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As the clinical failure of glioblastoma treatment is attributed by multiple components, including myelin-associated infiltration, assessment of the molecular mechanisms underlying such process and identification of the infiltrating cells have been the primary objectives in glioblastoma research. Here, we adopted radiogenomic analysis to screen for functionally relevant genes that orchestrate the process of glioma cell infiltration through myelin and promote glioblastoma aggressiveness. The receptor of the Nogo ligand (NgR1) was selected as the top candidate through Differentially Expressed Genes (DEG) and Gene Ontology (GO) enrichment analysis. Gain and loss of function studies on NgR1 elucidated its underlying molecular importance in suppressing myelin-associated infiltration in vitro and in vivo. The migratory ability of glioblastoma cells on myelin is reversibly modulated by NgR1 during differentiation and dedifferentiation process through deubiquitinating activity of USP1, which inhibits the degradation of ID1 to downregulate NgR1 expression. Furthermore, pimozide, a well-known antipsychotic drug, upregulates NgR1 by post-translational targeting of USP1, which sensitizes glioma stem cells to myelin inhibition and suppresses myelin-associated infiltration in vivo. In primary human glioblastoma, downregulation of NgR1 expression is associated with highly infiltrative characteristics and poor survival. Together, our findings reveal that loss of NgR1 drives myelin-associated infiltration of glioblastoma and suggest that novel therapeutic strategies aimed at reactivating expression of NgR1 will improve the clinical outcome of glioblastoma patients.

Background There have been no evidence-based guidelines on the optimal schedule for the radiological assessment of 1p/19q-codeleted glioma. This study aimed to recommend an appropriate radiological evaluation schedule for 1p/19q-codeleted glioma during the surveillance period through parametric modeling of the progression-free survival (PFS) curve. Methods A total of 234 patients with 1p/19q-codeleted glioma (137 grade II and 97 grade III) who completed regular treatment were retrospectively reviewed. The patients were stratified into each layered progression risk group by recursive partitioning analysis. A piecewise exponential model was used to standardize the PFS curves. The cutoff value of the progression rate among the remaining progression-free patients was set to 10% at each scan. Results Progression risk stratification resulted in 3 groups. The optimal magnetic resonance imaging (MRI) interval for patients without a residual tumor was every 91.2 weeks until 720 weeks after the end of regular treatment following the latent period for 15 weeks. For patients with a residual tumor after the completion of adjuvant radiotherapy followed by chemotherapy, the optimal MRI interval was every 37.5 weeks until week 90 and every 132.8 weeks until week 361, while it was every 33.6 weeks until week 210 and every 14.4 weeks until week 495 for patients with a residual tumor after surgery only or surgery followed by radiotherapy only. Conclusions The optimal radiological follow-up schedule for each progression risk stratification of 1p/19q-codeleted glioma can be established from the parametric modeling of PFS.

BackgroundGlioblastoma remains highly lethal due to its inevitable recurrence. This recurrence is found locally in most cases, indicating that post-surgical tumor-initiating cells (TICs) accumulate at tumor edge. These edge TICs then generate recurrent tumors harboring new core lesions. Here, we investigated the clinical significance of the edge-to-core transition (ECT) signature causing glioblastoma recurrence and sought to identify central mediators for ECT.MethodsFirst, we examined the association of the ETC-related expression changes and patient outcome in matched primary and recurrent samples (n=37). Specifically, we tested whether the combined decrease of the edge TIC marker PROM1 (CD133) with the increase of the core TIC marker CD109 representing ECT during the primary-to-recurrence progression indicates poorer patient outcome. We then investigated the specific molecular mediators that trigger tumor recurrence driven by the ECT signature. Subsequently, the functional and translational significance of the identified molecule was validated within our patient-derived tumor edge-TIC modelsin vitroandin vivo.ResultsPatients exhibiting a CD133down/CD109upsignature during recurrence representing ECT displayed a strong association with poorer progression-free survival and overall survival among all tested patients. Differential gene expression identified that PLAGL1 was tightly correlated with the core TIC marker CD109 and was linked to a shorter survival of glioblastoma patients. Experimentally, forced PLAGL1 overexpression enhanced, while its knockdown reduced, the glioblastoma edge-derived tumor growthin vivoand subsequent mouse survival, suggesting its essential role in the ECT-mediated glioblastoma development.ConclusionsECT is likely an ongoing lethal process in primary glioblastoma contributing to its recurrence partly in a PLAGL1/CD109-mediated mechanism.Key PointsECT is a pathobiological process contributing to glioblastoma lethalityThe CD133down/CD109upsignature is a novel prognostic molecular biomarker in ECTPLAGL1 regulates growth of edge-located tumor-initiating cellsImportance of the StudyVery few studies have sought to longitudinally characterize the transition of molecular landscapes from primary to recurrent glioblastoma. Post-surgical edge-located TICs are presumably the predominant source of tumor recurrence, yet this cellular subpopulation in glioblastoma remains largely uncharacterized. This study evaluates the significance of glioblastoma edge-derived core transition (ECT) for tumor recurrence in the primary-recurrent paired sample set. We elucidate a prognostically-significant shift in molecular and cellular phenotypes associated with ECT in the CD133down/CD109upgroup. Moreover, our results provide clinical and experimental evidence that PLAGL1 is a mediator of glioblastoma ECT and its subsequent tumor development by the direct transcriptional regulation of the core TIC marker CD109.

Background Despite extensive efforts on the genomic characterization of gliomas, very few studies have reported the genetic alterations of cerebellar glioblastoma (C-GBM), a rare and lethal disease. Here, we provide a systematic study of C-GBM to better understand its specific genomic features. Methods We collected a cohort of C-GBM patients and compared patient demographics and tumor pathologies with supratentorial glioblastoma (S-GBM). To uncover the molecular characteristics, we performed DNA and mRNA sequencing and DNA methylation arrays on 19, 6, and 4 C-GBM cases, respectively. Moreover, chemical drug screening was conducted to identify potential therapeutic options for C-GBMs. Results Despite differing anatomical origins of C-GBM and S-GBM, neither histological, cytological, nor patient demographics appeared significantly different between the 2 types. However, we observed striking differences in mutational patterns, including frequent alterations of ATRX, PDGFRA, NF1, and RAS and absence of EGFR alterations in C-GBM. These results show a distinct evolutionary path in C-GBM, suggesting specific therapeutic targeted options. Targeted-drug screening revealed that C-GBMs were more responsive to mitogen-activated protein kinase kinase (MEK) inhibitor and resistant to epidermal growth factor receptor inhibitors than S-GBMs. Also, differential expression analysis indicated that C-GBMs may have originated from oligodendrocyte progenitor cells, suggesting that different types of cells can undergo malignant transformation according to their location in brain. Master regulator analysis with differentially expressed genes between C-GBM and proneural S-GBM revealed NR4A1 as a potential therapeutic target. Conclusions Our results imply that unique gliomagenesis mechanisms occur in adult cerebellum and new treatment strategies are needed to provide greater therapeutic benefits for C-GBM patients. Key points 1. Distinct genomic profiles of 19 adult cerebellar GBMs were characterized. 2. MEK inhibitor was highly sensitive to cerebellar GBM compared with supratentorial GBM. 3. Master regulator analysis revealed NR4A1 as a potential therapeutic target in cerebellar GBM.

Background Cancer is a complex disease with profound genomic alterations and extensive heterogeneity. Recent studies on large-scale genomics have shed light on the impact of core oncogenic pathways, which are frequently dysregulated in a wide spectrum of cancer types. Aberrant activation of the hepatocyte growth factor (HGF) signaling axis has been associated with promoting various oncogenic programs during tumor initiation, progression, and treatment resistance. As a result, HGF-targeted therapy has emerged as an attractive therapeutic approach. However, recent clinical trials involving HGF-targeted therapies have demonstrated rather disappointing results. Thus, an alternative, in-depth assessment of new patient stratification is necessary to shift the current clinical course. Methods To address such challenges, we have evaluated the therapeutic efficacy of YYB-101, an HGF-neutralizing antibody, in a series of primary glioblastoma stem cells (GSCs) both in vitro and in vivo. Furthermore, we performed genome and transcriptome analysis to determine genetic and molecular traits that exhibit therapeutic susceptibility to HGF-mediated therapy. Results We have identified several differentially expressed genes, including MET, KDR, and SOX3, which are associated with tumor invasiveness, malignancy, and unfavorable prognosis in glioblastoma patients. We also demonstrated the HGF-MET signaling axis as a key molecular determinant in GSC invasion, and we discovered that a significant association in HGF expression existed between mesenchymal phenotype and immune cell recruitment. Conclusions Upregulation of MET and mesenchymal cellular state are essential in generating HGF-mediated therapeutic responses. Our results provide an important framework for evaluating HGF-targeted therapy in future clinical settings.

PURPOSE Preoperative diagnosis of prolactinomas is critical because medication of dopamine agonists instead of surgical resection has been regarded as a primary treatment. However, serum prolactin level alone is suboptimal for differentiating the prolactin producing adenoma or hyperprolactinemia-causing NFPAs. The author investigated the use of ratio of PRL levels to the tumor size as the optimal cutoff value for prolactin-producing tumor, comparing with the NFPA. METHOD We performed a retrospective review of patients who underwent the transsphenoidal surgery (TSS) for pituitary lesions in the single institute between January 2015 to May 2020. A total of 223 patients with hyperprolactinemia at the initial diagnosis were analyzed in the study, including NFPA patients (n=175) and prolactinoma patients (n=48). Receiver operating curve (ROC) analyses were performed for serum prolactin levels (PRL) and serum prolactin levels/tumor maximal diameter (PRL/MD). RESULT Prolactinoma group showed higher median values in serum PRL (258.6 μg/L) and smaller maximal tumor diameter (16.6 mm), compared to those of NFPA group (serum PRL 44.4 μg/L, p-value = 0.002 and MD 23.9 mm, p-value < 0.001). A moderate correlation was found between serum prolactin level and maximal diameters in prolactinomas (r=0.43, p=0.002), whereas a weak relationship was confirmed in NFPAs (r=0.17, p=0.028). The cutoff was 8.93 μg/L*mm (area under the curve [AUC] = 0.94) for PRL/MD and 99.43 μg/L for PRL (AUC = 0.91). In prolactinomas, there was no statistical difference between the PRL/MD of macroadenomas (n=36, 21.7μg/L*mm) and microadenoma (n=12, 16.8μg/L*mm) (p=0.109). CONCLUSION The serum PRL levels and tumor size exhibited stronger linear correlation in prolactinomas than in NFPAs. The PRL/MD ratio showed better diagnostic value for differentiating two pathologies than the serum PRL levels alone. These findings suggest PRL/MD ratio may be an alternative method to preoperative diagnosis of prolactinomas differentiating from hyperprolactinemia-causing NFPAs.

The dominant-negative effect of PTEN mutation has been described previously, suggesting that aberrant gain of function attributed to mutation might be more disastrous than deletion in respect to malignant potential. In present study, we explored the functional implications of hot spot mutations of PTEN in GBM tumors. Subcellular location of PTEN is important for its distinct function and spatial distribution within the cytoplasm is known to be associated with cellular locomotion. We evaluated the subcellular compartmentalization of different PTEN mutants and found that some PTEN mutants located at cellular edges of chemotaxing cells. Moreover, these PTEN mutations exhibited invasive phenotype, which was not disrupted by PI3K inhibitor, but microtubule inhibitors. This finding suggests that cytoskeletal assembly as a novel non-canonical pathway of PTEN, thus unraveling a novel therapeutic vulnerability of PTEN. Mutation-specific therapeutic options should be considered in treating GBM patients with PTEN mutations.

This study aimed to evaluate the efficacy and safety of fractionated gamma knife radiosurgery (GKS) for the treatment of orbital cavernous hemangioma (OCH). METHODS From January 2007 to June 2018, 34 patients who underwent fractionated GKS (median 20 Gy in 4 fractions) for OCH at a single tertiary institution were reviewed. Ophthalmic evaluations including exophthalmometry, best corrected visual acuity with the Snellen chart and Humphrey visual field were investigated. Changes in lesion volume were also analyzed. RESULTS The median age was 43 years (range, 10–67 years) and 18 patients were male (53%). The median clinical follow-up time was 42 months (range, 12–132 months). The most common presenting symptom was proptosis followed by visual impairment. Proptosis improved in all 27 patients. The mean value of proptosis was reduced from 2.9 mm to 1.1 mm (P < 0.001). Of 15 patients who showed decreased visual acuity preoperatively, 12 patients (80%) had improved in vision. Preoperative visual field defects were evident in 17 patients and resolved in 15 patients (88%) after treatment. The median tumor volume at the time of GKS was 2.2 cm3 (range, 0.2–8.5 cm3). Tumor shrinkage was observed in all patients and the mean volume reduction rate was 64%. No patient experienced GKS-related ocular morbidity, though two transient GKS-related adverse events (6%) were observed. CONCLUSION Fractionated GKS is an effective and safe option for the treatment of OCH, with significant reduction in tumor volume and improvement of ophthalmic outcomes.

Background Clinical benefits from standard therapies against glioblastoma (GBM) are limited in part due to intrinsic radio- and chemoresistance of GBM and inefficient targeting of GBM stem-like cells (GSCs). Novel therapeutic approaches that overcome treatment resistance and diminish stem-like properties of GBM are needed. Methods We determined the expression levels of ubiquitination-specific proteases (USPs) by transcriptome analysis and found that USP1 is highly expressed in GBM. Using the patient GBM-derived primary tumor cells, we inhibited USP1 by shRNA-mediated knockdown or its specific inhibitor pimozide and evaluated the effects on stem cell marker expression, proliferation, and clonogenic growth of tumor cells. Results USP1 was highly expressed in gliomas relative to normal brain tissues and more preferentially in GSC enrichment marker (CD133 or CD15) positive cells. USP1 positively regulated the protein stability of the ID1 and CHEK1, critical regulators of DNA damage response and stem cell maintenance. Targeting USP1 by RNA interference or treatment with a chemical USP1 inhibitor attenuated clonogenic growth and survival of GSCs and enhanced radiosensitivity of GBM cells. Finally, USP1 inhibition alone or in combination with radiation significantly prolonged the survival of tumor-bearing mice. Conclusion USP1-mediated protein stabilization promotes GSC maintenance and treatment resistance, thereby providing a rationale for USP1 inhibition as a potential therapeutic approach against GBM.

BACKGROUND: Survival outcomes for patients with glioblastoma remain poor, particularly for patients with unmethylated O(6)-methylguanine-DNA methyltransferase (MGMT) gene promoter. This phase II, randomized, open-label, multicenter trial investigated the efficacy and safety of 2 dose regimens of the selective integrin inhibitor cilengitide combined with standard chemoradiotherapy in patients with newly diagnosed glioblastoma and an unmethylated MGMT promoter. METHODS: Overall, 265 patients were randomized (1:1:1) to standard cilengitide (2000 mg 2×/wk; n = 88), intensive cilengitide (2000 mg 5×/wk during wk 1-6, thereafter 2×/wk; n = 88), or a control arm (chemoradiotherapy alone; n = 89). Cilengitide was administered intravenously in combination with daily temozolomide (TMZ) and concomitant radiotherapy (RT; wk 1-6), followed by TMZ maintenance therapy (TMZ/RT→TMZ). The primary endpoint was overall survival; secondary endpoints included progression-free survival, pharmacokinetics, and safety and tolerability. RESULTS: Median overall survival was 16.3 months in the standard cilengitide arm (hazard ratio [HR], 0.686; 95% CI: 0.484, 0.972; P = .032) and 14.5 months in the intensive cilengitide arm (HR, 0.858; 95% CI: 0.612, 1.204; P = .3771) versus 13.4 months in the control arm. Median progression-free survival assessed per independent review committee was 5.6 months (HR, 0.822; 95% CI: 0.595, 1.134) and 5.9 months (HR, 0.794; 95% CI: 0.575, 1.096) in the standard and intensive cilengitide arms, respectively, versus 4.1 months in the control arm. Cilengitide was well tolerated. CONCLUSIONS: Standard and intensive cilengitide dose regimens were well tolerated in combination with TMZ/RT→TMZ. Inconsistent overall survival and progression-free survival outcomes and a limited sample size did not allow firm conclusions regarding clinical efficacy in this exploratory phase II study.

Glioblastoma multiforme (GBM) is one of the deadliest central nervous system cancers, difficult to treat and largely impossible to cure. A considerable challenge in GBM therapy is treatment resistance and tumor recurrence, resulting in dismal patient prognosis. GBM aggression is often associated with a mesenchymal phenotype, increased expression of glycoproteins and the presence of tumor-initiating “stem-like” cells. Using patient-derived xenograft models, and immune competent syngeneic and transgenic glioma mouse models, we show that GBMs demonstrate increased contractility, and their tumors are surrounded by a stiffer ECM, that maintains and even further enhances integrin mechanosignaling. As a result of increased integrin signaling, these tumors also harbor a mesenchymal-like gene signature and phenotype, possess a bulky glycocalyx and demonstrate a stem-like phenotype. Bioinformatics analysis, expression profiling and limiting dilution studies reveal that these mechanically challenged tumors express more “bulky” glycoproteins such as mucins and CD44, as well as glycocalyx regulators, galectins. Considering that a large proportion of these bulky glycoproteins are also stem markers, we show that upregulation of the glycoproteins and their modulators leads to enhanced GBM stem-ness. Our findings suggest that there is a dynamic and reciprocal link between integrin mechanosignaling and a bulky glycocalyx, which promotes a mesenchymal, stem-like phenotype in GBMs. Thus, therapeutic strategies to target GBM tissue tension could reduce mortality and improve patient outcome.

Failure patterns in malignant gliomas have been described in previous literatures, however, studies were limited to analyze clinical features to account for predisposition to distinct failure patterns. Present study aimed to describe the landscape of failure patterns in malignant glioma from large cohort by integrating multi-omics data and investigate the genetic backgrounds of distinct failure patterns. A total of 423 cases from 325 patients who enrolled at the registry of IRCR at SMC were reviewed for their pattern of failure. Failure patterns were categorized into local, distant recurrence and leptomeningeal seeding regarding recurrent tumors’ spatial relation to primary location. Genomic data was available for 327 (DNAseq) and 259 samples (RNAseq), respectively. Glioblastoma was the most prevalent histologic type in study cohort (81.2%)) and majority of cases experienced the recurrence (79.0%). None of clinical parameters (e.g. age, sex, extent of operation and history of prior therapy) failed to show any significant association with failure patterns. Although local recurrence was most prevalent (63.8%) among failure patterns in malignant gliomas, considerable portion of patients (37.8%) demonstrated other types of failure patterns even in their initial relapse. Multivariate analysis demonstrated that failure pattern was significant prognostic factor to overall survival (remote recurrence, HR=1.59, p-value=0.009; leptomeningeal seeding, HR=2.17, p-value< 0.001). Genomic analysis including mutational profile revealed distinct molecular landscape of malignant gliomas according to failure patterns, which suggested that innate biologic characteristics of tumors might contribute to develop distinct failure patterns upon recurrence. PTEN mutation was significantly enriched in tumors of distant recurrence (p-value=0.026). We described the landscape of failure patterns in malignant gliomas by integrating clinical and genomic data. Considerable amount of malignant glioma patients experienced distinct failure patterns other than local recurrence and their clinical outcome as well as genetic background demonstrated invasive characteristic of these tumors.

BACKGROUND Toca 511 (vocimagene amiretrorepvec) is a cancer-selective, retroviral replicating vector encoding a codon optimized, heat stabilized cytosine deaminase that converts Toca FC (extended-release 5-fluorocytosine, 5-FC) into the anticancer agent 5-fluorouracil. Three Ph1 studies in patients with recurrent high grade glioma have demonstrated a tolerable safety profile and encouraging efficacy. METHODS Toca 5 is a multi-national, randomized, open-label Ph3 trial (NCT02414165) of Toca 511 & Toca FC versus standard of care (SOC) options that comprises Investigator’s choice of single agent chemotherapy (lomustine, temozolomide) or bevacizumab in patients who have undergone resection for first or second recurrence of glioblastoma or anaplastic astrocytoma. 403 patients were randomized 1:1 to the Toca arm or the SOC arm and stratified by IDH1 status, KPS, and geographic region. Primary endpoint was overall survival (OS), and secondary endpoints were durable response rate, durable clinical benefit rate, duration of durable response, and 12-month survival rate. The study used group sequential design including 2 interim analyses and 1 final analysis, and the stratified log-rank test are used for the analysis. RESULTS 271 events were observed for this analysis. Median follow-up was 22.8 months, and the Toca arm missed the primary endpoint (OS) compared to the SOC arm (11.1 months median compared to 12.2 months, HR=1.06, p=0.6154). All secondary endpoints showed no meaningful difference between the arms of the trial. The safety, tolerability and adverse event profile of Toca 511 and Toca FC was as expected for this patient population, with low incidences of Grade 3–4 adverse events. Pre-planned subgroup analyses showed compelling OS improvement in patients with secondary recurrence, and favorable trends in IDH1 mutant and AA population. Detailed data will be presented at the time of the conference.

DepartmentofNeurosurgery,SeoulNationalUniversityCollegeofMedicine,SeoulNationalUniversityHospital(C.-K.P., D.G.K., H.-W.J.); Department of Neurosurgery,Asan Medical Center, Universityof Ulsan CollegeofMedicine(J.H.K.);andDepartmentofNeurosurgery,SamsungMedicalCenter,SungkyunkwanUniversitySchoolof Medicine, Seoul, South Korea(D.-H.N., S.-B.C., H.J.S.); Department of Neurosurgery, Seoul NationalUniversity Bundang Hospital, Gyeonggi-do (C.-Y.K., Y.-H.K.); and Department of Internal Medicine (T.M.K.,S.-H.L., D.S.H.), Department of Radiology (S.H.C.), and Department of RadiationOncology (I.H.K.), SeoulNational University College of Medicine, Seoul NationalUniversity Hospital, Seoul, South KoreaBackground. To determine the benefit of surgical man-agement in recurrent glioblastoma, we analyzed a seriesof patients with recurrent glioblastoma who had under-gone surgery, and we devised a new scale to predicttheir survival.Methods. Clinical data from 55 consecutive patientswithrecurrentglioblastomawereevaluatedaftersurgicalmanagement. Kaplan–Meier survival analysis and Coxproportional hazards regression modeling were used toidentifyprognosticvariablesforthedevelopmentofapre-dictivescale.Afterthemultivariateanalysis,performancestatus(P ¼ .078)andependymalinvolvement(P ¼ .025)were selected for inclusion in the new prognostic scale.The devised scale was validated with a separate set of 96patients from3 different institutes.Results. A 3-tier scale (scoring range, 0–2 points) com-posed of additive scores for the Karnofsky performancestatus (KPS) (0 for KPS ≥ 70 and 1 for KPS , 70) andependymal involvement (0 for no enhancement and 1forenhancementoftheventriclewallinthemagneticres-onance imaging) significantly distinguished groups withgood(0points;mediansurvival,18.0months),intermedi-ate (1 point; median survival, 10.0 months), and poorprognoses (2 points; median survival, 4.0 months). Thenew scale was successfully applied to the validationcohort of patients showing distinct prognosis among thegroups (median survivals of 11.0, 9.0, and 4.0 monthsfor the 0-, 1-, and 2-point groups, respectively).Conclusions. Wedevelopedapracticalscaletofacilitatedecidingwhethertoproceedwithsurgicalmanagementinpatients with recurrent glioblastoma. This scale wasuseful for the diagnosis of prognostic groups and can beused to develop guidelines for patient treatment.Keywords: ependymal involvement, performance status,recurrent glioblastoma, scoring system,surgery.

Glioblastoma (GBM) is the most lethal and common type of primary brain tumor. Recent evidence suggests that a subpopulation of GBM cells (glioblastoma stem cells [GSCs]) is critical for tumor progression, invasion, and therapeutic resistance. We and others have demonstrated that MET, a receptor tyrosine kinase, positively regulates the stemness phenotype and radioresistance of GSCs. Here, we interrogated the downstream effector pathways of MET signaling in GSCs.We have established a series of GSCs and xenograft tumors derived from freshly dissociated specimens from patients with GBM and characterized a subpopulation enriched with MET activation (MET(high/+)). Through global expression profiling and subsequent pathways analysis, we identified signaling pathways that are enriched in MET(high/+) populations, one of which is Wnt/β-catenin signaling pathway. To determine molecular interaction and the biological consequences of MET and Wnt/β-catenin signaling, we used pharmacological and shRNA-mediated genetic inhibition and performed various molecular and cellular analyses, including flow cytometry, immunohistochemistry, and clonogenicity assays.We found that Wnt/β-catenin signaling is highly active in MET(high/+) cells, compared with bulk tumor cells. We also showed that Wnt/β-catenin signaling activities in GBM are directly modulated by the addition of ligand-mediated MET activation or MET inhibition. Furthermore, the ectopic expression of active-β-catenin (S37A and S45Y) rescued the phenotypic effects caused by MET inhibition.These data suggest that Wnt/β-catenin signaling is a key downstream effector of MET signaling and contributes to the maintenance of GSC and GBM malignancy.

Inflammatory microenvironment signalling plays a crucial role in tumour progression (i.e. cancer cell proliferation, survival, angiogenesis and metastasis) in many types of human malignancies. However, the role of inflammation in brain tumour pathology remains poorly understood. Here, we report that interferon regulatory factor 7 is a crucial regulator of brain tumour progression and heterogeneity. Ectopic expression of interferon regulatory factor 7 in glioma cells promotes tumorigenicity, angiogenesis, microglia recruitment and cancer stemness in vivo and in vitro through induction of interleukin 6, C-X-C motif chemokine 1 and C–C motif chemokine 2. In particular, interferon regulatory factor 7-driven interleukin 6 plays a pivotal role in maintaining glioma stem cell properties via Janus kinase/signal transducer and activator of transcription-mediated activation of Jagged-Notch signalling in glioma cells and glioma stem cells derived from glioma patients. Accordingly, the short hairpin RNA-mediated depletion of interferon regulatory factor 7 in glioma stem cells markedly suppressed interleukin 6-Janus kinase/signal transducer and activator of transcription-mediated Jagged-Notch-signalling pathway, leading to decreases in glioma stem cell marker expression, tumoursphere-forming ability, and tumorigenicity. Furthermore, in a mouse model of wound healing, depletion of interferon regulatory factor 7 suppressed tumour progression and decreased cellular heterogeneity. Finally, interferon regulatory factor 7 was overexpressed in patients with high-grade gliomas, suggesting its potential as an independent prognostic marker for glioma progression. Taken together, our findings indicate that interferon regulatory factor 7-mediated inflammatory signalling acts as a major driver of brain tumour progression and cellular heterogeneity via induction of glioma stem cell genesis and angiogenesis. * Abbreviations : CCL2 : C–C motif chemokine 2 CXCL1 : C-X-C motif chemokine 1 GSC : glioma stem cell IL6 : interleukin 6 IRF7 : interferon regulatory factor 7 JAK : Janus kinase shRNA : short hairpin RNA STAT : signal transducer and activator of transcription TNFα : tumour necrosis factor α

Glioblastoma multiforme (GBM) is the most malignant form of central nervous system tumor. Growth factors that are included as a supplement in a conditioned media is essential for culturing GBM cells. We discovered a subset of patient-derived cells that exhibit high cellular proliferation in the absence of supplemental growth factors. In order to identify autocrine growth factors that govern tumor cell growth, we utilized proteomics analysis from the growth-factor free conditioned media from two GBM cells and identified Midkine (MDK) as one of the prominent cytokines during GBM proliferation. Midkine is a major secretome in excess of 300 proteins. We inhibited tumor cells using recombinant lentiviral vector of MDK or neutralizing antibody. After MDK expression level was suppressed in vitro, cell cycle and cell proliferation rate were significantly down-regulated as well. Furthermore, pathway analysis has revealed specific pathways that are associated with reactive oxygen species stress were up-regulated.

BACKGROUND: Glioblastoma multiforme (GBM), the most common and aggressive malignant brain tumor, almost always recurs despite aggressive treatments combining surgery, radiation, and chemotherapy. Thus, understanding how individual tumors evolve in response to the standard treatments is essential for improved patient care. METHODS: Here, we describe our genomic analysis of the paired pre- and post-treatment tumors from 20 glioblastoma patients. RESULTS: Tumors also acquired diverse alterations that appeared to contribute to treatment resistance, such as the increased expression of CDK4/6 in the IDH1-mutated tumors and novel EGFR and MET mutations, in addition to TP53, RB1, and APC alterations that were previously implicated with treatment resistance. CONCLUSIONS: The patient-specific genomic alterations that arise following treatments may represent superior therapeutic targets for recurrent GBMs. This work suggests that assessing genomic changes in individual tumors after recurrence is paramount for precision neuro-oncology. SECONDARY CATEGORY: Tumor Biology.

We analyzed clinical data of 376 patients with histologically confirmed anaplastic oligodendroglioma or anaplastic oligoastrocytoma (AOA) from 2000 to 2010. Post-operative therapy was performed in 354 patients (94.1 %), of which 133 received radiotherapy (RT) alone and 189 received both RT and chemotherapy. The use of procarbazine, lomustine, and vincristine (PCV) decreased (57.6 % in 2000-2001 vs. 28.6 %in 2010) and the use of temozolomide (TMZ) increased (0 % in 2000-2001 vs. 61.9 % in 2010) over the study period. A combination of chemotherapy and RT was used more often than RT alone in young patients and patients with a good performance status. The 1p/19q co-deletion status and O-6-methyguanine-DNA methyltransferase methylation were analyzed since 2004. Among the patients who received chemotherapy, TMZ was used more often in patients with AOA and PCV was used more often in patients with the 1p/19q codeletion. Median progression-free survival (PFS) was 2.9 years and overall survival (OS) was 8.7 years. (5-year and 10-year OS rates were 58% and 45%, 5-year and 10-year PFS rates were 38% and 24%). Younger age, frontal lobe location of the tumor, gross total removal, 1p/19q codeletion, and initial RT were associated with longer PFS and OS rates. A clear improvement in progression-free and overall survival was observed for RT and combined CT/RT in compared with CT only. Postoperative RT appears to improve survival for entire group thus total removal and 1p/19q codeletion may not be sufficient criteria to omit RT as a treatment option. These results suggest that RT should continue to be offered as the standard treatment option. Taken together, treatment pattern for oligodendroglial tumors changed significantly across the study period in Korea. In particular, TMZ has replaced PCV, and the use of molecular markers as well as RT alone has increased, but a optimal therapeutic option remains to be defined though the prospective randomized studies.

GBM have been classified into four transcriptional subtypes, termed proneural, neural, classical, and mesenchymal, which are characterized by distinct genomic properties but reports on how transcriptional classification relates to clinical outcome have been conflicting. Methods for classification of new GBMs according to these subtypes have shown poor concordance. We used robust classification methods to classify TCGA samples and found that 37% of GBM could be assigned to multiple expression subtypes, suggesting that mutually exclusive subtype classification may be too strict for deriving robust biologic correlates. We observed that the neural GBM class showed a significant reduction in tumor cellularity, which could be traced to the presence of normal brain tissue. Additionally, mesenchymal GBM were associated with decreased tumor cell fractions which we related to an increase in the microglia. Consequently, microglial marker genes such as ITGAM and AIF1 were found to be highly expressed in thirteen mesenchymal GBM but could not be detected in neurosphere GBM models derived from them. Immunostaining unequivocally identified microglial cells as the source for ITGAM and AIF1 protein, confirming the tumor microenvironment as a key component of the mesenchymal class. GBM was previously described to undergo proneural-to-mesenchymal transition which has been hypothesized as a contributor to therapy resistance. Analysis of 67 matched primary-recurrent GBM pairs showed that most (48 of 67) GBM tumors retained their expression subtype after treatment but cases that showed a transition towards the mesenchymal class at recurrence were specifically associated with a decrease in tumor purity relative to their primary counterparts. We did not find evidence for a tumor cell intrinsic increase in mesenchymal gene expression. Our study provides critical insights into the origin of the neural and mesenchymal subtypes, their transition from other subtypes upon recurrence, and place emphasis on the contribution of the microenvironment in glioma biology.