Search

BACKGROUND Glioblastoma has a high degree of malignancy and poor prognosis. It is common to have in situ recurrence and intracranial metastasis, while extracranial metastasis is rare, and extracranial multiorgan metastasis is extremely rare. We report a case of glioblastoma with extracranial multiorgan metastasis, which will strengthen clinicians’ attention to the extracranial metastasis of glioblastoma and its treatment. CASE SUMMARY A male patient visited our hospital for treatment of dizziness and headache. Magnetic resonance imaging of the brain revealed a space-occupying lesion in the right temporoparietal occipital region. Chest computed tomography and abdominal ultrasound were normal, and no space-occupying lesions were observed in other organs of the body. The patient underwent surgery and diagnosed with glioblastoma. Postoperative concurrent radiotherapy and chemotherapy were completed. During the follow-up, the tumor was found to have metastasized to the scalp and neck, and a second tumor resection was performed. Postoperative follow-up revealed extracranial metastases to multiple extracranial organs including skull, scalp, ribs, spine, liver and lung. His family members refused further treatment, and requested only symptomatic treatment such as pain relief, and the patient died of systemic multiple organ failure. Survival time from diagnosis to death was 13 mo and from extracranial metastasis to death was 6 mo. CONCLUSION Glioblastoma extracranial metastasis is extremely rare, clinicians should always pay attention to its existence. The mechanism of glioblastoma extracranial metastasis is still unclear, and genetic and molecular studies are required.

Background The concept of combinational analysis between the methylation of O6-methylguanine-DNA methyltransferase (MGMT) and telomerase reverse transcriptase promoter (pTERT) mutation in glioblastoma (GBM) has been reported. The main study objective was to determine the prognosis of patients with GBM based on MGMT/pTERT classification, while the secondary objective was to estimate the temozolomide effect on the survival time of GBM with MGMT/pTERT classification. Methods A total of 50 GBM specimens were collected after tumor resection and were selected for investigating MGMT methylation and pTERT mutation. Clinical imaging and pathological characteristics were retrospectively analyzed. Patients with MGMT/pTERT classification were analyzed using survival analysis to develop the nomogram for forecasting and individual prognosis. Results All patients underwent resection (total resection: 28%, partial resection: 64%, biopsy: 8%). Thirty-two percent of all cases received adjuvant temozolomide with radiotherapy. Sixty-four percent of the case was found methylated MGMT, and 56% of the present cohort found pTERT mutation. Following combinational analysis of biomarkers, results showed that the GBMs with methylated MGMT and wild-type pTERT had a superior prognosis compared with other subtypes. Using Cox regression analysis with multivariable analysis, the extent of resection, postoperative chemoradiotherapy, MGMT/pTERT classification were associated with a favorable prognosis. Hence, a web-based nomogram was developed for deploying individual prognostication. Conclusions The interaction of MGMT methylation and pTERT mutation was confirmed for predicting prognosis. The results from the present study could help physicians create treatment strategies for GBM patients in real-world situations.

BACKGROUND Gross total resection (GTR) of contrast-enhancing tumor is associated with increased survival in primary glioblastoma. Recently, there has been increasing interest in performing supratotal resections (SpTRs) for glioblastoma. OBJECTIVE To address the published results, which have varied in part due to lack of consensus on the definition and appropriate use of SpTR. METHODS A crowdsourcing approach was used to survey 21 neurosurgical oncologists representing 14 health systems nationwide. Participants were presented with 11 definitions of SpTR and asked to rate the appropriateness of each definition. Participants reviewed T1-weighed postcontrast and fluid-attenuated inversion-recovery magnetic resonance imaging for 22 anatomically distinct glioblastomas. Participants were asked to assess the tumor location's eloquence, the perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans. RESULTS Most neurosurgeons surveyed (n = 18, 85.7%) agree that GTR plus resection of some noncontrast enhancement is an appropriate definition for SpTR. Overall, moderate inter-rater agreement existed regarding eloquence, equipoise, and personal treatment plans. The 4 neurosurgeons who had performed >10 SpTRs for glioblastomas in the past year were more likely to recommend it as their treatment plan (P

Objective: This study was designed to conduct molecular classification based on IDH1/2, TERT, ATRX, and DAXX changes in pediatric and adult primary glioblastoma (GB) and to analyze the potential interaction of LncRNA MALAT1 in the determined homogeneous subgroups. Methods: We analyzed the expression profiles of ATRX/DAXX and MALAT1 using the qRT-PCR method and IDH and TERT mutation status using DNA sequencing analysis in 85 primary pediatric and adult GB patients. Results: IDH1 mutation was observed in 5 (5.88%) and TERT mutation in 65 (76.47%) primary pediatric and adult GB patients. ATRX and DAXX were detected in 18 (21.18%) and 7 (8.24%) patients. TERT mutation and loss of ATRX/DAXX were associated with short overall survival (p < 0.001, p < 0.001, respectively). Patients carrying especially TERT C228T mutation had worse prognosis (p < 0.001). Six subgroups were obtained from the genetic analysis. Among the subgroups, MALAT1 was highly expressed in group A that had a single TERT mutation as compared to that in groups D and E (p = 0.001 and p < 0.001, respectively); further, high MALAT1 expression was associated with worse prognosis in patients with C228T mutation (p < 0.001). Conclusions: Our findings highlight that the presence of TERT C228T mutation and expression of MALAT1 can be used as primary targets during the follow-up of primary GB patients and in the development of new treatment strategies.

Background . Over the past 10–15 years, there has been a clearer understanding of the processes occurring in cells of the primary glioblastoma. However, the change in MGMT gene expression and its role after disease relapse remain understudied. Purpose : to study changes in MGMT gene expression in case of recurrent primary glioblastoma after the standard therapy; to determine influence of clinical factors and MGMt gene expression on relapse-free survival of patients. Materials and Methods . We carried out a prospective analysis of clinical and molecular genetic characteristics of 21 patients aged from 28 to 63 with primary glioblastoma before and after recurrence. Relative mRna expression of MGMT gene and mutations in IDH1/IDH2 genes were determined in surgical biopsies using PCR techniques. after the first surgery, all patients received radiation therapy (60 Gy) and chemotherapy with adjuvant temozolomide (2–18 cycles). the second-line chemotherapy was performed in 17 (80.9 %) patients, and 8 patients received (47 %, 8/17) temozolomide. Results. the relationship between the progression-free survival (PFs) and mRna expression of MGMT gene (73.5 vs 33 weeks, p=0.013) and objective response to therapy (88 vs 36 weeks, p=0.046) was found. The number of cycles of first-line chemotherapy with temozolomide influenced the duration of the first PFs (65 weeks vs 21.5 weeks, p=0,07). the first PFs was not affected by patients’ age (p=0.64), sex (p=0.17), Karnofsky performance scale index (p=0.43), extent of brain damage (p=0.41) and extent of the resection (p=0.27). after onset of relapse, mRna expression of MGMT gene remained the same, being 66.7 % (14/21). The increased expression was observed in 23.8 % (5/21) of cases, and decreased gene expression was observed in 9.5 % (2/21) of cases. the second PFs was affected by the extent of tumor resection, although there were no statistically significant differences (p=0.52). the effect of mRna expression of MGMT gene on the median second PFs was not revealed (p=0.39). no objective response to therapy was found in patients with a low mRna expression of MGMT gene. Conclusion . Recurrent glioblastoma becomes more resistant to further therapy. With the development of tumor recurrence, the predictive value of MGMT gene is lost and the role of the extent of cytoreductive surgery increases.

Background/aim Care is often palliative when patients are not fit and complete resection of glioblastomas cannot be achieved. This study aimed to identify predictors of survival after palliative radiotherapy. Patients and methods Thirty-one patients irradiated after biopsy or incomplete resection of primary glioblastoma were retrospectively analyzed. Median total dose, dose per fraction and equivalent dose in 2 Gy fractions (EQD2) were 45.0 Gy, 3.0 Gy and 46.0 Gy, respectively. Median number of fractions was 15, median treatment time 3 weeks. Ten patients received temozolomide. Six factors were evaluated for survival including location of glioblastoma, Karnofsky performance score (KPS), gender, age, EQD2 and temozolomide. Results KPS ≥60 showed a trend for improved survival (p=0.141). For other factors including EQD2, no significant association with survival was found. Conclusion Patients with a KPS ≤50 have a poor survival prognosis and appear good candidates for short-course radiotherapy. Selected patients with better KPS may be considered for more aggressive treatments.

Glioblastoma (GBM), the most common primary malignant brain tumor in adults, is associated with significant morbidity and mortality despite maximal safe resection followed by chemo- and radiotherapy. GBMs contain self-renewing, tumorigenic glioma stem cells that contribute to tumor initiation, heterogeneity, therapeutic resistance, and recurrence. Intratumoral heterogeneity (ITH) of GBMs is also a major contributing factor to poor clinical outcomes associated with these high-grade glial tumors. Herein, the authors summarize recent discoveries and advances in the molecular and phenotypic characterization of GBMs with particular focus on ITH. In so doing, they attempt to highlight recent advances in molecular signatures/properties and metabolic alterations in an effort to clarify translational implications that may ultimately improve clinical outcomes.

Background Glioblastoma is the most malignant tumor of the central nervous system. Several prediction models have been produced to aid in prognosis assessment. Age, a primary decision factor for prognosis, is associated with increased genomic alterations, however the exact link between increased age and poor prognosis is unknown. Objective In this study, we aimed to reveal the underlying cause of poor prognosis in elderly patients. Methods This study included data on 616 primary GBM tumor samples from the CGGA and TCGA databases and 41 nontumor brain tissue samples obtained from http://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE53890. Hallmarks and clinicopathological characteristics were evaluated in both tumor and nontumor brain tissues. The association between choice of treatment regimen and age was measured using ANOVA and Student's t test. Results Age was a robust predictor of poor prognosis in glioma. No age‐related hallmarks of cancer were detected, including pathological characteristics or mutations. However, treatment choice was strongly significantly different between old and young patients. Combined chemo‐radiation therapy could benefit old and young GBM patients, however, old patients are currently less likely to choose it. Conclusion The vast divergence in prognosis between young and old GBM patients is largely caused by choice of treatment rather than age‐related tumor genomic characteristics. Postoperative standard radio‐ and chemotherapy provide strong benefits to primary glioblastoma patients of all ages., The main reason of poorer prognosis in elder patients was conservative treatment choosing, while standard radio‐ and chemotherapy should be generalized in all age grade of patients.

INTRODUCTION Dendritic cells (DCs) are potent antigen presenting cells that can be exploited to initiate an adaptive anti-tumoral immune response. DC vaccine clinical trials for primary glioblastoma (GBM) have reported prolonged progression-free survival without any impact on overall survival (OS). We report a radiomics approach that identifies a subpopulation of patients with prolonged OS in clinical trial MC1272. METHODS Twenty adults with primary GBM undergoing standard-of-care therapy were enrolled in MC1272. Autologous DCs were pulsed with allogenic GBM cell lines to generate vaccines that were administered for up to twelve cycles. Standard brain imaging was obtained at the initiation of treatment and two months afterwards. An independent cohort of image-localized biopsies underwent RNA sequencing followed by cellular deconvolution to estimate T cell abundance. A machine learning model was trained to predict intratumoral T cell abundance from imaging features, and the model was applied to MC1272 patient imaging. RESULTS Voxelwise predictions of T cell abundance were generated for each patient’s pre- and post-treatment images. The difference in total intratumoral T cell abundance between imaging timepoints classified patients into increasing or decreasing T cell groups. Patients whose T cells increased had longer OS (median, 21 months) than those whose T cells decreased (median, 10 months; p=0.0035). The significance remained in a Cox proportional hazards analysis that adjusted for patient age and sex (p=0.011). CONCLUSIONS A spatially-resolved radiomics model detected that an intratumoral T cell influx after DC vaccine therapy was associated with prolonged OS. The “post-treatment” imaging in this study was obtained a mere two months after DC vaccine initiation, suggesting that our radiomics model can provide an early indication of treatment responsiveness and prognosis in these patients.

BACKGROUND Despite advances in the characterization of genomic alterations in glioblastoma patient survival remains poor. The aim of this single center retrospective study was to estimate prognostic factors affecting to survival for optimizing personalized treatment strategy in glioblastoma patients. MATERIAL AND METHODS 574 consecutive patients with primary glioblastoma treated at the Burdenko National Medical Research Center of Neurosurgery from 2014 to 2019 were included in this study (314 male /260 female). Survival data was analyzed using Kaplan-Meier with log-rank tests to assess statistical significance. A linear regression model was built to predict overall survival. RESULTS Older patients (> 45 years) had the worse prognosis than patients ≤ 45 (p = 2.37 * 10^-6). Female patients had advantages in overall survival (p = 0.014). Time interval from surgery to the starting of radiotherapy longer than 4 weeks was associated with worse overall survival (p = 0.062). Patients with positive IDH1/2 and MGMT had better prognosis than patients with wild type and MGMT negative (p = 0.000841, p = 0.000138, respectively). We revealed that there were significant differences in overall survival between patients who had progression on the first (p = 0.000312), second (p = 0.001046) and third (p = 0.00223) follow-up MRI after radiotherapy. Median survival times (from the date of surgery) were 17, 20, 23 months, respectively. The feature importance in the linear regression model was patient’s age, IDH1/2 mutation, MGMT promoter methylation status, progression on the first follow-up MRI and sex. CONCLUSION Older patient’s age, prolonged time between surgery and RT starting, male sex, negative IDH1/2 and MGMT, progression on the first MRI were associated with poor overall survival in glioblastoma patients. Our results suggested additional clinical, radiomics and molecular-genetic data should be added to improve the overall survival prediction. The results have been obtained under the support of the RFBR grant 18-29-01054

Simple Summary This reseach explored the safety and feasibility of combining local chemotherapy with fluorescence-guided resection in patients with a brain cancer, glioblastoma. The aim was to determine if the combination of fluorescence-guided surgery using 5-aminolevulinic acid and BCNU wafers left in the tumour cavity at the end of the operation was safe and did not prevent patients getting subsequent chemo-radiotherapy. The results showed that combining local chemotherapy with fluorescence-guided resection was tolerable in terms of surgical morbidity and overall toxicity. However, any potential therapeutic benefit requires further investigation, preferably with improved local delivery technologies. Abstract Background Glioblastoma (GBM) is the commonest primary malignant brain tumour in adults and effective treatment options are limited. Combining local chemotherapy with enhanced surgical resection using 5-aminolevulinic acid (5-ALA) could improve outcomes. Here we assess the safety and feasibility of combining BCNU wafers with 5-ALA-guided surgery. Methods We conducted a multicentre feasibility study of 5-ALA with BCNU wafers followed by standard-of-care chemoradiotherapy (chemoRT) in patients with suspected GBM. Patients judged suitable for radical resection were administered 5-ALA pre-operatively and BCNU wafers at the end resection. Post-operative treatment continued as per routine clinical practice. The primary objective was to establish if combining 5-ALA and BCNU wafers is safe without compromising patients from receiving standard chemoRT. Results Seventy-two patients were recruited, sixty-four (88.9%) received BCNU wafer implants, and fifty-nine (81.9%) patients remained eligible following formal histological diagnosis. Seven (11.9%) eligible patients suffered surgical complications but only two (3.4%) were not able to begin chemoRT, four (6.8%) additional patients did not begin chemoRT within 6 weeks of surgery due to surgical complications. Eleven (18.6%) patients did not begin chemoRT for other reasons (other toxicity (n = 3), death (n = 3), lost to follow-up/withdrew (n = 3), clinical decision (n = 1), poor performance status (n = 1)). Median progression-free survival was 8.7 months (95% CI: 6.4–9.8) and median overall survival was 14.7 months (95% CI: 11.7–16.8). Conclusions Combining BCNU wafers with 5-ALA-guided surgery in newly diagnosed GBM patients is both feasible and tolerable in terms of surgical morbidity and overall toxicity. Any potential therapeutic benefit for the sequential use of 5-ALA and BCNU with chemoRT requires further investigation with improved local delivery technologies.

Objective: Glioblastoma multiforme (GBM) is the most common primary malignant central nervous system (CNS) tumor. The Stupp regimen is the standard treatment , although the optimal number of temozolomide (TMZ) treatment cycles remains controversial. We compared the effects of standard 6 cycles versus >6 cycles of TMZ chemotherapy post-surgery with concurrent chemoradiotherapy on primary GBM patient survival. Patients and Methods: We performed a single center retrospective study of GBM patients that underwent total resection, concurrent chemoradiotherapy, and at least 6 cycles of adjuvant TMZ chemotherapy from June 2011 to August 2018. Patients were divided into 2 groups based on adjuvant TMZ treatment plan: Group A（n=27）: standard 6-cycle adjuvant TMZ therapy and Group B(n=26): >6 cycles of adjuvant TMZ therapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS). Continuous variables were analyzed by ANOVA, and the Kaplan-Meier method was used to evaluate PFS and OS. Univariate and multivariate COX analyses determined correlation between survival rates and covariates.Results: After follow-up, median PFS was 15 months in in Group A (95%CI 9.5-20.5) and 20.1 months in Group B (95%CI 15.9-24.4). Group A median OS was 19.4 months (95%CI 15.5-23.2), compared to 25.6 months in Group B (95%CI 20.4-30.8). The 2-year survival rate of Groups A and B was 36% was 66%, respectively (P=0.02). and 5-year survival was 7% in both. Multivariate COX regression analysis showed association between patient PFS and long-period adjuvant chemotherapy, but not OS. Conclusions: Long-term adjuvant TMZ chemotherapy benefits PFS and 2-year survival rate but not OS. We do not suggest prolonging TMZ maintenance therapy beyond six cycles in patients with glioblastoma after total resection.

Tumor treating fields, a noninvasive cancer treatment using low intensity alternating electric fields, offers clinical opportunities with unique challenges. This review focuses on the mechanism of action of this treatment, the known pre‐clinical and clinical experience, and the practical issues surrounding its use in the multidisciplinary management of patients with solid malignancies., Tumor‐treating fields (TTFields) are a noninvasive antimitotic cancer treatment consisting of low‐intensity alternating electric fields delivered to the tumor or tumor bed via externally applied transducer arrays. In multiple in vitro and in vivo cancer cell lines, TTFields therapy inhibits cell proliferation, disrupts cell division, interferes with cell migration and invasion, and reduces DNA repair. Human trials in patients with primary glioblastoma showed an improvement in overall survival, and trials in patients with unresectable malignant pleural mesothelioma showed favorable outcomes compared with historical control. This led to U.S. Food and Drug Administration approval in both clinical situations, paving the way for development of trials investigating TTFields in other malignancies. Although these trials are ongoing, the existing evidence suggests that TTFields have activity outside of neuro‐oncology, and further study into the mechanism of action and clinical activity is required. In addition, because TTFields are a previously unrecognized antimitotic therapy with a unique mode of delivery, the oncological community must address obstacles to widespread patient and provider acceptance. TTFields will likely join surgery, systemic therapy, and radiation therapy as a component of multimodality management of patients with solid malignancies. Implications for Practice. Tumor‐treating fields (TTFields) exhibit a broad range of antitumor activities. Clinically, they improve overall survival for patients with newly diagnosed glioblastoma. The emergence of TTFields has changed the treatment regimen for glioblastoma. Clinicians need to understand the practical issues surrounding its use in the multidisciplinary management of patients with glioblastoma. With ongoing clinical trials, TTFields likely will become another treatment modality for solid malignancies.

Introduction TP53 and MGMT alterations play a crucial role in glioblastoma (GB) pathogenesis. TP53 and MGMT function is affected by several pathologic mechanisms, such as point mutations or promoter methylation, which are well characterized. Expression of both genes can be regulated by other mechanisms as well, e.g., microRNAs (miRNAs). Moreover, cross-talk among various pathologic processes may occur, further affecting MGMT and TP53 functionality. Material and methods In 49 GB patients, we analyzed the possible associations between TP53 and its miRNA regulators miR-125b, miR-21, and miR-34a, as well as MGMT and its miRNA regulators miR-181d and miR-648. We evaluated the possible influence of mutational and methylation status on the pre-identified associations. Results In patients with immunohistochemistry-detected TP53 overexpression, expression levels of miR-34a and TP53 were negatively correlated (r = -0.56, p = 0.0195), and in patients with TP53 mutations, expression levels of TP53 and miR-21 were negatively correlated (r = -0.67, p = 0.0330). In patients with MGMT methylation, expression levels of MGMT were negatively correlated with miR-648 and miR-125b expression levels (r = -0.61, p = 0.0269 and r = -0.34, p = 0.0727, respectively). Conclusions Our findings demonstrate that selected miRNAs are significantly correlated with MGMT and TP53 levels, but the extent of this correlation differs regarding the TP53 and MGMT mutational and promoter methylation status.

Glioblastoma multiforme is a solid tumor with particular aspects due to its organ of origin and its development modalities. The brain is very sensitive to oxygen and glucose deprivation and it is the only organ that cannot be either transplanted or entirely removed. Furthermore, many clues and recent indirect experimental evidence indicate that the micro-infiltration of the whole brain parenchyma occurs in very early stages of tumor bulk growth or likely even before. As a consequence, the primary glioblastoma (IDH-wildtype, WHO 2016) is the only tumor where the malignant (i.e. distantly infiltrating the organ of origin) and deadly (i.e. leading cause to patient’s death) phases coincide and overlap in one single phase of its natural history. To date, the prognosis of optimally treated glioblastoma patients remains dismal despite recent fundamental progress in neurosurgical techniques which are enabling better maximal safe resection and survival outcome. Intratumor variegated heterogeneity of glioblastoma bulk due to trunk-branch evolution and very early micro-infiltration and settlement of neoplastic cells in the entire brain parenchyma are the reasons for resistance to current therapeutic treatments. With the aim of future innovative and effective therapies, this paper deals with the unique glioblastoma features, the appropriate research methods as well as the strategies to follow to overcome current causes of resistance.

Gross total resection for glioblastoma (GBM) has been associated with better prognosis. However, it is not always feasible, and the threshold for the extent of resection required for better prognosis has been controversial. Therefore, we compared the survival and clinical outcomes of patients with GBM who had undergone partial resection (PR) or biopsy.Of the 110 patients, 32 and 78, who had undergone PR and biopsy, respectively, were enrolled to identify any differences in clinical outcomes. No differences were found in patient demographics between the 2 groups, except for tumor location and mean tumor volume (P = 0.02 and P0.01, respectively). Propensity score matching between the PR and biopsy groups was performed, in which 20 patients each in the PR and biopsy groups were matched.The overall survival (OS) and progression-free survival (PFS) did not differ significantly between the PR and biopsy groups (P = 0.84 and P = 0.48, respectively). After propensity score matching, the differences in OS and PFS between the 2 groups were still not statistically significant (P = 0.51 and P = 0.75, respectively). The hazard ratios for OS and PFS for the PR group compared with biopsy were 0.98 and 0.73, respectively; however, the difference was not statistically significant (P = 0.96 and P = 0.39, respectively). The surgical complication rate was greater in the PR group (14 of 32; 43.7%) than in the biopsy group (9 of 78; 11.5%; P0.01).PR failed to improve survival compared with biopsy for patients with GBM. Moreover, the surgical complication rate in the PR group was greater than that in the biopsy group.

MicroRNAs (miRs) are non-coding master regulators of transcriptome that could act as tumor suppressors (TSs) or oncogenes (oncomiRs). We aimed to systematically investigate the relevance of miRs as prognostic biomarkers in primary glioblastoma multiforme (GBM) treated with postoperative radio(chemo)therapy (PORT). For hypothesis generation, tumor miR expression by Agilent 8x15K human microRNA microarrays and survival data from 482 GBM patients of The Cancer Genome Atlas (TCGA cohort) were analyzed using Cox-PH models. Expression of candidate miRs with prognostic relevance (miR-221/222, miR-17-5p, miR-18a, miR-19b) was validated by qRT-PCR using Taqman technology on an independent validation cohort of GBM patients (n = 109) treated at Heidelberg University Hospital (HD cohort). In TCGA, 50 miRs showed significant association with survival. Among the top ranked prognostic miRs were members of the two miR families miR-221/222 and miR-17-92. Loss of miR-221/222 was correlated with improved prognosis in both cohorts (TCGA, HD) and was an independent prognostic marker in a multivariate analysis considering demographic characteristics (age, sex, Karnofsky performance index (KPI)), molecular markers (O-6-methylguanine-DNA methyltransferase (MGMT) methylation, IDH mutation status) and PORT as co-variables. The prognostic value of miR-17-92 family members was ambiguous and in part contradictory by direct comparison of the two cohorts, thus warranting further validation in larger prospective trials.

Recent advances in single-cell RNA sequencing technologies enable deep insights into cellular development, gene regulation, and phenotypic diversity by measuring gene expression for thousands of cells in a single experiment. This results in high-throughput datasets and requires the development of new types of computational approaches to extract the useful and valuable underlying biological information of individual cells in heterogeneous biological populations. To addresses these approaches, in this paper, we introduce a deep learning technique to classify single cell types data from five primary Glioblastomas. We show that the deep learning method has the ability to correctly infer and classify cell type not used during the training process of the algorithm. Further, the deep learning method has the ability to identify the predictor variable Aquaporin 4 (AQP4), as the most important to make these predictions. Such computational approaches, as those presented in this study will enable researchers to better characterize the intratumoral heterogeneity in primary Glioblastoma.

BACKGROUND GBM is driven by various genomic alterations. Next generation sequencing (NGS) may reveal targetable alterations. The goal of this study was to describe how NGS can inform targeted therapy (TT) selection. METHODS The medical records of patients (pts) with GBM from 2017–2019 were reviewed. Pts with actionable mutations were included in the analysis. At first progression (PD1), two cohorts of pts were defined: cohort A received TT, while cohort B received physician’s choice chemotherapy (PCC). Regression analyses were used to determine OS and PFS between cohorts. A stratified cox model was utilized to assess the effect of TT, where KPS level (low vs high) was utilized as a stratification factor. A heat map was generated describing the landscape of mutations. Disease response in cohort A was graded per RANO criteria. RESULTS There were 38 GBM pts with actionable alterations. Cohort A had 15 (39%) pts and cohort B had 23 (61%) pts. Of the 26 common alterations, 11 (42%) were deemed actionable. Pts with higher KPS were more likely to receive TT. Pts with a KPS ≥ 70 had a longer PFS while on TT. Although not well powered, pts in cohort A had a longer median OS relative to cohort B (HR 0.37 CI 0.10–1.38). The objective response rate (ORR) was 93%, with afatinib and cabozantinib resulting in complete response, one pt had progressive disease while on TT. CONCLUSION NGS for recurrent GBM yields a high rate of actionable alterations. Pts that go on TT are often younger and with higher KPS. This likely plays into their improved survival; however, it is notable that the high ORR reflects the value of NGS in deciding on TT to match alterations that are likely to respond. In conclusion, patient selection and availability of NGS impacts outcomes in recurrent GBM.

Gross total resection (GTR) of contrast-enhancing tumor is associated with significantly increased overall survival in primary glioblastoma (GBM). Even when achieved, recurrence is likely, in part due to malignant cells infiltrating outside enhanced regions. Subsequently, there has been increasing interest in performing supratotal resections (SpTRs) for GBM. Published results have varied in part due to a lack of consensus on the definition of SpTR in GBM and its appropriate use. A crowdsourcing approach was used to survey 21 academic neurosurgical oncologists representing 13 health systems nationwide. Participants’ demographics including fellowship training status, years of experience, and operative volume with various techniques was collected. Participants were presented with 11 definitions of SpTR from published, peer-reviewed studies and asked to rate the appropriateness of each definition. Subsequently, participants reviewed T1-weighed post-contrast and FLAIR MR imaging videos in the axial, coronal, and sagittal planes for 22 GBMs. Participants were asked to assess eloquence of the tumor’s location, perceived equipoise of enrolling patients in a randomized clinical trial comparing GTR to SpTR, and their own personal surgical treatment plans. Most neurosurgeons surveyed (n=18, 85.7%) agree or strongly agree that GTR plus resection of some non-contrast enhancement is an appropriate definition for SpTR. Overall, there was only moderate inter-rater agreement, measured using sample variance and the index of qualitative variation, regarding eloquence, equipoise, and personal treatment plans. Neurosurgeons who performed more than 10 SpTRs for GBMs in the past year were more likely than counterparts to recommend it as their personal treatment plan (p< 0.005). Anterior temporal and right frontal GBMs were considered the best randomization candidates. We established a consensus definition for SpTR of GBM and identified anatomically distinct locations deemed most amenable to SpTR. These results will be used to plan prospective trials further investigating the potential clinical utility of SpTR for GBMs.

BackgroundSex is recognized as a significant determinant of outcome among glioblastoma patients, but the relative prognostic importance of glioblastoma features has not been thoroughly explored for sex differences.MethodsCombining multi-modal MR images, biomathematical models, and patient clinical information, this investigation assesses which pretreatment variables have a sex-specific impact on the survival of glioblastoma patients. Pretreatment MR images of 494 glioblastoma patients (299 males and 195 females) were segmented to quantify tumor volumes. Cox proportional hazard (CPH) models and Student’s t-tests were used to assess which variables were associated with survival outcomes.ResultsAmong males, tumor (T1Gd) radius was a predictor of overall survival (HR=1.027, p=0.044). Among females, higher tumor cell net invasion rate was a significant detriment to overall survival (HR=1.011, pConclusionDespite similar distributions of the MR imaging parameters between males and females, there was a sex-specific difference in how these parameters related to outcomes, which emphasizes the importance of considering sex as a biological factor when determining patient prognosis and treatment approach.

Patients with glioblastoma almost always suffer a recurrence of an aggressive treatment resistant tumour and succumb within months highlighting the need to develop treatment options for recurrent glioblastoma. One potential target is prostate specific membrane antigen (PSMA) expressed on the new vessels in primary glioblastoma tumours. This study compared the expression of PSMA in primary and recurrent glioblastoma tumours. Formalin-fixed paraffin-embedded sections of primary and matched recurrent tumours from 13 patients with glioblastoma were processed for PSMA immunohistochemical labelling. PSMA expression was scored from digitally scanned sections using a categorical system (Total PSMA expression = PSMA label intensity (0–3) x percent PSMA-positive blood vessels). Little PSMA labelling was observed in any adjacent ‘unaffected’ brain tissue. PSMA was localised to blood vessels including those displaying microvascular proliferation in 12/13 primary and 9/13 recurrent glioblastoma tumours. Total PSMA expression scores ranged from 0 – 230 (maximum score = 300) and was divided into low and high expression based on a median split (median = 57) of PSMA expression across all tumours. Regression analysis showed a significant difference in PSMA expression between primary and recurrent glioblastoma (p = 0.04) with PSMA being highly expressed in ~70% of primary and only 31% of recurrent glioblastoma. Three cases displayed high expression in both primary and recurrent glioblastoma and one case had no PSMA expression at all. In conclusion, whilst higher expression of PSMA was detected in more primary tumours, 70%+ of all primary and recurrent tumours expressed PSMA to some extent adding evidence that this may be a useful target for treatment of glioblastoma. Larger cohorts and other techniques for detecting PSMA are needed to provide further evidence for PSMA’s utility as a target and to further define which glioblastoma patients are most likely to benefit from this approach.

Objective To report our experience in the use of 3 T intraoperative magnetic resonance imaging (MRI) in neurosurgical procedures for tumors, and to evaluate the criteria for increasing the extension of resection. Material and methods This retrospective study included all consecutive intraoperative MRI studies done for neuro-oncologic disease in the first 13 months after the implementation of the technique. We registered possible immediate complications, the presence of tumor remnants, and whether the results of the intraoperative MRI study changed the surgical management. We recorded the duration of surgery in all cases. Results The most common tumor was recurrent glioblastoma, followed by primary glioblastoma and metastases. Complete resection was achieved in 28%, and tumor remnants remained in 72%. Intraoperative MRI enabled neurosurgeons to improve the extent of the resection in 85% of cases. The mean duration of surgery was 390 ± 122 min. Conclusion Intraoperative MRI using a strong magnetic field (3 T) is a valid new technique that enables precise study of the tumor resection to determine whether the resection can be extended without damaging eloquent zones. Although the use of MRI increases the duration of surgery, the time required decreases as the team becomes more familiar with the technique.

Introduction: Glioblastoma is one of the most common and most aggressive malignant primary tumors of the central nervous system which originates in astrocyte cells accounting for ~12 to 15 of all intracranial neoplasms. Its development to extracranial areas is very rare, occurring in

Background: Delta-like ligand 4 (DLL4) is a key Notch ligand implicated in tumor angiogenesis. However, previous studies have shown that the DLL4-Notch signaling inhibits tumor angiogenesis but promotes tumor progression in primary glioblastoma. The underlying mechanism remains unknown. Methods: Tumor tissues from 70 patients with primary glioblastoma were analyzed by immunohistochemistry for the expression of DLL4, microvessel density (MVD), and Ki67 labeling index. The degree of tumor contrast enhancement (DTCE) on preoperative magnetic resonance imaging was also evaluated. The effect on prognosis was assessed based on Kaplan–Meier survival and Cox proportional hazard models. Results: Results showed that the DTCE was negatively correlated with DLL4 but positively correlated with MVD (r = −0.260, 0.593, P < 0.05). The Ki67 labeling index was shown to be positively correlated with both DLL4 and MVD (r = 0.346, 0.346, P < 0.05). Univariate analysis indicated a significant correlation of high DLL4 and Ki67 labeling index expression with shorter progression-free survival (PFS) and overall survival (OS) (P < 0.05). Multivariate analysis confirmed high DLL4 and MVD expression as unfavorable prognostic indicators for PFS and OS (P < 0.05), and the hazard ratio of DLL4 was higher than MVD for both PFS and OS (P < 0.05). Conclusion: We conclude that the DLL4-Notch signaling improves tumor vascular function and contributes to the survival of malignant cells, resulting in less MVD but more tumor progression in primary glioblastoma.

INTRODUCTION Glioblastoma has limited therapeutic options and is associated with a poor prognosis. Treatment, clinical outcomes, and prognostic factors remain poorly characterised outside of the selected population enrolled in clinical trials. METHODS Demographic, tumour molecular profiles, treatment, and survival data was collated for patients who underwent a biopsy or resection diagnostic of de novo glioblastoma at our centre between July 2011 and December 2015. We used multivariate proportional hazards models to examine the association of potential prognostic markers with survival. RESULTS 490 patients were identified: 60% were male with a median age of 59 years. 60% of patients had surgical debulking, and 40% biopsy only. Subsequently, 56% had standard chemoradiotherapy, 25% non-standard chemo/radio-therapy, and 19% no further treatment; 22% of patients who had adjuvant therapy had surgery at relapse, 37% second-line chemotherapy, and 11% third-line chemotherapy. Median survival was 9.2 months (IQR 7.9-10.3 months), with survival at 12- and 24-months 41% and 13% respectively. In multivariate analysis, longer survival was associated with debulking surgery vs biopsy alone (14.9 vs 8 months) (HR 0.54 [95%CI 0.41-0.70]); subsequent treatment after diagnosis (HR 0.12 [0.08-0.16]) (standard chemoradiotherapy [16.9 months] vs non-standard regimens [9.2 months] vs none [2.0 months]); tumour MGMT promotor methylation (HR 0.71 [0.58-0.87]); and younger age (hazard ratio vs age< 50: 1.70 [1.26-2.30] for ages 50-59; 3.53 [2.65-4.70] for ages 60-69; 4.82 [3.54-6.56] for ages 70+). IDH mutation was associated with longer survival (HR 0.64 [0.66-0.97] in univariate but not multivariate analysis. CONCLUSION Median survival for patients with glioblastoma is less than a year. Younger age, debulking surgery, treatment with chemoradiotherapy, and MGMT promotor methylation are independently associated with longer survival.

BACKGROUND: Gross total resection (GTR) of contrast-enhancing tumor is associated with increased survival in primary glioblastoma. Recently, there has been increasing interest in performing supratotal resections (SpTRs) for glioblastoma. OBJECTIVE: To address the published results, which have varied in part due to lack of consensus on the definition and appropriate use of SpTR. METHODS: A crowdsourcing approach was used to survey 21 neurosurgical oncologists representing 14 health systems nationwide. Participants were presented with 11 definitions of SpTR and asked to rate the appropriateness of each definition. Participants reviewed T1-weighed postcontrast and fluid-attenuated inversion-recovery magnetic resonance imaging for 22 anatomically distinct glioblastomas. Participants were asked to assess the tumor location's eloquence, the perceived equipoise of enrolling patients in a randomized trial comparing gross total to SpTR, and their personal treatment plans. RESULTS: Most neurosurgeons surveyed (n = 18, 85.7%) agree that GTR plus resection of some noncontrast enhancement is an appropriate definition for SpTR. Overall, moderate inter-rater agreement existed regarding eloquence, equipoise, and personal treatment plans. The 4 neurosurgeons who had performed >10 SpTRs for glioblastomas in the past year were more likely to recommend it as their treatment plan (P

Background: According to the development of new treatment modalities, patients with malignant brain tumor have longer survival and they have more chances to have stroke. Study Population: We retrospectively reviewed 509 patients with ischemic stroke and 445 patients with hemorrhagic stroke who visited Kyoto University Hospital between January 2010 and December 2019 and the association with malignant brain tumor was analyzed. The frequency of stroke in 287 patients with primary glioblastoma and 217 patients with metastatic brain tumor was also analyzed. Results: Twenty one (4.1%) patients with ischemic stroke and 26 (5.1%) patients with hemorrhagic stroke patients had malignant brain tumor, and most tumors were either malignant glioma or metastatic brain tumor. A medical history of cranial irradiation was seen in 66.7% of patients with ischemic stroke, and 80% of hemorrhagic stroke occurred within the tumor before starting the treatments. Either ischemic or hemorrhagic stroke occurred in 9.1% of patients with glioblastoma and 4.1% of patients with metastatic brain tumor, and the number of ischemic and hemorrhagic were almost the same. In patients with glioblastoma, nearly half of the stroke cases were associated with bevacizumab. Half of the cases of bevacizumab-related stroke were asymptomatic, while asymptomatic cases were seen in 21.4% for non-bevacizumab cases. Discussion: Stroke is not an uncommon complication in patients with malignant brain tumor but only a restricted number of cases were preventable. Including the cases of bevacizumab-related stroke, which is often asymptomatic, accurate diagnosis and the second prevention would be important.

Glioblastoma is the most common form of primary brain cancer in adults and one of the deadliest of human cancers. Seizures are one of the most frequent presentations of glioblastoma. The use of anti-epileptic drugs (AEDs) in glioblastoma patients suffering from seizures is well accepted. However, the role of long-term AED use in patients with glioblastoma without a history of seizures is controversial. Here, we performed a review of the literature to identify studies that examined the use of AEDs in seizure-free glioblastoma patients. We identified one randomized controlled study suggesting no clinical benefit of seizure prophylaxis in this population. Three of the four retrospective studies identified in our search recapitulated this finding, while the remaining study suggested a benefit for prophylactic AED use. All identified studies were focused on seizure incidence in the post-operative period, ranging from 1 week to long-term follow up. Implications of these findings are reviewed herein.

Glioblastoma multiforme (GBM) is located most frequently in the cerebral hemispheres. Glioblastoma presenting as an extraaxial mass of cerebellopontine angle (CPA) is very rare in adults. We report a rare case of GBM arising in the CPA. The patient was a 71-year-old female, who complained of progressive gait disturbance and poor memory. Initial magnetic resonance imaging (MRI) revealed a 1.4×1.3 cm mass in the left CPA, with broad base to the petrous bone, showing homogenous enhancement. Follow-up MRI showed a rapid increase in size of mass (2.7×2.2 cm) with a necrotic portion. A stereotactic biopsy was done under the guidance of navigation system, and the histopathologic diagnosis was GBM, World Heath Organization grade IV. Further surgical resection was not performed considering her general condition, and the patient underwent concurrent chemotherapy with radiation therapy. Although rare, the possibility of glioblastoma should be included in the differential diagnosis of atypical CPA tumor.

Primary glioblastoma (GB) is the most aggressive type of brain tumors. While mutations in isocitrate dehydrogenase (IDH) genes are frequent in secondary GBs and correlate with a better prognosis, most primary GBs are IDH wild-type. Recent studies have shown that the long noncoding RNA metastasis associated lung adenocarcinoma transcript-1 (MALAT1) is associated with aggressive tumor phenotypes in different cancers. Our aim was to clarify the prognostic significance of MALAT1 in IDH1/2 wild-type primary GB tumors. We analyzed IDH1/2 mutation status in 75 patients with primary GB by DNA sequencing. The expression of MALAT1 was detected in the 75 primary GB tissues and 5 normal brain tissues using reverse transcription quantitative PCR (RT-qPCR). The associations between MALAT1 expression, IDH1/2 mutation status, and clinicopathological variables of patients were determined. IDH1 (R132H) mutation was observed in 5/75 primary GBs. IDH2 (R172H) mutation was not detected in any of our cases. MALAT1 expression was significantly upregulated in primary GB vs. normal brain tissues (p = 0.025). Increased MALAT1 expression in IDH1/2 wild-type primary GBs correlated with patient age and tumor localization (p = 0.032 and p = 0.025, respectively). A multivariate analysis showed that high MALAT1 expression was an unfavorable prognostic factor for overall survival (p = 0.034) in IDH1/2 wild-type primary GBs. High MALAT1 expression may have a prognostic role in primary GBs independent of IDH mutations.

Temozolomide (TMZ) has been the standard-of-care chemotherapy for glioblastoma (GBM) patients for more than a decade. Despite this long time in use, significant questions remain regarding how best to optimize TMZ therapy for individual patients. Understanding the relationship between TMZ response and factors such as number of adjuvant TMZ cycles, patient age, patient sex, and image-based tumor features, might help predict which GBM patients would benefit most from TMZ, particularly for those whose tumors are not MGMT methylated. Using a cohort of 90 newly-diagnosed GBM patients treated according to the Stupp protocol, we examined the relationships between several patient and tumor characteristics and volumetric and survival outcomes during adjuvant chemotherapy. Volumetric changes in MR imaging abnormalities during adjuvant therapy were used to assess TMZ response. T1Gd volumetric response is associated with younger patient age, increased number of TMZ cycles, longer time to nadir volume, and decreased tumor invasiveness. Moreover, increased adjuvant TMZ cycles corresponded with improved volumetric response only among more nodular tumors, and this volumetric response was associated with improved survival outcomes. Finally, in a subcohort of patients with known MGMT methylation status, MGMT methylated tumors were more diffusely invasive than unmethylated tumors, suggesting that the improved response in nodular tumors is not driven by a preponderance of MGMT methylated tumors. Our finding that less diffusely invasive tumors are associated with greater volumetric response to TMZ suggests that patients with these tumors may benefit from additional cycles of adjuvant TMZ, even for those without MGMT methylation.

OBJECTIVES: Gross total resection (GTR) for glioblastoma (GBM) is associated with a better prognosis. However, GTR is not always feasible and the threshold of the extent of resection for better prognosis is controversial. Therefore, we compared the survival and clinical outcomes of GBM between partial resection (PR) and biopsy. Methods Thirty-two and 78 patients who underwent PR and biopsy, respectively, were enrolled this study to identify differences in clinical outcomes. There were no differences in patient demographics between the PR and biopsy groups except for tumor location and mean tumor volume (p=0.02 and

Background Cadherin-11, a cell-to-cell adhesion molecule, is associated with higher tumor grade and decreased patient survival. The purpose of this study was to investigate the clinical significance of cadherin-11 expression in the progression and prognosis of a newly diagnosed primary glioblastoma (GBL). Methods Between 2007 and 2016, 52 out of 178 patients diagnosed with a GBL and satisfied the following criteria: 1) a new primary GBL, 2) gross-total resection, 3) immunohistochemically-available tissue, and 4) standardized adjuvant treatment. Results In terms of staining intensity, the low-intensity cadherin-11 group showed longer progression-free survival (PFS) than the high-intensity cadherin-11 group (median PFS, 12.0 months [95% CI, 11.1–12.9] vs. median PFS, 6.0 months [95% CI, 3.7–8.3]; p

INTRODUCTION Clinical trials have demonstrated that the use of low intensity alternating electric fields, known as Tumor Treating Fields (TTFields), via the Optune™ device extends overall survival times in patients with glioblastoma when combined with standard chemotherapy. In addition to survival time, quality of life (QOL) is an important factor in treatment decisions for life-limiting diagnoses. Examinations of the impact of TTFields on QOL have yielded mixed RESULTS: Here, we describe patient-reported symptoms in patients with glioblastoma undergoing treatment with TTFields and compare symptom burden and associated interference with daily life to that of a historic non-TTFields cohort. METHODS Patients with primary glioblastoma who chose treatment with the Optune™ device were prospectively enrolled and asked to complete the brain tumor-specific MD Anderson Symptom Inventory (MDASI-BT) approximately every 8 weeks through cessation of active disease treatment. MDASI-BT assessments were examined for symptom frequency, severity, and relationships between symptom severity and interference with daily life. These results were also compared with a matched cohort of patients who did not chose TTFields treatment and completed MDASI-BT assessments as part of a previous study. RESULTS The most commonly reported symptoms for Optune™ users were fatigue, sleep disturbance and speaking/word finding. Fatigue and sleep disturbance were also among the symptoms rated as most severe, along with feeling drowsy/sleepy. Interference with general activities and overall enjoyment of life as both were reported as both the most common and most severe impacts on daily life. When compared with historic data from non-Optune™ users at the same point in treatment, we found no difference in either symptom burden (p=0.48) or interference scores (p=0.72). CONCLUSION Attention to both survival benefit and symptom experience related to treatment options can inform patient decisions and direct approaches to symptom management as well as improved QOL.

Introduction: Clinical application of survival prediction of primary glioblastoma (pGBM) using preoperative images remains challenging due to a lack of robustness and standardization of the method. This research focused on validating a machine learning-based texture analysis model for this purpose using internal and external cohorts. Method: We included all cases of IDH wild-type pGBM available of preoperative MRI (T1WI, T2WI, and Gd-T1WI) from the databases of Kansai Molecular Diagnosis Network for CNS tumors (KN) and The Cancer Genome Atlas (TCGA). Of 242 cases from KN, we assigned 137 cases as a training dataset (D1), and the remaining 105 cases as an internal validation dataset (D2). Furthermore, we extracted 96 cases from TCGA as an external validation dataset (D3). Preoperative MRI scans were semi-quantitatively analyzed, leading to the acquisition of 489 texture features as explanatory variables. Dichotomous overall survival (OS) with a 16.6 months cutoff was regarded as the response variable (short/long OS). We employed Lasso regression for feature selection, and a survival prediction model constructed for D1 via cross-validation (M1) was applied to D2 and D3 to ensure the model robustness. Results: The population of predicted short OS by M1 significantly showed poorer prognosis in D2 (median OS 11.1 vs. 19.4 months; log-rank test, p=0.03), while there was no significant difference in D3 (median OS 14.2 vs. 11.9 months; p=0.61). In the comparative analysis using t-SNE, there was little variation in the feature distribution among three datasets. Conclusion: We were able to validate the prediction model in the internal but not in the external cohort. The presented result supports the use of machine learning-based texture analysis for survival prediction of pGBM in a localized population or country. However, further consideration is required to achieve a universal prediction model for pGBM, irrespective of regional difference.

Following publication of the original article [1], the authors reported an error in the author group.

BACKGROUND: Cancer cells reorganize their metabolic pathways to gain nutrients such as glucose and glutamine because of their anabolic needs. Anaerobic glycolysis increases the total glycolysis in hypoxic conditions and normal oxygen conditions, which is known as the “Warburg effect”. The α-Enolase (ENO1), a glycolytic enzyme, produces ATP, through converting 2-phosphoglycerat to phosphoenolpyruvate and contributes to the “Warburg effect”. In various tumors as breast cancer, pancreatic cancer and gastric cancer the expression of ENO1 is augmented. The aim of the study is to examine whether ENO1 is also higher expressed in gliomas and meningiomas. It was also of interest whether the therapy with temozolomide in gliomas changes the concentration of ENO1. MATERIAL AND METHODS: To determine the expression of ENO1 in meningiomas, qPCR and Western Blots were performed. All experiments were done in triplicates.ß-Actin and MRLP19 were used as reference genes. The meningioma samples were sorted in grad I, grade II, grade III. Non-tumorous brain tissue was used as control group. The protein level of ENO1 in glioma were measured through Western Blot. The glioma samples used were sorted in non-tumorous brain tissue, grade II, grade III, secondary and primary glioblastoma with and without temozolomide. All samples used for Western Blots were incubated with mouse monoclonal anti-ENO1 antibody. A secondary HPR-linked anti-mouse antibody was used to make the lanes visible. ß-Actin was used as a loading control antibody. RESULTS: The qPCR data showed a higher ENO1 expression in control samples than grade I meningioma (5.6 ± 2.403 vs. 2.907 ± 1.931, p= 0.002). In grade II and III the concentration was higher compared to grade I (4.994 ± 2.064 vs. 2.907 ± 1.931, p= 0.002; 4.98 ± 2.385 vs 2.907 ± 1.931vs, p= 0.01). The Western Blot data showed a higher ENO1 concentration in control samples than in meningioma tissues (control: 1.262 ± 0.256 vs. grade I: 1.037 ± 0.16, p=0.047; control vs. grade II: 0.961 ± 0.119, p= 0.012; control vs. grade III: 0.966 ± 0.1311, p= 0.015). Western Blots showed an upregulation of ENO1 in grade II gliomas compared to all groups (2.00 ± 0.66 vs. control: 1.00 ± 0.247, p=0.0031; vs. grade III: 1.173 ± 0.369, p= 0.010; vs. secondary GBM: 0.902 ± 0.199, p= 0.0006). Secondary GBM had lower ENO1 concentration than treated secondary GBM (0.902 ± 0.199 vs. 1.231 ± 0.199, p=0.021). An enhanced expression could be seen in treated secondary GBM compared to treated primary GBM (1.231 ± 0.199 vs. 0.902 ± 0.1336, p= 0.029). CONCLUSION: In meningiomas no difference was found between the different grades on the posttranslational level. However, ENO1 level was lowered in meningiomas compared to healthy tissue. Grade II gliomas showed higher ENO1 expression than high grade gliomas. This data suggests that ENO1 could play a role in brain tumors.

To discover novel biological targets in glioblastoma, genomic and immunological analysis were performed using The Cancer Genome Atlas (TCGA) data set. The RNA-seq data of 156 primary glioblastoma cases were subjected to CIBERSORT to detect tumor infiltrating cell fractions. Principal component analysis was performed on this data to detect factors that strongly contribute to the first principal component, and hierarchical clustering was performed. Survival curves were compared for each of the derived clusters. Finally, Gene Set Enrichment Analysis (GSEA) using HALLMARK Gene Set was performed. In the principal component analysis, we detected seven factors (NK cells resting, T cell regulatory, NK cells activated, Macrophage type 0, T cell gamma delta, Macrophage type 2, Macrophage type 1) which strongly contribute to the first principal component. Based on these seven factors, hierarchical cluster analysis resulted in T cell regulatory (Treg), Macrophage type 0 (M0), Macrophage type 2 (M2) and Macrophage type 1 (M1) clusters. There was no significant difference between these groups in CD8 T cell. M2 and M1 clusters displayed better OS with a significant difference. TNFA signaling via NFκB in Treg group, IFNα response, IFNγ response and ALLOGRAFT response in M2 group, G2M CHECKPOINT, GLYCOLYSIS, WNTβ catenin signaling, MITOTIC SPINDLE and TGFβ signaling in M1 group were upregulated. In conclusion, tumor microenvironment of glioblastoma can be divided into 4 immunological subtypes, Treg, M0, M1, and M2. Because of the contribution of innate immunity for shaping the tumor microenvironment of glioblastoma, immunotherapies targeting these innate immune cells are anticipated.

INTRODUCTION Neuroimaging dogma for glioblastoma asserts that hyperintensity on T1Gd MRI reveals the bulk of the tumor, while T2/FLAIR signal indicates edema. However, it is unclear whether this edema results from immune response or increased tumor cells. Further, one significant driver of the known sex differences in glioblastoma may be differences in immune response, due to the X-linkage of many immune genes. Based on this, we hypothesized that assumptions regarding tumor cellularity in T2/FLAIR images should be tailored to the biological sex of the patient. METHODS Using a retrospective cohort of 18 primary glioblastoma patients receiving multiple image-localized biopsies (82 total) and standard MRI, we assessed: distance of biopsy from T1Gd and T2 areas; a pathologist’s score of percent tumor cell density; and an imaging-based invasion metric, D/ρ. This metric is derived from the biomathematical Proliferation-Invasion model of glioma growth, which features two parameters, net growth rate (ρ) and net invasion rate (D). Their ratio D/ρ is related to degree of invasion, and is estimated from volumetric measurements of MRI abnormalities. Additionally, 25 patient-derived xenograft models implanted in females were grown until moribund, at which point brains were excised and stained for DAPI (to show all cells) and Lamin (to highlight tumor cells). Image processing of lamin-stained sections defines contours of intensity correlating with cell density. RESULTS Outside both the T1Gd and T2 region, male patient biopsies had higher tumor cell densities than females. Males also tended to have higher invasion metrics. Although each set derived from different patients, preclinical metrics of invasion were positively correlated with clinical invasion in females but negatively correlated in males. CONCLUSION Our preliminary finding that cell distribution patterns correlate with imaging metrics differently between the sexes supports the hypothesis that the degree of tumor cell density represented on certain MRI sequences may be sex-specific.

Background Gliomas are usually located in the supratentorial region and are extremely rare at the cerebellopontine angle (CPA). Consequently, gliomas in the CPA are easy to misdiagnose preoperatively. Case Description This paper presents a 55-year-old man with an extraaxial CPA glioblastoma arising from the proximal portion of cranial nerve (CN) VIII. Preoperative imaging findings suggested an acoustic neuroma. The tumor was removed subtotally, and it was completely separated from the brainstem and cerebellum. The histopathologic examination showed a glioblastoma. Conclusions To our knowledge, this case is the second report of a true primary extraaxial CPA glioblastoma. Therefore glioma should be considered in the differential diagnosis of CPA masses with atypical imaging features, although they are extremely rare.

Glioblastoma multiforme is the most common primary malignant brain tumor in adults. In addition to poor response to treatment, a high recurrence rate contributes to the poor prognosis. The purpose of this study was to investigate the genetical and clinical characteristics of recurrent glioblastoma. We used whole transcriptome sequencing data to examine the distribution of molecular subtypes and gene signatures in 22 recurrent glioblastoma taken from the Chinese population, and further analyzed biological progression of the tumors, when compared with primary glioblastoma. The proportion of the classical subtype in recurrent ones (22%) was lower than that in primary glioblastoma (36%). The frequency of IDH1 mutations in recurrent glioblastomas was nearly twice that in primary glioblastomas. TP53 mutations were fewer in proneural recurrent glioblastomas (20%) but frequent in classical recurrent glioblastomas (80%). The most common sites of recurrent glioblastomas were the temporal lobe (41%). In patients diagnosed with recurrent glioblastoma multiforme, 64% were younger than 50 years. Gene set enrichment analysis revealed that chromatin fracture, repair, and remodeling genes were enriched in recurrent glioblastoma. Our results highlight the differences in clinical features, molecular subtypes and gene alterations between primary and recurrent glioblastoma and may be helpful for targeted therapy for recurrent glioblastoma.

Metabolism in tumor cells depends mainly on glycolysis and thus hyperglycemia has been shown to influence tumor properties in various tumor entities. In this retrospective study we set out to determine if hyperglycemic serum levels during radiation therapy impact patient survival and progression patterns in primary glioblastoma (GBM).We retrospectively analyzed glucose serum levels, survival and progression patterns on magnetic resonance imaging (MRI) in 262 GBM patients receiving radiation therapy. Hyperglycemia was classified as mild (180 mg/dL) or excessive (≥ 300 mg/dL), and isolated (one hyperglycemic event) or persistent (≥ 3 hyperglycemic events). The multivariate Cox proportional hazards ratio was used to assess the influence of cofactors on survival.Persistent mild (HR = 2.23; p0.001) and excessive hyperglycemia (HR = 2.51; p0.001) were associated with a decrease in overall survival rates, even when considering the covariate corticosteroid therapy. Here metabolic imbalances did not affect the progression-free interval (p = 0.402), the occurrence of distant (p = 0.587) and multifocal progression (p = 0.445).Our findings support the theory that hyperglycemia during radiation therapy in GBM patients is an unfavorable prognostic cofactor for survival and is detrimental to the survival rates independent of corticosteroid therapy. However, no significant effects of hyperglycemic metabolism on the progression-free interval and recurrence patterns were found.

Background The Neurologic Assessment in Neuro-Oncology (NANO) scale is a standardized objective metric designed to measure neurological function in neuro-oncology. Current neuroradiological evaluation guidelines fail to use specific clinical criteria for progression. Objective To determine if the NANO scale was a reliable assessment tool in glioblastoma (GBM) patients and whether it correlated to survival. Methods Our group performed a retrospective review of all patients with newly diagnosed GBM from January 1, 2010, through December 31, 2012, at our institution. We applied the NANO scale, Karnofsky performance score (KPS), Eastern Cooperative Oncology Group (ECOG) scale, Macdonald criteria, and the Response Assessment in Neuro-Oncology (RANO) criteria to patients at the time of diagnosis as well as at 3, 6, and 12 mo. Results Initial NANO score was correlated with overall survival at time of presentation. NANO progression was correlated with decreased survival in patients at 6 and 12 mo. A decrease in KPS was associated with survival at 3 and 6 mo, an increase in ECOG score was associated only at 3 mo, and radiological evaluation (RANO and Macdonald) was correlated at 3 and 6 mo. Only the NANO scale was associated with patient survival at 1 yr. NANO progression was the only metric that was linked to decreased overall survival when compared to RANO and Macdonald at 6 and 12 mo. Conclusion The NANO scale is specific to neuro-oncology and can be used to assess patients with glioma. This retrospective analysis demonstrates the usefulness of the NANO scale in glioblastoma.

Background Typical recurrence of glioblastoma occurs locally, usually within 2 cm from the original lesion. With improvement of surgical techniques, more aggressive surgical strategies have become feasible, resulting in a significantly increased rate of complete resection. We investigated whether these improvements are also reflected by tumor recurrence pattern. Methods Inclusion criteria were first diagnosis of glioblastoma with standard adjuvant radiochemotherapy and histologically proven tumor recurrence. Patients were divided according to recurrence pattern: local recurrence, distant recurrence, or both recurrence patterns. Data were correlated with extent of resection, molecular tumor configuration, clinical status, and survival data. Results This single-center retrospective study included 97 patients with glioblastoma treated between 2007 and 2014. Local, distant, and combined tumor recurrence patterns were observed in 77 (79.3%), 10 (10.3%), and 10 patients (10.3%). Median progression-free survival of all patients was 8 months; median overall survival was 20 months. Median progression-free survival was 7 months for patients with local recurrence, 13 months for patients with distant recurrence, and 9 months for patients with both recurrence patterns (P = 0.646). Median overall survival in the 3 groups was 21 months, 20 months, and 14 months (P = 0.098). No correlation between methylguanine–deoxyribonucleic acid methyltransferase methylation status and recurrence pattern was observed. Conclusions Despite complete resection of contrast-enhancing tumor, most recurrences occurred locally. Patients with distant tumor recurrence demonstrated increased progression-free survival. Therefore, to gain local control, we may need to shift toward a more aggressive supramarginal resection, using extensive intraoperative monitoring to avoid permanent deficits.

BACKGROUND AND PURPOSE: The heterogeneity of glioblastoma contributes to the poor and variant prognosis. The aim of this retrospective study was to assess the glioblastoma heterogeneity with MR imaging textures and to evaluate its impact on survival time. MATERIALS AND METHODS: A total of 133 patients with primary glioblastoma who underwent postcontrast T1-weighted imaging (acquired before treatment) and whose data were filed with the survival times were selected from the Cancer Genome Atlas. On the basis of overall survival, the patients were divided into 2 groups: long-term (≥12 months, n = 67) and short-term (