers is crucial to foster the development of effective treatments. However, a systematic analysis of fatty acid synthase across pan-cancers has not been carried out. METHODS: We investigated the oncogenic roles of fatty acid synthase in 33 cancers based on the cancer genome atlas and gene expression omnibus. RESULTS: Fatty acid synthase is profoundly expressed in most cancers and is an important factor in predicting the outcome of cancer patients. Further, the level of S207 phosphorylation was found to be improved in several neoplasms (e.g., colon cancer). Fatty acid synthase expression is related to tumor-infiltrating immune cells in tumors (e.g., CD8+ T-cell infiltration level in cervical squamous cell carcinoma). Moreover, hormone receptor binding- and fatty acid metabolic process-associated pathways are involved in the functional mechanisms of fatty acid synthase. CONCLUSIONS: This study provides a complete understanding of the oncogenic role of fatty acid synthase in human tumors.

TGFB3 downregulation causing chordomagenesis and its tumor suppression role maintained by Smad7.

Chordoma is a rare bone tumor arising from notochordal remnants, but the underlying mechanism remains elusive. By integrated mRNA and microRNA analyses, we found significant downregulation of TGFB3 along with upregulation of its inhibitor, miR-29 family in chordoma comparing with notochord. Somatic copy number gains of miR-29 loci in chordoma highlighted a mechanism of inactivation of TGFB3 signaling in tumor formation. In zebrafish, knockout and knockdown homologous tgfb3 resulted in a chordoma-like neoplasm. On the other hand, Smad7 negative feedback regulation of transforming growth factor-ß (TGF-ß) signaling is retentive in chordoma cell UM-Chor1 despite its disruption in most cancer cells (e.g. A549). Therefore, contrary to other cancers, exogenous TGF-ß activated Smad7 by downregulating miR-182 and inhibited cell migration and invasion in UM-Chor1. Meanwhile, TGF-ß decreased chordoma characteristic protein Brachyury. Altogether, downregulation of TGFB3 causes chordomagenesis, showing a feasible target for therapies. The retention of Smad7 negative regulation may maintain the suppressor role of TGF-ß in chordoma.

MicroRNA-221/222 Inhibits the Radiation-Induced Invasiveness and Promotes the Radiosensitivity of Malignant Meningioma Cells.

The controversy of adjuvant radiotherapy of meningiomas is at least partially due to the insufficient understanding on meningioma cells' response to irradiation and the shortage of radiosensitivity-promotion methods. MicroRNA-221 and microRNA-222 were identified as critical regulators of radiosensitivity in several other tumors. However, their effect in meningiomas has yet to be confirmed. Therefore, the malignant meningioma IOMM-Lee cells were adopted, transfected with microRNA-221/222 mimics or inhibitors, and irradiated with different dosages. The effects of radiation and microRNA-221/222 were then assessed in vitro and in vivo. Radiation dose increases and microRNA-221/222 downregulation synergistically inhibited cell proliferation and colony formation, prevented xenograft tumor progression, and promoted apoptosis, but antagonistically regulated cell invasiveness. Pairwise comparisons revealed that only high-dose radiations (6 and 8 Gy) can significantly promote cell invasiveness in comparison with unirradiated counterparts. Further comparisons exhibited that downregulating the microRNA-221/222 expression can reverse this radiation-induced cell invasiveness to a level of untransfected and unirradiated cells only if cells were irradiated with no more than 6 Gy. In addition, this approach can promote IOMM-Lee's radiosensitivity. Meanwhile, we also detected that the dose rate of irradiation affects cell cycle distribution and cell apoptosis of IOMM-Lee. A high dose rate irradiation induces G0/G1 cell cycle arrest and apoptosis-promoting effect. Therefore, for malignant meningiomas, high-dose irradiation can facilitate cell invasiveness significantly. Downregulating the microRNA-221/222 level can reverse the radiation-induced cell invasiveness while enhancing the apoptosis-promoting and proliferation-inhibiting effects of radiation and promoting cell radiosensitivity.

High Copy-Number Variation Burdens in Cranial Meningiomas From Patients With Diverse Clinical Phenotypes Characterized by Hot Genomic Structure Changes.

Meningiomas, as the most common primary tumor of the central nervous system, are known to harbor genomic aberrations that associate with clinical phenotypes. Here we performed genome-wide genotyping for cranial meningiomas in 383 Chinese patients and identified 9,821 copy-number variations (CNVs). Particularly, patients with diverse clinical features had distinct tumor CNV profiles. CNV burdens were greater in high-grade (WHO grade II and III) samples, recurrent lesions, large tumors (diameter >4.3 cm), and those collected from male patients. Nevertheless, the level of CNV burden did not relate to tumor locations, peritumoral brain edema, bone invasion, or multiple lesions. Overall, the most common tumor CNVs were the copy-number gain (CNG) at 22q11.1 and the copy-number losses (CNLs) at 22q13.2, 14q11.2, 1p34.3, and 1p31.3. Recurrent lesions were featured by the CNLs at 1p31.3, 6q22.31, 9p21.3, and 11p12, and high-grade samples had more CNVs at 4q13.3 and 6q22.31. Meanwhile, large tumors were more likely to have the CNVs at 1p31.3 and 1p34.3. Additionally, recurrence prediction indicated the CNLs at 4p16.3 (p = 0.009, hazard ratio = 5.69) and 10p11.22 (p = 0.037, hazard ratio = 4.53) were candidate independent risk factors.

Prognostic and predictive value of an immune infiltration signature in diffuse lower-grade gliomas.

BACKGROUNDLower-grade gliomas (LGGs) vary widely in terms of the patient's overall survival (OS). There is no current, valid method that could exactly predict the survival. The effects of intratumoral immune infiltration on clinical outcome have been widely reported. Thus, we aim to develop an immune infiltration signature to predict the survival of LGG patients.METHODSWe analyzed 1216 LGGs from 5 public data sets, including 2 RNA sequencing data sets and 3 microarray data sets. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select an immune infiltration signature and build a risk score. The performance of the risk score was assessed in the training set (329 patients), internal validation set (140 patients), and 4 external validation sets (405, 118, 88, and 136 patients).RESULTSAn immune infiltration signature consisting of 20 immune metagenes was used to generate a risk score. The performance of the risk score was thoroughly verified in the training and validation sets. Additionally, we found that the risk score was positively correlated with the expression levels of TGF-ß and PD-L1, which were important targets of combination immunotherapy. Furthermore, a nomogram incorporating the risk score, patient's age, and tumor grade was developed to predict the OS, and it performed well in all the training and validation sets (C-index: 0.873, 0.881, 0.781, 0.765, 0.721, and 0.753).CONCLUSIONThe risk score based on the immune infiltration signature has reliable prognostic and predictive value for patients with LGGs and is a potential biomarker for the cotargeting immunotherapy.FUNDINGThis work was supported by The National Natural Science Foundation of China (grant nos. 81472370 and 81672506), the Natural Science Foundation of Beijing (grant no. J180005), the National High Technology Research and Development Program of China (863 Program, grant no. 2014AA020610), and the National Basic Research Program of China (973 Program, grant no. 2014CB542006).

MicroRNA-195 Functions as a Tumor Suppressor by Directly Targeting Fatty Acid Synthase in Malignant Meningioma.

OBJECTIVE: Meningiomas are among the most common primary intracranial tumors. Up to 20% of cases will show increased malignancy at histological examination (World Health Organization grade II or III). Effective pharmacotherapy, except for radiotherapy, is lacking. Therefore, it is necessary to study the pathogenesis of malignant meningioma to provide more treatment strategies. METHODS: RNA sequencing and micro-RNA (miRNA) microarray detection were applied to identify differentially expressed messenger RNAs (mRNAs) and miRNAs in benign and malignant meningioma. The miRDB and TargetScan databases were used to predict the potential interaction between miRNAs and mRNAs. A proliferation assay was used to evaluate the cell growth. A wound healing assay and Transwell assay were performed to assess the cell migration and invasion abilities, respectively. The interaction between miRNA and mRNA was identified using a luciferase reporter assay. RESULTS: We found fatty acid synthase (FASN) was significantly upregulated in malignant meningioma compared with benign meningioma. Knockdown of FASN significantly inhibited proliferation, migration, and invasion of IOMM-Lee cells. Moreover, miR-195 was verified to directly target FASN using a luciferase reporter assay. Upregulation of miR-195 also significantly inhibited proliferation, migration, and invasion of IOMM-Lee cells. Furthermore, we performed bioinformatics analysis to predict the competing endogenous RNAs (ceRNAs) and found that NUP210, SPIRE2, SLC7A1, and DMTN might function as ceRNAs of FASN by sponging miR-195 in meningioma. CONCLUSIONS: Our results have suggested a tumor suppressive role for miR-195 in the tumorigenesis and progression of malignant meningioma by targeting FASN. In addition, NUP210, SPIRE2, SLC7A1, and DMTN might act as ceRNAs to regulate FASN expression by sponging miR-195.

Identification and validation of a 21-mRNA prognostic signature in diffuse lower-grade gliomas.

PURPOSE: Diffuse low-grade and intermediate-grade gliomas, also known as lower-grade gliomas (LGGs), are a class of central nervous system tumors. Overall survival varies greatly between patients, highlighting the importance of evaluating exact outcomes to facilitate individualized clinical management. We aimed to identify an mRNA-based prognostic signature to predict the survival of patients with LGGs. METHODS: A total of 874 LGGs from two public datasets were included. Least absolute shrinkage and selection operator (LASSO) Cox regression was used to select the most prognostic mRNAs and build a risk score. A nomogram incorporating the risk score and clinical factors was established for individualized survival prediction. The performance of the nomogram was assessed in the training set (329 patients), internal validation set (140 patients), and external validation set (405 patients). RESULTS: 21 most prognostic mRNAs remained following the LASSO Cox regression. The 21-mRNA signature successfully stratified patients into high- and low-risk groups (P < 0.001 for all datasets in Kaplan-Meier analysis). Subsequent gene set enrichment analysis identified 19 essential biological processes in high-risk LGGs. Furthermore, a nomogram incorporating the risk score, age, grade, and 1p/19q status was developed with favorable calibration and high predictive accuracy in the training set and validation sets (C-index: 0.877, 0.878, and 0.812, respectively). CONCLUSION: The 21-mRNA signature has reliable prognostic value for LGGs and might facilitate the effective stratification and individualized management of patients.

Primary intracranial malignant melanoma: proposed treatment protocol and overall survival in a single-institution series of 15 cases combined with 100 cases from the literature.

OBJECTIVE: The overall survival and pertinent adverse factors for primary intracranial malignant melanoma (PIMM) have not been previously determined. This aim of this study was to determine the rates of progression-free survival (PFS) and overall survival (OS) and identify the adverse factors for PIMM. METHODS: This study included 15 cases from the authors' own series and 100 cases with detailed clinical data that were obtained from the literature from 1914 to 2018 using the Ovid Medline, EMBASE, PubMed, Cochrane, and EBSCO databases. Patient demographics, treatment (surgery, chemotherapy, and radiotherapy [RT]), PFS, and OS were reviewed. Data from prior publications were processed and used according to PRISMA guidelines. RESULTS: Diffuse lesions were identified in 24 (20.9%) patients, who had a younger age (p < 0.001). The mean follow-up time was 16.6 months, and 76 (66.1%) deaths occurred. The 6-month, 1-year, 3-year, and 5-year OS rates of the whole cohort were 62.8%, 49.9%, 28.9%, and 17.2%, respectively, with an estimated median survival time (EMST) of 12.0 months. The multivariate analysis revealed that gross-total resection (GTR) (HR 0.299, 95% CI 0.180-0.497, p < 0.001), radiotherapy (HR 0.577, 95% CI 0.359-0.929, p = 0.024), and chemotherapy (HR 0.420, 95% CI 0.240-0.735, p = 0.002) predicted a better OS. The EMST was 5.0 months in patients with diffuse-type PIMM and 13.0 months in patients with the solitary type. Patients receiving GTR with adjuvant RT and/or chemotherapy (GTR + [RT and/or chemo]) had significantly higher 1-year and 5-year OS rates (73.0% and 40.1%, respectively) and a longer EMST (53 months) than patients who underwent GTR alone (20.5 months) or RT and/or chemotherapy without GTR (13.0 months). CONCLUSIONS: Optimal outcomes could be achieved by radical resection plus postoperative radiotherapy and/or chemotherapy. Patients with diffuse PIMM have a more severe clinical spectrum and poorer survival than patients with solitary PIMM. Immunotherapy and targeted therapy show promise as treatment options for PIMM based on results in patients with brain metastases from extracranial melanoma.