Mutational Landscape of Secondary Glioblastoma Guides MET-Targeted Trial in Brain Tumor.

Low-grade gliomas almost invariably progress into secondary glioblastoma (sGBM) with limited therapeutic option and poorly understood mechanism. By studying the mutational landscape of 188 sGBMs, we find significant enrichment of TP53 mutations, somatic hypermutation, MET-exon-14-skipping (METex14), PTPRZ1-MET (ZM) fusions, and MET amplification. Strikingly, METex14 frequently co-occurs with ZM fusion and is present in ∼14% of cases with significantly worse prognosis. Subsequent studies show that METex14 promotes glioma progression by prolonging MET activity. Furthermore, we describe a MET kinase inhibitor, PLB-1001, that demonstrates remarkable potency in selectively inhibiting MET-altered tumor cells in preclinical models. Importantly, this compound also shows blood-brain barrier permeability and is subsequently applied in a phase I clinical trial that enrolls MET-altered chemo-resistant glioma patients. Encouragingly, PLB-1001 achieves partial response in at least two advanced sGBM patients with rarely significant side effects, underscoring the clinical potential for precisely treating gliomas using this therapy.

CHIT1-positive microglia drive motor neuron ageing in the primate spinal cord.

Ageing is a critical factor in spinal-cord-associated disorders1, yet the ageing-specific mechanisms underlying this relationship remain poorly understood. Here, to address this knowledge gap, we combined single-nucleus RNA-sequencing analysis with behavioural and neurophysiological analysis in non-human primates (NHPs). We identified motor neuron senescence and neuroinflammation with microglial hyperactivation as intertwined hallmarks of spinal cord ageing. As an underlying mechanism, we identified a neurotoxic microglial state demarcated by elevated expression of CHIT1 (a secreted mammalian chitinase) specific to the aged spinal cords in NHP and human biopsies. In the aged spinal cord, CHIT1-positive microglia preferentially localize around motor neurons, and they have the ability to trigger senescence, partly by activating SMAD signalling. We further validated the driving role of secreted CHIT1 on MN senescence using multimodal experiments both in vivo, using the NHP spinal cord as a model, and in vitro, using a sophisticated system modelling the human motor-neuron-microenvironment interplay. Moreover, we demonstrated that ascorbic acid, a geroprotective compound, counteracted the pro-senescent effect of CHIT1 and mitigated motor neuron senescence in aged monkeys. Our findings provide the single-cell resolution cellular and molecular landscape of the aged primate spinal cord and identify a new biomarker and intervention target for spinal cord degeneration.

An Optimized Proteomics Approach Reveals Novel Alternative Proteins in Mouse Liver Development.

Alternative ORFs (AltORFs) are unannotated sequences in genome that encode novel peptides or proteins named alternative proteins (AltProts). Although ribosome profiling and bioinformatics predict a large number of AltProts, mass spectrometry as the only direct way of identification is hampered by the short lengths and relative low abundance of AltProts. There is an urgent need for improvement of mass spectrometry methodologies for AltProt identification. Here, we report an approach based on size-exclusion chromatography for simultaneous enrichment and fractionation of AltProts from complex proteome. This method greatly simplifies the variance of AltProts discovery by enriching small proteins smaller than 40 kDa. In a systematic comparison between 10 methods, the approach we reported enabled the discovery of more AltProts with overall higher intensities, with less cost of time and effort compared to other workflows. We applied this approach to identify 89 novel AltProts from mouse liver, 39 of which were differentially expressed between embryonic and adult mice. During embryonic development, the upregulated AltProts were mainly involved in biological pathways on RNA splicing and processing, whereas the AltProts involved in metabolisms were more active in adult livers. Our study not only provides an effective approach for identifying AltProts but also novel AltProts that are potentially important in developmental biology.

Dexmedetomidine administration during brain tumour resection for prevention of postoperative delirium: a randomised trial.

BACKGROUND: Delirium is common, especially after neurosurgery. Dexmedetomidine might reduce delirium by improving postoperative analgesia and sleep quality. We tested the primary hypothesis that dexmedetomidine administration during intracerebral tumour resection reduces the incidence of postoperative delirium. METHODS: This randomised, double-blind, placebo-controlled trial was conducted in two tertiary-care hospitals in Beijing. We randomised 260 qualifying patients to either dexmedetomidine (n=130) or placebo (n=130). Subjects assigned to dexmedetomidine were given a loading dose of 0.6 µg kg-1 followed by continuous infusion at 0.4 µg kg-1 h-1 until dural closure; subjects in the placebo group were given comparable volumes of normal saline. The primary outcome was the incidence of delirium, which was assessed with the Confusion Assessment Method twice daily during the initial 5 postoperative days. RESULTS: The average (standard deviation) age of participating patients was 45 (12) yr, duration of surgery was 4.2 (1.5) h, and patients assigned to dexmedetomidine were given an average of 126 (45) µg of dexmedetomidine. There was less delirium during the initial 5 postoperative days in patients assigned to dexmedetomidine (22%, 28 of 130 patients) than in those given placebo (46%, 60 of 130 patients) with a risk ratio of 0.51 (95% confidence interval: 0.36-0.74, P<0.001). Postoperative pain scores with movement, and recovery and sleep quality were improved by dexmedetomidine (P<0.001). The incidence of safety outcomes was similar in each group. CONCLUSIONS: Prophylactic intraoperative dexmedetomidine infusion reduced by half the incidence of delirium during the initial 5 postoperative days in patients recovering from elective brain tumour resection. CLINICAL TRIAL REGISTRATION: NCT04674241.

Tumor microenvironment is associated with clinical and genetic properties of diffuse gliomas and predicts overall survival.

Tumor microenvironment (TME) is a complex and dynamic evolving environment which facilitates tumor proliferation and progression. We aimed at investigating the characteristics of tumor microenvironment and its prognostic value in gliomas. Transcriptome data of 702 glioma samples from The Cancer Genome Atlas were included as training dataset, while 325 samples from Chinese Glioma Genome Atlas database and 268 samples from GSE16011 database were used to validate. We found that the infiltration of stromal and immune cell varied in gliomas of different grades and pathological types, and was associated with poor prognosis. Based on the gene expression profile, we constructed a TME-related signature (TMERS), which was closely related to clinical features and genomic variation of gliomas. In TMERS-high group, specific gene mutations and increased copy number alternations were observed. Kaplan-Meier survival and Cox regression analysis showed that TMERS was an independent prognostic indicator. Then we developed a nomogram prognostic model to predict 1-year, 3-year and 5-year survival of patients. Functional analysis confirmed that TMERS could reflect the status of glioma microenvironment, and immunological analysis showed that macrophages were significantly enriched in the TMERS-high group. We established a novel TME-related signature for predicting prognosis and provided new insights into immunotherapy.

Comprehensive analysis of the LncRNAs, MiRNAs, and MRNAs acting within the competing endogenous RNA network of LGG.

Messenger RNA (mRNA) and long noncoding RNA (lncRNA) targets interact via competitive microRNA (miRNA) binding. However, the roles of cancer-specific lncRNAs in the competing endogenous RNA (ceRNA) networks of low-grade glioma (LGG) remain unclear. This study obtained RNA sequencing data for normal solid tissue and LGG primary tumour tissue from The Cancer Genome Atlas database. We used a computational method to analyse the relationships among the mRNAs, lncRNAs, and miRNAs in these samples. Gene ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis was used to predict the biological processes (BPs) and pathways associated with these genes. Kaplan-Meier survival analysis was used to evaluate the association between the expression levels of specific mRNAs, lncRNAs, and miRNAs and overall survival. Finally, we created a ceRNA network describing the relationships among these mRNAs, lncRNAs, and miRNAs using Cytoscape 3.5.1. A total of 2555 differentially expressed (DE) mRNAs, 218 DElncRNAs, and 192 DEmiRNAs were identified using R. In addition, GO and KEGG pathway analysis of the mRNAs and lncRNAs in the ceRNA network identified 10 BPs, 10 cell components, 10 molecular functions, and 48 KEGG pathways as selectively enriched. A total of 55 lncRNAs, 50 miRNAs, and 10 mRNAs from this network were shown to be closely associated with overall survival in LGG. Finally, 59 miRNAs, 235 mRNAs, and 17 lncRNAs were used to develop a ceRNA network comprising 313 nodes and 1046 edges. This study helps expand our understanding of ceRNA networks and serves to clarify the underlying pathogenesis mechanism of LGG.

PABPC1 relevant bioinformatic profiling and prognostic value in gliomas.

Aim: We aimed at investigating molecular features and potential clinical value of PABPC1 in gliomas. Materials & methods: We assembled totally 1000 glioma samples with mRNA expression data from Chinese Glioma Genome Atlas and The Cancer Genome Atlas. We utilized R language as the main analysis tool. Gene Ontology was performed for functional analysis. Results: PABPC1 was downregulated in gliomas with higher malignance and PABPC1 may contribute as potential predictor of proneural subtype in gliomas. Higher expression of PABPC1 was significantly related to better prognosis and related to biological process of translation. Conclusion: Our finding improves the understanding of PABPC1 as a novel biomarker with potential therapeutic connotations.

Predicting the likelihood of postoperative seizure status based on mRNA sequencing in low-grade gliomas.

AIM: No comprehensive and objective methods yet exist for predicting postoperative seizure. PATIENTS & METHODS: mRNA-seq data and corresponding postoperative seizure status of 109 low-grade glioma samples were obtained from Chinese Glioma Genome Atlas database and divided into two sets randomly. Logistic regression and receiver operating characteristic analysis with risk score method were used to develop a ten-gene prediction model. RESULTS: Considering gene number and area under the curve of receiver operating characteristic, a ten-gene model was generated which showed an area under the curve of 0.9965 in training set. Patients with high-risk scores had higher probability of postoperative seizure compared with those with low-risk scores. CONCLUSION: This is the first prediction model for postoperative seizures in gliomas, integrating multiple genes. Clinical application may help patients with postoperative seizure control.

RNA-seq of 272 gliomas revealed a novel, recurrent PTPRZ1-MET fusion transcript in secondary glioblastomas.

Studies of gene rearrangements and the consequent oncogenic fusion proteins have laid the foundation for targeted cancer therapy. To identify oncogenic fusions associated with glioma progression, we catalogued fusion transcripts by RNA-seq of 272 gliomas. Fusion transcripts were more frequently found in high-grade gliomas, in the classical subtype of gliomas, and in gliomas treated with radiation/temozolomide. Sixty-seven in-frame fusion transcripts were identified, including three recurrent fusion transcripts: FGFR3-TACC3, RNF213-SLC26A11, and PTPRZ1-MET (ZM). Interestingly, the ZM fusion was found only in grade III astrocytomas (1/13; 7.7%) or secondary GBMs (sGBMs, 3/20; 15.0%). In an independent cohort of sGBMs, the ZM fusion was found in three of 20 (15%) specimens. Genomic analysis revealed that the fusion arose from translocation events involving introns 3 or 8 of PTPRZ and intron 1 of MET. ZM fusion transcripts were found in GBMs irrespective of isocitrate dehydrogenase 1 (IDH1) mutation status. sGBMs harboring ZM fusion showed higher expression of genes required for PIK3CA signaling and lowered expression of genes that suppressed RB1 or TP53 function. Expression of the ZM fusion was mutually exclusive with EGFR overexpression in sGBMs. Exogenous expression of the ZM fusion in the U87MG glioblastoma line enhanced cell migration and invasion. Clinically, patients afflicted with ZM fusion harboring glioblastomas survived poorly relative to those afflicted with non-ZM-harboring sGBMs (P < 0.001). Our study profiles the shifting RNA landscape of gliomas during progression and reveled ZM as a novel, recurrent fusion transcript in sGBMs.

CDC20 with malignant progression and poor prognosis of astrocytoma revealed by analysis on gene expression.

The malignant transformation of astrocytoma may result from the accumulation of multiple genetic alterations. Current research shows that diffuse astrocytoma (AIIs, WHO grade II) is inherently predisposed to recur locally, and to spontaneously progress to anaplastic astrocytoma (AAIIIs, WHO grade III) and eventually secondary glioblastoma (sGBMIVs, WHO grade IV). The aim of the study was to identify and validate the important gene(s) associated with malignant progression and poor prognosis of astrocytoma. Average expression levels of 82 samples (35 AIIs, 13 AAIIIs and 34 sGBMIVs) were compared to each other through no-paired student test. Candidate genes were screened by DAVID and Kaplan-Meier survival analysis. Further, the significant candidate genes were validated through real-time PCR(qPCR), western blot and immunohistochemistry (IHC) in different grades of glioma. Finally, the association of target gene and clinical molecular characterization was analyzed by Chi-squared analysis. The cell-division cycle protein 20(CDC20, p = 0.0129) and the polo-like kinase 1(PLK1, p = 0.0046) were screened by statistical and Kaplan-Meier survival analysis. The expression levels of CDC20 and PLK1 rose significantly through real-time PCR(qPCR), western blot and IHC. A chi-squared analysis showed that patients with CDC20 high-expression differ from patients with CDC20 low-expression in terms of WHO classification (p < 0.0001), karnofsky performance score (KPS, p < 0.0001), isocitrate dehydrogenase mutation (IDH1, p < 0.0001), phosphatase and tensin homolog mutation (PTEN, p = 0.027) and epidermal growth factor receptor protein amplification (EGFR, p = 0.048). Moreover, the biological processes analyses indicate CDC20 might have an essential role in astrocyte cell proliferation. We demonstrated that the expression level of CDC20 increases significantly along with malignant progression and poor prognosis of astrocytoma.

A glioma classification scheme based on coexpression modules of EGFR and PDGFRA.

We hypothesized that key signaling pathways of glioma genesis might enable the molecular classification of gliomas. Gene coexpression modules around epidermal growth factor receptor (EGFR) (EM, 29 genes) or platelet derived growth factor receptor A (PDGFRA) (PM, 40 genes) in gliomas were identified. Based on EM and PM expression signatures, nonnegative matrix factorization reproducibly clustered 1,369 adult diffuse gliomas WHO grades II-IV from four independent databases generated in three continents, into the subtypes (EM, PM and EM(low)PM(low) gliomas) in a morphology-independent manner. Besides their distinct patterns of genomic alterations, EM gliomas were associated with higher age at diagnosis, poorer prognosis, and stronger expression of neural stem cell and astrogenesis genes. Both PM and EM(low)PM(low) gliomas were associated with younger age at diagnosis and better prognosis. PM gliomas were enriched in the expression of oligodendrogenesis genes, whereas EM(low)PM(low) gliomas were enriched in the signatures of mature neurons and oligodendrocytes. The EM/PM-based molecular classification scheme is applicable to adult low-grade and high-grade diffuse gliomas, and outperforms existing classification schemes in assigning diffuse gliomas to subtypes with distinct transcriptomic and genomic profiles. The majority of the EM/PM classifiers, including regulators of glial fate decisions, have not been extensively studied in glioma biology. Subsets of these classifiers were coexpressed in mouse glial precursor cells, and frequently amplified or lost in an EM/PM glioma subtype-specific manner, resulting in somatic copy number alteration-dependent gene expression that contributes to EM/PM signatures in glioma samples. EM/PM-based molecular classification provides a molecular diagnostic framework to expedite the search for new glioma therapeutic targets.

PTBP1 induces ADAR1 p110 isoform expression through IRES-like dependent translation control and influences cell proliferation in gliomas.

Internal ribosomal entry site (IRES)-mediated translation initiation is constitutively activated during stress conditions such as tumorigenesis and hypoxia. The RNA editing enzyme ADAR1 plays an important role in physiology and pathology. Initially, we found that the ADAR1 p150 or p110 transcript levels were decreased in glioma cells compared with normal astrocyte cells. In contrast, protein levels of ADAR1 p110 were significantly upregulated in glioma tissues and cells. This expression pattern indicated translationally controlled regulation. We identified an 885-nt sequence that was located between AUG1 and AUG2 within the ADAR1 mRNA that exhibited IRES-like activity. Furthermore, we confirmed that the translational mode of ADAR1 p110 was mediated by PTBP1 in glioma cells. The protein levels of PTBP1 and ADAR1 were cooperatively expressed in glioma tissues and cells. Knocking down ADAR1 p110 significantly decreased cell proliferation in three types of glioma cells (T98G, U87MG and A172). The removal of a minimal IRES-like sequence in a p150-overexpression construct could effectively abolish p110 induction and resulted in the slight suppression of cell proliferation compared with ADAR1-p150 overexpression in siPTBP1-treated T98G cells. In summary, our study revealed a mechanism whereby ADAR1 p110 can be activated by PTBP1 through an IRES-like element in glioma cells, and ADAR1 is essential for the maintenance of gliomagenesis.

High expression of CXCR3 is an independent prognostic factor in glioblastoma patients that promotes an invasive phenotype.

Chemokines are a superfamily of small heparin-binding cytokines that induce leukocytes to migrate to sites of inflammation or injury through interacting with specific transmembrane G protein-coupled receptors. Currently, attention is focused on chemokine/chemokine receptor pairs and their ability to promote tumor cell migration and angiogenesis. The chemokine receptor CXCR3 is involved in tumor metastasis and is used as a prognostic biomarker. However, its relationship with the clinicopathological features of primary glioblastoma multiforme (pGBM) and its potential prognostic value have yet to be investigated. Here, we report that high CXCR3 expression conferred poor survival in pGBM patients. Further analysis showed that CXCR3 served as an independent prognostic biomarker for pGBM patients. In addition, functional assays indicated that CXCR3 induced glioma cell invasion. Therefore, this evidence indicates CXCR3 is an independent prognostic factor for pGBM patients and promotes an invasive phenotype, which suggests a new potential biotarget for glioblastoma multiforme therapy.

HDAC4, a prognostic and chromosomal instability marker, refines the predictive value of MGMT promoter methylation.

Chromosomal instability is a hallmark of human cancers and is closely linked to tumorigenesis. The prognostic value of molecular signatures of chromosomal instability (CIN) has been validated in various cancers. However, few studies have examined the relationship between CIN and glioma. Histone deacetylases (HDACs) regulate chromosome structure and are linked to the loss of genomic integrity in cancer cells. In this study, the prognostic value of HDAC4 expression and its association with markers of CIN were investigated by analyzing data from our own and four other large sample databases. The results showed that HDAC4 expression is downregulated in high- as compared to low-grade glioma and is associated with a favorable clinical outcome. HDAC4 expression and CIN were closely related in glioma from both functional and statistical standpoints. Moreover, the predictive value of the O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status-a widely used glioma marker-was refined by HDAC4 expression level, which was significantly related to CIN in our study. In conclusion, we propose that HDAC4 expression, a prognostic and CIN marker, enhances the predictive value of MGMT promoter methylation status for identifying patients who will most benefit from radiochemotherapy.

A single aspergillus fumigatus intracranial abscess in an immunocompetent patient with parietal lobe tumorectomy.

Aspergillosis of the central nervous system is a rare fungal infection that is mainly reported in patients with immune deficiency, such as AIDS patients and organ transplant patients treated with immunosuppressive agents, and is uncommon among patients with intact immune function. We report here a rare case of intracranial aspergillosis in a patient who had previously undergone a parietal lobe tumorectomy. Aspergillus fumigatus was confirmed by histopathology, and susceptibility tests reported that this infection should respond to voriconazole. We believe the immunosuppression resulting from surgical trauma and glucocorticosteroid treatment may be contributing to the infection, and therefore management of these two factors may improve the prognosis.

Whole-genome microRNA expression profiling identifies a 5-microRNA signature as a prognostic biomarker in Chinese patients with primary glioblastoma multiforme.

BACKGROUND: More reliable clinical outcome prediction is required to better guide more personalized treatment for patients with primary glioblastoma multiforme (GBM). The objective of this study was to identify a microRNA expression signature to improve outcome prediction for patients with primary GBM. METHODS: A cohort of Chinese patients with primary GBM (n = 82) was analyzed using whole-genome microRNA expression profiling with patients divided into a training set and a testing set. Cox regression and risk-score analyses were used to develop a 5-microRNA signature using 41 training samples. The signature was validated in 41 other test samples, in an independent cohort of 35 patients with GBM, and in the Cancer Genome Atlas data set. RESULTS: Patients who had high risk scores according to the 5-microRNA signature had poor overall survival and progression-free survival compared with patients who had low risk scores. Multivariate Cox analysis indicated that the 5-microRNA signature was an independent prognostic biomarker after adjusting for other clinicopathologic and genetic factors, such as extent of resection, temozolomide chemotherapy, preoperative Karnofsky performance status score, isocitrate dehydrogenase 1 (IDH1) mutation, and O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. CONCLUSIONS: The 5-microRNA signature was identified as an independent risk predictor that identified patients who had a high risk of unfavorable outcome, demonstrating its potential for personalizing cancer management. The authors concluded that this signature should be evaluated in further prospective studies.

BMP4, a strong better prognosis predictor, has a subtype preference and cell development association in gliomas.

BACKGROUND: The bone morphogenetic family proteins (BMP) are phytogenetically conserved proteins, which are essential for embryonic development. The key regulatory subunit, the bone morphogenetic protein 4 (BMP4), is overexpressed and associated with tumor metastasis in a variety of cancers. However, the prognostic and molecular features of gliomas with BMP4 expression is still unclear. METHODS: We obtained whole genome mRNA expression microarray data of 220 glioma samples of all grades from Chinese Glioma Genome Atlas (CGGA) database (http://www.cgga.org.cn) as discovery set. Of the 123 high-grade gliomas in this set, 33 Grade III tumors and 88 GBMs were analyzed by Kaplan-Meier method. Immunohistochemistry was used for validating the expression of BMP4 in another 77 glioma samples. Three additional datasets were obtained as validation sets. Gene ontology (GO) analysis and gene set variation analysis (GSVA) were used for functional annotation of BMP4. RESULTS: In the discovery set, BMP4 overexpression was significantly associated with low grade as well as the lower mortality of high-grade gliomas in survival analysis (log-rank, p<0.05 in GBM patients and p<0.01 in anaplastic gliomas, respectively). BMP4 also showed a Proneural subtype, G1 subtype and Isocitrate Dehydrogenase 1 (IDH1) mutation preference and cell development association. The results of validation 4 datasets showed similar findings. The overexpression of BMP4 was also detected in low grade gliomas compared to the high grade ones by immunohistochemistry (p<0.05, chi-square test). CONCLUSION: BMP4 expression was independently associated with grade and good prognosis in grade III and grade IV gliomas, suggesting BMP4 as a novel biomarker with potential important therapeutic implications.

Management and survival rates in patients with glioma in China (2004-2010): a retrospective study from a single-institution.

To analyze the clinical characteristics and prognostic factors in patients with glioma in an academic institute in China. From October 2004 to August 2010, total 1,285 patients were diagnosed as glioma at the Glioma Center of Beijing Tiantan Hospital. Clinical and molecular pathology features and survival rates were analyzed. The median overall survival (OS) times were 78.1, 37.6 and 14.4 months for low-grade glioma (WHO grade II), anaplastic glioma (WHO grade III) and glioblastoma (WHO grade IV), respectively. In patients with low-grade glioma, age, preoperative Karnofsky performance scale (KPS), pathological type, radiotherapy, O(6)-methylguanine-DNA methyltransferase (MGMT) expression and Ki-67 expression, were significantly associated with OS in multivariate analyses; and preoperative KPS and radiotherapy were significantly associated with progression-free survival (PFS). For anaplastic gliomas, age, preoperative KPS, pathological type, extent of resection, radiotherapy, p53 expression and phosphatase and tensin homolog (PTEN) expression were associated with OS. For glioblastomas, age, preoperative KPS, pathology type, extent of resection, radiotherapy and chemotherapy were associated with OS; and age, gender, preoperative KPS, extent of resection, radiotherapy and chemotherapy were associated with PFS. This is the largest survey for glioma management in China to date. We found significant differences in age, presenting symptoms and the expression of p53, MGMT, PTEN, and Ki-67 among patients with different types of glioma. Age, preoperative KPS, tumor grades, radiotherapy, chemotherapy and Ki-67 expression were significantly associated with clinical prognosis.

[Whole-genome messenger RNA profiling reveals genes involved in malignant progression of glioma].

OBJECTIVE: To employ whole-genome messenger RNA profiling to identify the genes involved in malignant progression in glioma. METHODS: The whole genome expressed genes were profiled in 220 glioma patients from the Chinese Glioma Genome Atlas (97 LGGs and 123 HGGs). The differential expressed genes between LGG and HGG were identified by SAM analysis. Microarray data were validated by immunohistochemistry. RESULTS: Among all the detected genes, the genes up-regulated mostly in high-grade glioma were IGFBP-2, CKLF, PTTG1, OSTCL and PTTG2 while those down-regulated mostly SEC31, RRP7B, HOOK3, SNRPN and CSMD3. Validation of IGFBP-2 with immunohistochemical staining showed a good correlation with the microarray data. CONCLUSION: A panel of potential genes of malignant transformation may serve as future targets of gene therapy for glioma.

PTPRZ1-METFUsion GENe (ZM-FUGEN) trial: study protocol for a multicentric, randomized, open-label phase II/III trial.

BACKGROUND: PTPRZ1-MET fusion was reported to associate with glioma progression from low-grade to high-grade glioma, which was a target by a MET inhibitor vebreltinib. However, little is known about the further efficacy of vebreltinib among more glioma patients. This trial aims to evaluate the safety and efficacy of vebreltinib enteric-coated capsules in the treatment of sGBM/IDH mutant glioblastoma patients with the ZM fusion gene. METHODS: This multicentric, randomized, open-label, controlled trial plans to include 19 neurosurgical centers and recruit 84 sGBM or IDH mutant glioblastoma patients with the ZM fusion gene. This trial enrolls sGBM or IDH mutant glioblastoma patients with the inclusion criteria and without the exclusion criteria. It was registered with chinadrugtrials.org.cn (CTR20181664). The primary efficacy endpoint is overall survival (OS). The secondary endpoints are progression-free survival (PFS) and objective response rate (ORR). DISCUSSION: If proven effective, this targeted multifaceted intervention protocol will be extended for more glioma patients as a protocol to evaluate the safety and efficacy of MET inhibitors. TRIAL REGISTRATION: It was registered with chinadrugtrials.org.cn (CTR20181664).