Functional brain imaging interventions for radiation therapy planning in patients with glioblastoma: a systematic review.

RATIONALE: This systematic review aims to synthesise the outcomes of different strategies of incorporating functional biological markers in the radiation therapy plans of patients with glioblastoma to support clinicians and further research. METHODS: The systematic review protocol was registered on PROSPERO (CRD42021221021). A structured search for publications was performed following PRISMA guidelines. Quality assessment was performed using the Newcastle-Ottawa Scale. Study characteristics, intervention methodology and outcomes were extracted using Covidence. Data analysis focused on radiation therapy target volumes, toxicity, dose distributions, recurrence and survival mapped to functional image-guided radiotherapy interventions. RESULTS: There were 5733 citations screened, with 53 citations (n = 32 studies) meeting review criteria. Studies compared standard radiation therapy planning volumes with functional image-derived volumes (n = 20 studies), treated radiation therapy volumes with recurrences (n = 15 studies), the impact on current standard target delineations (n = 9 studies), treated functional volumes and survival (n = 8 studies), functionally guided dose escalation (n = 8 studies), radiomics (n = 4 studies) and optimal organ at risk sparing (n = 3 studies). The approaches to target outlining and dose escalation were heterogeneous. The analysis indicated an improvement in median overall survival of over two months compared with a historical control group. Simultaneous-integrated-boost dose escalation of 72-76 Gy in 30 fractions appeared to have an acceptable toxicity profile when delivered with inverse planning to a volume smaller than 100 cm[Formula: see text]. CONCLUSION: There was significant heterogeneity between the approaches taken by different study groups when implementing functional image-guided radiotherapy. It is recommended that functional imaging data be incorporated into the gross tumour volume with appropriate technology-specific margins used to create the clinical target volume when designing radiation therapy plans for patients with glioblastoma.

Recognition of Differentially Expressed Molecular Signatures and Pathways Associated with COVID-19 Poor Prognosis in Glioblastoma Patients.

Glioblastoma (GBM) is a type of brain cancer that is typically very aggressive and difficult to treat. Glioblastoma cases have been reported to have increased during COVID-19. The mechanisms underlying this comorbidity, including genomic interactions, tumor differentiation, immune responses, and host defense, are not completely explained. Therefore, we intended to investigate the differentially expressed shared genes and therapeutic agents which are significant for these conditions by using in silico approaches. Gene expression datasets of GSE68848, GSE169158, and GSE4290 studies were collected and analyzed to identify the DEGs between the diseased and the control samples. Then, the ontology of the genes and the metabolic pathway enrichment analysis were carried out for the classified samples based on expression values. Protein-protein interactions (PPI) map were performed by STRING and fine-tuned by Cytoscape to screen the enriched gene module. In addition, the connectivity map was used for the prediction of potential drugs. As a result, 154 overexpressed and 234 under-expressed genes were identified as common DEGs. These genes were found to be significantly enriched in the pathways involved in viral diseases, NOD-like receptor signaling pathway, the cGMP-PKG signaling pathway, growth hormone synthesis, secretion, and action, the immune system, interferon signaling, and the neuronal system. STAT1, CXCL10, and SAMDL were screened out as the top 03 out of the top 10 most critical genes among the DEGs from the PPI network. AZD-8055, methotrexate, and ruxolitinib were predicted to be the possible agents for the treatment. The current study identified significant key genes, common metabolic signaling networks, and therapeutic agents to improve our perception of the common mechanisms of GBM-COVID-19.

Moderately hypofractionated versus conventionally fractionated radiation therapy with temozolomide for young and fit patients with glioblastoma: an institutional experience and meta-analysis of literature.

PURPOSE: Shorter hypofractionated radiation therapy (HF-RT) schedules may have radiobiological, patient convenience and healthcare resource advantages over conventionally fractionated radiation therapy (CF-RT) in glioblastoma (GBM). We report outcomes of young, fit GBM patients treated with HF-RT and CF-RT during the COVID-19 pandemic, and a meta-analysis of HF-RT literature in this patient subgroup. METHODS: Hospital records of patients with IDH-wildtype GBM treated with HF-RT (50 Gy/20 fractions) and CF-RT (60 Gy/30 fractions) between January 2020 and September 2021 were reviewed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariable analysis was performed using Cox regression analysis. A systematic search and meta-analysis of studies from January 2000 to January 2022 was performed. RESULTS: 41 patients were treated (HF-RT:15, CF-RT:26). For both HF-RT and CF-RT groups, median age was 58 years and 80-90% were ECOG 0-1. There were more methylated tumours in the HF-RT group. All patients received concurrent/adjuvant temozolomide. At 19.2 months median follow-up, median OS was 19.8 months and not-reached for HF-RT and CF-RT (p = 0.5), and median PFS was 7.7 and 5.8 months, respectively (p = 0.8). HF-RT or CF-RT did not influence OS/PFS on univariable analysis. Grade 3 radionecrosis rate was 6.7% and 7.7%, respectively. 15 of 1135 studies screened from a systematic search were eligible for meta-analysis. For studies involving temozolomide, pooled median OS and PFS with HF-RT were 17.5 and 9.9 months (927 and 862 patients). Studies using shortened HF-RT schedules reported 0-2% Grade 3 radionecrosis rates. CONCLUSION: HF-RT may offer equivalent outcomes and reduce treatment burden compared to CF-RT in young, fit GBM patients.

SARS-CoV-2 Permissive glioblastoma cell line for high throughput antiviral screening.

Despite the great success of the administered vaccines against SARS-CoV-2, the virus can still spread, as evidenced by the current circulation of the highly contagious Omicron variant. This emphasizes the additional need to develop effective antiviral countermeasures. In the context of early preclinical studies for antiviral assessment, robust cellular infection systems are required to screen drug libraries. In this study, we reported the implementation of a human glioblastoma cell line, stably expressing ACE2, in a SARS-CoV-2 cytopathic effect (CPE) reduction assay. These glioblastoma cells, designated as U87.ACE2+, expressed ACE2 and cathepsin B abundantly, but had low cellular levels of TMPRSS2 and cathepsin L. The U87.ACE2+ cells fused highly efficiently and quickly with SARS-CoV-2 spike expressing cells. Furthermore, upon infection with SARS-CoV-2 wild-type virus, the U87.ACE2+ cells displayed rapidly a clear CPE that resulted in complete cell lysis and destruction of the cell monolayer. By means of several readouts we showed that the U87.ACE2+ cells actively replicate SARS-CoV-2. Interestingly, the U87.ACE2+ cells could be successfully implemented in an MTS-based colorimetric CPE reduction assay, providing IC50 values for Remdesivir and Nirmatrelvir in the (low) nanomolar range. Lastly, the U87.ACE2+ cells were consistently permissive to all tested SARS-CoV-2 variants of concern, including the current Omicron variant. Thus, ACE2 expressing glioblastoma cells are highly permissive to SARS-CoV-2 with productive viral replication and with the induction of a strong CPE that can be utilized in high-throughput screening platforms.

Expressions and significances of CTSL, the target of COVID-19 on GBM.

INTRODUCTION: Cathepsin L (CTSL) is a kind of the SARS-entry-associated CoV-2's proteases, which plays a key role in the virus's entry into the cell and subsequent infection. We investigated the association between the expression level of CTSL and overall survival in Glioblastoma multiforme (GBM) patients, to better understand the possible route and risks of new coronavirus infection for patients with GBM. METHODS: The expression level of CTSL in GBM was analyzed using TCGA and CGGA databases. The relationship between CTSL and immune infiltration levels was analyzed by means of the TIMER database. The impact of CTSL inhibitors on GBM biological activity was tested. RESULTS: The findings revealed that GBM tissues had higher CTSL expression levels than that of normal brain tissues, which was associated with a significantly lower survival rate in GBM patients. Meanwhile, the expression level of CTSL negatively correlated with purity, B cell and CD8+ T cell in GBM. CTSL inhibitor significantly reduced growth and induced mitochondrial apoptosis. CONCLUSION: According to the findings, CTSL acts as an independent prognostic factor and can be considered as promising therapeutic target for GBM.

A New Perspective on Cancer Therapy: Changing the Treaded Path?

During the last decade, we have persistently addressed the question, "how can the innate immune system be used as a therapeutic tool to eliminate cancer?" A cancerous tumor harbors innate immune cells such as macrophages, which are held in the tumor-promoting M2 state by tumor-cell-released cytokines. We have discovered that these tumor-associated macrophages (TAM) are repolarized into the nitric oxide (NO)-generating tumoricidal M1 state by the dietary agent curcumin (CC), which also causes recruitment of activated natural killer (NK) cells and cytotoxic T (Tc) cells into the tumor, thereby eliminating cancer cells as well as cancer stem cells. Indications are that this process may be NO-dependent. Intriguingly, the maximum blood concentration of CC in mice never exceeds nanomolar levels. Thus, our results submit that even low, transient levels of curcumin in vivo are enough to cause repolarization of the TAM and recruitment NK cells as well as Tc cells to eliminate the tumor. We have observed this phenomenon in two cancer models, glioblastoma and cervical cancer. Therefore, this approach may yield a general strategy to fight cancer. Our mechanistic studies have so far implicated induction of STAT-1 in this M2→M1 switch, but further studies are needed to understand the involvement of other factors such as the lipid metabolites resolvins in the CC-evoked anticancer pathways.