Glioblastoma multiforme (GBM) is a primary brain tumor known for its short survival time, typically 14-18 months from diagnosis to fatality. Managing GBM poses significant challenges due to factors like the formidable blood-brain barrier, the immunosuppressive conditions within GBM, and the intricacies of surgical procedures. Currently, the typical treatment for GBM combines surgical procedures, radiation therapy, and chemotherapy using temozolomide. Unfortunately, this conventional approach has not proven effective in substantially extending the lives of GBM patients. Consequently, researchers are exploring alternative methods for GBM management. One promising avenue receiving attention in recent years is immunotherapy. This approach has successfully treated cancer types like non-small cell lung cancer and blood-related malignancies. Various immunotherapeutic strategies are currently under investigation for GBM treatment, including checkpoint inhibitors, vaccines, chimeric antigen receptor (CAR) T-cell therapy, and oncolytic viruses. A comprehensive review of 26 high-quality studies conducted over the past decade, involving thorough searches of databases such as PubMed and Google Scholar, has been conducted. The findings from this review suggest that while immunotherapeutic strategies show promise, they face significant limitations and challenges in practical application for GBM treatment. The study emphasizes the importance of combining diverse approaches, customizing treatments for individual patients, and ongoing research efforts to improve GBM patients\' outlook.

With the advancement in medicine leading to the discovery of anti-vascular endothelial growth factor drugs, numerous oncologists are now commonly using antiangiogenic medications to improve outcomes and attain disease control. Thus, the significance of prognostic and predictive indicators in patient selection has become increasingly imperative. These biomarkers have the capacity to be highly effective and can easily be implemented in various diagnostic and therapeutic settings on a large scale. Overall, it has the potential of significantly decreasing mortality in a fatal disease and possibly achieving partial or complete remission. Many clinical trials have shown the efficacy of bevacizumab in treating malignancies. However, there are currently no known predictive or prognostic biomarkers for bevacizumab in glioblastoma multiforme (GBM). Several clinical studies have evaluated bevacizumab-induced hypertension as a potential marker in patients with different malignancies, including recurrent glioblastoma multiforme (rGBM). This systematic review was performed to determine the association of bevacizumab-induced hypertension with outcomes in patients with advanced brain cancer and to assess whether hypertension (HTN) can be used as a prognostic factor. The review was conducted according to Preferred Reporting Items for Systematic Review and Meta-Analysis (PRISMA) guidelines, and the databases were searched from January 2012 to June 2022. This review aimed to evaluate six published studies to investigate the relationship between hypertension and the outcomes of patients with rGBM treated with bevacizumab. Among the included publications, four out of six were retrospective and featured a positive result regarding hypertension being used as an independent predictive factor of survival outcomes in rGBM. However, two studies showed negative results. This can be attributed to the limited subsets of patients and the duration of the studies. In conclusion, bevacizumab-induced hypertension may represent a prognostic factor in patients with rGBM.

Glioblastoma multiforme (GBM) patients continue to suffer a poor prognosis. The blood brain barrier (BBB) comprises one of the obstacles for therapy, creating a barrier that decreases the bioavailability of chemotherapeutic agents in the central nervous system. Previously, a vascularized temporoparietal fascial scalp flap (TPFF) lining the resection cavity was introduced in a trial conducted in our institution, in newly-diagnosed GBM patients in an attempt to bypass the BBB after initial resection. In this paper, we report on a new technique to bypass the BBB after re-resection and potentially to allow tumor antigens to be surveilled by the immune system. The study aims to assess the feasibility of performing a cranial transposition and revascularization of autologous omentum after re-resection of GBM. Laparoscopically harvested omental free flap was transposed to the resection cavity by a team consisting of neurosurgeons, otolaryngologists, and general surgeons. This was done as part of a single center, single arm, open-label, phase I study. Autologous abdominal omental tissue was harvested laparoscopically on its vascularized pedicle in 2 patients, transposed as a free flap, revascularized using external carotid artery, and carefully laid into the tumor resection cavity. Patients did well postoperatively returning to baseline activities. Graft viability was confirmed by cerebral angiogram. Omental cranial transposition of a laparoscopically harvested, vascularized flap, into the cavity of re-resected GBM patients is feasible and safe in the short term. Further studies are needed to ascertain whether such technique can improve progression free survival and overall survival in these patients.

[This corrects the article DOI: 10.3389/fonc.2021.636632.].

Glioblastoma multiforme (GBM) is the most common brain malignancy and major cause of high mortality in patients with GBM, and its high recurrence rate is its most prominent feature. However, the pathobiological mechanisms involved in recurrent GBM remain largely unknown. Here, whole-transcriptome sequencing (RNA-sequencing, RNA-Seq) was used in characterizing the expression profile of recurrent GBM, and the aim was to identify crucial biomarkers that contribute to GBM relapse. Differentially expressed RNAs in three recurrent GBM tissues compared with three primary GBM tissues were identified through RNA-Seq. The function and mechanism of a candidate long noncoding RNA (lncRNA) in the progression and recurrence of GBM were elucidated by performing comprehensive bioinformatics analyses, such as functional enrichment analysis, protein-protein interaction prediction, and lncRNA-miRNA-mRNA regulatory network construction, and a series of in vitro assays. As the most significantly upregulated gene identified in recurrent GBM, HSPA1A is mainly related to antigen presentation and the MAPK signaling pathway, as indicated by functional enrichment analysis. HSPA1A was predicted as the target gene of the lncRNA NONHSAT079852.2. qRT-PCR revealed that NONHSAT079852.2 was significantly elevated in recurrent GBM relative to that in primary GBM, and high NONHSAT079852.2 expression was associated with the poor overall survival rates of patients with GBM. The knockdown of NONHSAT079852.2 successfully induced tumor cell apoptosis, inhibited the proliferation, migration, invasion and the expression level of HSPA1A in glioma cells. NONHSAT079852.2 was identified to be a sponge for hsa-miR-10401-3p through luciferase reporter assay. Moreover, HSPA1A was targeted and regulated by hsa-miR-10401-3p. Collectively, the results suggested that NONHSAT079852.2 acts as a sponge of hsa-mir-10401-3p and thereby enhances HSPA1A expression, promotes tumor cell proliferation and invasion, and leads to the progression and recurrence of GBM. This study will provide new insight into the regulatory mechanisms of NONHSAT079852.2-mediated competing endogenous RNA in the pathogenesis of recurrent GBM and evidence of the potential of lncRNAs as diagnostic biomarkers or potential therapeutic targets.

BACKGROUND: Elderly patients constitute an expanding part of our society. Due to a continuously increasing life expectancy, an optimal quality of life is expected even into advanced age. Glioblastoma (GBM) is more common in older patients, but they are still often withheld from efficient treatment due to worry of worse tolerance and have a significantly worse prognosis compared to younger patients. Our retrospective observational study aimed to investigate the therapeutic benefit from a second resection in recurrent glioblastoma of elderly patients.
METHODS: We included a cohort of 39 elderly patients (> 65 years) with a second resection as treatment option in the case of a tumor recurrence. A causal inference model was built by multiple non- and semiparametric models, which was used to identify matched patients from our elderly GBM database which comprises 538 patients. The matched cohorts were analyzed by a Cox-regression model adjusted by time-dependent covariates.
RESULTS: The Cox-regression analysis showed a significant survival benefit (Hazard Ratio: 0.6, 95% CI 0.36-0.9, p-value = 0.0427) for the re-resected group (18.0 months, 95% CI 13.97-23.2 months) compared to the group without re-resection (10.1 months, 95% CI 8.09-20.9 months). No differences in the co-morbidities or hemato-oncological side effects during chemotherapy could be detected. Anesthetic- and surgical complications were rare and comparable to the complication rate of patients undergoing the first-line resection.
CONCLUSIONS: Taken together, in elderly patients, re-resection is an acceptable treatment option in the recurrent state of a glioblastoma. The individual evaluation of the patients\' medical status as well as the chances of withstanding general anesthesia needs to be done in close interdisciplinary consultation. If these requirements are met, elderly patients benefit from a re-resection.

Glioblastoma multiforme (GBM) universally recurs with dismal prognosis. We evaluated the efficacy of standard treatment strategies for patients with recurrent GBM (rGBM). From two centers in the Netherlands, 299 patients with rGBM after first-line treatment, diagnosed between 2005 and 2014, were retrospectively evaluated. Four different treatment strategies were defined: systemic treatment (SYST), re-irradiation (RT), re-resection followed by adjuvant treatment (SURG) and best supportive care (BSC). Median OS for all patients was 6.5 months, and median PFS (excluding patients receiving BSC) was 5.5 months. Older age, multifocal lesions and steroid use were significantly associated with a shorter survival. After correction for confounders, patients receiving SYST (34.8%) and SURG (18.7%) had a significantly longer survival than patients receiving BSC (39.5%), 7.3 and 11.0 versus 3.1 months, respectively [HR 0.46 (p < 0.001) and 0.36 (p < 0.001)]. Median survival for patients receiving RT (7.0%) was 9.2 months, but this was not significantly different from patients receiving BSC (p = 0.068). Patients receiving SURG compared to SYST had a longer PFS (9.0 vs. 4.3 months, respectively; p < 0.001), but no difference in OS was observed. After adjustments for confounders, patients with rGBM selected for treatment with SURG or SYST do survive significantly longer than patients who are selected for BSC based on clinical parameters. The value of reoperation versus systemic treatment strategies needs further investigation.

The role of surgical resection in progressive or recurrent glioblastoma multiforme (GBM) lack of high level of evidence. The aim of this evaluation was to assess the role of surgical resection in relapsing GBM, in relation to the extent of surgical resection (EOR) and the amount of residual tumor volume (RTV). Among patients treated for newly diagnosed GBM between September 2008-December 2014, 64 patients with recurrent GBM were included in this retrospective evaluation. All patients underwent surgical resection followed by adjuvant treatments, chemotherapy and/or radiotherapy Results were evaluated in terms of local control (LC) rate, progression free survival (PFS) and patients overall survival (OS). Gross total resection (GTR) (>90%) was achieved in 48 (75%) patients and subtotal resection (STR) in 16 (25%). RTV was 0 in 40 (62.5%) patients and >0 in 24 (37.5%). No severe postoperative morbidity occurred. The median LC time was 6.0 ± 0.1 months (95% CI 5.29-8.55), with a 1 and 2 years LC rate of 29.4 ± 6.9%. The median PFS time was 6.8 ± 0.8 months, with a 1 year PFS rate of 27.2 ± 7.2% (95% CI 14.2-41.9). The median OS time was 10.3 ± 0.5 months (95% CI 7.6-10.4) with a 1 and 2 years OS rate of 22.5 ± 6.7% (95% CI 10.9-36.6). On univariate analysis EOR and RTV were recorded as conditioning LC and survival. These data was confirmed also in multivariate analysis only for RTV (p < 0.01). Recurrent GBM can take advantage of repeated surgery in selected patients with younger age and good clinical status. The entity of surgical resection was confirmed as conditioning survival.

Optimal treatment of recurrent glioblastoma multiforme (rGBM) in elderly and/or frail patients remains virtually unexplored, the best supportive care (BSC) only is routinely administered due to the fatal prognosis. We evaluated the impact of different treatment methods on post-progression survival (PPS) and overall survival (OS) of such patients. Data from 98 elderly and/or frail rGBM patients, treated initially with 1-week or 3-week radiotherapy (RT) within the phase III IAEA study (2010-2013), were analyzed. KPS at relapse and salvage treatment methods were recorded. Kaplan-Meier method was used to estimate PPS and OS for different treatment modalities. Eighty-four patients experienced recurrence: 47 (56%) received BSC, 21 (25%)-chemotherapy (CHT), 8 (9.5%)-surgery, 3 (3.5%)-RT, for 5 (6%) the data was unavailable. Median OS from randomization for all 84 patients was 35 weeks: 55 versus 30 weeks for any treatment versus BSC, p < 0.0001. Median PPS was 15 weeks: 23 weeks with any treatment versus 9 weeks with BSC, p < 0.0001. For local treatment (surgery and/or RT) median PPS was 51 versus 21 weeks for CHT, p = 0.36. In patients with poor KPS (≤60) at relapse median PPS was 9 weeks with BSC versus 21 weeks with any treatment, p = 0.014. In poor KPS patients median PPS for local treatment was 14 weeks versus 21 weeks with CHT, p = 0.88. An active therapeutic approach may be beneficial for selected elderly and/or frail rGBM patients. Poor KPS patients may also benefit from active treatment, but there is no benefit of local treatment over CHT.

Malignant gliomas continue to have a dismal prognosis despite all available treatments and advances made in understanding molecular mechanisms and signaling pathways. Conventional treatments, such as surgery, chemotherapy and radiation, have been used with limited success. Bevacizumab is a recently described molecule, which inhibits endothelial proliferation and prevents formation of new blood vessels in tumor. However, this treatment confers increased hemorrhage risk and impairs wound healing. Therefore, the timing of surgery for patients receiving bevacizumab, who are in need of surgery, is critical. We performed a literature review to establish the appropriate timing between the cessation of bevacizumab therapy and surgical intervention. Our literature review indicated that the optimum time between cessation of bevacizumab therapy and surgery was 4 weeks. The timing for re-initiation of bevacizumab post-surgery was at least 2 weeks. The duration of preoperative cessation of bevacizumab treatment is critical in preventing life threatening surgical complications. The interval between the surgery and re-initiation of bevacizumab can be shortened. However, more studies are needed to ascertain the exact timing of preoperative and postoperative therapy.