Sertoli cells, lining the walls of the seminiferous tubules, are in close contact with and regulate all aspects of the development of the germ cells. Clusterin, is a glycoprotein produced abundantly by Sertoli cells, and associated with either apoptosis or cell survival. Zinc is present in high concentrations in the testis and required for sperm development by an as yet unknown mechanism. Permeation of zinc into cells via voltage-gated calcium channels (VGCCs), however, is suggested to induce cell death. We examined the possibility that Zn(2+) acts via clusterin to regulate germ cell survival. Employing an ex vivo model of mouse testis, we have assessed the role of permeation of heavy metal ions on clusterin production and secretion. Up-regulation of clusterin expression and its secretion was observed after a short exposure to zinc or to cadmium under depolarizing conditions. Expression of zinc transporter-1 (ZnT-1), previously shown to regulate Zn(2+) influx, increased following prolonged application of zinc or cadmium to the explants and prevented clusterin up-regulation by subsequent exposure to these ions. Inhibition of the MAPK and PI3K pathways reduced the up-regulation of clusterin following the intracellular rise of Zn(2+) or Cd(2+). Neutralization of secreted clusterin by an antibody or attenuation of clusterin up-regulation by inhibition of Zn(2+) permeation via the LTCC, reduced cell death in cultured seminiferous tubule cells. Taken together, our results indicate that Zn(2+) and Cd(2+) influx induce expression and secretion of clusterin, thereby linking metal homeostasis and germ cell fate.

Glioblastoma multiforme (GBM) is known for its dismal prognosis, though its dependence on patients' readily available RBCs parameters is not fully established. In this work, 170 GBM patients, diagnosed and treated in Soroka University Medical Center (SUMC) over the last 12 years were retrospectively inspected for their survival dependency on pre-operative RBCs parameters. Besides KPS and tumor resection supplemented by oncological treatment, age under 70 (HR = 0.4, 95% CI 0.24-0.65, p = 0.00073), low hemoglobin level (HR = 1.79, 95% CI 1.06-2.99, p = 0.031), and Red Cell Distribution Width (RDW) <14% (HR = 0.57, 95% CI 0.37-0.88, p = 0.018) were found to be prognostic of patients' overall survival in multivariate analysis, accounting for a false discovery rate of < 5% due to multiple hypothesis testing. According to these results, a stratification tree was made, from which a favorable route highlighted a subgroup of nearly 30% of the cohorts' patients whose median overall survival was 21.1 months (95% CI 16.2-27.2)-higher than the established chemo-radiation standard first-line treatment regimen overall median survival average of about 15 months. The beneficial or detrimental effect of RBCs parameters on GBM prognosis and its possible causes is discussed. Keywords: glioblastoma multiforme (GBM), hemoglobin, RDW (red cell distribution width), prognostic factors, overall survival KEY POINTS-GBM resection followed by oncological treatment of patients under the age of 70 with normal hemoglobin level and RDW < 14% enhance patients' survival.-Measures aimed to normalize hemoglobin levels and RDW prior to surgical intervention may be useful in order to improve GBM patients' prognosis.

<b><i>Background:</i></b> Recent studies have shown that the peripheral blood pretreatment neutrophil/lymphocyte ratio (NLR) is a prognostic measure in various cancers. The few studies evaluating NLR in glioblastoma multiforme (GBM) patients yielded inconsistent results. <b><i>Objectives:</i></b> The primary objective of our study was to test the ability of pretreatment NLR to predict the overall survival (OS) and progression-free survival (PFS) of patients with GBM treated by combined modality therapy (surgery, radiation, and temozolomide chemotherapy). A secondary objective was to evaluate the toxicity of the combined modality protocol in a consecutive series of patients treated in our center, in the context of a real-world universal health-care setting. <b><i>Methods:</i></b> We analyzed 89 patients with GBM in a retrospective cohort analysis who were treated in Soroka University Medical Center’s Oncology Department between the years 2005–2016. We analyzed NLR as a dichotomous variable at 3 cut-off points, 2.5, 3 and 4, as a predictor of OS and PFS. Methylation status of the O⁶-methylguanine-DNA methyltransferase (MGMT) promoter was not determined. <b><i>Results:</i></b> No significant correlation was found between NLR and either OS or PFS. Factors that predicted a shorter OS were age and extent of surgery. Patients over 70 years of age had a statistically significant shorter OS, 12.5 months (95% CI: 10.4–14.5 months) versus 17.6 months (95% CI: 14.2–21.1 months) in those 70 years of age and younger (<i>p</i> = 0.004). The OS of patients undergoing partial resection (12.7 months 95% CI: 8.3–17.1 months) or biopsy only (9.3 months 95% CI: 7.8–24.6 months), was significantly shorter than that of patients undergoing total resection (18.9 months, 95% CI: 11.8–26.0 months; <i>p</i> = 0.035). There were no treatment-related deaths. The most common grade III–IV toxicities were thrombocytopenia, 12.4%, and fatigue, 13.5%. <b><i>Conclusions:</i></b> In our cohort of GBM patients treated with combined modality therapy, pretreatment NLR was not prognostic. Toxicity of treatment was acceptable. Investigation of the NLR with larger groups of patients selected by MGMT status is warranted.

Background Tumor-Treating Fields (TTFields) is an emerging treatment modality for glioblastoma (GBM). Studies have shown a good safety profile alongside improved efficacy in newly diagnosed GBM (ndGBM), while a less clear effect was shown for recurrent GBM (rGBM). Despite regulatory support, sectors of the neuro-oncology community have been reluctant to accept it as part of the standard treatment protocol. To establish an objective understanding of TTFields' mechanism of action, safety, efficacy, and economical implications, we conducted a systematic literature review and meta-analysis. Methods A systematic search was conducted in PubMed, Scopus, and Cochrane databases. Twenty studies met the pre-defined inclusion criteria, incorporating 1,636 patients (542 ndGBM and 1,094 rGBM), and 11,558 patients (6,403 ndGBM and 5,155 rGBM) analyzed for the clinical outcomes and safety endpoints, respectively. Results This study demonstrated improved clinical efficacy and a good safety profile of TTFields. For ndGBM, pooled median OS and PFS were 21.7 (95%CI=19.6-23.8) and 7.2 (95%CI=6.1-8.2) months, respectively. For rGBM, pooled median OS and PFS were 10.3 (95%CI=8.3-12.8) and 5.7 (95%CI=2.8-10) months, respectively. Compliance of ≥75% was associated with an improved OS and the predominant adverse events were dermatologic, with a pooled prevalence of 38.4% (95%CI=32.3-44.9). Preclinical studies demonstrated TTFields' diverse molecular mechanism of action, its potential synergistic efficacy, and suggest possible benefits for certain populations. Conclusions This study supports the use of TTFields for GBM, alongside the standard-of-care treatment protocol and provides a practical summary, discussing the current clinical and pre-clinical aspects of the treatment and their implication on the disease course.

BACKGROUND Upfront laser interstitial thermal therapy (LITT) can be used as part of the treatment paradigm in difficult-to-access newly diagnosed glioblastoma multiforme (ndGBM) cases. The extent of ablation, though, is not routinely quantified; thus, its specific effect on patients' oncological outcomes is unclear. OBJECTIVE To methodically measure the extent of ablation in the cohort of patients with ndGBM and its effect, and other treatment-related parameters, on patients' progression-free survival (PFS) and overall survival (OS). METHODS A retrospective study was conducted on 56 isocitrate dehydrogenase 1/2 wild-type patients with ndGBM treated with upfront LITT between 2011 and 2021. Patient data including demographics, oncological course, and LITT-associated parameters were analyzed. RESULTS Patient median age was 62.3 years (31-84), and the median follow-up duration was 11.4 months. As expected, the subgroup of patients receiving full chemoradiation was found to have the most beneficial PFS and OS (n = 34). Further analysis showed that 10 of them underwent near-total ablation and had a significantly improved PFS (10.3 months) and OS (22.7 months). Notably, 84% excess ablation was detected which was not related to a higher rate of neurological deficits. Tumor volume was also found to influence PFS and OS, but it was not possible to further corroborate this finding because of low numbers. CONCLUSION This study presents data analysis of the largest series of ndGBM treated with upfront LITT. Near-total ablation was shown to significantly benefit patients' PFS and OS. Importantly, it was shown to be safe, even in cases of excess ablation and therefore could be considered when using this modality to treat ndGBM.