Search Results (129)

Temozolomide (TMZ) remains the cornerstone of chemotherapeutic agent for glioblastoma (GBM), yet intrinsic and acquired resistance severely limits its clinical benefit. While O⁶-methylguanine-DNA methyltransferase (MGMT)–mediated repair of TMZ-induced O6-methylguanine (O⁶-meG) lesions has been extensively studied, the DNA mismatch repair (MMR) pathway is increasingly recognized as a key determinant of TMZ cytotoxicity. Canonical MMR, mediated by MutSα (MSH2–MSH6) and MutLα (MLH1–PMS2) complexes, recognizes O⁶-meG: thymine mispairs generated during replication and initiates futile repair cycles that culminate in replication stress, replication fork collapse, and apoptotic signaling; intact canonical MMR is, therefore, required for TMZ-induced cell death. Disruption of canonical MMR, frequently via acquired MSH6 mutations, confers TMZ tolerance and drives hypermutated recurrent GBM. Beyond mismatch correction, MMR proteins perform non-canonical functions in DNA damage signaling, replication stress responses, transcriptional regulation, chromatin dynamics, and immune modulation. These activities may shift the outcome from cytotoxic futile repair toward replication stress adaptation, Translesion synthesis (TLS)-mediated lesion tolerance, immune remodeling, and therapeutic resistance. Notably, partial attenuation or functional diversion of MMR may decouple lesion recognition from cytotoxic signaling, enabling TLS-mediated lesion tolerance without complete loss of MMR activity. This review integrates current insights into canonical and non-canonical MMR functions in GBM, defines their distinct contributions to TMZ sensitivity and resistance, and highlights therapeutic opportunities to exploit MMR-associated dependencies, including synthetic lethal strategies and immunotherapeutic vulnerabilities linked to MMR deficiency-driven hypermutation. Full article

Background/Objectives: Glioblastoma (GBM) comprises a contrast-enhancing (CE) mass and peritumoral hyperintensity on fluid-attenuated inversion recovery (FLAIR) on magnetic resonance imaging (MRI). Although a smaller residual FLAIR lesion volume (FLV) after gross total resection (GTR) is associated with longer survival, the clinical observation of rapid FLV reduction within the first postoperative month remains unknown. We evaluated the independent prognostic contributions of early and late FLV reduction in patients with newly diagnosed GBM, isocitrate dehydrogenase (IDH)-wildtype, who underwent GTR. Methods: In a retrospective cohort of 51 adults with GBM, IDH-wildtype, who underwent GTR and standard chemoradiotherapy, semi-automated FLV was measured on MRI preoperatively, immediately postoperatively (FLV0), at 1 month (FLV1), and at 3 months (FLV3). FLV changes were expressed as percentage changes relative to the preceding timepoint (ΔFLV0-1, ΔFLV1-3). Using a 3-month landmark analysis, multivariable Cox models for overall survival (OS) were fitted, adjusted for age, O6-methylguanine-DNA-methyltransferase promoter (pMGMT) methylation, and postoperative Karnofsky Performance Status (KPS). Results: In the multivariable 3-month landmark analysis, each 10-percentage-point early FLV reduction (∆FLV0-1^[10-pp]) was associated with lower mortality risk (hazard ratio [HR] 0.91, 95% confidence interval [CI] 0.82–0.99, p = 0.037) whereas a late FLV reduction (∆FLV1-3^[10-pp]) showed a smaller association with OS (HR 0.99, 95% CI 0.98–1.00, p = 0.043). In an exploratory dichotomized analysis at a 20% reduction threshold, early responders (∆FLV0-1 ≥ 20%) had markedly better OS (HR 0.33, p = 0.010). Conclusions: In selected patients with GBM, IDH-wildtype, who achieved radiographic GTR and received standard chemoradiotherapy, early postoperative FLV reduction at 1 month independently predicted longer OS, with a substantially larger effect than late reduction. Prospective multi-center validation is required before clinical implementation. Full article

Chronic exposure to fine particulate matter (${\mathrm{PM}}_{2.5}$) derived from residential wood combustion is a major environmental health concern in southern Chile and other cold-climate regions. Although ${\mathrm{PM}}_{2.5}$ has been linked to adverse reproductive outcomes, it remains unclear whether sustained exposure induces pregestational uterine alterations that compromise reproductive competence before the first pregnancy. This study evaluated the effects of chronic wood smoke-derived ${\mathrm{PM}}_{2.5}$ exposure on uterine morphology and molecular markers in nulliparous rats. A two-generation exposure model was used to assess cumulative effects. Second-generation (G2) female Sprague Dawley rats continuously exposed from conception were housed in filtered air (FA, control; $n=12$) or ${\mathrm{PM}}_{2.5}$-containing ambient air (NFA; $n=12$) until reproductive maturity (82 days). Uterine horns were analyzed by histology, planimetry, immunohistochemistry, immunofluorescence, and second harmonic generation microscopy. Markers of hypoxia, inflammation, extracellular matrix remodeling, angiogenesis, proliferation, apoptosis, and DNA repair were quantified. Chronic ${\mathrm{PM}}_{2.5}$ exposure increased hypoxia-inducible factor 1$\alpha$, tumor necrosis factor-$\alpha$, vascular endothelial growth factor A, and collagen types I, III, and IV, while transforming growth factor-$\beta$ expression and Ki-67-positive proliferating cells were reduced. Exposed rats showed increased apoptosis and decreased nuclear expression of ${\mathrm{O}}^6$-methylguanine-DNA methyltransferase, indicating impaired DNA repair capacity. Second harmonic generation imaging demonstrated increased collagen deposition with marked fibrillar disorganization. These findings indicate that chronic wood smoke-derived ${\mathrm{PM}}_{2.5}$ exposure induces hypoxia-driven structural and molecular alterations in the uterus of nulliparous rats before first pregnancy, including extracellular matrix remodeling, inflammatory imbalance, angiogenic dysregulation, reduced proliferation, and compromised DNA repair, suggesting early disruption of uterine homeostasis and increased susceptibility to adverse reproductive outcomes. Full article

Background: Severe neurocognitive decline is often seen in elderly glioblastoma patients after treatment with radiation and chemotherapy. But the mechanism behind their deterioration is unclear. We describe one such patient with concomitant primary age-related tauopathy (PART) in bilateral hippocampi. Case presentation: An 88-year-old woman experienced unsteadiness, memory loss, and slurred speech that was caused by an epithelioid glioblastoma with wild-type isocitrate dehydrogenase-1 and methylated promoter of O⁶-methylguanine-DNA methyltransferase. She was treated with gross total resection, followed by intensity-modulated radiotherapy and daily temozolomide. Shortly after starting treatment, she developed fatigue, anorexia, and neurocognitive impairment, which were refractory to corticosteroids. After two cycles of adjuvant temozolomide, she experienced impulsivity, disorientation, hallucinations, somnolence, and incontinence despite stable neuroimaging findings. Treatment was subsequently discontinued, and she died 20 months from the time of her glioblastoma diagnosis. Autopsy revealed tau-positive neurofibrillary tangles, but rare Aβ plaques, in the trans-entorhinal and entorhinal cortices of both hippocampi. These findings are consistent with a diagnosis of PART. Conclusions: Undiagnosed tauopathy could be a negative modifier of glioblastoma treatment. The identification of PART and other tauopathies as risk factors in the elderly population may be important to guide treatment decision. Full article

Glioblastoma (GB) classical treatment with the alkylating drug temozolomide (TMZ) is not effective mainly due to chemoresistance mechanisms, particularly those mediated by O6-methylguanine-DNA methyltransferase (MGMT). In this context, polyethylene glycol (PEG)-coated poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) were developed to deliver tamoxifen (TAX), a clinically approved non-alkylating drug with reported anti-GB activity. The NP formulation was optimized using a factorial design and subsequently functionalized with lactoferrin (Lf) to enhance GB targeting. The Lf-conjugated optimized formulation exhibited a mean diameter of 193 ± 6 nm, a polydispersity index (PDI) of 0.11 ± 0.04, a zeta potential of −18.2 ± 6.8 mV, and an encapsulation efficiency (EE) of 68.6 ± 1.8%. The NPs exhibited a sustained release profile for up to 23 days, and remained stable under physiological conditions. Cell uptake studies, conducted in human GB cells (U87, U251, and T98G) and healthy astrocytes, demonstrated enhanced internalization of Lf-NPs in GB cells compared with non-conjugated NPs, suggesting uptake through Lf-binding site-mediated endocytosis. Cytotoxicity assays further indicated that Lf-conjugation improved the antiproliferative efficacy of TAX-loaded NPs relative to non-functionalized formulations, particularly in GB cells. Moreover, combination studies with TMZ showed that the developed NPs were able to sensitize GB cells to treatment with this alkylating agent. In sum, this work supports the potential of the developed Lf-decorated TAX-loaded PLGA NPs as a nanoplatform for targeted delivery against GB. Full article

Background: Clinical target volume (CTV) delineation in glioblastoma remains debated, particularly in the era of modern chemoradiation and image-guided radiotherapy. Whether reduced CTV margins can preserve oncological outcomes without increasing marginal or out-of-field failures remains uncertain. We evaluated the association of the gross tumor volume (GTV)-to-CTV margin with survival, patterns of failure, and its interaction with O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status. Materials and Methods: We retrospectively analyzed a single-center cohort of patients with glioblastoma treated with conventionally fractionated chemoradiation (58–60 Gy in 29–33 fractions). Patients were categorized into two predefined margin groups: <1.5 cm and 1.5 cm. The primary endpoint was overall survival (OS); secondary endpoints included progression-free survival (PFS) and patterns of failure. Survival was assessed using Kaplan–Meier estimates and Cox regression, including an interaction term with MGMT status. Results: Among 102 eligible patients, 95 were included in the margin-based OS analysis. Reduced margins (<1.5 cm; applied range 1.0–1.4 cm) were not associated with worse OS, either overall or within MGMT subgroups. No significant differences were observed in PFS or recurrence patterns, with overlapping distributions and no increase in marginal or out-of-field recurrences. MGMT methylation and gross total resection were independently associated with improved survival, while no statistically significant interaction between margin and MGMT status was detected. Conclusions: In this retrospective exploratory cohort, reduced GTV-to-CTV margins were not associated with a clear signal of worse survival or less favorable recurrence patterns. These findings are consistent with the oncological adequacy of margins around 15 mm and justify cautious prospective evaluation of whether further reduction can be achieved safely, including formal assessment of toxicity, neurocognitive outcomes, and quality of life. Full article

Background: Among adult primary brain tumours, glioblastoma (GBM) carries the worst prognosis. Magnetic resonance imaging (MRI) serves to diagnose and guide treatment, despite recognised constraints. Advanced MRI techniques—magnetic resonance spectroscopy (MRS), amide proton transfer-weighted imaging (APTw), diffusion-weighted imaging (DWI), perfusion-weighted imaging (PWI), and quantitative susceptibility mapping (QSM)—reveal GBM characteristics that conventional sequences cannot detect. The 2021 World Health Organization reclassification disrupted established imaging–biology relationships, necessitating isocitrate dehydrogenase wildtype (IDHwt) GBM-specific evidence integration. This review synthesises biological insights provided by advanced MRI in preoperative IDHwt GBM. Methods: We conducted a scoping review following the PRISMA-ScR framework, querying five databases (PubMed, Scopus, Cochrane, EBSCO, and Embase) to identify literature using advanced MRI to investigate biological correlates in IDHwt GBM. Results: MRS ratios were associated with tumour presence and Ki-67 expression. APTw demonstrated robust associations with cellularity but failed to predict O6-methylguanine-DNA methyltransferase promoter (MGMTp) methylation. DWI exhibited variable utility; certain metrics linked to cellularity, while apparent diffusion coefficient values were inconsistent but useful for predicting MGMTp status, telomerase reverse transcriptase promoter mutations, and CD163+ macrophage infiltration. PWI showed relationships with cellularity, micro-vessel area, and MGMTp status. QSM features correlated with Ki-67, ferritin, and immune markers. Conclusions: Advanced MRI demonstrates potential for biological stratification of GBM, though protocol variability and limited reproducibility hinder clinical translation. Standardised pipelines and prospective multicentre validation must precede clinical adoption, before these techniques can benefit patients. Full article

Background: The prognosis of glioblastoma (GBM) patients remains poor. Dendritic cell (DC) vaccination has been investigated as an immunotherapy option, mainly in early-phase clinical studies. Herein, we report the feasibility, safety, and descriptive clinical and radiological outcomes of a retrospective series of newly diagnosed GBM patients treated with standard radio-chemotherapy and autologous DC vaccination as compassionate use. Methods: We retrospectively reviewed the medical and radiological records of patients with newly diagnosed GBM who received autologous tumor lysate–pulsed DC vaccination in addition to standard-of-care treatment at a tertiary academic center between 2009 and 2017. Clinical data, treatment characteristics, adverse events, survival outcomes, and radiological responses were collected and analyzed descriptively. Results: Twenty-four patients were included. All patients underwent surgical resection and were further treated with autologous tumor lysate–DC vaccination and standard radio-chemotherapy. Histology of GBM was confirmed in all patients. The first vaccine was administered in 75% of patients after a median of 21 days (range: 6–30 days) following surgery and prior to radiotherapy initiation. DC vaccination was continued following radiotherapy at specific time points, with no observed significant adverse events. Median OS was 21.1 months (95% CI, 27.9–75.0 months), and median PFS was 10.3 months (95% CI, 15.6–26.6 months). Presence of O6-methylguanine DNA methyltransferase (MGMT) promoter methylation was associated with longer survival and higher 12-month PFS rates, consistent with its established prognostic value. Radiological responses were retrospectively assessed according to RANO and RANO 2.0 criteria. Conclusions: In this retrospective single-center series, autologous DC vaccination administered as compassionate use in combination with standard radio-chemotherapy was feasible and safe in routine clinical practice. Survival and radiological outcomes are reported descriptively and should be interpreted with caution given the absence of a control cohort. These findings support further prospective controlled studies to properly assess the clinical role of DC vaccination in newly diagnosed GBM. Full article

Gliomas are among the most challenging brain tumors to treat, owing to their marked heterogeneity and the aberrant signaling networks that sustain tumor growth and resistance to therapy. Quercetin, a dietary flavonoid widely found in fruit and vegetables, exhibits documented anticancer activity, prompting the development of optimized derivatives with improved biological potency. In earlier work, we synthesized and evaluated a series of quercetin derivatives and identified the acylated compound 3-O-decanoylquercetin (Q-3-Dec) as particularly effective in reducing glioma cell viability. In this study, we explored Q-3-Dec as a multi-target agent, which concomitantly impairs NF-κB/STAT3-dependent survival signaling, mitochondrial function, and O6-Methylguanine-DNA Methyltransferase (MGMT) expression, a DNA repair enzyme closely associated with chemoresistance, in glioma cells. In U373-MG glioma cells, treatment with 50 μM Q-3-Dec triggered pronounced, time-dependent morphological changes and an early loss of mitochondrial membrane potential after 3 h. With prolonged exposure, Q-3-Dec markedly decreased NF-κB and STAT3 phosphorylation and reduced the expression of the anti-apoptotic proteins Bcl-2 and survivin, alongside a significant decrease in MGMT levels. These combined effects culminated in a progressive increase in cell death, reaching approximately 30% after 48 h. Together, these findings position Q-3-Dec as a multi-node modulator of glioma survival, supporting its potential for further preclinical development to improve future therapeutic strategies against glioma. Full article

Background/Objectives: Although O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a key predictive biomarker in glioblastoma, its association with clinical and lifestyle characteristics remains poorly understood. Methods: We retrospectively analyzed 105 patients who underwent surgical treatment for glioblastoma at Kyungpook National University Hospital between August 2012 and April 2022 to evaluate the relationship between MGMT promoter methylation status and clinical and lifestyle factors. Collected variables included age, sex, body weight, body height, smoking history, and comorbidities such as hypertension, diabetes mellitus, and hyperlipidemia. Results: Current smoking was significantly associated with MGMT promoter methylation in both univariate and multivariate analyses (adjusted odds ratio [OR], 4.6; p = 0.03). Additionally, a history of hypertension was associated with MGMT promoter methylation after multivariate adjustment (adjusted OR, 3.6; p = 0.03). Conclusions: MGMT promoter methylation in glioblastoma was associated with current smoking and a history of hypertension, suggesting lifestyle-related factors may influence epigenetic mechanisms underlying MGMT promoter methylation in glioblastoma. Full article

Precise molecular characterization of glioblastoma (GB) is fundamental for accurate risk stratification and therapeutic planning. DNA methylation profiling reliably identifies key molecular features, including O(6)-methylguanine-DNA methyltransferase (MGMT) promoter methylation status and specific molecular subtypes, such as receptor tyrosine kinase (RTK) I and II, and the mesenchymal (MES) subtype. In this study, we investigated the hypothesized correlation between these molecular profiles and preferential tumor locations, which could reveal a link to underlying tumor biology. We analyzed 227 GB patients characterized by DNA methylation profiling. To map significant clusters of tumor occurrence across subtypes and subcomponents, we performed voxel-wise analysis of differential involvement, utilizing 500 permutations to correct for multiple comparisons. While uncorrected frequency differential maps suggested localization tendencies for the RTK I, RTK II, and MES subtypes, stringent statistical correction revealed only one robust association: the non-enhancing component of MES tumors showed significant clustering in the left frontal lobe, the insula, and the temporal lobe. Contrary to prior literature, we observed no significant hemispheric preference regarding MGMT promoter methylation status. Our findings challenge prior assumptions regarding the spatial distinctiveness of GB subtypes and highlight the need to further elucidate the mechanisms governing tumorigenesis and spatial growth patterns. Full article

Despite technological progress, glioblastoma (GBM) continues to confer dismal prognoses. Modern neuroimaging methods are assuming an ever greater role in diagnosing and monitoring brain tumors. This review shows current neuroimaging approaches and systemic therapeutic strategies for glioblastoma, with a focus on emerging and innovative treatments. Advances in multiparametric magnetic resonance imaging—MRI (diffusion, perfusion, and spectroscopy) and novel positron emission tomography (PET) tracers, complemented by radiomics and artificial intelligence (AI), now refine tumor delineation, differentiate progression from treatment effects, and may help predict treatment responses. Maximal safe resection followed by chemoradiotherapy with temozolomide remains the standard, with the greatest benefit seen in O⁶-methylguanine DNA methyltransferase (MGMT) promoter-methylated tumors. Bevacizumab and other targeted modalities offer mainly progression-free, not overall survival, gains. Immune checkpoint inhibitors (e.g., nivolumab) have not improved survival in unselected GBM, while early multi-antigen CAR-T (chimeric antigen receptor T-cell) strategies show preliminary bioactivity without established durability. While actionable alterations (NTRK fusions and BRAF V600E) justify selective targeted therapy trials, their definitive benefit in classical GBM is unproven. Future priorities include harmonized imaging molecular integration, AI-driven prognostic modeling, novel PET tracers, and strategies to breach or transiently open the blood–brain barrier to enhance drug delivery. Convergence of these domains may convert diagnostic precision into improved patient outcomes. Full article

Background: This narrative review summarizes recent progress in artificial intelligence (AI), especially radiomics and deep learning, for non-invasive diagnosis and molecular profiling of gliomas. Methodology: A thorough literature search was conducted on PubMed, Scopus, and Embase for studies published from January 2020 to July 2025, focusing on clinical and technical research. In key areas, these studies examine AI models’ predictive capabilities with multi-parametric Magnetic Resonance Imaging (MRI) and Positron Emission Tomography (PET). Results: The domains identified in the literature include the advancement of radiomic models for tumor grading and biomarker prediction, such as Isocitrate Dehydrogenase (IDH) mutation, O6-methylguanine-dna methyltransferase (MGMT) promoter methylation, and 1p/19q codeletion. The growing use of convolutional neural networks (CNNs) and generative adversarial networks (GANs) in tumor segmentation, classification, and prognosis was also a significant topic discussed in the literature. Deep learning (DL) methods are evaluated against traditional radiomics regarding feature extraction, scalability, and robustness to imaging protocol differences across institutions. Conclusions: This review analyzes emerging efforts to combine clinical, imaging, and histology data within hybrid or transformer-based AI systems to enhance diagnostic accuracy. Significant findings include the application of DL to predict cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion and chemokine CCL2 expression. These highlight the expanding capabilities of imaging-based genomic inference and the importance of clinical data in multimodal fusion. Challenges such as data harmonization, model interpretability, and external validation still need to be addressed. Full article

Glioblastoma multiforme (GBM), the most aggressive primary brain tumor in adults, has a poor prognosis due to rapid recurrence and treatment resistance. This review examines the evolution of radiotherapy (RT) for GBM management, from whole-brain RT to modern techniques like intensity-modulated RT (IMRT) and volumetric modulated arc therapy (VMAT), guided by 2023 European Society for Radiotherapy and Oncology (ESTRO)-European Association of Neuro-Oncology (EANO) and 2025 American Society for Radiation Oncology (ASTRO) recommendations. The standard Stupp protocol (60 Gy/30 fractions with temozolomide [TMZ]) improves overall survival (OS) to 14.6 months, with greater benefits in O6-methylguanine-DNA methyltransferase (MGMT)-methylated tumors (21.7 months). Tumor Treating Fields (TTFields) extend median overall survival (mOS) to 31.6 months in MGMT-methylated patients and 20.9 months overall in supratentorial GBM (EF-14 trial). However, 80–90% of recurrences occur within 2 cm of the irradiated field due to tumor infiltration and radioresistance driven by epidermal growth factor receptor (EGFR) amplification, phosphatase and tensin homolog (PTEN) mutations, cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletions, tumor hypoxia, and tumor stem cells. Pseudoprogression, distinguished using Response Assessment in Neuro-Oncology (RANO) criteria and positron emission tomography (PET), complicates response evaluation. Targeted therapies (e.g., bevacizumab; PARP inhibitors) and immunotherapies (e.g., pembrolizumab; oncolytic viruses), alongside advanced imaging (multiparametric magnetic resonance imaging [MRI], amino acid PET), support personalized RT. Ongoing trials evaluating reirradiation, hypofractionation, stereotactic radiosurgery, neoadjuvant therapies, proton therapy (PT), boron neutron capture therapy (BNCT), and AI-driven planning aim to enhance efficacy for GBM IDH-wildtype, but phase III trials are needed to improve survival and quality of life. Full article

Background/Objectives: The conventional treatment of glioblastoma (GBM) with alkylating agents is not curative. The protein O6-methylguanine DNA methyltransferase (MGMT) is a significant limitation, being able to repair drug-induced DNA damage. Thus, exploring non-alkylating agents already approved by the FDA is imperative. The antidepressant fluoxetine (FL) has been explored due to its anti-cancer properties. However, its first-pass effect and its non-targeted distribution to brain tissue are major limitations of FL’s administration, which is conventionally orally administered. Thus, the primary objective of this work was the development of poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs) tailored with folic acid (FA) for FL delivery to GBM cells. Methods: A Central Composite Design (CCD) was applied to optimize the NPs. Results: The developed FA-functionalized PLGA NPs exhibited physicochemical properties suitable for brain-targeted delivery. The final formulation presented an average diameter of 167 ± 8 nm, a polydispersity index (PdI) of 0.23 ± 0.07, and a zeta potential of −22.2 ± 0.3 mV. The encapsulation efficiency (EE) and loading capacity (LC) values were 44.4 ± 3.8% and 3.1 ± 0.3%, respectively. In vitro studies demonstrated that the NPs are stable in storage and simulated physiological conditions and can maintain a controlled and slow-release profile of FL for 17 days. In vitro cell uptake experiments demonstrated that conjugation with FA enhances the NPs’ internalization in GBM cells overexpressing folate receptors through endocytosis mediated by this receptor. Furthermore, in vitro cytotoxicity experiments demonstrated that the FL encapsulation in the developed NPs maintains drug efficacy, as well as it was able to increase cell sensitivity to treatment with an alkylating agent. Conclusions: These results suggest that the developed NPs are effective nanocarriers, either as a standalone therapy or as a chemosensitizer in combination with the standard GBM treatment. Full article