Search Results (600)

Glioblastoma (GBM) is the most prevalent and devastating form of primary brain tumors in adults, with dismal survival despite advancements in treatment modalities. The current study sought to develop clinically significant prognostic models for GBM patients by comprehensively profiling MGMT, NUPR1, NDRG2, and GLI1 gene promoter methylation in GBM tissues vs. non-neurooncological disease (NND) and their association with clinical characteristics and therapeutic outcome. This was further evaluated by in silico functional enrichment analysis. NUPR1, NDRG2, and GLI1 gene promoter methylation were significant epigenetic discriminators between GBM and NND. However, NDRG2 methylation was the sole independent predictor for neoplastic lesions (OR = 1.71, 95% CI [1.25–3.57], p = 0.028). Multivariable Cox regression analysis revealed that NUPR1 promoter hypermethylation was significantly correlated with a lower risk of mortality (HR = 0.96, 95% CI [0.96–0.99], p = 0.002), while multiple tumor sites were linked to an increased risk of mortality in the univariate model (HR = 4.44, 95% CI [1.42–13.88], p = 0.01). A heatmap correlation matrix identified a robust positive correlation among the MGMT and NUPR1 methylation status (r = 0.93, p < 0.001). NUPR1 and MGMT promoter hypermethylation was associated with a favorable response to temozolomide therapy. Patients with NUPR1 and MGMT hypermethylation exhibited extended OS and PFS compared to those with hypomethylation levels, whereas GLI1 and NDRG2 hypermethylation were linked to shorter PFS. In conclusion, the multi-faceted epigenetic panel adopted in the current study captures different aspects of GBM biology and moves towards a more comprehensive model that reflects the molecular heterogeneity of GBM as insights for personalized therapy. Full article

Accurate brain tumor segmentation in both adult and pediatric populations remains a challenge due to substantial differences in brain anatomy, tumor distribution, and subregion size. This study proposes a unified segmentation framework based on nnU-Net, integrating encoder-level self-supervised pretraining with a lightweight, boundary-aware decoder. The encoder is initialized using a large-scale 3D masked autoencoder pretrained on brain MRI, while the decoder is trained with a hybrid loss function that combines region-overlap and boundary-sensitive terms. A harmonized training and evaluation protocol is applied to both the BraTS-GLI (adult) and BraTS-PED (pediatric) cohorts, enabling fair cross-cohort comparison against baseline and advanced nnU-Net variants. The proposed method improves mean Dice scores from 0.76 to 0.90 for adults and from 0.64 to 0.78 for pediatric cases, while reducing HD95 from 4.42 to 2.24 mm and from 9.03 to 6.23 mm, respectively. These results demonstrate that combining encoder-level pretraining with decoder-side boundary supervision significantly enhances segmentation accuracy across age groups without adding inference-time computational overhead. Full article

Background: Glioblastoma multiforme (GBM), the most aggressive primary brain malignancy in adults, is associated with poor prognosis and recurrence despite standard of care and newer immunotherapies. This warrants exploration of synergistic approaches such as combination immunotherapy for improved tumor control. Methods: We initiated a systematic review of articles from 2015–2025 in PubMed, Embase, Scopus, Cochrane, and Web of Science if they assessed immunotherapy for GBM. Results: We included 49 studies (n = 3002 patients) with no significant demographic differences across publications. Combination immunotherapy regimens demonstrated higher pooled ORRs in limited comparative analyses, though findings were driven by a small number of studies. Single-arm analysis for overall survival (OS), progression-free survival (PFS), treatment-related adverse events (TRAEs), and ORR showed no significant differences among the groups. However, treatment–control arm analysis showed pooled ORs of 9.51 for combination immunotherapies and 0.44 in the control group. Conclusions: Combining immunotherapeutics across mechanisms may potentiate immune response effectiveness against GBM. Full article

While research on high-incidence tumors such as breast, prostate, and lung cancer has led to significant increases in patient survival in recent years, this has not been the case for low-incidence tumors such as high-grade gliomas, the most common and lethal brain tumors, for which the last significant therapeutic advance dates back to 2005. The high infiltration capacity of these tumors into normal brain tissue essential for both vegetative and relational life, the tumor microenvironment, with poor immunological activity, the multiple resistance mechanisms, and the unattractiveness of research investments due to the limited number of patients have made, and continue to make, the path to achieving significant improvements in the survival of patients with high-grade gliomas long and arduous. The objective of this article is to update the slow but continuous radiotherapeutic progress for adult and pediatric high-grade gliomas to the second half of 2023. We analyzed the progress of preclinical and clinical research on both adult and pediatric high-grade gliomas, with a particular focus on improvements in radiotherapy. Interactions between non-radiant new therapies and radiotherapy were also covered. A literature search was conducted in PubMed using the terms (“glioma* and radio*”) and the time limit of 1 July 2023 to 31 December 2023. The inclusion and exclusion criteria for the review were relevance to advances in radiotherapy for high-grade gliomas in adults and children. Treating patients with advanced disease progression only, using “historical” data as controls, as well as repurposing drugs developed for purposes completely different from their intended use, were the major (but not the only) methods to assess risk of bias in the included studies. The effect measures used in the synthesis or presentation of the results were tabulated and/or displayed in figures. A total of 100 relevant references were reviewed. Advances in preclinical studies and in clinical radiotherapy treatment planning, innovative fractionation, use of radioisotopes/radiopharmaceuticals, radiosensitization procedures, and radiation-induced damage were focused on. While this analysis may be limited by the relatively short publication period, high-grade glioma research remains impacted, especially at the clinical level, by potential issues with trial design, such as treating patients with advanced disease progression, using “historical” data as controls, and repurposing drugs developed for completely different purposes than intended. Addressing these aspects of high-grade glioma research could improve its efficacy, which often remains low despite the associated costs. Full article

Background/Objectives: Although Tumor-Treating Fields (TTFields) therapy is an established treatment modality for adult glioblastoma, clinical data on its efficacy in pediatric brain tumors are extremely scarce. The present study aimed to evaluate the safety of TTFields therapy for pediatric diffuse high-grade glioma (HGG) and to conduct an exploratory analysis of its efficacy. Methods: A prespecified, interim analysis was performed to determine whether the study should be continued on the basis of safety and feasibility data on the first three patients. The target population was children aged 5 to 17 years with newly diagnosed, supratentorial HGG or its first recurrence following frontline therapy. After completion of initial, local treatment for the tumor (surgical removal and/or radiotherapy), all patients received TTFields therapy using Optune^TM for 28 days per course for up to 26 courses until disease progression. Results: The interim analysis, which was completed in October 2022, included three female patients aged 14, 17, and 9 years. All had a histological grade 4 tumor, two of which were radiation-induced, secondary HGG. No serious, treatment-related toxicities or device-related issues were observed. All three patients were able to continue using the device for 75% or more of the time in accordance with the protocol, suggesting that the treatment was feasible. The MRI findings of two patients indicated that the treatment has a potential antitumor effect. Based on these results, the study was resumed and is currently being continued at multiple centers. Conclusions: The initial results of the prespecified, interim analysis demonstrated that TTFields therapy was safe and feasible for children with HGG. This study was funded by the Japan Agency for Medical Research and Development (AMED) and was registered with the Japan Registry of Clinical Trials (jRCTs032200423). Full article

Central nervous system (CNS) tumors consist of a diverse set of malignancies that remain clinically challenging due to their biological complexity, high morbidity, and limited responsiveness to current therapies. A growing body of genomic evidence has revealed that dysregulation of the mitogen-activated protein kinase (MAPK) signaling pathway is a recurrent and unifying characteristic across many pediatric and adult CNS tumor entities. Alterations affecting upstream receptor tyrosine kinases (RTKs), RAS GTPases, RAF kinases, and other associated regulators contribute to MAPK signaling pathway hyperactivation, shaping tumor behavior, therapy response and resistance. These aberrations ranging from hotspot mutations such as BRAF V600E and oncogenic fusions like BRAF–KIAA1549 are particularly enriched in gliomas and glioneuronal tumors, highlighting MAPK signaling as a key oncogenic driver. The expanding availability of molecularly targeted compounds, including selective inhibitors of RAF, MEK and ERK, has begun to transform treatment approaches for specific molecular subtypes. However, the clinical benefit of MAPK-directed therapies is frequently limited by restricted blood–brain barrier (BBB) penetration, intratumoral heterogeneity, parallel pathway reactivation, and an immunosuppressive tumor microenvironment (TME). In this review, we synthesize current knowledge on MAPK pathway alterations in CNS tumors and evaluate the therapeutic landscape of MAPK inhibition, with emphasis on approved agents, emerging compounds, combination strategies, and novel drug-delivery technologies. We also discuss mechanisms that undermine treatment efficacy and highlight future directions aimed at integrating MAPK-targeted therapy into precision-based management of brain tumors. Full article

Background and Clinical Significance: Fourth-ventricular epidermoid cysts are rare intracranial lesions. They account for fewer than 1% of all primary brain tumors. Fourth-ventricular epidermoid cysts grow slowly because they are closely related to brainstem, cerebellum, and major blood vessels, so their treatment requires special caution. Because the cyst capsule attaches to functionally sensitive locations, complete removal is usually not possible without compromising some aspect of brain or spinal cord function. Surgical decision-making always involves weighing the need to remove the entire cyst against the potential loss of function of the affected area. The following case study describes how a patient was treated with a focus on the relationship between the cyst and surrounding anatomy, allowing for successful decompression with minimal risk to the patient’s neurologic status. Case Presentation: A young adult female patient was hospitalized with progressive truncal ataxia, disequilibrium and occipital headache accompanied by papilledema. Her physical examination disclosed significant dysfunction of the midline cerebellar region (SARA score = 18/40, ICARS score = 42/100), gaze-evoked nystagmus and bilaterally elevated grade II papilledema. MRI and MRA demonstrated a large, lobulated, nonenhancing, avascular mass located within the fourth ventricle, encroaching upon the dorsal medulla and obstructing both the foramen of Magendie and foramina of Luschka—findings typical of an epidermoid cyst. Microsurgical resection was accomplished via a median suboccipital craniectomy using a telovelar approach along the embryonic cerebellomedullary fissure to protect the integrity of the vermis and brainstem. The cyst contained layers of keratin embedded in a thin, translucent capsule. The capsule was carefully dissected away from the floor of the fourth ventricle. A very narrow band of capsule attached to the rhomboid fossa was intentionally spared to avoid damaging the cranial nerves. The patient had normal cerebrospinal fluid circulation restored and normal ventricular pulsation observed during surgery. Histopathology confirmed a benign epidermoid cyst consisting of keratinizing stratified squamous epithelium containing cholesterol clefts and laminated keratin debris. After surgery, the patient exhibited continuous neurological improvement including restoration of balance, disappearance of her headaches, and normalization of ocular pursuit. Sequential imaging studies were conducted post-operatively at one week, one month, three months, five months, and seven months to document stable decompression of the fourth ventricle, re-expansion of the fourth ventricle, and no evidence of cyst recurrence. Post-operative course was uncomplicated and the patient has remained free of symptoms and fully independent functionally at most recent follow-up. Conclusions: This case illustrates that when anatomically oriented, “maximal safe resection” can result in long-lasting decompression and clinically meaningful improvement in neurological function in patients with fourth-ventricular epidermoid cysts. Restoration of the patient’s natural cerebrospinal fluid pathway and preservation of neural interface relationships is more beneficial than pursuing aggressive removal of the cyst capsule. Although the risk of late recurrence is present even after nearly total removal, continuous radiologic monitoring is necessary to identify any recurrence. These experiences illustrate that with the principles of surgical restraint and anatomical guidance, there can be a balance between long-term stability and low operative risk. Full article

Gliomas are the most common malignant primary brain tumors in adults. The treatment of high-grade gliomas is very limited due to their diffuse infiltration, high plasticity, and resistance to conventional therapies. Although they were long considered passive massive lesions, they are now regarded as functionally integrated components of neural circuits, as they form authentic electrochemical synapses with neurons. This allows them to mimic neuronal activity to drive tumor growth and invasion. Ultrastructural studies show presynaptic vesicles in neurons and postsynaptic densities in glioma cell membranes, while electrophysiological recordings detect postsynaptic currents in tumor cells. Tumor microtubules (TMs), dynamic cytoplasmic protrusions enriched in AMPA receptors, are the structures responsible for glioma–glioma and glioma–neuron connectivity, also contributing to treatment resistance and tumor network integration. In these connections, neurons release glutamate that mainly activates their AMPA receptors in glioma cells, while gliomas release excess glutamate, causing excitotoxicity, altering the local excitatory-inhibitory balance, and promoting a hyperexcitable and pro-tumorigenic microenvironment. In addition, certain gliomas, such as diffuse midline gliomas, have altered chloride homeostasis, which makes GABAergic signaling depolarizing and growth promoting. Synaptogenic factors, such as neuroligin-3 and BDNF, further enhance glioma proliferation and synapse formation. These synaptic and paracrine interactions contribute to cognitive impairment, epileptogenesis, and resistance to surgical and pharmacological interventions. High functional connectivity within gliomas correlates with shorter patient survival. Therapies such as AMPA receptor antagonists (perampanel), glutamate release modulators (riluzole or sulfasalazine), and chloride cotransporter inhibitors (NKCC1 blockers) aim to improve outcomes for patients. Full article

Temozolomide (TMZ) remains foundational in the management of adult-type diffuse gliomas in general, and glioblastoma specifically. However, its efficacy harbors an evolutionary trade-off. TMZ drives its cytotoxicity through generating O⁶-methylguanine lesions, especially active in MGMT-silenced, mismatch repair (MMR)-proficient tumors. By selecting for acquired MMR-deficient subclones, often via MSH6 inactivation, this process escalates into a hypermutator phenotype, generating thousands of de novo alterations. This is a hallmark of the mutational signature known as SBS11, characterized by C>T transitions, which is associated with TMZ treatment. The hypermutator phenotype drives heterogeneity, therapeutic resistance, spatial diversification, and distant recurrence. Despite harboring a mutational burden comparable to melanoma and lung cancer, TMZ-induced hypermutation does not sensitize gliomas to immune checkpoint blockade. This resistance reflects the profoundly immunosuppressive brain microenvironment, impaired antigen presentation, marked transcriptional plasticity, and perhaps also the frequent use of corticosteroids. Emerging strategies aim to exploit vulnerabilities created by TMZ-mediated genomic instability, including PARP, ATR, WEE1, and AURKA inhibition; alternative alkylators; metabolic rewiring; and G-quadruplex stabilization. Notably, the real-time detection of evolving mutational signatures via CSF-based liquid biopsies may enable adaptive therapy before radiographic progression. By reframing TMZ as a potent evolutionary agent rather than a conventional chemotherapy, this review synthesizes recent mechanistic insights and translational opportunities to guide a next-generation, evolution-informed treatment paradigm for glioma. Full article

Glioblastoma (GBM) is the most common malignant primary brain tumor in adults. Since numerous studies highlight the significance of cholinergic system components in tumor development, acetylcholine (ACh) and the differential activation of its receptors could play a crucial role in GBM progression. The aim of this study was to test this hypothesis by assessing the relevance of the cholinergic system in GBM cells and their microenvironment. We analyzed bulk RNA-seq expression data using the TIMER2.0 web server, focusing on the impact of patient survival in relation to muscarinic receptors (CHRM) and neutrophil infiltration in low-grade glioma (LGG) and GBM. Our analysis revealed a marked decrease in survival associated with all CHRMs, particularly in LGG. Moreover, GBM showed higher neutrophil infiltration and reduced survival, especially in relation to CHRM3. These findings were validated in the U251 cell line and in human GBM tumor biopsies (GBM-b), which also displayed CHRM3 expression. Additionally, we show that GBM cells exposed to cholinergic stimulation exhibited increased vascular endothelial growth factor (VEGF), IL-8 production, and PD-L1 expression, while the VEGF increase was blocked by tiotropium (Tio), a CHRM3 antagonist. Similarly, polymorphonuclear cells from GBM patients (PMN-p) displayed increased PD-L1 expression and IL-8 production upon cholinergic stimulation. Finally, as we previously reported on the relevance of thymic stromal lymphopoietin (TSLP) in GBM pathophysiology, here, we found that TSLP upregulated CHRM3 expression. Our findings highlight the importance of the cholinergic system in the tumor microenvironment, where it may act directly on tumor cells or influence neutrophil physiology, thereby modulating tumor progression. Full article

The tumor microenvironment (TME) plays an important role in the development, progression, and treatment response of pediatric cancers, yet remains less elucidated compared to adult malignancies. Pediatric tumors are unique with a low mutational burden, an immature immune landscape, and unique stromal interactions. The resultant “cold” immune microenvironments limits the effectiveness of conventional immunotherapies. This review summarizes the key cellular and non-cellular components of the pediatric TME—including T cells, NK cells, tumor-associated macrophages, cancer-associated fibroblasts, extracellular matrix remodeling, angiogenesis, and hypoxia—and describes how these elements shape tumor behavior and therapy resistance. The role of TME in common pediatric cancers like leukemia, lymphoma, neuroblastoma, brain tumors, renal tumors, and sarcomas is discussed. Emerging therapeutic strategies targeting immune checkpoints, macrophage polarization, angiogenic pathways, and stromal barriers are discussed. Full article

Heat-killed Lactiplantibacillus plantarum SNK12 (SNK), isolated from a traditional Japanese fermented food, has been suggested to influence sleep quality, but human data on sleep improvement with heat-killed lactic acid bacteria (postbiotics) remain limited. We conducted a randomized controlled trial to test whether heat-killed SNK (≥1 × 10¹¹ cells/day for 4 weeks) improves sleep quality and alters stress-related immune and neuroendocrine biomarkers. Healthy adults received SNK or a placebo for 4 weeks. The primary outcome was the Oguri–Shirakawa–Azumi Sleep Inventory MA version (OSA-MA) factor “Sleepiness on Rising”; secondary outcomes were other OSA-MA factors and the stress-related biomarkers salivary cortisol and plasma tumor necrosis factor-α (TNF-α). Compared with placebo, SNK improved Sleepiness on Rising (p = 0.032) and Initiation and Maintenance of Sleep (p = 0.010). Salivary cortisol (p = 0.016) and plasma TNF-α (p = 0.037) were also lower with SNK, and no safety concerns emerged. These concomitant changes in subjective sleep indices and stress-related biomarkers are consistent with modulation of hypothalamic–pituitary–adrenal axis activity and inflammatory pathways along the gut–brain axis. SNK may, therefore, represent a practical postbiotic option to support sleep quality. Full article

Background/Objective: Gliomas are the most common primary brain tumors in adults, with recurrence rates varying by tumor grade and initial treatment. Reoperation is a key strategy for managing recurrence; however, its impact on functional status and health-related quality of life (HRQoL) remains insufficiently defined. While HRQoL and neurocognitive outcomes have been described after primary treatment, far less is known following reoperation. This systematic review synthesizes available evidence on postoperative functional outcomes and summarizes HRQoL reporting in the reoperation literature. Methods: A systematic search of PubMed and Google Scholar retrieved 1336 articles. After removing duplicates (n = 76) and screening full texts (n = 42), 15 studies (total n = 1934; reoperation group n = 947) met the inclusion criteria. Studies were eligible if they employed validated functional or HRQoL instruments (e.g., Karnofsky Performance Status [KPS], FACT-G, SF-36, and EQ-5D-L). Due to limited and heterogeneous HRQoL reporting, only KPS could be aggregated for meta-analysis, and HRQoL measures were descriptively summarized. Results: Fixed-effect meta-analysis demonstrated a modest decline in postoperative KPS compared with preoperative scores (−3.28, 95% CI: −3.69 to −2.86; p < 0.001), though heterogeneity was high (I² ≈ 97%). The random-effects model, accounting for interstudy variability, showed no significant overall change (+0.16 KPS, 95% CI: −4.04 to +4.35; p = 0.94; I² ≈ 48%). The 95% prediction interval (−14.1 to +14.4) indicated that individual centers may observe either improvement or decline. Sensitivity analyses identified a small outlier study as a major contributor to heterogeneity; its exclusion did not materially alter the results. Conclusions: Across heterogeneous observational cohorts, reoperation for recurrent glioma was not associated with a consistent decline in functional status as measured by KPS, although substantial variability and uncertainty in outcomes remain. HRQoL reporting remains sparse and inconsistent, underscoring the need for prospective, multicenter studies employing standardized HRQoL instruments to better define quality-of-life trajectories after reoperation. Full article

Background: Glioblastoma is the most common and malignant primary brain tumor in adults, with current treatment presenting limited effectiveness. Therapeutic resistance stems largely from its marked molecular and cellular heterogeneity. Multitarget small molecules (MSMs) have emerged as a promising strategy for treating complex diseases such as cancer. In the present work, we generated a novel family of indole-based MSMs engineered to inhibit histone deacetylases (HDACs), monoamine oxidases (MAOs) and cholinesterases (ChEs) while simultaneously acting as histamine H₃ receptor (H3R) antagonists and sigma-1 receptor (S1R) agonists. Methods: To accomplish this, we combined selected pharmacophoric moieties from the parent compounds Contilisant and the HDAC pan-inhibitor Belinostat. Nine MSMs were synthesized. Results: Most of them showed cytotoxic activity in glioma cells. Among them, three molecules (MTP142, MTP156 and MTP150) were prioritized based on potency; these compounds impaired glioma stem cell (GSC) activity and were predicted to cross the blood–brain barrier. In vivo and multi-omic analyses centered on MTP150 showed significant tumor growth inhibition, both as monotherapy and in combination with temozolomide (TMZ). Transcriptomic and proteomic profiling of patient-derived GSCs revealed MTP150-induced disruption of cell cycle regulation pathways. Conclusions: Our data reveal the efficacy of a novel family of MSMs in the pre-clinical setting of glioblastoma. Full article

Background: Traumatic brain injury (TBI) initiates a complex sequence of inflammatory, glial, and metabolic events that evolve dynamically and contribute substantially to secondary brain injury. This study aimed to characterize the temporal serum dynamics of tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), glial fibrillary acidic protein (GFAP), and insulin following severe diffuse TBI in a rat model, with the goal of delineating the coordinated progression of inflammatory, astroglial, and metabolic responses. Methods: Severe diffuse TBI was induced in adult male Sprague–Dawley rats using the Marmarou weight-drop model. Animals were randomized into five groups (sham, 1 h, 6 h, 24 h, 72 h; n = 10 per group). Serum TNF-α, IL-6, GFAP, and insulin levels were quantified using ELISA assays. Group differences were assessed using one-way ANOVA with Tukey’s post hoc test or Kruskal–Wallis analysis with Dunn’s correction where appropriate. Results were expressed as mean ± SD. Results: TNF-α demonstrated a biphasic pattern, declining at 6 h before peaking significantly at 24 h (p < 0.05) and subsequently decreasing at 72 h. IL-6 exhibited mild suppression at 6 h followed by a significant secondary elevation at 24 h (p < 0.05), with persistently elevated levels at 72 h. GFAP showed delayed kinetics, decreasing at 6 h but rising progressively to a peak at 24 h, consistent with subacute astroglial activation. Insulin levels declined at 6 h and increased significantly at 24 h and 72 h (p < 0.05), indicating evolving metabolic adaptation. Overall, cytokine activity preceded glial and endocrine changes, revealing a sequential inflammatory–glial–metabolic cascade. Conclusions: This study delineates the temporal serum profiles of TNF-α, IL-6, GFAP, and insulin after severe diffuse TBI, revealing a coordinated transition from acute inflammation to astroglial activation and metabolic adaptation. These results support the utility of multimodal biomarker panels for phase-specific characterization of secondary injury and identify GFAP and IL-6 as promising subacute markers with translational relevance. The findings should be interpreted as descriptive temporal patterns rather than mechanistic evidence, pending confirmation with complementary molecular analyses. Full article