Search Results (1,165)

Schwann cells, the principal glial cells of the peripheral nervous system, play a central role in nerve repair following injury. Upon injury, mature Schwann cells dedifferentiate into repair Schwann cells. These processes are governed by complex gene regulatory networks, yet the quantitative dynamics of these processes remain unclear. Here, using a bottom-up systems biology approach, we constructed an endogenous regulatory network model based on experimentally validated interactions, without relying on high-throughput data as input. The model captures Schwann cell dedifferentiation dynamics and reveals a potential landscape composed of stable states and intermediate transition states. Simulations recapitulate post-injury trajectories and confirm the role of c-Jun upregulation in maintaining repair capacity. Furthermore, the model predicts multiple potential therapeutic targets, including tumor protein p53 (P53), c-Jun N-terminal kinase (JNK), and phosphatase and tensin homolog (PTEN), for sustaining repair competence. We also identify intrinsic heterogeneity within repair Schwann cells. Furthermore, we uncover key transition states that simultaneously connect repair-competent cells to both repair-deficient and apoptotic phenotypes. These intermediate states may represent critical regulatory bottlenecks and serve as key cellular targets for improving peripheral nerve regeneration. Overall, this work provides new insights into the precise regulation of Schwann cell fate and establishes a theoretical framework for regenerative medicine and clinical strategies in peripheral nerve repair. Full article

Glioblastoma multiforme (GBM), isocitrate dehydrogenase (IDH)-wildtype, is the most aggressive primary malignant tumor of the central nervous system, characterized by poor prognosis and high recurrence rates despite standard multimodal treatment. This study investigates the molecular response of glioblastoma cells to 5-aminolevulinic acid (5-ALA)-based photodynamic therapy (PDT), focusing on gene expression changes associated with apoptosis, ferroptosis, and oxidative stress. Human glioblastoma T98G cells were treated with 5-ALA followed by light irradiation, and gene expression was analyzed using RT-qPCR. PDT induced moderate upregulation of pro-apoptotic genes (BAX, CASP3, FAS) alongside increased expression of the anti-apoptotic gene BCL2, indicating simultaneous activation of cell death and survival pathways. Ferroptosis-related genes showed mixed responses, with slight upregulation of ACSL4 and downregulation of GPX4, suggesting increased susceptibility to lipid peroxidation. The most significant change was observed in GCH1 expression, reflecting activation of oxidative stress response mechanisms. However, none of the observed changes reached statistical significance, likely due to the limited sample size. These findings demonstrate that PDT induces a complex and dual biological response in glioblastoma cells, involving both cytotoxic and adaptive mechanisms. This may limit therapeutic efficacy and contribute to treatment resistance. The results support the rationale for combining PDT with targeted molecular therapies aimed at inhibiting antioxidant defenses and anti-apoptotic pathways. Additionally, personalized therapeutic strategies based on tumor molecular profiles may enhance treatment outcomes. Further studies with larger sample sizes and functional validation are required to confirm these preliminary observations. Full article

Vertigo, dizziness, and oculomotor disturbances may occur as manifestations of immune-mediated disorders affecting the inner ear, central vestibular pathways, or multisystem autoimmune disease. Although uncommon, these conditions are clinically important because delayed recognition may lead to irreversible hearing loss, vestibular dysfunction, or neurological disability. This review summarizes the clinical presentation, diagnostic approach, and treatment of immune-mediated vestibular and oculomotor disorders. We suggest a practical classification into isolated immune-mediated inner ear disease, systemic autoimmune disorders with audio-vestibular involvement, and autoimmune disorders of the central or peripheral nervous system affecting balance and eye movements. Red flags for such conditions include bilateral or progressive symptoms, fluctuating audio-vestibular deficits, associated neurological signs, and accompanied autoimmune disease. Corticosteroids remain the main first-line treatment in many of these disorders, mainly due to missing data from controlled trials. Steroid-sparing immunosuppressants, biologics, and tumor-directed therapies are effective in many cases; however, because of the missing data, they are only used in selected entities without any other choice. A structured neuro-otological and immunological workup is essential to improve diagnostic accuracy and enable timely therapy. Full article

Methylthioadenosine phosphorylase (MTAP) immunohistochemistry (IHC) has emerged as a valuable diagnostic, prognostic, and therapeutic biomarker in modern oncologic pathology, primarily serving as a surrogate for CDKN2A/B homozygous deletion due to their close genomic proximity at chromosome 9p21. This review aims to systematically evaluate the clinical utility, diagnostic accuracy, and technical limitations of MTAP IHC across a diverse spectrum of human malignancies, while contextualizing its role within current molecular testing algorithms. We first examine the established diagnostic and grading performance of MTAP loss in central nervous system neoplasms and thoracic tumors, particularly malignant pleural mesothelioma, followed by an analysis of its emerging prognostic value in gastrointestinal, cutaneous, and genitourinary malignancies. Furthermore, we discuss the therapeutic implications of MTAP deficiency, focusing on the biological consequences of methylthioadenosine accumulation and the resulting synthetic vulnerabilities in the PRMT5/MAT2A pathway. By synthesizing diagnostic precision, prognostic relevance, and translational therapeutic insights, this review provides a comprehensive framework for integrating MTAP IHC into routine surgical pathology workflows and personalized oncology. Full article

Radiotherapy (RT) has traditionally been considered a local treatment modality; however, accumulating evidence suggests that it can induce systemic antitumor responses outside the irradiated field. The classical abscopal effect, defined as the regression of non-irradiated tumor lesions following localized RT, has gained renewed attention in the era of immune checkpoint inhibitors (ICIs). Preclinical and clinical studies have demonstrated that RT can promote immunogenic cell death, antigen presentation, cytokine release, and adaptive immune activation, processes that may contribute to systemic antitumor immunity, particularly when combined with ICIs. Clinically apparent abscopal responses remain rare and heterogeneous, and the biological mechanisms underlying these phenomena are not completely understood. Systemic tumor regression has occasionally been observed in clinical settings that do not involve checkpoint blockade, including RT alone, chemotherapy-containing regimens, and central nervous system-directed therapies. These findings suggest that radiation-associated systemic antitumor responses may arise through overlapping immunologic mechanisms involving both innate and adaptive immunity, tumor microenvironment remodeling, and treatment-associated cellular stress. This review summarizes the current clinical evidence and biological mechanisms underlying radiation-associated systemic antitumor responses and discusses emerging concepts extending beyond the conventional RT–immunotherapy paradigm. We further examined unresolved challenges, including treatment heterogeneity, biomarker limitations, pseudoprogression, and difficulties in mechanistic confirmation. Finally, we propose that the broader “beyond-abscopal” framework may serve as a hypothesis-generating conceptual model for investigating systemic tumor responses across diverse treatment contexts while emphasizing the need for cautious interpretation and prospective translational validation. Full article

Gliomas account for over half of all primary malignant tumors of the central nervous system and remain associated with poor prognosis. Although irinotecan is an effective chemotherapeutic agent, its clinical utility is limited by systemic toxicity, prompting interest in phytochemicals such as ellagic acid (EA) as potential sensitizers. This study aimed to investigate whether EA enhances the antiproliferative and pro-apoptotic effects of irinotecan in C6 glioma cells. C6 glioma cells were treated with EA (100 µM), irinotecan (100 µM), or their combination for 24, 48, and 72 h. Cell proliferation was assessed by BrdU assay, p53 and caspase-3 protein expression by immunocytochemistry (H-SCORE), and multidrug resistance gene 1 (MDR1), MGMT, p53, and caspase-3 mRNA levels by RT-qPCR. EA significantly enhanced irinotecan-mediated suppression of proliferation at 24 h (p < 0.001), 48 h (p < 0.001), and 72 h (p < 0.001), with the combination producing the strongest inhibition across all time points. Immunocytochemical p53 expression increased significantly in all treatment groups at 24 h and 48 h (EA: p < 0.01; irinotecan: p < 0.01; EA + irinotecan: p < 0.01) and remained elevated at 72 h (p < 0.05). Caspase-3 immunoreactivity showed robust early activation at 24 h (Ir: p < 0.05; EA: p < 0.01), persisted at 48 h (p < 0.01), and remained significantly elevated in the EA group at 72 h (p < 0.001). At the mRNA level, irinotecan induced the highest p53 expression at 24 h (p < 0.001), with sustained elevation at 48 h and 72 h (p < 0.001 and p < 0.05, respectively). Caspase-3 mRNA peaked at 24 h only in the irinotecan group (p < 0.001). EA significantly increased MDR1 and MGMT transcription at 24 h and 48 h (p < 0.001), whereas the EA + irinotecan combination attenuated this increase and remained close to control levels at early time points. MGMT remained significantly elevated in EA and EA + irinotecan groups through 72 h (p < 0.001). EA cooperatively enhanced the antitumor activity of irinotecan primarily by enhancing proliferation inhibition and modulating drug-resistance gene expression, while maintaining, rather than further augmenting, apoptotic protein markers comparable to those induced by single-agent treatments. These findings support EA as a promising adjunct to irinotecan-based glioma therapy. Full article

Gliomas are the most frequently encountered tumors in the central nervous system, with limited therapeutic effectiveness owing to their highly invasive nature, intratumoral heterogeneity, and presence of the blood–brain barrier (BBB). Low-Density Lipoprotein Receptor-Related Protein 1 (LRP1) is a large, multifunctional transmembrane endocytic receptor that regulates lipid metabolism, cell signaling, and endocytosis in various body tissues, including the brain. LRP1 mediates tumor cell proliferation, invasion, and angiogenesis in gliomas through various cellular signaling mechanisms, including the SP1/PI3K/AKT pathway and MAPK/ERK. The occurrence of LRP1 in the BBB and the recent identification of its increased expression in gliomas have suggested it as a promising therapeutic target for receptor-mediated nanoparticle delivery and treatment of gliomas. LRP1-mediated transcytosis is now being used to enhance the BBB penetration of chemotherapy drugs and radiosensitizers in gliomas, which has resulted in increased overall survival of patients secondary to increased antitumor effectiveness of therapies. Despite the effective preclinical role of LRP1-targeted therapy in glioma models, clinical translation is challenging due to significant heterogeneity in the expression patterns of LRP1 across various subtypes of gliomas, which may affect the clinical responsiveness of drug therapy. Furthermore, concerns related to the pharmacokinetics of therapy and receptor saturation kinetics have rendered its clinical applicability challenging. Full article

Aim: This study aims to identify the primary differential MRI features between gliosarcoma (GS) and glioblastoma (GBM) based on a comprehensive review of existing literature. Given their close relationship, identifying preoperative neuroradiological markers is essential for distinguishing these two entities. Methods and Analysis: We reviewed studies involving patients with histologically confirmed GS and primary GBM. Our analysis, aligned with the 2021 WHO Classification of Tumors of the Central Nervous System, evaluated specific radiological characteristics in order to determine their diagnostic value in differential diagnosis. Results: While GS is categorized as a variant of GBM, distinct radiological patterns emerged from our literature review. Gliosarcomas are typically larger due to their sarcomatous component and exhibit more intense contrast enhancement and frequent cortical involvement. Notably, hemorrhagic patterns are more prevalent in GS, whereas GS displays less necrosis and a lower incidence of midline-crossing edema compared to GBM. Conversely, glioblastomas more frequently present with cystic components and pial involvements as well as a higher risk of ependymal invasion. Conclusions: Although specific radiological features—such as hemorrhage frequency and tumor size—can strongly suggest GS over GBM diagnosis, no single feature was considered pathognomonic. Among radiological tools, MRI remains the most important for guiding a diagnostic suspicion, but histopathological confirmation remains the gold standard for definitive diagnosis. Full article

Theranostics is a novel approach that integrates diagnostic and therapeutic efficacy on a single platform, holding great promise for precision medicine by enabling real-time monitoring of disease progression and therapeutic response. Despite significant advances, the successful development and delivery of theranostic systems are critically limited by multiple biological barriers present at systemic, tissue, cellular, anatomical, and immunological levels. These barriers restrict bioavailability, target accessibility, and therapeutic efficacy, while often increasing off-target accumulation and adverse effects. This review provides a comprehensive overview of the major biological barriers encountered in theranostic development, including physiological barriers such as plasma protein binding, renal clearance, and hepatic metabolism; anatomical barriers like endothelial linings, the blood–brain barrier (BBB), and the tumor microenvironment; cellular barriers involving membrane permeability, intracellular trafficking, and endo-lysosomal entrapment; and immunological barriers such as immune recognition, inflammatory responses, and complement activation. Special emphasis is placed on the BBB, highlighting its structural complexity, transport mechanisms, and strategies such as molecular Trojan-horse technology, receptor-mediated and adsorptive-mediated transcytosis, and nanocarrier-based approaches to enhance central nervous system delivery. The review further discusses targeted delivery challenges, including receptor heterogeneity and multidrug resistance, and critically evaluates current strategies to overcome these barriers through surface functionalization, stimuli-responsive systems, biomimetic carriers, and controlled-release mechanisms. Finally, recent advances, clinical challenges, and future perspectives—including personalized theranostics, artificial intelligence—assisted design, and next-generation barrier-penetrating systems—are explored. Overall, this review aims to provide a structured understanding of biological barriers in theranostics and highlight innovative approaches to improve their translational potential. Full article

Fatty acid-binding protein 7 (FABP7) is a multifunctional lipid chaperone that is enriched in radial glia and astrocytes within the central nervous system (CNS) and is frequently upregulated in glioma. Beyond its established roles in glial development, lipid homeostasis, and circadian regulation, growing evidence positions FABP7 at the intersection of tumor metabolism, neuronal activity, and immune modulation in the brain. In this review, we integrate the physiological functions of FABP7 in glial cells with its tumor-intrinsic and microenvironmental roles in glioma. We summarize how gliomas co-opt FABP7-dependent metabolic, transcriptional, and post-transcriptional programs to promote stemness, lipid remodeling (e.g., altered fatty acid composition, lipid droplet formation, and lipid peroxidation resistance), inflammatory signaling, and invasive growth, including nuclear FABP7-mediated transcriptional activation linked to oncogene status. Furthermore, we discuss the role of FABP7 in shaping the tumor–neuro–immune interface, including regulating immunosuppressive gene networks, pro-tumoral macrophage polarization, resistance to T-cell-induced ferroptosis and immunotherapy, and tumor microtube-mediated integration into neuronal circuits to support glioma progression. Finally, we highlight therapeutic opportunities and challenges, including small-molecule FABP7 inhibitors, brain-directed delivery strategies, chronotherapeutic considerations, and combination approaches with immunotherapy. Collectively, this work positions FABP7-centered metabolic, circadian, and neuro-immune networks as potential vulnerabilities in glioma, linking fundamental glial biology to glioma therapeutics. Full article

Glioblastoma (GB) is the most aggressive primary central nervous system tumor in adults and the most common malignant primary brain tumor, representing approximately 50.9% of all malignant CNS tumors, with a median overall survival of approximately 14.6 months despite standard multimodal treatment, consisting of surgical resection, concurrent radiotherapy, and temozolomide (TMZ), followed by adjuvant TMZ (Stupp protocol). Tumor recurrence is inevitable and attributed to diffuse infiltration of neoplastic cells into the brain parenchyma, marked intratumoral heterogeneity, the presence of glioma stem cells, and the protection conferred by the BBB. Flavonoids are plant-derived polyphenolic compounds with more than 8000 identified. They have attracted growing interest as potential therapeutic agents because of their capacity to modulate multiple oncogenic signaling pathways and their favorable toxicity profile. Here we synthesize the preclinical evidence on the main flavonoids with documented activity in GB models, with emphasis on quercetin, apigenin, luteolin, and EGCG, while distinguishing glioblastoma-specific evidence from indirect findings derived from other experimental systems. We analyze their underlying molecular mechanisms, including induction of apoptosis through the intrinsic and extrinsic pathways, inhibition of cell proliferation and angiogenesis, suppression of migration and invasion, epigenetic modulation, and, particularly, the capacity to target the glioma stem cell population. We also examine the limited oral bioavailability and restricted penetration across the BBB, as these factors remain major barriers to translational development. We conclude with an analysis of emerging nanotechnological strategies, targeted delivery systems, and synergistic combinations with conventional chemotherapeutic agents, together with a cautious assessment of the current clinical evidence, which remains insufficient to support the use of flavonoids outside controlled clinical trials. Full article

Background: Childhood cancer survivors have a higher risk of developing malignancies later in life compared with individuals of similar age in the general population. In Spain, population-based evidence on second malignant neoplasms (SMNs) is limited. This study aimed to estimate survival following childhood cancer diagnosis and to assess the risk of SMNs in Spain. Methods: This population-based registry study used data from 12 cancer registries within the Spanish Network of Cancer Registries (REDECAN). All malignancies of sites and non-malignant central nervous system (CNS) tumors diagnosed before age 15 were included. Age-standardized incidence rates (ASIRw) for 2015–2019 were calculated. Five- and 10-year age-adjusted observed survival rates for 1990–1999 and 2000–2009 were estimated. SMN risk was assessed using standardized incidence ratios (SIRs) and excess absolute risks (EARs). Results: The ASIRw for 2015–2019 was 181.3 per million child-years. Ten-year survival increased from 71.3% in 1990–1999 to 75.5% in 2000–2009. The overall risk of developing an SMN was significantly elevated (SIR = 5.67) at 20 years. Conclusions: Although survival for childhood cancer in Spain was around 75% in 2000–2009, childhood cancer survivors remain at substantially increased risk of SMNs for at least two decades. Efforts to reduce treatment-related toxicity while maintaining survival gains are essential. Full article

Background and Objectives: Magnetic resonance imaging (MRI) is essential for monitoring patients with diffuse gliomas after surgery and adjuvant therapy. However, the prognostic significance of imaging findings observed on the first post-treatment MRI remains incompletely defined in routine clinical practice. This study aimed to evaluate whether MRI features identified on the first post-treatment examination are associated with recurrence-free survival after near-total resection (NTR), defined for this real-world cohort as ≥80% volumetric tumor removal (which differs from the RANO Resect Group definition of GTR). Materials and Methods: Consecutive adult patients with histologically confirmed diffuse gliomas diagnosed between 2021 and 2024 were screened for eligibility (n = 283) and classified according to the 2021 WHO Classification of Tumors of the Central Nervous System. The first post-treatment MRI was defined as the earliest follow-up examination performed after completion of all initially planned therapy (surgery alone in patients without indication for adjuvant therapy; post-radiotherapy ± chemotherapy in the remaining patients), and not the immediate postoperative scan. Patients with available first post-treatment MRI were included (n = 149), resulting in a final cohort of 139 cases after exclusion of outliers. The evaluated MRI corresponded to the first follow-up examination after treatment (mean interval ~120 days after surgery). Logistic regression models were used to assess associations between post-treatment MRI features and recurrence-free survival at one and two years after NTR, with exploratory analyses for reoperation and reirradiation. Results: Residual tumor identified on the first post-treatment MRI was associated with lower odds of recurrence-free survival (RFS) at one and two years after NTR. Postoperative functional status also demonstrated an independent association with tumor control. Other imaging variables showed associations in univariable analyses but did not remain independent predictors after adjustment. Exploratory analyses of reoperation and reirradiation suggested additional clinical influences, including patient age. Conclusions: In this real-world cohort with heterogeneous tumor subtypes and treatment regimens, residual tumor on first follow-up MRI was the most consistent imaging correlate of reduced RFS, alongside postoperative functional status. These hypothesis-generating findings should be validated in stratified, prospective cohorts. Full article

Background/Objectives: Efficacy endpoint selection in adult primary central nervous system (CNS) tumor trials remains challenging because conventional solid tumor frameworks do not adequately capture the anatomical, radiographic, and biological complexity of brain tumors. In particular, postoperative irregular residual lesions, non-enhancing tumor components, and treatment-related imaging changes complicate the interpretation of objective response and progression. This narrative review examines the current landscape of endpoint selection in adult primary CNS tumor trials and discusses strategies for standardization in the Response Assessment in Neuro-Oncology (RANO) 2.0 era from integrated regulatory science and clinical perspectives. Methods: This study was conducted as a narrative review intended to provide a regulatory science-oriented synthesis of efficacy endpoint evaluation in adult primary CNS tumor trials. The literature search primarily utilized PubMed and ClinicalTrials.gov, supplemented by major consensus guidelines, pivotal clinical trials, and regulatory documents from the major regulatory authorities, including those in the United States, Europe, and Japan, published over the past two decades. Search terms included combinations of keywords such as “brain tumor,” “glioblastoma,” “meningioma,” “Phase I,” “Phase II,” “efficacy endpoint,” and “RANO”. In addition to the literature synthesis, this review incorporates findings from our previously published empirical analyses regarding endpoint selection in Phase II glioblastoma trials, Phase II meningioma trials, and Phase I brain tumor trials. Results: Response Evaluation Criteria in Solid Tumors-based response assessment remains fundamentally limited in neuro-oncology. Across recent early-phase trials, substantial heterogeneity persists in endpoint selection and in the operational definitions of objective response rate, progression-free survival, and progression. RANO 2.0 is intended to provide a more unified and implementation-oriented framework by refining baseline definition, progression confirmation, non-enhancing lesion interpretation, and the role of minor response, while improving compatibility with contemporary molecular classification and immunotherapy-era trial design. However, important implementation challenges remain, including potential reproducibility concerns in complex imaging assessments, operational complexity, imaging standardization, and the need for independent central review. Conclusions: Standardization of endpoint strategies in adult primary CNS tumor trials should move beyond simple adoption of conventional solid tumor metrics toward a disease-specific, harmonized framework integrating imaging, clinical context, tumor biology, and regulatory interpretability. This review provides a regulatory science-oriented synthesis linking response assessment criteria, early-phase adult primary CNS tumor trial endpoint trends, empirical analyses, and emerging endpoint frameworks. RANO 2.0 represents an important step toward this goal, but it should be regarded as an evolving framework that requires continued validation, international collaboration, and implementation-focused refinement. Full article

Importance: A comprehensive analysis of childhood cancer and cancer predisposition syndromes (CPSs) incidence can provide insights that lead to improvements and modifications in treatment protocols through personalized therapy, thereby reducing toxicity. Purpose: This study aimed to analyze age-specific hospital-based childhood cancer rates and the distribution of CPSs in a 20-year pediatric cohort from the region. Materials: A total of 2190 patients, aged from birth to 17 years, diagnosed with any type of neoplasm classified by ICD-10 codes at Karol Jonscher’s Clinical Hospital of Poznan University of Medical Sciences (KJCH PUMS) between 1 January 2000, and 31 December 2019, were included, with 193 (8.8%) having an underlying CPS. Results: The pediatric population of the Greater Poland Region has declined over the past two decades. The most common diagnoses can be grouped into three main categories: (1) leukemias, involving 704 patients (32.1%); (2) central nervous system (CNS) tumors, represented by 382 children (17.4%); and (3) lymphomas, including 279 patients (12.7%), together accounting for 1353 cases (61.8%). The age-specific hospital-based case rate for childhood cancer (all types combined) peaked in the 0–28 days age group at 71.8 per 100,000 person-years (95% CI: 52.2–96.4), with a trend to decrease with age and a slight increase among adolescents aged 16–17 years (13.6 per 100,000, 95% CI: 12.0–15.4). The age-specific incidence of CPS-positive cancers declined from 18.0 (95% CI: 8.2–29.4) per 100,000 person-years in the first month of life to 0.7 (95% CI: 0.3–1.2) in 16–17-year-olds. CPS-positive children were diagnosed at significantly younger ages for four cancer types: liver and intrahepatic bile duct tumors (C22: A = 0.097, adjusted p < 0.001), myeloid leukemia (C92: A = 0.179, adjusted p < 0.001), lymphoid leukemia (C91: A = 0.309, adjusted p = 0.007), and renal tumors (C64: A = 0.335, adjusted p = 0.013). Conclusions: CPSs likely play a significant and underestimated role in pediatric cancers, especially during early childhood. Improving access to genetic testing could greatly enhance risk assessment, personalized treatment, and long-term outcomes in pediatric oncology. Full article