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Purpose: In the phase 2 REGOMA trial, regorafenib improved overall survival, as compared with lomustine, in glioblastoma (GBM) patients at first progression after chemoradiation. Recently, some real-life trials showed similar impact on survival but a higher rate of adverse events than in REGOMA, thus raising concerns over tolerability. The aim of this study was to assess the efficacy and tolerability of a lower intensity regorafenib regimen., Patients and Methods: Regorafenib daily dose was gradually increased from 80 to 160 mg across the first 2 cycles. Progression-free survival (PFS) and overall survival (OS) were defined as time from regorafenib initiation and disease progression or death., Results: Sixty-six GBM patients were included. Median age was 60.0 years. Median PFS and OS following regorafenib were 2.7 and 7.1 months, respectively. Best RANO response to regorafenib were partial response (PR) in 10 (15.1%), stable disease in 17 (25.8%), and progressive disease in 39 (59.1%) patients. Forty-six (69.7%) patients presented adverse events of any grade, and 21 (31.8%) grade 3-4 toxicity. In a multivariable analysis, higher age and absence of MGMTp methylation were significantly associated with poorer disease control after regorafenib., Conclusions: Our study is the largest observational real-life study on the use of regorafenib. Our lower intensity regimen proved as effective as the standard 160 mg daily schedule (mPFS and mOS being 2.7 vs 2.0 months and 7.1 vs 7.4 months in our study vs REGOMA, respectively). Moreover, we observed a higher rate of PRs as compared with REGOMA (15.0% vs 3.0%)., (© 2022. The Author(s), under exclusive licence to Springer Science+Business Media, LLC, part of Springer Nature.)

The G105G SNP (rs11554137) in the IDH1 gene is observed in about 10-15% of patients with a diffuse glioma. Data regarding its impact on gliomas are poor and partially conflicting, possibly due to the evolving classification of CNS tumors. The aim of this study was to investigate the G105G SNP prognostic significance in a homogenous cohort of IDH-wildtype glioblastomas, in agreement with the 2021 WHO classification. The study analyzed 211 patients by collecting several clinico-pathological and molecular characteristics, including the age, lesion localization, number of involved lobes, type of surgical treatment, disease outcome and MGMT promoter methylation status. PFS and DSS curves were plotted according to the Kaplan-Meier method and statistical analyses were performed using parametric and non-parametric tests. A total of 32 patients out of 211 (15.2%) were found to be G105G SNP carriers. No significant impact of the IDH1 G105G SNP on patients' outcomes was observed in terms of PFS and DSS, while MGMT promoter methylation and gross total resection resulted as key prognostic factors in our cohort as expected. No prognostic impact of the IDH1 G105G SNP was detected in this strict cohort of IDH-wildtype glioblastomas. Analysis of larger cohorts is warranted to address the sample size limitations.

Glioblastoma (GBM) is a fatal tumor whose aggressiveness, heterogeneity, poor blood-brain barrier penetration, and resistance to therapy highlight the need for new targets and clinical treatments. A step toward clinical translation includes the eradication of GBM tumor-initiating cells (TICs), responsible for GBM heterogeneity and relapse. By using patient-derived TICs and xenograft orthotopic models, we demonstrated that the selective lysine-specific histone demethylase 1 inhibitor DDP_38003 (LSD1i) is able to penetrate the brain parenchyma in vivo in preclinical models, is well tolerated, and exerts antitumor activity in molecularly different GBMs. LSD1 genetic targeting further strengthens the role of LSD1 in GBM TIC maintenance. GBM TIC plasticity supports their adaptation and survival under a plethora of environmental stresses, including nutrient deficiency and proteostasis perturbation. By mimicking these stresses in vitro, we found that LSD1 inhibition hampers the induction of the activating transcription factor 4 (ATF4), the master regulator of the integrated stress response (ISR). The resulting aberrant ISR sensitizes GBM TICs to stress-induced cell death, hampering tumor aggressiveness. Functionally, LSD1i interferes with LSD1 scaffolding function and prevents its interaction with CREBBP, a critical ATF4 activator. By disrupting the interaction between CREBBP and LSD1-ATF4 axis, LSD1 inhibition prevents GBM TICs from overcoming stress and sustaining GBM progression. The effectiveness of the LSD1 inhibition in preclinical models shown here places a strong rationale toward its clinical translation for GBM treatment.

Neuron glial antigen 2 (NG2) is a chondroitin sulphate proteoglycan 4 (CSPG4) that occurs in developing and adult central nervous systems (CNSs) as a marker of oligodendrocyte precursor cells (OPCs) together with platelet-derived growth factor receptor α (PDGFRα). It behaves variably in different pathological conditions, and is possibly involved in the origin and progression of human gliomas. In the latter, NG2/CSPG4 induces cell proliferation and migration, is highly expressed in pericytes, and plays a role in neoangiogenesis. NG2/CSPG4 expression has been demonstrated in oligodendrogliomas, astrocytomas, and glioblastomas (GB), and it correlates with malignancy. In rat tumors transplacentally induced by N -ethyl- N -nitrosourea (ENU), NG2/CSPG4 expression correlates with PDGFRα, Olig2, Sox10, and Nkx2.2, and with new vessel formation. In this review, we attempt to summarize the normal and pathogenic functions of NG2/CSPG4, as well as its potential as a therapeutic target.

Angiogenesis is one of the hallmarks of cancer, including brain tumors. Malignant gliomas have the highest degree of vascular proliferation among solid tumors; thus, angiogenic pathways represent an attractive target to interfere with tumor growth. Up to date VEGF pathway targeting with specific drugs has yielded interesting therapeutics results. In particular bevacizumab, a monoclonal antibody against VEGF-A, has shown clinical activity in malignant gliomas, especially glioblastomas, in terms of a high response rate on MRI and a significant increase in progression-free survival.

The optimal combination of bevacizumab with cytotoxic or cytostatic drugs in recurrent glioblastoma is unknown. We performed a phase 2 trial of combined bevacizumab and fotemustine for patients with glioblastoma at first relapse after radiotherapy and temozolomide. The primary endpoint was 6-month progression-free survival (PFS), while secondary endpoints were overall survival (OS), response rate based on RANO criteria and toxicity. Fifty-four patients with recurrent GBM were enrolled. The authors observed a 6-month PFS rate of 42.6% (95% CI 29.3-55.2) and a median PFS of 5.2 months (95% CI 3.8-6.6). The median OS was 9.1 months (95% CI 7.3-10.3). Twenty-eight patients (52%) had a radiographic response, and a significant neurological improvement with steroid reduction was observed in 25/42 symptomatic patients (60%). MGMT promoter methylation was significantly associated with improved PFS in univariate analysis. Most unifocal tumors at baseline had a focal enhancing progression (76%), while the diffuse non-enhancing progression accounted for 9.5%. Response or survival were not associated with any pattern of progression. Survival after failure of treatment was short. Twelve out of 54 patients (22%) discontinued fotemustine for grade 3/4 myelotoxicity, while 4/54 (7.4%) discontinued bevacizumab. This study failed to demonstrate a superiority of the combination of bevacizumab and fotemustine over either bevacizumab or fotemustine alone as historical controls. Future studies should explore alternative regimens of combination of the two drugs.

Introduction. Elderly glioblastoma (GBM) patients often show limited response to treatment and poor outcome. Here, we provide a case series of elderly GBM patients from our Institution, in whom we assessed the clinical characteristics, feasibility of surgical resection, response to adjuvant treatments, and outcome, along with the impact of comorbidities and clinical status on survival. Patients and Methods. We included patients ≥ 65-year-old. We collected information about clinical and molecular features, extent of resection, adjuvant treatments, treatment-related complications, and outcome. Results. We included 135 patients. Median age was 71 years. In total, 127 patients (94.0%) had a Karnofsky Performance Status (KPS) ≥70 and 61/135 (45.2%) a Charlson Comorbidity Score (CCI) > 3. MGMTp methylation was found in 70/135 (51.9%). Subtotal resections (STRs), gross-total resections (GTRs), and biopsies were 102 (75.6%), 10 (7.4%) and 23 (17.0%), respectively. Median progression-free survival and overall survival (mOS) were 8.0 and 10.5 months for the whole cohort. Notably, GTR and radio-chemotherapy with temozolomide in patients with MGMTp methylation were associated with significantly longer mOS (32.8 and 44.8 months, respectively). In a multivariable analysis, risk of death was affected by STR vs. GTR (HR 2.8, p = 0.002), MGMTp methylation (HR 0.55, p = 0.007), and KPS at baseline ≥70 (HR 0.43, p = 0.031). Conversely, CCI and post-surgical complications were not significant. Conclusions. Elderly GBM patients often have a dismal prognosis. However, it is possible to identify a subgroup with favourable clinical and molecular features, who benefit from GTR and radio-chemotherapy with temozolomide. A comprehensive prognostic score is needed to guide treatment modality and predict the outcome. [ABSTRACT FROM AUTHOR]

Glioblastoma (GBM) is the most aggressive primary brain tumour. As GBM incidence is associated with age, elderly people represent a consistent subgroup of patients. Elderly people with GBM show dismal prognosis (about 6 months) and limited response to treatments. Age is a negative prognostic factor, which correlates with clinical frailty, poorer tolerability to surgery or adjuvant radio-chemotherapy, and higher occurrence of comorbidities and/or secondary complications. The aim of this paper is to review the clinical and molecular characteristics, current therapeutic options, and prognostic factors of elderly patients with GBM. [ABSTRACT FROM AUTHOR]

Suppressor of Lin‐12‐like (C. elegans) (SEL1L) participates in the endoplasmic reticulum‐associated protein degradation pathway, malignant transformation and stem cell biology. We explored the role of SEL1L in 110 adult gliomas, of different molecular subtype and grade, in relation to cell proliferation, stemness, glioma‐associated microglia/macrophages (GAMs), prognostic markers and clinical outcome. SEL1L protein expression was assessed by immunohistochemistry and Western blotting. Genetic and epigenetic alterations were detected by molecular genetics techniques. SEL1L was overexpressed in anaplastic gliomas (World Health Organization [WHO] grade III) and in glioblastoma (GB, WHO grade IV) with the highest labelling index (LI) in the latter. Immunoreactivity was significantly associated with histological grade (p = 0.002) and cell proliferation index Ki‐67/MIB‐1 (p = 0.0001). In GB, SEL1L co‐localised with stemness markers Nestin and Sox2. Endothelial cells and vascular pericytes of proliferative tumour blood vessels expressed SEL1L suggesting a role in tumour neo‐vasculature. GAMs consistently expressed SEL1L. SEL1L overexpression was significantly associated with TERT promoter mutations (p = 0.0001), EGFR gene amplification (p = 0.0013), LOH on 10q (p = 0.0012) but was mutually exclusive with IDH1/2 mutations (p = 0.0001). SEL1L immunoreactivity correlated with tumour progression and cell proliferation, conditioning poor patient survival and response to therapy. This study emphasises SEL1L as a potential biomarker for the most common subgroup of TERT mutant/EGFR amplified/IDH‐WT GBs. [ABSTRACT FROM AUTHOR]

Background: Despite the aggressiveness of multimodal treatment, glioblastoma (GBM) is still a challenge for neurosurgeons, neurooncologists, and radiotherapists. A surgical approach is still a cornerstone in GBM therapeutic management, as the extent of resection is strongly related both to overall survival and progression-free survival. From this perspective, the use of photodynamic molecules could represent an interesting tool to achieve maximal and safe resection. Being able to trace the lesion's edges, indeed, could allow to improve the extent of resection and to minimize residual tumor while sparing normal tissue. The use of 5-aminolevulinic acid (5-ALA) as a photodynamic tracer is well established due to its strict correlation both with cellularity and metabolic activity of the GBM cell clones. Objective: Our study aims to define whether a different molecular asset of GBM (especially investigating IDH 1/2 mutation, proliferation index, and MGMT promoter methylation) results in different fluorescence expression, possibly because of differences in metabolic pathways due to different genotypes. Methods: Patients undergoing surgery for GBM removal at our Institute (Dep. Of Neurosurgery, Ospedale Città della Salute e della Scienza, University of Turin, Italy) were retrospectively reviewed. Patients with histological diagnosis confirmation and to whom 5-ALA was given before surgery were included. The whole surgical procedure was recorded and then analyzed by three different people (a medical student, a resident, and a senior surgeon with an interest in neurooncology and experience in using 5-ALA) and a score was assigned to the different degrees of intraoperative fluorescence. The degree of fluorescence was then matched with the genotype. Results: A trend of grade 2 fluorescence (i.e., "strong") was observed in the IDH 1/2 wild-type (WT) genotype, suggesting a more intense metabolic activity in this particular subgroup, while, no or weak fluorescence was observed more often in the IDH 1/2 mutated tumors, suggesting a lower metabolic activity. No relations were found between fluorescence grade and MGMT promoter methylation or, interestingly, cellularity. As a secondary analysis, more epileptogenicity of the IDH 1/2 mutated GBM was noticed, similarly to other recent literature. Conclusion: Our results do not support the use of 5-ALA as a diagnostic tool, or a way to substitute the molecular profiling, but confirm 5-ALA as a powerful metabolic tracer, able to easily detect the pathological cells, especially in the IDH WT genotype, and in this perspective, further studies will be necessary to better describe the metabolic activity of GBM cells. [ABSTRACT FROM AUTHOR]