Nodular Melanoma in a 53-year-old Male with Glioblastoma Multiforme: A Rare Case Report.

Although melanoma only accounts for 1% of skin cancers, it is responsible for most skin cancer deaths. Glioblastoma multiforme, a high-grade astrocytoma, is the most aggressive and devastating primary brain tumor. These two diseases remain to be the biggest therapeutic challenge in both specialties of dermatology and neuro-oncology. A 53-year-old Filipino male who presented with a 2-year history of generalized dark brown and black patches on the body developed weakness and numbness of the left extremities. Biopsy and immunohistochemical staining of the skin revealed nodular melanoma with adjacent regressing melanoma. Biopsy of the intracranial mass showed glioblastoma multiforme. One month after the partial excision of the intracranial mass, the patient expired due to brain herniation. Nodular melanoma and glioblastoma multiforme may occur concomitantly in a patient. A review of the literature suggests a shared genetic predisposition. Its existence carries a poor prognosis and requires early detection to start aggressive treatment.

Exploring the potentials of S4, a selective androgen receptor modulator, in glioblastoma multiforme therapy.

Glioblastoma multiforme (GBM) ranks among the prevalent neoplastic diseases globally, presenting challenges in therapeutic management. Traditional modalities have yielded suboptimal response rates due to its intrinsic pathological resistance. This underscores the imperative for identifying novel molecular targets to enhance therapeutic efficacy. Literature indicates a notable correlation between androgen receptor (AR) signaling and GBM pathogenesis. To mitigate the adverse effects associated with androgenic modulation of AR, scientists have pivoted towards the synthesis of non-steroidal anabolic agents, selective androgen receptor modulators (SARMs). Among these, S4, used as a supplement by the bodybuilders to efficiently grow muscle mass with favourable oral bioavailability has emerged as a candidate of interest. This investigation substantiates the anti-oncogenic potential of S4 in temozolomide-responsive and -resistant GBM cells through cellular and molecular evaluations. We observed restriction in GBM cell growth, and motility, coupled with an induction of apoptosis, reactive oxygen species (ROS) generation, and cellular senescence. S4 exposure precipitated the upregulation of genes associated with apoptosis, cell-cycle arrest, DNA damage response, and senescence, while concurrently downregulating those involved in cellular proliferation. Future research endeavours are warranted to delineate the mechanisms underpinning S4's actions, assess its antineoplastic effects in-vivo, and its ability to penetrate the blood-brain barrier.

MicroRNA-143 overexpression enhances the chemosensitivity of A172 glioblastoma cells to carmustine.

As an aggressive malignancy, glioblastoma multiforme (GBM) is the most common type of brain tumor. The existing treatments have shown limited achievement in increasing the overall survival of patients. Therefore, identifying the key molecules involved in GBM will provide new potential therapeutic targets. Carmustine is an alkylating agent used as a supplementary therapeutic option for GBM. However, the extensive use of carmustine has been limited by uncertainty about its efficacy. MicroRNAs (miRNAs) are essential in post-transcriptional gene regulation. Many aberrantly expressed miRNAs have been detected in various types of human cancer, including GBM. In this study, we evaluated the potential therapeutic effect of miR-143 in combination with carmustine on GBM cells. A172 cells were transfected with miR-143 mimics and then treated with carmustine. To assess the cell viability, apoptosis induction, and cell cycle progression, the MTT assay, Annexin V/PI apoptosis assay, and flow cytometry were used, respectively. Furthermore, qRT-PCR assay was applied to evaluate the expression level of genes related to apoptosis. The obtained results evidenced that miR-143 transfection could promote the sensitivity of A172 cells to carmustine and enhance carmustine-induced apoptosis via modulating the expression levels of Caspase-3, Caspase-9, Bax, and Bcl-2. Also, our results revealed that combination therapy could effectively diminish cell cycle progression in A172 cells. In conclusion, these results confirmed that miR-143 could enhance carmustine-mediated suppression of cell proliferation and improve the chemosensitivity of A172 cells to this chemotherapeutic agent. Therefore, miR-143 combination therapy may be a promising GBM treatment approach.

Metal-Doping Strategy for Carbon-Based Sonosensitizer in Sonodynamic Therapy of Glioblastoma.

Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor and known for its challenging prognosis. Sonodynamic therapy (SDT) is an innovative therapeutic approach that shows promise in tumor elimination by activating sonosensitizers with low-intensity ultrasound. In this study, a novel sonosensitizer is synthesized using Cu-doped carbon dots (Cu-CDs) for the sonodynamic treatment of GBM. Doping with copper transforms the carbon dots into a p-n type semiconductor having a bandgap of 1.58 eV, a prolonged lifespan of 10.7 µs, and an improved electron- and hole-separation efficiency. The sonodynamic effect is efficiency enhanced. Western blot analysis reveals that the Cu-CDs induces a biological response leading to cell death, termed as cuproptosis. Specifically, Cu-CDs upregulate dihydrosulfanyl transacetylase expression, thereby establishing a synergistic therapeutic effect against tumor cell death when combined with SDT. Furthermore, Cu-CDs exhibit excellent permeability through the blood-brain barrier and potent anti-tumor activity. Importantly, the Cu-CDs effectively impede the growth of glioblastoma tumors and prolong the survival of mice bearing these tumors. This study provides support for the application of carbon-based nanomaterials as sonosensitizers in tumor therapy.

Role of Non-coding RNAs in the Response of Glioblastoma to Temozolomide.

Chemotherapy and radiotherapy are widely used in clinical practice across the globe as cancer treatments. Intrinsic or acquired chemoresistance poses a significant problem for medical practitioners and researchers, causing tumor recurrence and metastasis. The most dangerous kind of malignant brain tumor is called glioblastoma multiforme (GBM) that often recurs following surgery. The most often used medication for treating GBM is temozolomide chemotherapy; however, most patients eventually become resistant. Researchers are studying preclinical models that accurately reflect human disease and can be used to speed up drug development to overcome chemoresistance in GBM. Non-coding RNAs (ncRNAs) have been shown to be substantial in regulating tumor development and facilitating treatment resistance in several cancers, such as GBM. In this work, we mentioned the mechanisms of how different ncRNAs (microRNAs, long non-coding RNAs, circular RNAs) can regulate temozolomide chemosensitivity in GBM. We also address the role of these ncRNAs encapsulated inside secreted exosomes.

Prognostic Role of Platelet-to-Lymphocyte and Neutrophil-to-Lymphocyte Ratios in Patients Irradiated for Glioblastoma Multiforme.

Background/Aim: Previous studies suggested pre-operative platelet-to-lymphocyte ratio (PLR) and neutrophil-to-lymphocyte ratio (NLR) to be predictive factors in patients with glioblastoma multiforme (GBM). This study investigated the prognostic role of PLR and NLR prior to or at the beginning of radiotherapy. Patients and Methods: In 80 patients with GBM receiving conventionally fractionated radiotherapy plus concurrent temozolomide following resection or biopsy, 12 factors including PLR and NLR were retrospectively evaluated regarding progression-free survival (PFS) and overall survival (OS). Results: On multivariable analyses, PLR ≤150, Karnofsky performance score (KPS) 90-100, and O6-methylguanine-DNA methyltransferase promoter methylation were significantly associated with improved PFS. Single lesion, KPS 90-100, and adjuvant chemotherapy were significantly associated with OS; PLR ≤150 showed a trend. NLR ≤3 showed a trend for associations with PFS and OS on univariable analyses. Conclusion: PLR prior to or at the beginning of radiotherapy was associated with treatment outcomes in patients irradiated for GBM and should be considered in future clinical trials.

CENPA facilitates glioma stem cell stemness and suppress ferroptosis to accelerate glioblastoma multiforme progression by promoting GBP2 transcription.

The function of glioma stem cells (GSCs) is closely related to the progression of glioblastoma multiforme (GBM). Centromere protein A (CENPA) has been confirmed to be related to the poor prognosis of GBM patients. However, whether CENPA regulates GSCs function to mediate GBM progression is still unclear. GSCs were isolated from GBM cells. The expression of CENPA and guanylate-binding protein 2 (GBP2) was examined by quantitative real-time PCR and western blot. GSCs proliferation and stemness were assessed using EdU assay and sphere formation assay. Cell ferroptosis was evaluated by detecting related factors. The interaction between CENPA and GBP2 was analyzed by ChIP assay and dual-luciferase reporter assay. Animal experiments were conducted to measure the effect of CENPA knockdown on the tumorigenicity of GSCs in vivo. CENPA was upregulated in GBM tissues and GSCs. CENPA knockdown inhibited GSCs proliferation, stemnness, and promoted ferroptosis. GBP2 was overexpressed in GBM tissues and GSCs, and CENPA enhanced GBP2 transcription by binding to its promoter region. CENPA overexpression accelerated GSCs proliferation and stemnness and suppressed ferroptosis, while GBP2 knockdown reversed these effects. Downregulation of CENPA reduced the tumorigenicity of GSCs by decreasing GBP2 expression in vivo. In conclusion, CENPA enhanced GBP2 transcription to increase its expression, thus accelerating GSCs proliferation and stemnness and repressing ferroptosis. Our findings promote a new idea for GBM treatment.

The prognostic effect of neutrophil-to-lymphocyte ratio and De Ritis ratio in glioblastoma multiforme patients.

AIMS: Individuals with a higher De Ritis ratio (aspartate transaminase/alanine transaminase) and neutrophil-to-lymphocyte ratio (NLR) have an inferior survival in varied malignancies. To our knowledge, the prognostic potential of the De Ritis ratio and NLR to predict the survival in nonmetastatic glioblastoma multiforme (GBM) patients remains unclear. In this study, we aimed to explore the prognostic power of the De Ritis ratio and NLR in patients with nonmetastatic glioblastoma multiforme. METHODS: Data of 262 patients with glioblastoma multiforme have been retrospectively analyzed. Their age, gender, tumor characteristics, AST/ALT ratio, NLR and hemogram values, including age at diagnosis and date of diagnosis were recorded. RESULTS: The median survival time of the study group was 21 months (95% CI: 19‒23 months). The first-year and second-year survival rates were 73.0% and 40.5%, respectively. The univariate analysis revealed that the correlation of survival with age, gender, left/right location of tumor, mean platelet volume and De Ritis ratio did not reach the level of significance. The univariate analysis of the prognostic potential of NLR indicated that a 1-unit increase in NLR value translates to a 1.05 times higher risk of death (95% CI: 1.01‒1.09). CONCLUSION: The results of this study lead to the observation that NLR value can serve as an effective prognostic marker in predicting the outcomes of patients with glioblastoma multiforme. It can be positioned as an easily accessible and cost-effective biomarker for establishing appropriate therapeutic strategies (Tab. 2, Fig. 1, Ref. 20).

Single-cell transcriptomic analysis identifies downregulated phosphodiesterase 8B as a novel oncogene in IDH-mutant glioma.

Introduction: Glioma, a prevalent and deadly brain tumor, is marked by significant cellular heterogeneity and metabolic alterations. However, the comprehensive cell-of-origin and metabolic landscape in high-grade (Glioblastoma Multiforme, WHO grade IV) and low-grade (Oligoastrocytoma, WHO grade II) gliomas remains elusive. Methods: In this study, we undertook single-cell transcriptome sequencing of these glioma grades to elucidate their cellular and metabolic distinctions. Following the identification of cell types, we compared metabolic pathway activities and gene expressions between high-grade and low-grade gliomas. Results: Notably, astrocytes and oligodendrocyte progenitor cells (OPCs) exhibited the most substantial differences in both metabolic pathways and gene expression, indicative of their distinct origins. The comprehensive analysis identified the most altered metabolic pathways (MCPs) and genes across all cell types, which were further validated against TCGA and CGGA datasets for clinical relevance. Discussion: Crucially, the metabolic enzyme phosphodiesterase 8B (PDE8B) was found to be exclusively expressed and progressively downregulated in astrocytes and OPCs in higher-grade gliomas. This decreased expression identifies PDE8B as a metabolism-related oncogene in IDH-mutant glioma, marking its dual role as both a protective marker for glioma grading and prognosis and as a facilitator in glioma progression.

Glioblastoma Multiforme miRNA based Comprehensive Study to Validate Phytochemicals for Effective Treatment against Deadly Tumour through In Silico Evaluation.

BACKGROUND: Glioblastoma Multiforme (GBM) is a prevalent and deadly type of primary astrocytoma, constituting over 60% of adult brain tumors, and has a poor prognosis, with a high relapse rate within 7 months of diagnosis. Despite surgical, radiotherapy, and chemotherapy treatments, GBM remains challenging due to resistance. MicroRNA (miRNAs) control gene expression at transcriptional and post-transcriptional levels by targeting their messenger RNA (mRNA), and also contribute to the development of various neoplasms, including GBM. METHODS: The present study focuses on exploring the miRNAs-based pathogenesis of GBM and evaluating most potential plant-based therapeutic agents with in silico analysis. Gene chips were retrieved from the Gene Expression Omnibus (GEO) database, followed by the Robust- RankAggereg algorithm to determine the Differentially Expressed miRNAs (DEMs). The predicted targets were intersected with the GBM-associated genes, and Gene Ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analysis of the overlapping genes was performed. At the same time, five phytochemicals were selected for the Connectivity map (CMap), and the most efficient ones were those that had undergone molecular docking analysis to obtain the potential therapeutic agents. RESULTS: The hsa-miR-10b, hsa-miR-21, and hsa-miR-15b were obtained, and eight genes were found to be associated with glioma pathways; VSIG4, PROCR, PLAT, and ITGB2 were upregulated while, CAMK2B, PDE1A, GABRA1, and KCNJ6 were downregulated. The drugs Resveratrol and Quercetin were identified as the most prominent drugs. CONCLUSION: These miRNAs-based drugs can be used as a curative agent for the treatment of GBM. However, in vivo, experimental data, and clinical trials are necessary to provide an alternative to conventional GBM cancer chemotherapy.

TRP-2 / gp100 DNA vaccine and PD-1 checkpoint blockade combination for the treatment of intracranial tumors.

Intracranial tumors present a significant therapeutic challenge due to their physiological location. Immunotherapy presents an attractive method for targeting these intracranial tumors due to relatively low toxicity and tumor specificity. Here we show that SCIB1, a TRP-2 and gp100 directed ImmunoBody® DNA vaccine, generates a strong TRP-2 specific immune response, as demonstrated by the high number of TRP2-specific IFNγ spots produced and the detection of a significant number of pentamer positive T cells in the spleen of vaccinated mice. Furthermore, vaccine-induced T cells were able to recognize and kill B16HHDII/DR1 cells after a short in vitro culture. Having found that glioblastoma multiforme (GBM) expresses significant levels of PD-L1 and IDO1, with PD-L1 correlating with poorer survival in patients with the mesenchymal subtype of GBM, we decided to combine SCIB1 ImmunoBody® with PD-1 immune checkpoint blockade to treat mice harboring intracranial tumors expressing TRP-2 and gp100. Time-to-death was significantly prolonged, and this correlated with increased CD4+ and CD8+ T cell infiltration in the tissue microenvironment (TME). However, in addition to PD-L1 and IDO, the GBM TME was found to contain a significant number of immunoregulatory T (Treg) cell-associated transcripts, and the presence of such cells is likely to significantly affect clinical outcome unless also tackled.

The thrombin receptor (PAR1) is associated with microtubules, mitosis and process formation in glioma cells.

The cell surface protease-activated receptor 1 (PAR1) is overexpressed in glioblastoma multiforme (GBM). We studied the function and structure of intracellular microtubule (MT) and PAR1 in a tubulin-mediated process. We found that exposure to thrombin increased the percentage of proliferative, S, and M phases cells, affected morphology, and increased process elongation. PAR1 antagonist inversely affects these measures, increases tubulin end-binding protein 3 (EB3) mRNA expression in C6 cells, and reduces EB3 comet length, track length, and duration in neuroblastoma cells. In addition, immunofluorescence staining suggests that PAR1 is in close association with the MT α-tubulin and with coagulation cascade proteins during cell division stages. Our findings support PAR1 involvement in MT dynamics.

The effects of the combination therapy of chemotherapy drugs on the fluctuations of genes involved in the TLR signaling pathway in glioblastoma multiforme therapy.

One of the most lethal and aggressive types of malignancies with a high mortality rate and poor response to treatment is glioblastoma multiforme (GBM). This means that modernizing the medications used in chemotherapy, in addition to medicines licensed for use in other illnesses and chosen using a rationale process, can be beneficial in treating this illness. Meaningly, drug combination therapy with chemical or herbal originations or implanting a drug wafer in tumors to control angiogenesis is of great importance. Importantly, the primary therapeutic hurdles in GBM are the development of angiogenesis and the blood-brain barrier (BBB), which keeps medications from getting to the tumor. This malignancy can be controlled if the drug's passage through the BBB and the VEGF (vascular endothelial growth factor), which promotes angiogenesis, are inhibited. In this way, the effect of combination therapy on the genes of different main signaling pathways like TLRs may be indicated as an impressive therapeutic strategy for treating GBM. This article aims to discuss the effects of chemotherapeutic drugs on the expression of various genes and associated translational factors involved in the TLR signaling pathway.

Gene expression profiling and the isocitrate dehydrogenase mutational landscape of temozolomide­resistant glioblastoma.

Glioblastoma multiforme (GBM) is an aggressive brain cancer that occurs more frequently than other brain tumors. The present study aimed to reveal a novel mechanism of temozolomide resistance in GBM using bioinformatics and wet lab analyses, including meta-Z analysis, Kaplan-Meier survival analysis, protein-protein interaction (PPI) network establishment, cluster analysis of co-expressed gene networks, and hierarchical clustering of upregulated and downregulated genes. Next-generation sequencing and quantitative PCR analyses revealed downregulated [tyrosine kinase with immunoglobulin and epidermal growth factor homology domains 1 (TIE1), calcium voltage-gated channel auxiliary subunit α2Δ1 (CACNA2D1), calpain 6 (CAPN6) and a disintegrin and metalloproteinase with thrombospondin motifs 6 (ADAMTS6)] and upregulated [serum amyloid (SA)A1, SAA2, growth differentiation factor 15 (GDF15) and ubiquitin specific peptidase 26 (USP26)] genes. Different statistical models were developed for these genes using the Z-score for P-value conversion, and Kaplan-Meier plots were constructed using several patient cohorts with brain tumors. The highest number of nodes was observed in the PPI network was for ADAMTS6 and TIE1. The PPI network model for all genes contained 35 nodes and 241 edges. Immunohistochemical staining was performed using isocitrate dehydrogenase (IDH)-wild-type or IDH-mutant GBM samples from patients and a significant upregulation of TIE1 (P<0.001) and CAPN6 (P<0.05) protein expression was demonstrated in IDH-mutant GBM in comparison with IDH-wild-type GBM. Structural analysis revealed an IDH-mutant model demonstrating the mutant residues (R132, R140 and R172). The findings of the present study will help the future development of novel biomarkers and therapeutics for brain tumors.

Novel tetrahydroquinoline derivatives induce ROS-mediated apoptosis in glioblastoma cells.

Current treatment for Glioblastoma Multiforme (GBM) is not efficient due to its aggressive nature, tendency to infiltrate surrounding brain tissue, and chemotherapy resistance. Tetrahydroquinoline scaffolds are emerging as a new class of drug for treating many human cancers including GBM. This study investigates the cytotoxicity effect of eight novel derivatives of 2-((3,4-dihydroquinolin-1(2H)-yl)(aryl)methyl)phenol, containing substitute 1 with reduced dihydroquinoline fused with cyclohexene ring and substitute 2 with phenyl and methyl group. The 4-position of the aryl ring was determinant for the desired cytotoxicity, and out of the 8 synthesized compounds, the 4-trifluoromethyl substituted derivative (4ag) exhibited the most anti-GBM potential effect compared to the standard chemotherapeutic agent, temozolomide (TMZ), with IC50 values of 38.3 µM and 40.6 µM in SNB19 and LN229 cell lines, respectively. Our results demonstrated that 4ag triggers apoptosis through the activation of Caspase-3/7. In addition, 4ag induced intracellular reactive oxygen species (iROS) which in turn elevated mitochondrial ROS (mtROS) and causes the disruption of the mitochondrial membrane potential (Δψmt) in both GBM cells. This compound also exhibited anti-migratory properties over the time in both the cell lines. Overall, these findings suggest that tetrahydroquinoline derivative, 4ag could lead to the development of a new drug for treating GBM.

Revolutionizing Brain Tumor Care: Emerging Technologies and Strategies.

Glioblastoma multiforme (GBM) is one of the most aggressive forms of brain tumor, characterized by a daunting prognosis with a life expectancy hovering around 12-16 months. Despite a century of relentless research, only a select few drugs have received approval for brain tumor treatment, largely due to the formidable barrier posed by the blood-brain barrier. The current standard of care involves a multifaceted approach combining surgery, irradiation, and chemotherapy. However, recurrence often occurs within months despite these interventions. The formidable challenges of drug delivery to the brain and overcoming therapeutic resistance have become focal points in the treatment of brain tumors and are deemed essential to overcoming tumor recurrence. In recent years, a promising wave of advanced treatments has emerged, offering a glimpse of hope to overcome the limitations of existing therapies. This review aims to highlight cutting-edge technologies in the current and ongoing stages of development, providing patients with valuable insights to guide their choices in brain tumor treatment.

A recent insight of applications of gold nanoparticles in glioblastoma multiforme therapy.

The application of gold nanoparticles (AuNPs) in cancer therapy, particularly targeted therapy of glioblastoma multiforme (GBM), is an up-and-coming field of research that has gained much interest in recent years. GBM is a life-threatening malignant tumour of the brain that currently has a 95 % death rate with an average of 15 months of survival. AuNPs have proven to have wide clinical implications and compelling therapeutic potential in many researches, specifically in GBM treatment. It was found that the reason why AuNPs were highly desired for GBM treatment was due to their unique properties that diversified the applications of AuNPs further to include imaging, diagnosis, and photothermal therapy. These properties include easy synthesis, biocompatibility, and surface functionalization. Various studies also underscored the ability of AuNPs to cross the blood-brain-barrier and selectively target tumour cells while displaying no major safety concerns which resulted in better therapy results. We attempt to bring together some of these studies in this review and provide a comprehensive overview of safety evaluations and current and potential applications of AuNPs in GBM therapy that may result in AuNP-mediated therapy to be the new gold standard for GBM treatment.

Comprehensive analysis of lncRNA-associated ceRNA network reveals novel potential prognostic regulatory axes in glioblastoma multiforme.

Deciphering the lncRNA-associated competitive endogenous RNA (ceRNA) network is essential in decoding glioblastoma multiforme (GBM) pathogenesis by regulating miRNA availability and controlling mRNA stability. This study aimed to explore novel biomarkers for GBM by constructing a lncRNA-miRNA-mRNA network. A ceRNA network in GBM was constructed using lncRNA, mRNA and miRNA expression profiles from the TCGA and GEO datasets. Seed nodes were identified by protein-protein interaction (PPI) network analysis of deregulated-mRNAs (DEmRNAs) in the ceRNA network. A lncRNA-miRNA-seed network was constructed by mapping the seed nodes into the preliminary ceRNA network. The impact of the seed nodes on the overall survival (OS) of patients was assessed by the GSCA database. Functional enrichment analysis of the deregulated-lncRNAs (DElncRNA) in the ceRNA network and genes interacting with OS-related genes in the PPI network were performed. Finally, the positive correlation between seed nodes and their associated lncRNAs and the expression level of these molecules in GBM tissue compared with normal samples was validated using the GEPIA database. Our analyzes revealed that three novel regulatory axes AL161785.1/miR-139-5p/MS4A6A, LINC02611/miR-139-5p/MS4A6A and PCED1B-AS1/miR-433-3p/MS4A6A may play essential roles in GBM pathogenesis. MS4A6A is upregulated in GBM and closely associated with shorter survival time of patients. We also identified that MS4A6A expression positively correlates with genes related to tumour-associated macrophages, which induce macrophage infiltration and immune suppression. The functional enrichment analysis demonstrated that DElncRNAs are mainly involved in neuroactive ligand-receptor interaction, calcium/MAPK signalling pathway, ribosome, GABAergic/Serotonergic/Glutamatergic synapse and immune system process. In addition, genes related to MS4A6A contribute to immune and inflammatory-related biological processes. Our findings provide novel insights to understand the ceRNA regulation in GBM and identify novel prognostic biomarkers or therapeutic targets.

Robust AI-Driven Segmentation of Glioblastoma T1c and FLAIR MRI Series and the Low Variability of the MRIMath© Smart Manual Contouring Platform.

Patients diagnosed with glioblastoma multiforme (GBM) continue to face a dire prognosis. Developing accurate and efficient contouring methods is crucial, as they can significantly advance both clinical practice and research. This study evaluates the AI models developed by MRIMath© for GBM T1c and fluid attenuation inversion recovery (FLAIR) images by comparing their contours to those of three neuro-radiologists using a smart manual contouring platform. The mean overall Sørensen-Dice Similarity Coefficient metric score (DSC) for the post-contrast T1 (T1c) AI was 95%, with a 95% confidence interval (CI) of 93% to 96%, closely aligning with the radiologists' scores. For true positive T1c images, AI segmentation achieved a mean DSC of 81% compared to radiologists' ranging from 80% to 86%. Sensitivity and specificity for T1c AI were 91.6% and 97.5%, respectively. The FLAIR AI exhibited a mean DSC of 90% with a 95% CI interval of 87% to 92%, comparable to the radiologists' scores. It also achieved a mean DSC of 78% for true positive FLAIR slices versus radiologists' scores of 75% to 83% and recorded a median sensitivity and specificity of 92.1% and 96.1%, respectively. The T1C and FLAIR AI models produced mean Hausdorff distances (<5 mm), volume measurements, kappa scores, and Bland-Altman differences that align closely with those measured by radiologists. Moreover, the inter-user variability between radiologists using the smart manual contouring platform was under 5% for T1c and under 10% for FLAIR images. These results underscore the MRIMath© platform's low inter-user variability and the high accuracy of its T1c and FLAIR AI models.

Exhaustive in vitro evaluation of the 9-drug cocktail CUSP9 for treatment of glioblastoma.

The CUSP9 protocol is a polypharmaceutical strategy aiming at addressing the complexity of glioblastoma by targeting multiple pathways. Although the rationale for this 9-drug cocktail is well-supported by theoretical and in vitro data, its effectiveness compared to its 511 possible subsets has not been comprehensively evaluated. Such an analysis could reveal if fewer drugs could achieve similar or better outcomes. We conducted an exhaustive in vitro evaluation of the CUSP9 protocol using COMBImageDL, our specialized framework for testing higher-order drug combinations. This study assessed all 511 subsets of the CUSP9v3 protocol, in combination with temozolomide, on two clonal cultures of glioma-initiating cells derived from patient samples. The drugs were used at fixed, clinically relevant concentrations, and the experiment was performed in quadruplicate with endpoint cell viability and live-cell imaging readouts. Our results showed that several lower-order drug combinations produced effects equivalent to the full CUSP9 cocktail, indicating potential for simplified regimens in personalized therapy. Further validation through in vivo and precision medicine testing is required. Notably, a subset of four drugs (auranofin, disulfiram, itraconazole, sertraline) was particularly effective, reducing cell growth, altering cell morphology, increasing apoptotic-like cells within 4-28 h, and significantly decreasing cell viability after 68 h compared to untreated cells. This study underscores the importance and feasibility of comprehensive in vitro evaluations of complex drug combinations on patient-derived tumor cells, serving as a critical step toward (pre-)clinical development.