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Glioblastoma is a malignant brain tumor with mean overall survival of less than 15 months. Blood vessel leakage and peritumoral edema lead to increased intracranial pressure and augment neurological deficits which profoundly decrease the quality of life of glioblastoma patients. It is unknown how the dynamics of cerebrospinal fluid (CSF) turnover are affected during this process. By monitoring the transport of CSF tracers to the systemic blood circulation after infusion into the cisterna magna, we demonstrate that the outflow of CSF is dramatically reduced in glioma-bearing mice. Using a combination of magnetic resonance imaging (MRI) and near-infrared (NIR) imaging, we found that the circulation of CSF tracers was hindered after cisterna magna injection with reduced signals along the exiting cranial nerves and downstream lymph nodes, which represent the major CSF outflow route in mice. Due to blockage of the normal routes of CSF bulk flow within and from the cranial cavity, CSF tracers were redirected into the spinal space. In some mice, impaired CSF clearance from the cranium was compensated by a lymphatic outflow from the sacral spine.

Abstract BACKGROUND Ventricular entry during glioblastoma resection and tumor contact with the subventricular zone (SVZ) have both been shown to associate with development of hydrocephalus, leptomeningeal dissemination, distant parenchymal recurrence, and decreased survival. However, prior studies did not analyze these variables together in a single-patient population; therefore, it is unknown which is an independent predictor of these outcomes. OBJECTIVE To conduct a comparative outcome analysis of surgical ventricular entry and SVZ contact by glioblastoma in a retrospective cohort of 232 patients. METHODS Outcomes studied included hydrocephalus, leptomeningeal dissemination, distant tumor recurrences, and progression-free (PFS) and overall (OS) survival. The Cox proportional regression analyses were adjusted for age at diagnosis, preoperative Karnofsky performance status score, extent of resection, temozolomide and radiation treatments, and tumor molecular status (specifically, IDH1/2 mutation and MGMT promoter methylation). RESULTS Surgical ventricular entry, SVZ-contacting glioblastoma, hydrocephalus, leptomeningeal dissemination, and distant recurrences were observed in 85 (36.6%), 114 (49.1%), 19 (8.2%), 78 (33.6%), and 59 (25.4%) patients, respectively. Multivariate, adjusted analysis revealed SVZ tumor contact—but not ventricular entry—associated with hydrocephalus (hazard ratio, HR, 4.20 [1.13-15.7], P = .03), leptomeningeal dissemination (HR 1.93 [1.14-3.28], P = .01), PFS (HR 2.10 [1.53-2.88], P < .001), and OS (HR 1.90 [1.35-2.67], P < .001). Distant recurrences were not associated with either. No interaction between the 2 variables was statistically noted. CONCLUSION SVZ contact by glioblastoma was independently associated with the development of hydrocephalus, leptomeningeal dissemination, and decreased survival. SVZ tumor contact was associated with ventricular entry during surgical resections, which did not independently correlate with these outcomes.

Despite some evidence of a possible link between epileptogenesis and tumorigenesis in glioblastoma, the prognostic value of epilepsy at presentation has been debated over the years. We performed a systematic review and meta-analysis to summarize all published data evaluating the prognostic significance of seizures as a presenting manifestation of glioblastoma. A comprehensive search of five databases from inception to December 2023 was conducted. Included studies underwent meta-analysis, with subgroup analyses performed to identify sources of heterogeneity. Fifteen studies were included in the analysis. Seizures were considered a favorable prognostic factor in seven studies, while eight studies found no differences in overall survival between patients with seizures and those with other presenting symptoms. Eleven studies were included in the meta-analysis. The overall pooled analysis indicated a potentially favorable prognostic impact of seizures at the clinical onset of glioblastoma (HR 0.73; 95% CI 0.61–0.87). However, subgroup analysis within studies focusing on IDH-wild type cases showed no discernible impact from preoperative seizures. Retrospective design, poor quality in reporting results, and heterogeneity in tumor characteristics and therapies are the main limitations of included studies. Future prospective studies on large, homogeneous cohorts of patients with IDH-wild type glioblastoma are warranted. Overall, these findings suggest that while seizures may hold some prognostic value, further research is essential to clarify their role. Understanding the true prognostic role of seizures at clinical onset may enhance our ability to predict patient outcomes and guide clinical decision-making.

Background The 2021 classification of central nervous system tumors significantly alters the defined category of glioblastoma (GBM). This study aims to evaluate the clinical relevance of glioma-related epilepsy (GRE) in patients with the newly classified GBM, IDH-wildtype. Methods A single-center retrospective cohort study was performed. The correlation of GRE with clinicopathological features was explored via appropriate inter-group statistical methods. Kaplan-Meier analysis was employed to assess the prognostic value of preoperative GRE with respect to overall survival (OS) and progression-free survival (PFS). Multivariate binary logistic regression analysis was carried out to identify potential risk factors associated with inadequate seizure control. Results The final cohort included 294 patients. Preoperative GRE was observed in 22.4% of newly diagnosed and 19.7% of recurrent GBM cases. In patients with newly diagnosed GBM, GRE was significantly associated with younger age ( p  < 0.001). Moreover, survival analysis confirmed the prognostic significance of preoperative GRE for improved OS and PFS ( p  = 0.012 and 0.004, respectively) in the same population. Moreover, in newly diagnosed GBM cases, preoperative GRE was identified as the independent risk factor for inadequate postoperative seizure control (OR 4.009, 95% CI 1.447–11.106, p  = 0.008). Conclusion The current study comprehensively describes the clinical correlations of GRE in GBM, IDH-wildtype. The incidence of preoperative GRE in GBM patients is approximately 20%. Among patients with newly diagnosed GBM, IDH-wildtype, preoperative GRE is more likely to occur in younger individuals and is associated with prolonged survival outcomes. Furthermore, a history of preoperative GRE may increase the risk of inadequate postoperative seizure control in this population.

The relationship between type 2 diabetes mellitus (DM2) and hyperglycemia with cancer patients remains controversial also in the setting of patients with glioblastoma multiforme (GBM), the most common and aggressive form of astrocytoma with a short overall survival (OS) and poor prognosis. A systematic search of two databases was performed for studies published up to 19 August 2020, reporting the OS of patients with DM2 or high blood sugar level and GBM and the clinical risk of diabetic patients for development of GBM. According to PRISMA guidelines, we included a total of 20 papers reporting clinical data of patients with GBM and diabetes and/or hyperglycemia. The aim of this review was to investigate the effect of DM2, hyperglycemia and metformin on OS of patients with GBM. In addition, we evaluated the effect of these factors on the risk of development of GBM. This review supports accumulating evidence that hyperglycemia, rather than DM2, and elevated BMI are independent risk factors for poor outcome and shorter OS in patients with GBM. GBM patients with normal weight compared to obese, and diabetic patients on metformin compared to other therapies, seems to have a longer OS. Further studies are needed to understand better these associations.

Purpose Sonodynamic therapy, which combines a tumor cell-selective sonosensitizer with ultrasound, is gaining attention as a promising new treatment approach for glioblastoma. The objective of this case study is to report on the first applications of 5-aminolevulinic acid (5-ALA) in combination with low-intensity, non-targeted ultrasound as neo-adjuvant treatment in therapy naïve glioblastoma. Methods Three patients with therapy naïve newly diagnosed glioblastoma were treated once before cytoreductive surgery with 5-ALA in combination with hemispheric, low-intensity, non-targeted ultrasound, assuming cell death to be triggered by non-ablative activation of 5-ALA-induced, tumor selective porphyrins. Results No adverse effects were noted. Post-procedural MRI indicated a decrease in apparent diffusion coefficient values in tumors, suggesting cytotoxic effects. Relative cerebral blood volumes and leakage were increased for two patients with available perfusion imaging. Tissue obtained during surgery suggested increased cleaved-caspase III expression, a marker of apoptosis. Conclusion We saw an immediate marked imaging response indicating cytotoxic edema and indications of a histopathology response from just a single treatment. Correlation to clinical outcomes and extension of overall survival remains to be seen. A Phase 1 safety study has been submitted for regulatory approval.

Purpose This is a phase-I study of gefitinib in combination with temozolomide in patients with gliomas. The goal of the study was to define the maximum tolerated dose (MTD) and to characterize the pharmacokinetics of gefitinib when combined with temozolomide. Patients and methods Patients were stratified according to co-administration of enzyme-inducing anti-epileptic drugs (EIAEDs). There were 26 evaluable patients enrolled (16 on EIAEDs, 10 not on EIAEDs). All but seven patients had Glioblastoma Multiforme (GBM), and only six cases had a Karnosfsky Performance Status (KPS) of less than 80; median age was 51 years. All had received prior radiotherapy and 14 patients had no prior chemotherapy. The starting dose of temozolomide was 150 mg/m 2 /day for 5 days every 28 days and could be escalated to a maximum dose of 200 mg/m 2 /day in subsequent cycles. The starting dose of gefitinib was 500 mg/day given by mouth on a continuous basis. Dose-limiting toxicity was assessed in cycle one only. Results For patients on EIAEDs, the MTD of gefitinib was 1,000 mg/day in combination with temozolomide. Dose-limiting toxicity (DLT) was due to diarrhea, nausea and vomiting. For patients not on EIAEDs, the MTD was 250 mg/day in combination with temozolomide. The DLT was due to increases in liver transaminases. Rash was not a significant toxicity at these dose levels. The peak concentration and AUC 0-24hr at the 500 mg dose level was 1.8 and 2.5-fold lower, respectively, in the EIAED group compared to the non-EIAED group; trough levels of gefitinib increased in both groups consistent with the reported terminal half-life ranging from 27 to 51 h. Conclusion The recommended phase-2 dose of gefitinib when used in combination with temozolomide is 1,000 and 250 mg/day, respectively, for patients on or not on EIAEDs.

The Karnofsky Performance Scale (KPS) score is a widespread metric to stratify patient prognosis and determine appropriate management in glioblastoma multiforme(GBM). Low preoperative KPS values have been associated with shorter overall survival (OS). However, surgical resection can have a dramatic effect on a patient’s functional status which subsequently alters their KPS score. To determine the predictive value of preoperative verses postoperative KPS scores in terms of OS in patients with GBM. We conducted a retrospective review of 163 patients who underwent initial surgical intervention for pathologically proven GBM at our institution between 2003 and 2013. Pre and postoperative performance status, demographic, operative, and treatment variables were recorded for each patient. Multivariate regression analysis identified predictors of prolonged OS. The adequacy index was calculated to compare the predictive value of preoperative and postoperative KPS score. Median preoperative and postoperative KPS scores were 70 and 80, respectively. Overall, 92 (57 %) patients experienced an improvement in their KPS score, 40 (25 %) remained stable, and 29 (18 %) declined. Higher postoperative KPS ( P  = 0.0001), radiation therapy ( P  < 0.0001), younger age ( P  = 0.0443) and the absence of diabetes ( P  = 0.0006) were each independently associated with increased OS in a multivariate regression model. Postoperative KPS score has superior predictive value compared to pre-operative KPS score ( A  = 0.758 vs. 1.002). Postoperative KPS scores have superior predictive capabilities in terms of OS in GBM and should replace preoperative KPS scores when estimating prognosis in this population.

The progression of glioblastomas is associated with a variety of neurological impairments, such as tumor-related epileptic seizures. Seizures are not only a common comorbidity of glioblastoma but often an initial clinical symptom of this cancer entity. Both, glioblastoma and tumor-associated epilepsy are closely linked to one another through several pathophysiological mechanisms, with the neurotransmitter glutamate playing a key role. Glutamate interacts with its ionotropic and metabotropic receptors to promote both tumor progression and excitotoxicity. In this review, based on its physiological functions, our current understanding of glutamate receptors and glutamatergic signaling will be discussed in detail. Furthermore, preclinical models to study glutamatergic interactions between glioma cells and the tumor-surrounding microenvironment will be presented. Finally, current studies addressing glutamate receptors in glioma and tumor-related epilepsy will be highlighted and future approaches to interfere with the glutamatergic network are discussed.

Purpose/objective(s) Treatment related lymphopenia is a known toxicity for glioblastoma (GBM) patients and several single-institution studies have linked lymphopenia with poor survival outcomes. We performed a systematic review and pooled analysis to evaluate the association between lymphopenia and overall survival (OS) for GBM patients undergoing chemotherapy and radiation therapy (RT). Materials/methods Following PRISMA guidelines, a systematic literature review of the MEDLINE database and abstracts from ASTRO, ASCO, and SNO annual meetings was conducted. A pooled analysis was performed using inverse variance-weighted random effects to generate a pooled estimate of the hazard ratio of association between lymphopenia and OS. Results Ten of 104 identified studies met inclusion criteria, representing 1,718 patients. The lymphopenia cutoff value varied (400–1100 cells/uL) and as well as the timing of its onset. Studies were grouped as time-point (i.e., lymphopenia at approximately 2-months post-RT) or time-range (any lymphopenia occurrence from treatment-start to approximately 2-months post-RT. The mean overall pooled incidence of lymphopenia for all studies was 31.8%, and 11.8% vs. 39.9% for time-point vs. time-range studies, respectively. Lymphopenia was associated with increased risk of death, with a pooled HR of 1.78 (95% CI 1.46–2.17, P < 0.00001) for the time-point studies, and a pooled HR of 1.38 (95% CI 1.24–1.55, P < 0.00001) for the time-point studies. There was no significant heterogeneity between studies. Conclusion These results strengthen observations from previous individual single-institution studies and better defines the magnitude of the association between lymphopenia with OS in GBM patients, highlighting lymphopenia as a poor prognostic factor.