Survival In Glioblastoma Multiforme Research Articles

Optimizing Glioblastoma, IDH-wildtype Treatment Outcomes : A Radiomics and Support Vector Machine -Based Approach to Overall Survival Estimation.

Glioblastoma multiforme (GBM), particularly the IDH-wildtype type, represents a significant clinical challenge due to its aggressive nature and poor prognosis. Despite advancements in medical imaging and its modalities, survival rates have not improved significantly, demanding innovative treatment planning and outcome prediction approaches. This study utilizes a Support Vector Machine (SVM) classifier using radiomics features to predict the overall survival (OS) of GBM, IDH-wildtype patients to short (< 12 Months) and long (>=12 Months) survivors. A dataset comprising multi-parametric MRI (mpMRI) scans from 574 patients was analyzed. Radiomic features were extracted from T1, T2, FLAIR, and T1-Gd sequences. Low variance features were removed, and Recursive Feature Elimination (RFE) was used to select the most informative features. The SVM model was trained using a k-fold cross-validation approach. Furthermore, clinical parameters such as age, gender, and MGMT promoter methylation status were integrated to enhance prediction accuracy. The model showed reasonable results in terms of cross-validated AUC of 0.84 (95% CI: 0.80-0.90) with (p-value < 0.001) effectively categorizing patients into short and long survivors. Log-rank test (Chi-square statistics) analysis for the developed model was 0.00029 along with the 1.20 Cohen's d effect size. Most importantly, clinical data integration further refined the survival estimates, providing a more fitted prediction that considers individual patient characteristics by Kaplan-Meier curve with p-value<0.0001. The proposed method significantly enhances the predictive accuracy of OS outcomes in GBM, IDH-wildtype patients. By integrating detailed imaging features with key clinical indicators, this model offers a robust tool for personalized treatment planning, potentially improving OS.

Abstract 5594: Exploring genetic determinants: A comprehensive analysis of SERPINB family variants and prognosis in Jordanian glioblastoma multiforme patients

Abstract Background: Glioblastoma multiforme (GBM) is a major concern with high fatality rate. In Jordan, the incidence of GBM has notably increased, emphasizing the urgency for population-specific research. Serpins are serine proteinase inhibitors, with several Serpins being overexpressed in cancer cells however the exact mechanism by which they affect GBM progression remains unclear. Thus, we aim to analyze the single-nucleotide polymorphism (SNP) of SERPINB11 and its association with GBM survival. Methods: A cohort of 63 GBM patients recruited from King Abdullah University Hospital (KAUH) in Jordan, underwent genomic DNA extraction, polymorphism analysis, and overall survival (OS) assessments. The Serpin B family were validated using The Cancer Genome Atlas (TCGA-GBM) cohort of 160 patients. We constructed a risk-score using the principal component analysis for the following Serpin genes: Serpinb3, Serpinb5, Serpinb6, Serpinb11, and Serpinb12, and patients were grouped into high- vs. low-risk based on median cutoff. Univariable Cox models were used to study the survival outcomes, differential expression analysis between the high- and low-risk groups was carried out to identify the differentially expressed genes (DEGs), gene ontology (GO and tumor microenvironment analyses were carried out. Results: In our primary cohort, we identified a significant association between rs4940595 (SERPINB11) SNP and survival, with the G/T- genotype showing worse prognosis compared to the G/G-T/T genotype in the over dominant model (HR: 2.75, 95% CI: 1.29-5.88, p-value=0.009). In the TCGA validation-cohort, alterations in the SERPINB3gene showed significantly worse OS (Median: 9.53 vs. 14.3, p-value=0.044) compared to the no alteration group. Univariable Cox showed worse PFS outcomes with higher SERPINB5 (HR: 1.67, 95% CI: 1.15-2.43, p-value=0.007) and SERPINB6 expression (HR: 1.44, 95% CI: 1.06-1.96, p-value=0.021). A Serpin B 5-gene risk score was constructed revealing significant association with IDH mutation status and a trend towards worse PFS in the high-risk group. Upregulated DEGs showed GO enrichment in cytokine regulation and production, positive regulation of leukocyte activation and MAPK cascade. While the downregulated DEGs were enriched in forebrain development, and negative regulation of neuron differentiation. The high-risk group showed a significantly higher infiltration of M2 macrophages and activated mast cells. Conclusion: Our findings showed a significant role of the Serpin B family with GBM survival in the Jordanian population. Molecular analyses showed potential mechanisms underlying these associations. Our exploration of SERPINB family and associated SNPs provides valuable insights into the molecular landscape of GBM, paving the way for potential targeted interventions and personalized treatment strategies. Citation Format: Sohaib Al-Khatib, Mohammad Nitham Almajali, Ayah Al-Bzour, Joud Al-Ramadneh, Laila Sa'd, Noor Othman. Exploring genetic determinants: A comprehensive analysis of SERPINB family variants and prognosis in Jordanian glioblastoma multiforme patients [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 5594.

Abstract 427: A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype

Abstract Background: Glycogen plays an important role in glucose homeostasis and contributes to key functions related to brain cancer cell survival in glioblastoma multiforme (GBM) disease progression. Such adaptive molecular mechanism is dependent on the glycogenolytic pathway and intracellular glucose-6-phosphate (G6P) sensing by brain cancer cells residing within those highly hypoxic tumors. The involvement of components of the glucose-6-phosphatase (G6Pase) system remains however elusive. Objective: We questioned the gene expression levels of components of the G6Pase system in GBM tissues and their functional impact in the control of the invasive and brain cancer stem cells (CSC) phenotypes. Methods: In silico analysis of transcript levels in GBM tumor tissues was done by GEPIA. Total RNA was extracted and gene expression of G6PC1-3 as well as of SLC37A1-4 members analyzed by qPCR in four human brain cancer cell lines and from clinically annotated brain tumor cDNA arrays. Transient siRNA-mediated gene silencing was used to assess the impact of TGF-β-induced epithelial-to-mesenchymal transition (EMT) and cell chemotaxis. Three-dimensional (3D) neurosphere cultures were generated to recapitulate the brain CSC phenotype. Results: Higher expression in G6PC3, SLC37A2, and SLC37A4 was found in GBM tumor tissues in comparison to low-grade glioma and healthy tissue. The expression of these genes was also found elevated in established human U87, U251, U118, and U138 GBM cell models compared to human HepG2 hepatoma cells. SLC37A4/G6PC3, but not SLC37A2, levels were induced in 3D CD133/SOX2-positive U87 neurospheres when compared to 2D monolayers. Silencing of SLC37A4/G6PC3 altered TGF-β-induced EMT biomarker SNAIL and cell chemotaxis. Conclusion: Two members of the G6Pase system, G6PC3 and SLC37A4, associate with GBM disease progression and regulate the metabolic reprogramming of an invasive and CSC phenotype. Such molecular signature may support their role in cancer cell survival and chemoresistance and become future therapeutic targets. Citation Format: Sima Torabidastgerdooei, Borhane Annabi. A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 427.

RAR-Dependent and RAR-Independent RXR Signaling in Stem-like Glioma Cells.

Retinoic acid (RA) exerts pleiotropic effects during neural development and regulates homeostasis in the adult human brain. The RA signal may be transduced through RXR (retinoid-X receptor)-non-permissive RA receptor/RXR heterodimers or through RXR-permissive RXR heterodimers. The significance of RA signaling in malignant brain tumors such as glioblastoma multiforme (GBM) and gliosarcoma (GS) is poorly understood. In particular, the impact RA has on the proliferation, survival, differentiation, or metabolism of GBM- or GS-derived cells with features of stem cells (SLGCs) remains elusive. In the present manuscript, six GBM- and two GS-derived SLGC lines were analyzed for their responsiveness to RAR- and RXR-selective agonists. Inhibition of proliferation and initiation of differentiation were achieved with a RAR-selective pan-agonist in a subgroup of SLGC lines, whereas RXR-selective pan-agonists (rexinoids) supported proliferation in most SLGC lines. To decipher the RAR-dependent and RAR-independent effects of RXR, the genes encoding the RAR or RXR isotypes were functionally inactivated by CRISPR/Cas9-mediated editing in an IDH1-/p53-positive SLGC line with good responsiveness to RA. Stemness, differentiation capacity, and growth behavior were preserved after editing. Taken together, this manuscript provides evidence about the positive impact of RAR-independent RXR signaling on proliferation, survival, and tumor metabolism in SLGCs.

A molecular signature for the G6PC3/SLC37A2/SLC37A4 interactors in glioblastoma disease progression and in the acquisition of a brain cancer stem cell phenotype.

Glycogen plays an important role in glucose homeostasis and contributes to key functions related to brain cancer cell survival in glioblastoma multiforme (GBM) disease progression. Such adaptive molecular mechanism is dependent on the glycogenolytic pathway and intracellular glucose-6-phosphate (G6P) sensing by brain cancer cells residing within those highly hypoxic tumors. The involvement of components of the glucose-6-phosphatase (G6Pase) system remains however elusive. We questioned the gene expression levels of components of the G6Pase system in GBM tissues and their functional impact in the control of the invasive and brain cancer stem cells (CSC) phenotypes. In silico analysis of transcript levels in GBM tumor tissues was done by GEPIA. Total RNA was extracted and gene expression of G6PC1-3 as well as of SLC37A1-4 members analyzed by qPCR in four human brain cancer cell lines and from clinically annotated brain tumor cDNA arrays. Transient siRNA-mediated gene silencing was used to assess the impact of TGF-β-induced epithelial-to-mesenchymal transition (EMT) and cell chemotaxis. Three-dimensional (3D) neurosphere cultures were generated to recapitulate the brain CSC phenotype. Higher expression in G6PC3, SLC37A2, and SLC37A4 was found in GBM tumor tissues in comparison to low-grade glioma and healthy tissue. The expression of these genes was also found elevated in established human U87, U251, U118, and U138 GBM cell models compared to human HepG2 hepatoma cells. SLC37A4/G6PC3, but not SLC37A2, levels were induced in 3D CD133/SOX2-positive U87 neurospheres when compared to 2D monolayers. Silencing of SLC37A4/G6PC3 altered TGF-β-induced EMT biomarker SNAIL and cell chemotaxis. Two members of the G6Pase system, G6PC3 and SLC37A4, associate with GBM disease progression and regulate the metabolic reprogramming of an invasive and CSC phenotype. Such molecular signature may support their role in cancer cell survival and chemoresistance and become future therapeutic targets.

Molecular signature to predict quality of life and survival with glioblastoma using Multiview omics model.

Glioblastoma multiforme (GBM) patients show a variety of signs and symptoms that affect their quality of life (QOL) and self-dependence. Since most existing studies have examined prognostic factors based only on clinical factors, there is a need to consider the value of integrating multi-omics data including gene expression and proteomics with clinical data in identifying significant biomarkers for GBM prognosis. Our research aimed to isolate significant features that differentiate between short-term (≤ 6 months) and long-term (≥ 2 years) GBM survival, and between high Karnofsky performance scores (KPS ≥ 80) and low (KPS ≤ 60), using the iterative random forest (iRF) algorithm. Using the Cancer Genomic Atlas (TCGA) database, we identified 35 molecular features composed of 19 genes and 16 proteins. Our findings propose molecular signatures for predicting GBM prognosis and will improve clinical decisions, GBM management, and drug development.

An Insight into Emerging Phytocompounds for Glioblastoma Multiforme Therapy.

Despite intense research in the field of glioblastoma multiforme (GBM) therapeutics, the resistance against approved therapy remains an issue of concern. The resistance against the therapy is widely reported due to factors like clonal selection, involvement of multiple developmental pathways, and majorly defective mismatch repair (MMR) protein and functional O6- methylguanine DNA methyltransferase (MGMT) repair enzyme. Phytotherapy is one of the most effective alternatives to overcome resistance. It involves plant-based compounds, divided into several classes: alkaloids; phenols; terpenes; organosulfur compounds. The phytocompounds comprised in these classes are extracted or processed from certain plant sources. They can target various proteins of molecular pathways associated with the progression and survival of GBM. Phytocompounds have also shown promise as immunomodulatory agents and are being explored for immune checkpoint inhibition. Therefore, research and innovations are required to understand the mechanism of action of such phytocompounds against GBM to develop efficacious treatments for the same. This review gives insight into the potential of phytochemical-based therapeutic options for GBM treatment.

Ceramide Is Involved in Temozolomide Resistance in Human Glioblastoma U87MG Overexpressing EGFR.

Glioblastoma multiforme (GBM) is the most frequent and deadly brain tumor. Many sphingolipids are crucial players in the regulation of glioma cell growth as well as in the response to different chemotherapeutic drugs. In particular, ceramide (Cer) is a tumor suppressor lipid, able to induce antiproliferative and apoptotic responses in different types of tumors including GBM, most of which overexpress the epidermal growth factor receptor variant III (EGFRvIII). In this paper, we investigated whether Cer metabolism is altered in the U87MG human glioma cell line overexpressing EGFRvIII (EGFR+ cells) to elucidate their possible interplay in the mechanisms regulating GBM survival properties and the response to the alkylating agent temozolomide (TMZ). Notably, we demonstrated that a low dose of TMZ significantly increases Cer levels in U87MG cells but slightly in EGFR+ cells (sensitive and resistant to TMZ, respectively). Moreover, the inhibition of the synthesis of complex sphingolipids made EGFR+ cells sensitive to TMZ, thus involving Cer accumulation/removal in TMZ resistance of GBM cells. This suggests that the enhanced resistance of EGFR+ cells to TMZ is dependent on Cer metabolism. Altogether, our results indicate that EGFRvIII expression confers a TMZ-resistance phenotype to U87MG glioma cells by counteracting Cer increase.

Systematic integration of m6A regulators and autophagy-related genes in combination with long non-coding RNAs predicts survival in glioblastoma multiforme

Glioblastoma multiforme (GBM) is probably the only tumor in which a unique epigenetic alteration, namely methylation of the MGMT gene, possesses direct clinical relevance. Now with the emergence of aberrant N6 methyladenosine (m6A) modifications (the most common epigenetic modification of mRNA, closely linked to the autophagy process) in cancer, the epi-transcriptomic landscape of GBM pathobiology has been expanded. Considering this, herein, we systematically analyzed m6A regulators, assessed their correlation with autophagy-related genes (ATG), and established a long non-coding RNAs (lncRNA)-dependent prognostic signature (m6A-autophagy-lncRNAs) for GBM. Our analysis identified a novel signature of five long non-coding RNAs (lncRNAs: ITGA6-AS1, AC124248.1, NFYC-AS1, AC025171.1, and AC005229.3) associated with survival of GBM patients, and four among them clearly showed cancer-associated potential. We further validated and confirmed the altered expression of two lncRNAs (AC124248.1, AC005229.3) in GBM associated clinical samples using RT-PCR. Concerning the prognostic ability, the obtained signature determined high-/low-risk groups in GBM patients and showed sensitivity to anticancer drugs. Collectively, the m6A-autophagy-lncRNAs signature presented in the study is clinically relevant and is the first attempt to systematically predict the potential interaction between the three key determinants (m6A, autophagy, lncRNA) in cancer, particularly in GBM.

Retrospective Review of the Factors Limiting Optune Initiation in GBM patients

Tumor Treating Fields (TTFields) are a proven treatment that prolongs survival in Glioblastoma Multiforme (GBM) patients. The duration of usage of TTFields correlates with its effectiveness. This study aims to identify socioeconomic and clinical factors that prevent GBM patients at a single institution from starting and remaining on TTFields treatment. This is a retrospective review from a single institution. Data were analyzed for each patient with a diagnosis of GBM that was seen in new patient consultation with a radiation oncologist. Data from 2015 to present were available. 178 patients were included in the study. Insurance status (private vs Medicare/Medicaid vs uninsured), zip code, expected income status, race, ethnicity, preferred primary language, work status, performance status (KPS) at time of diagnosis, and family support at home (Spouse vs Other) were analyzed. For those that initiated TTFields, we examined the duration of treatment, usage rates, patient reported tolerability, and reasons for discontinuation. Early termination of treatment was defined as treatment with TTFields for less than 3 months. Of the 178 diagnosed GBM patients, 96 (54%) were offered TTFields and 48 (27%) agreed to treatment, with 46 actually starting. Of 89 Non-Hispanic patients, 53 were offered TTFields (60%) whereas of 73 Hispanic patients, 35 were offered TTFields (48%) (no statistically significant difference). The number one reason for refusing TTFields treatment was rapid deterioration (14/48 patients). The next most common reason was the patient feeling overwhelmed by managing or wearing the device (10/48) as well as the patient's decision to participate in any other clinical trial (10/48). The 3-month dropout rate for patients who received TTFields was 35% (17/48). 5 of the 17 stopped early due to skin rash or annoyance with the device. Patient's median income and insurance status did not predict whether they would start TTFields. 33 out of 109 (31%) patients with spousal support at home started treatment with TTFields compared to 13 of 69 (19%) of those without spousal support (p = .0895, Chi-Square test). TTFields were offered to more patients each successive year, but many patients had no documented discussion offering TTFields, which may indicate room for improvement at our institution. Median income and insurance status did not play a role in patient access to TTFields, most likely due to Novocure sponsorship of un- or under-insured patients. Among those who declined treatment, 21% did so because of perceived difficulty managing the device. The strongest single trend predictive of successful initiation of TTFields is spousal support at home. Further interventions may focus on improving patient support at home, such as home health nursing visits or community support.

Effect of Concomitant and Adjuvant Temozolomide on Prognosis and Survival in Glioblastoma Multiforme

Objective: Glioblastoma multiforme (GBM) is the most common malignant primary brain tumor in adults. The most common problem in the follow-up after GBM treatment is the lack of local control. This study aims to evaluate the efficacy and safety of Temozolomide (TMZ) in cases who received post-surgical radiotherapy and TMZ treatment in GBM compared to cases who received only radiotherapy treatment after surgery. Materials and Methods: The cases diagnosed with GBM were divided into two groups. The first group was divided into cases that received only radiotherapy after surgery, and the second group (combined treatment group) was divided into cases that received post-surgical radiotherapy and TMZ treatment. 28 cases who received radiotherapy and TMZ treatment after surgery and 26 cases who received only radiotherapy after surgery were included in the study. Local fractionated radiotherapy (60 Gy total dose: 2 Gyx5 days/week for 6 weeks) was applied to all cases. Only in the second group, 75 mg/m2/day 7 days/week orally, 200 mg/m2/day 5 days as monotherapy for 6 weeks, and six cycles of TMZ every 28 days were administered concomitantly. In addition to the effect of TMZ on prognosis and survival, the effects of age, gender, and resection size on progression-free survival (PSS) and overall survival (GSS) were evaluated in both groups. Results: There was no statistically significant benefit in terms of both PFS and OS in both groups for age and gender, a statistically significant benefit was found for resection size (total-subtotal). At the end of the study, PFS was 14 months in the combined treatment group and 6 months in the radiotherapy alone group (P&amp;lt;0.0001). OS was 16 months in the combined treatment group and 12.5 months in the radiotherapy alone group (P=0.0354). Conclusion: Combined (RT + TMZ) treatment after total surgical treatment was found to be more effective on prognosis and survival than radiotherapy alone.

NQO1 drives glioblastoma cell aggressiveness through EMT induction via the PI3K/Akt/mTOR/Snail pathway.

Glioblastoma multiforme (GBM) is the most frequent and lethal cancer derived from the central nervous system, of which the mesenchymal (MES) subtype seriously influences the survival and prognosis of patients. NAD(P)H: quinone acceptor oxidoreductase 1 (NQO1) serves an important role in the carcinogenesis and progression of various types of cancer; however, the specific mechanism underlying the regulatory effects of NQO1 on GBM is unclear. Thus, the present study aimed to explore the role and mechanism of NQO1 in GBM progression. The results of bioinformatics analysis and immunohistochemistry showed that high expression of NQO1 was significantly related to the MES phenotype of GBM and shorter survival. In addition, MTT, colony formation, immunofluorescence and western blot analyses, and lung metastasis model experiments suggested that silencing NQO1 inhibited the proliferation and metastasis of GBM cells invitro and invivo. Furthermore, western blotting showed that the activity of the PI3K/Akt/mTOR signaling pathway was revealed to be inhibited by downregulation of NQO1 expression, whereas it was enhanced by overexpression of NQO1. Notably, co‑immunoprecipitation and ubiquitination experiments suggested that Snail was considered an important downstream target of NQO1 in GBM cells. Snail knockdown could eliminate the promoting effect of ectopic NQO1 on the proliferation and invasion of GBM cells, and reduce its effects on the activity of PI3K/Akt/mTOR signaling pathway. These results indicated that NQO1 could promote GBM aggressiveness by activating the PI3K/Akt/mTOR signaling pathway in a Snail‑dependent manner, and NQO1 and its relevant pathways may be considered novel targets for GBM therapy.

Differential expression of the circadian clock network correlates with tumour progression in gliomas

BackgroundGliomas are tumours arising mostly from astrocytic or oligodendrocytic precursor cells. These tumours are classified according to the updated WHO classification from 2021 in 4 grades depending on molecular and histopathological criteria. Despite novel multimodal therapeutic approaches, the vast majority of gliomas (WHO grade III and IV) are not curable. The circadian clock is an important regulator of numerous cellular processes and its dysregulation had been found during the progression of many cancers, including gliomas.ResultsIn this study, we explore expression patterns of clock-controlled genes in low-grade glioma (LGG) and glioblastoma multiforme (GBM) and show that a set of 45 clock-controlled genes can be used to distinguish GBM from normal tissue. Subsequent analysis identified 17 clock-controlled genes with a significant association with survival. The results point to a loss of correlation strength within elements of the circadian clock network in GBM compared to LGG. We further explored the progression patterns of mutations in LGG and GBM, and showed that tumour suppressor APC is lost late both in LGG and GBM. Moreover, HIF1A, involved in cellular response to hypoxia, exhibits subclonal losses in LGG, and TERT, involved in the formation of telomerase, is lost late in the GBM progression. By examining multi-sample LGG data, we find that the clock-controlled driver genes APC, HIF1A, TERT and TP53 experience frequent subclonal gains and losses.ConclusionsOur results show a higher level of disrgulation at the gene expression level in GBM compared to LGG, and indicate an association between the differentially expressed clock-regulated genes and patient survival in both LGG and GBM. By reconstructing the patterns of progression in LGG and GBM, our data reveals the relatively late gains and losses of clock-regulated glioma drivers. Our analysis emphasizes the role of clock-regulated genes in glioma development and progression. Yet, further research is needed to asses their value in the development of new treatments.

Role of extent of resection on the survival of glioblastoma multiforme

Background. Glioblastoma Multiforme (GBM) is the most prevalent form of brain cancer. The effect of Extent of Resection (EOR) on GBM survival is controversial. EOR degree, pre- and postoperative tumour volume estimation, and significance to residual tumour volume are still challenged. GBM has a 14-month Overall Survival (OS) rate. There is no evidence of a link between EOR and OS survival. We wish to determine whether GBM tumour removal increases survival. Methods. At the Regional Center for Neurosurgery and Neurology in Uzhhorod, Ukraine, we conducted a retrospective evaluation of 86 consecutive patients diagnosed with glioblastoma who underwent surgery between January 1, 2010, and December 31, 2020, and who are being followed until January 1, 2022. Patients were selected if they met the following criteria: they were at least 18 years old, they had a diagnosis of glioblastoma (primary, secondary, or recurrent), they were either IDH mutants or wild types, they had an MRI within 2 weeks before surgery, and they had another MRI within 72 hours after surgery. Before and after surgery, we did a volumetric analysis of gadolinium-enhanced T1 MRI scans of the tumour to figure out EOR. Partial resection (PR) is &lt;70%, sub-total resection (STR) is 70-90%, near-total resection (NTR) is 91-99%, and gross total resection (GTR) is &gt;99%. By comparing pre- and post-operative volumes with the EOR, the Kaplan-Meier survival curve and Cox's regression analysis determined the impact of the EOR on survival rates. Many researchers considered a p value of 0.05 or below to be significant. Results. A total of 86 patients were included in the analysis after being subjected to the criteria used to narrow the pool of potential participants. The average length of time people lived was 15 months. For PR patients, the median survival time was 3 months, for STR patients it was 10 months, and for NTR patients it was 16 months. Patients receiving GTR, on the other hand, had a considerably better outcome, with a median survival time of 36 months. This data demonstrate a direct correlation between EOR and survival rates. It was discovered that EOR improvement affected post-op survival. High EOR patients have a better prognosis for survival. Adjuvant therapy, pre- and post-operative KPS score, pre- and post-operative tumour volume, and gender also contributed significantly to enhanced survival. Conclusion. Patients with glioblastoma appear to benefit from a more aggressive treatment strategy that combines maximal safe resection with the use of salvage adjuvant therapy. There was a correlation between complete resection (gross total resection) of intracranial GBM and improved survival. Whenever feasible, complete surgical removal of the tumour is recommended.

Prognostic value of preoperative hematological markers in patients with glioblastoma multiforme and construction of random survival forest model

ObjectiveIn recent years, an increasing number of studies have revealed that patients’ preoperative inflammatory response, coagulation function, and nutritional status are all linked to the occurrence, development, angiogenesis, and metastasis of various malignant tumors. The goal of this study is to determine the relationship between preoperative peripheral blood neutrophil to lymphocyte ratio (NLR), monocyte to lymphocyte ratio (MLR), systemic immune-inflammatory index (SII), platelet to lymphocyte ratio (PLR), and platelet to fibrinogen ratio (FPR). Prognostic nutritional index (PNI) and the prognosis of glioblastoma multiforme (GBM) patients, as well as establish a forest prediction model that includes preoperative hematological markers to predict the individual GBM patient’s 3-year survival status after treatment.MethodsThe clinical and hematological data of 281 GBM patients were analyzed retrospectively; overall survival (OS) was the primary endpoint. X-Tile software was used to determine the best cut-off values for NLR, SII, and PLR, and the survival analysis was carried out by the Kaplan–Meier method as well as univariate and multivariate COX regression. Afterward, we created a random forest model that predicts the individual GBM patient’s 3-year survival status after treatment, and the area under the curve (AUC) is used to validate the model’s effectiveness.ResultsThe best cut-off values for NLR, SII, and PLR in GBM patients’ preoperative peripheral blood were 2.12, 537.50, and 93.5 respectively. The Kaplan–Meier method revealed that preoperative GBM patients with high SII, high NLR, and high PLR had shorter overall survival, and the difference was statistically significant. In addition to clinical and pathological factors. Univariate Cox showed NLR (HR = 1.456, 95% CI: 1.286 ~ 1.649, P < 0.001) MLR (HR = 1.272, 95% CI: 1.120 ~ 1.649, P < 0.001), FPR (HR = 1.183,95% CI: 1.049 ~ 1.333, P < 0.001), SII (HR = 0.218,95% CI: 1.645 ~ 2.127, P < 0.001) is related to the prognosis and overall survival of GBM. Multivariate Cox proportional hazard regression showed that SII (HR = 1.641, 95% CI: 1.430 ~ 1.884, P < 0.001) is also related to the overall survival of patients with GBM. In the random forest prognostic model with preoperative hematologic markers, the AUC in the test set and the validation set was 0.907 and 0.900, respectively.ConclusionHigh levels of NLR, MLR, PLR, FPR, and SII before surgery are prognostic risk factors for GBM patients. A high preoperative SII level is an independent risk factor for GBM prognosis. The random forest model that includes preoperative hematological markers has the potential to predict the individual GBM patient’s 3-year survival status after treatment,and assist the clinicians for making a good clinical decision.

Abstract 3100: The development of pleotropic small molecule kinase inhibitors (SKMIs) for the treatment of glioblastoma multiforme (GBM)

Abstract Glioblastoma multiforme (GBM) is an aggressive stage IV brain cancer that is difficult to detect, typically inoperable, and associated with a poor prognosis. Challenges in targeting GBM arise from the involvement of various pro-survival pathways, being comprised of four different cellular states, and displaying heterogeneity between each tumor. Marketed FDA-approved drugs for GBM have demonstrated limited efficacy, toxicity issues, resistance, and poor BBB penetrance. Further probing into pathway breakdowns led to the discovery of the DYRKs (dual-specificity tyrosine-regulated kinase), CLKs (CDC-like kinases), PDGFRA/B (platelet-derived growth factor receptor), and PI3Kα (phosphoinositide 3-kinase) involvement and overexpression. The upregulation of these kinases are found to be prominently involved in GBM cell proliferation, survival, replication, aggression, metastasis, and resistance. Herein, we believe that the development of pleiotropic competitive inhibitors for the treatment of GBM could be a promising therapeutic option based on literature precedence and current data from research. DYR726, a water-soluble, pleiotropic inhibitor [IC50 PDGFRA/B/PI3Kα/CLk2/3DYRK1a/2/3 ( 53.0/48.0/6.2/15.13/137/4/38.6/11.2 nM)] has demonstrated in vitro cellular efficacy across various GBM cell lines. When treated in non-cancerous cell lines, DYR726 displayed an optimal therapeutic window, which is not observed in any glioma drugs currently in clinical trials. At 1µM concentrations, complete dissociation of the formation of neural stem cells and neurosphere growth in glioma cells are observed. Reduction in metastasis and proliferation are found when treated with DYR726 over three weeks. In vitro efficacy against current approved FDA treatment options and clinical candidates has been extensively tested across numerous GBM cell lines. When benched against one of the best PI3K kinase inhibitors in the clinic, Buparlisib, DYR726 was comparable, indicating a disruption in the RTK signaling survival pathway that is commonly associated with GBM. DYR726 performed favorably against Avapritinib (clinical trials for gliomas are beginning at Stanford) and when treated against FDA-approved combination treatment Dabrafenib+Trametinib (for 2% of glioma patients), it performed identically, suggesting that DYR726 can inhibit the cells at the same rate as the new FDA drug. Within patient-derived cell lines, it behaves identically to Buparlisib, and DYR726 has been shown to outperform AstraZenecas’ Osimertinib (which was significantly less potent) and Tafinlars’ Dabrafenib (displayed no effect). Based on the significance of efficacy, this series is on the CRUK Glasgow Cancer Center grant renewal as a potential Phase 0 within the next five years. Citation Format: Alessandra Fistrovich, Vasudah Tandon, Carly Cabel, Laura Basantes, Curtis Thorne, William Montfort, Sourav Banerjee, Christopher Hulme. The development of pleotropic small molecule kinase inhibitors (SKMIs) for the treatment of glioblastoma multiforme (GBM) [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3100.

Cellular and molecular features related to exceptional therapy response and extreme long-term survival in glioblastoma.

Glioblastoma Multiforme (GBM) remains the most common malignant primary brain tumor with a dismal prognosis that rarely exceeds beyond 2 years despite extensive therapy, which consists of maximal safe surgical resection, radiotherapy, and/or chemotherapy. Recently, it has become clear that GBM is not one homogeneous entity and that both intra-and intertumoral heterogeneity contributes significantly to differences in tumoral behavior which may consequently be responsible for differences in survival. Strikingly and in spite of its dismal prognosis, small fractions of GBM patients seem to display extremely long survival, defined as surviving over 10 years after diagnosis, compared to the large majority of patients. Although the underlying mechanisms for this peculiarity remain largely unknown, emerging data suggest that still poorly characterized both cellular and molecular factors of the tumor microenvironment and their interplay probably play an important role. We hereby give an extensive overview of what is yet known about these cellular and molecular features shaping extreme long survival in GBM.

Dendritic Cells as Adjuvant Therapy to Decrease Mortality for Glioblastoma Patients: Meta-Analysis

Highlight: Dendritic cells (DC) are one type of immune therapy that is being explored to improve treatment effectiveness in glioblastoma multiforme (GBM). DC was predicted to improve survival rates in GBM patients within 3 years. Effects of DC in the fifth year need to be explored to prove their. effectiveness in increasing the GBM survival rate. ABSTRACT Introduction: Glioblastoma multiforme (GBM) is a primary neoplasm of the central nervous system with a low survival rate, requiring more effective treatment to improve long-term survival. Dendritic cell (DC) therapy is expected to reduce tumor progressivity. Obective: The purpose of this meta-analysis was to analyze the administration of DC in reducing mortality in GBM patients. Methods: A systematic literature search was conducted using the PRISMA method through the Embase database, PubMed, and the Cochrane Controlled Trials Register for relevant studies between giving DC to GBM patients with conventional therapy on the number of living patients compared to controls. Article quality was assessed using the Newcastle-Ottawa Scale and statistically analyzed using RevMan 5.4. Results: Of the 14 articles, the rates of reduction in the probability of death during the first three years after initiation of therapy were 26%, 36%, and 38%, respectively [1st-y HR: 0.74 (0.57-0.95), I2: 15%, p=0.02; 2nd-y HR: 0.64 (0.51-0.81), I2: 14%, p=0.0002; 3rd-y HR: 0.62 (0.48-0.81), I2: 0%, p=0.0004]. However, there was no difference after 5 years [HR 0.81 (0.62-1.06), I2: 0%, p=0.13]. Conclusion: The DC vaccine reduces the likelihood of death in the early years of therapy but has not been proven for long-term therapy.

Survival Analysis and Factors Affecting Treatment Outcome in Glioblastoma Multiforme: A Cohort Study

Introduction: High-grade gliomas, especially Glioblastoma Multiforme (GBM), are the most prevalent primary brain tumours in adults. Treating GBM is challenging due to resistant tumour cells, resulting in a dismal prognosis. While GBM often develops spontaneously, familial gliomas have also been identified in 1% of cases. Primary and secondary glioblastoma are the subtypes that affect patients of varying ages and develop via different paths. Aim: To estimate the two year survival and to assess factors affecting survival in patients diagnosed with GBM and to evaluate the “ability for self-care” following treatment. Materials and Methods: The cohort study investigated treatment outcomes in GBM using a sample of 65 patients from the Department of Radiation Oncology at Government Medical College Thrissur, a tertiary care centre in Kerala, India. The patients were diagnosed between January 2018 and December 2019. Survival and the factors determining survival were explored through case records and telephonic interviews with primary caregivers. Median survival and two year survival rates were calculated. The study examined possible associations of survival with patient-related, tumourrelated, and treatment-related factors. Patient-related factors assessed were age, gender, and Eastern Cooperative Oncology Group (ECOG) performance status at diagnosis. Tumour-related factors assessed included tumour location, laterality, and volume based on pretreatment Magnetic Resonance Imaging (MRI). Treatment-related factors such as extent of surgery, postoperative radiotherapy, and chemotherapy were also assessed. Data analysis was performed using the Statistical Package for Social Sciences (SPSS version 21.0). Qualitative variables were expressed in percentage and compared using the Chi-square test or Fisher’sexact test. Quantitative variables were expressed as mean and standard deviation and compared using unpaired t-tests. Telephonic interviews with primary caregivers were conducted to assess the “ability for self-care” following treatment. Results: The study included a total of 65 cases, with a mean patient age of 54 years. Out of the patients, 45 (68%) patients were male, while 20 (32%) patients were female. The median survival for GBM was found to be eight months. The one year and two year survival rates were 18.46% (12 patients) and 10.8% (7 patients), respectively. The survivors had a mean age of 48 years. There were no statistically significant differences in survival based on sex (p-value=0.527), tumour location (p-value=0.765), and laterality (p-value=0.596). Survival was found to be related to ECOG performance status at diagnosis (p-value=0.001) and tumour volume (p-value=0.002). Among the patients, 37 (58%) patients were able to perform self-care after treatment, while 28 (42%) patients were unable to do so. Conclusion: The survival of patients with GBM is related to ECOG performance status at diagnosis and the pretreatment volume of the tumour. The evidence was insufficient to establish a relationship between survival and the administration of postoperative radiotherapy and chemotherapy. Despite multimodality treatment protocols, the survival of patients with GBM remains dismal. A tailored treatment protocol that weighing morbidity of treatment and cost effectiveness on one side and survival on the other side is the need of the hour.

DNAR-04. BOTH P53 CODON 72 ARG/ARG AND PRO/ARG GENOTYPES IN GLIOBLASTOMA MULTIFORME PATIENTS HAVE A BETTER PROGNOSIS IN BEVACIZUMAB TREATMENT

Abstract BACKGROUND In glioblastoma multiforme (GBM), bevacizumab increased progression-free survival but it has failed to improve overall survival (OS) in controlled trials. This study, therefore, aimed to retrospectively analyze the polymorphisms of p53 codon 72 and the clinical characteristics of GBM specimens from Taiwanese patients. METHODS The polymorphisms of p53 codon 72 in 99 patients with GBM treated at Taichung Veterans General Hospital in Taiwan from 2007 to 2017 were analyzed using direct DNA sequencing and PCR-RFLP analysis. RESULTS We found that among these GBM patients, the polymorphisms of p53 codon 72 were not directly associated with the overall survival of GBM, both the Arg/Arg and Arg/Pro genotypes were associated with significant benefits in terms of overall survival in patients treated with CCRT plus bevacizumab compared to patients treated with CCRT alone. CONCLUSIONS This pilot study suggests that both the Arg/Arg and Arg/Pro genotypes of p53 codon 72 polymorphism may have value as independent prognostic or predictive parameters for bevacizumab treatment response and failure. Relatedly, the results of the study further demonstrate the utility of stratifying GBM patientsaccording to bevacizumab sensitivity.