OBJECTIVES:This meta-synthesis integrates qualitative evidence on how brain tumor patients' experiences of treatment decision-making consultations in order to identify the essential elements of a patient-centered consultation framework tailored to their needs. METHODS:We used a Thomas and Harden's approach. Systematic search was conducted in Web of Science, PubMed, Embase, and Scopus for studies until June 15th, 2025. All included studies were critically appraised using the Joanna Briggs Institute (JBI) Critical Appraisal Checklist for Qualitative Research. The study was registered on PROSPERO with registration number CRD42023457607. RESULTS:This synthesis identified four analytical themes that should guide healthcare providers: (1) consultations must address emotional and existential concerns; (2) communication should be personalized; (3) decision-making must remain flexible, allowing patients to delegate control to trusted others when desired; and (4) the irreplaceable and multifaceted roles of family and social support. CONCLUSIONS:Our findings reveal a persistent gap in shared decision-making among brain tumor patients, many of whom defer decisions to physicians due to emotional distress, cognitive limitations, and informational barriers. Enhancing patient-centered care therefore requires strategies that strengthen trust, support patient engagement, and address these structural and emotional challenges. PRACTICE IMPLICATIONS:Clinical consultation should consider about patients' emotional and existential concerns, incorporate personalized communication, adopt a flexible approach to decision-making, and appropriately involve family and social support.

Abstract Glioblastoma (GBM) is the most malignant brain tumor, characterized by frequent resistance to standard therapy, Temozolomide (TMZ), which is highly related to GBM metabolic rewiring. The transmembrane protein CD47 is known for its role in innate immune suppression by binding to SIRPα on myeloid cells. However, non-canonical CD47 pathway activated by thrombospondin 1 (TSP1) suggests a different role for CD47 in tumor progression, and whether this signaling axis modulates GBM metabolism remains unclear. Our patient biopsy data revealed strong CD47 immunoreactivity in GBM compared with adjacent normal tissue (n=21, p < 0.05). Paired (recurrent/primary) GBM patient RNA-Seq (n=14) shows that CD47 is upregulated in recurrent tumors, and high CD47 levels, along with high TSP1 expression in TCGA GBM database, are associated with poor survival, suggesting the importance of the non-canonical CD47 pathway in GBM. In CD47-overexpressing GBM cells, RNA-Seq revealed enrichment of OXPHOS, fatty acid metabolism, and phospholipid synthesis. Lipidomics confirmed CD47-driven upregulation of cardiolipin (CL), suggesting metabolic rewiring via non-canonical CD47 signaling. Patient tumors and TMZ-resistant GBM cells similarly showed induction of CL biosynthesis and remodeling enzymes, which regulate mitochondrial function by incorporating fatty acids. The key enzyme of monounsaturated FA (MUFA) synthesis, Stearoyl-CoA Desaturase, is increased in recurrent tumors. MUFA-CL is studied to promote stable and efficient mitochondrial respiration, whereas polyunsaturated FA (PUFA)-CL is prone to damage by mitochondrial stress. We found that GBM cells pretreated with MUFA oleate increased the mitochondrial spare capacity compared to PUFA linoleic acid incubation. Further, we showed that TSP1 activates CL processing in GBM cells and suggested that the non-canonical CD47 pathway may promote TMZ resistance by increasing MUFA-CL to prevent TMZ-induced mitochondrial stress. Interestingly, CD47 knockdown using different shRNAs showed distinct gene enrichments between metabolism and immune phagocytosis. Also, anti-sense morpholinos targeting CD47 (CD47M) reduced FA-dependent mitochondrial respiration and the activity of key enzymes involved in CL processing in GBM cells. Moreover, TMZ combined with CD47M significantly reduced the GBM viability. On the other hand, we found that targeting non-canonical CD47 on microglia produced the opposite effect to that in cancer cells, with increased OXPHOS and FA metabolism. This alteration significantly increases microglia-mediated killing of GBM. Further, human GBM organoids showed that CD47M pre-treated microglia increased organoid transparency, indicating increased microglial cytotoxicity toward patient-derived GBM cells. Taking together, our data suggests that targeting the non-canonical CD47 pathway may be a potential approach for TMZ-resistant GBM and enhance microglia-mediated cytotoxicity. Citation Format: Yu-Ting Tsai, Mitra Kooshki, Jamie Sagastume, Valerie Payne, Ashley Szymonski, Pin-Yuan Chen, Jian-Ying Chuang, Tsung-I Hsu, Shay Soker, Glenn Lesser, David Soto-Pantoja. Non-canonical CD47 enhances cardiolipin biosynthesis and remodeling in Temozolomide-resistant establishment and reduces microglia-mediated cytotoxicity in glioblastoma progression [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Brain Cancer; 2026 Mar 23-25; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2026;86(6_Suppl):Abstract nr A017.

Background Low-grade gliomas (LGGs) are slow-growing primary brain tumors for which the optimal treatment to prolong progression-free survival (PFS) in adults remains debated. This network meta-analysis compares the efficacy of various treatment modalities for improving PFS in adult patients with LGG. Methods We systematically searched PubMed, Embase, and the Cochrane Library from inception to September 22, 2025 for studies evaluating PFS outcomes in adult LGG. Included studies were analyzed following PRISMA guidelines using a frequentist framework random-effects network meta-analysis with survival modeling. Results Seventeen trials involving 3,588 patients were included. Compared with biopsy alone, gross total resection with radiation (GTRR; HR = 0.47), subtotal resection with radiation and chemotherapy (STRRC; HR = 0.49), gross total resection alone (GTR; HR = 0.59), subtotal resection with chemotherapy (STRC; HR = 0.66), and subtotal resection with radiation (STRR; HR = 0.67) all significantly reduced progression risk (all p < 0.05). GTRR, STRRC, GTR, and STRC also outperformed subtotal resection alone (STR; HR = 0.57, 0.59, 0.70, and 0.79 respectively; all p < 0.05). SUCRA analysis ranked GTRR (84.7%) and STRRC (82.2%) as the most effective regimens. Conclusions These results demonstrate that combination therapies—particularly gross total resection with radiation or subtotal resection with radiation and chemotherapy—significantly improve PFS in adult LGG patients. PROSPERO registration number: CRD42023470802.

Glioblastoma (GBM) frequently recurs after temozolomide (TMZ) therapy and exhibits substantial redox plasticity. Our previous work showed that the effects of hydrogen peroxide (H2O2) vary with its level and between parental and TMZ-resistant GBM cells. Succinate dehydrogenase subunit D (SDHD), a membrane-anchoring component of mitochondrial complex II, is positioned at the interface of electron transport and redox homeostasis, but its regulation in GBM remains unclear. We therefore examined whether SDHD expression changes across distinct H2O2-responsive contexts involving aquaporins (AQPs) and AKT. TCGA transcriptomic analysis showed higher SDHD mRNA expression in WHO grade IV than in grade II/III gliomas, whereas paired primary/recurrent high-grade glioma samples showed heterogeneous SDHD changes at recurrence. TMZ reduced SDHD, and SDHD knockdown decreased intracellular reactive oxygen species. Combined redox perturbation reduced SDHD, whereas AKT inhibition restored SDHD expression. Under receptor-associated signaling conditions, EGFRvIII expression or CXCL12 stimulation increased measured H2O2 together with AQP3, AKT Ser473 phosphorylation, and SDHD. In TMZ-resistant cells, pharmacological perturbation of aquaporin-associated signaling decreased AQP9 together with AKT Ser473 phosphorylation and SDHD. An AQP3-targeting compound further reduced cell density when combined with TMZ. Together, these findings suggest that changes in SDHD expression are consistent with a compensatory redox response in GBM cells and that its regulation varies with the nature of H2O2-associated signaling during TMZ-related stress.

2066 Background: Glioblastoma (GBM) is a highly malignant brain tumor characterized by an immunosuppressive microenvironment and rapid development of therapeutic resistance. In GBM, myeloid cells can comprise 30–50% of the tumor and critically regulate its immune microenvironment. Evidence from aging and CNS diseases suggests that microglia can adopt dysfunctional states of exhaustion and tolerance that extend beyond the M1/M2 paradigm, thus prompting us to investigate whether these phenotypes contribute to immune escape and progression of GBM. Methods: Paired RNA-seq of tumor specimens from newly diagnosed and recurrent GBM patients (n=14) was used to examine aging-related gene expression during treatment and progression. Open-access human glioma single-cell RNA-seq data (GSE182109) were analyzed to characterize exhaustion and tolerance across macrophage subpopulations based on molecular/metabolic signatures. Results: Patient tumor RNA-Seq revealed that the aging-related TREM2-APOE axis is present in recurrent GBM, suggesting accelerated brain aging. Single-cell RNA-seq identified nine myeloid clusters, including four microglial states (homeostatic-, activated-, AP-, and a-microglia) and two macrophage populations (anti-inflammatory and immunosuppressive). We found that AP-microglia showed disease-associated activation, with high CD45/CD11C/TREM2 expression and concurrent upregulation of the exhaustion markers PD-L1 and CD38. Moreover, microglial activation-related signaling in AP-microglia includes increased STAT1/2-IRF9 signaling, which can promote immunosuppression by inducing PD-L1. On the other hand, a-microglia is unique in its high expression of activation-restraining and tolerance markers, such as SPRY/P2RY13, rather than the classic microglial marker TMEM119/P2RY12. Both AP-microglia and a-microglia are shown to lose expression of the inflammatory cytokines TNF-α and IL-1β, consistent with the characteristics of exhausted and tolerized microglia. Unlike resident microglia, the immunosuppressive macrophage cluster exhibits a monocyte-tolerized phenotype, with downregulated FABP4 and increased SOD2, CLEC4E, and SLC2A6. It also shows a similar panel of LPS-induced monocyte exhaustion with TLR4/MyD88/SRC and STAT3/IL-10 upregulation. Conclusions: Our analysis indicates that AP-microglia are exhausted and a-microglia are tolerized in GBM, with shared markers of dysfunction across macrophages linking myeloid impairment to immune suppression and treatment-associated brain aging. These findings implicate myeloid exhaustion in GBM immune escape and identify potential therapeutic targets.

Glioblastoma (GBM) is an incurable brain tumor with poor survival outcomes. Its progression and recurrence are strongly influenced by infiltrative growth of tumor cells and tumor microenvironment (TME) components, particularly tumor-associated macrophages (TAMs). To identify potential therapeutic targets for controlling GBM, we investigated how the ribosomal protein S19 (RPS19)–complement 5a receptor 1 (C5AR1) axis reprograms TAMs, promoting inflammation-mediated responses and tumor progression. To identify critical contributors for GBM progression, we collected single-cell RNA sequencing data from human GBM tumor masses and adjacent tissues, as well as from healthy brains and GL261-bearing mouse brains. The data were analyzed and validated using public GBM databases. Clinical specimens, in vitro, and in vivo approaches were conducted to elucidate underlying mechanisms and confirm therapeutic targets. Tumor-derived RPS19 and C5AR1+ TAMs are noted as key contributors to postoperative GBM progression. Trajectory and spatial transcriptomics revealed that C5AR1+ Inflammatory TAM1 emerged as a precursor of protumoral TAMs, whereas C5AR1 expression followed a trajectory similar to that of inflammatory TAM1 and was enriched around necrotic regions. Under stress conditions, tumor-released RPS19 selectively activates pro-inflammatory macrophages and microglia resulting in IL-1β upregulation via the Akt-PU.1/SPI1 axis. Increased IL-1β levels reprogram astrocytes toward A1-like phenotypes, contributing to neuroinflammation, cerebral edema, and upregulating astrocyte-derived tumor-supporting factors, such as CCL2, TGF-β1, and IL-6, further accelerating tumor growth. Pharmacological interruption of the RPS19-C5AR1 axis alleviated TAM-mediated inflammation, mitigated cerebral edema, and ultimately extended survival in an orthotopic GBM murine model. We elucidated a novel intercellular mechanism by which RPS19 drives GBM progression through IL-1β-mediated TME evolution. Thus, the RPS19–C5AR1 axis can be targeted to alleviate inflammation and cerebral edema, thereby improving clinical outcomes in GBM.

Background: Delirium is a common symptom following a traumatic brain injury that is often overlooked by healthcare professionals. Early detection of posttraumatic delirium is crucial to improving patient outcomes and quality of life. The 4 As Test (4AT: alertness, attention, abbreviated mental test-4, and acute mental changes) is a brief and rapid tool for delirium assessment with acceptable reliability and validity. However, the 4AT has not yet been translated for use in the Taiwanese population. Objective: To translate the 4AT into Traditional Chinese (TC-4AT), assess its reliability and validity, and explore the clinical effects of delirium in patients with a traumatic brain injury. Methods: This prospective observational study was conducted at the neurosurgery wards of 2 Taiwanese hospitals. Patients who were aged 20 years or older, were diagnosed with a traumatic brain injury, and had a Glasgow Coma Scale score between 13 and 15 were included. Interrater reliability was assessed, and validity was verified using criterion-related comparisons with the Short Confusion Assessment Method. The Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria were employed to assess the sensitivity and specificity of the TC-4AT for screening posttraumatic brain injury delirium. Results: A total of 100 patients with an average age of 67 years were enrolled, of whom 10% were diagnosed with delirium based on the Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition criteria. The interrater reliability of the TC-4AT was 1.00. Patients with delirium tended to have a longer hospital stay than those without delirium (13 days vs. 7 days) although the difference was nonsignificant (P = 0.28). In terms of criterion validity, patients diagnosed with delirium using the Short Confusion Assessment Method had a significantly higher score on the TC-4AT than those not diagnosed with delirium (P < 0.001). The receiver operating characteristic curve indicated that the optimal cutoffpoint was 4, with sensitivity, specificity, and area under the characteristic curve of 0.90, 0.94, and 0.96, respectively. Conclusion: The TC-4AT is an accurate tool for delirium assessment that aids early detection and in informed decision-making in preventive care.

Glioblastoma (GBM) remains uniformly fatal because the standard temozolomide (TMZ) + radiotherapy regimen is quickly thwarted by epigenetic adaptations that reactivate proliferation and blunt DNA-damage responses; mounting evidence implicates simultaneous up-regulation of lysine-specific demethylase 1 (KDM1A/LSD1) and histone deacetylase 2 (HDAC2) as a central driver of this resistance, yet no brain-penetrant agent has been available to co-target both enzymes. Here we show that MPT0G521, a dual KDM1A/HDAC inhibitor able to cross the blood–brain barrier, reverses this adaptive program. Integrated analyses of TMZ- and radiation-resistant GBM lines, public bulk datasets and 66 000 single cells revealed concerted over-expression of KDM1A and HDAC2, tight co-regulation with 50 core cell-cycle genes, and enrichment of LSD1-high NPC/OPC-like populations at invasive margins; high expression of either gene predicted significantly worse overall survival in CGGA cohorts (log-rank p < 0.01). In both parental and TMZ-resistant A172 and patient-derived Pt#3 cells, MPT0G521 produced dose- and time-dependent growth inhibition, suppressed clonogenicity, induced G2/M arrest, and triggered caspase-3/PARP-mediated apoptosis. Mechanistically, treatment raised H3K4me1/2 and H3K9/K14ac without altering core histone levels, confirming effective blockade of KDM1A demethylase and HDAC deacetylase activities. These findings identify KDM1A/HDAC2 over-expression as a tractable epigenetic vulnerability in therapy-refractory GBM and position MPT0G521 as a promising lead compound for overcoming TMZ resistance and improving clinical outcomes.

OBJECTIVE: The study aims to evaluate the outcomes of surgical intervention in eclamptic patients with malignant posterior reversible encephalopathy syndrome (PRES) complicated by intracerebral hemorrhage (ICH). METHODS: A retrospective review of 22 eclamptic women diagnosed with PRES between January 2013 and November 2023 was conducted. Patients were categorized into 4 groups: group 1 (no ICH, Glasgow Coma Scale 15, and no signs of increased intracranial pressure [IICP]), group 2 (no ICH, Glasgow Coma Scale <15, with neurological deficits), group 3 (ICH <10 ml, no mass effect, and no signs of IICP), and group 4 (ICH >10 ml, with mass effect and signs of IICP). Patient demographics, obstetrical outcomes, radiological findings, and functional recovery (measured by modified Rankin Scale [mRS]) were analyzed. RESULTS: No patients in groups 1 or 2 required surgery, while all patients in group 4 underwent surgical intervention. At presentation, group 4 exhibited significantly worse mRS scores (mean 4.4) compared to groups 1 (mean 1.2) and 2 (mean 2.29, P< 0.001). However, at the 1- and 2year follow-ups, mRS scores were comparable across all groups (P = 0.458 and P = 0.883, respectively), reflecting substantial recovery regardless of initial severity. CONCLUSIONS: Eclamptic women with malignant PRES and ICH can achieve long-term outcomes comparable to those without hemorrhagic transformation through timely surgical intervention following American Heart Association guidelines, though the natural course of such cases remains unclear.

Conductive bioinks, integrated with 3D bioprinting and electrical stimulation, are essential for advancing neural tissue engineering. This study developed a SilMA/Pectin/MXene-soybean phospholipids (SP) bioink, where SilMA (silk fibroin modified with glycidyl methacrylate) provides a structural base, pectin enhances printability and shear-thinning properties, and MXene-SP improves conductivity through superior dispersibility. Increasing pectin and MXene-SP concentrations reduced the hydrogel's Young's modulus, promoting neural stem cell (NSC) differentiation into neurons. Electrochemical analyses revealed that higher MXene-SP levels decreased impedance and increased redox current, while conductivity measurements showed improved performance compared to unmodified MXene. NSCs encapsulated in the bioink achieved maximum proliferation under electrical stimulation at 300 μA for 10 min daily over 5 days. Neuronal differentiation positively correlated with MXene-SP concentration and stimulation intensity. Synaptic activity and vesicle recycling, assessed using FM1-43 dye, were significantly enhanced under electrical stimulation. This study successfully developed a biocompatible conductive bioink capable of inducing neuronal differentiation. Electrical stimulation further promoted cell proliferation, neuronal differentiation, and enhanced synaptic function. This bioink shows great potential for future applications in neural tissue engineering.

Supplementary Figure 6. The effect of an AKT inhibitor on AKT/GSK-3β/β-catenin pathway and miR-30a-5p expression in acrolein-treated glioma cells.

BACKGROUND AND OBJECTIVES:Combining focused ultrasound (FUS)-induced blood-brain barrier opening with bevacizumab (BEV) has demonstrated survival benefits in preclinical models. This study aimed to evaluate the safety and feasibility of repeated FUS-BEV treatments in patients with recurrent glioblastoma and to explore imaging and serum biomarkers in relation to disease status. METHODS:This was a prospective, single-arm, open-label pilot trial. The primary end point was 6-month progression-free survival (PFS). Disease progression was assessed according to the Response Assessment in Neuro-Oncology criteria by independent radiological review. Radiological response was evaluated using fluid-attenuated inversion-recovery sequences to compare FUS-exposed vs nonexposed regions. Plasma cell-free DNA (cfDNA) concentrations were measured before and after FUS treatment. RESULTS:Between July 2020 and August 2023, 6 patients received a median of 14.5 sessions of biweekly FUS-BEV (10 mg/kg). The median PFS was 11 months, with a 6-month PFS rate of 66.7%. The only FUS-related adverse event was transient scalp heating (grade 1; 1.9%). A fluid-attenuated inversion recovery normalization effect emerged within 1 month after treatment. Plasma cfDNA increased significantly post-FUS, with total cfDNA rising 2.03 ± 0.76-fold, EGFR cfDNA 1.77 ± 0.76-fold, and HMBS cfDNA 1.68 ± 0.66-fold. CONCLUSION:Repeated FUS-BEV treatment is safe and feasible in patients with recurrent glioblastoma. Randomized controlled trials are warranted to confirm its therapeutic efficacy and validate imaging and liquid biopsy biomarkers.

BACKGROUND:Neuropathic pain is a complex condition that can be challenging to manage, despite the availability of a variety of pharmacologic and non-pharmacologic treatment approaches. This narrative review aimed to synthesize preclinical evidence on the therapeutic effects and underlying mechanisms of focused ultrasound (FUS) in neuropathic pain models. METHODS:We conducted a narrative literature search using PubMed to identify preclinical studies investigating the use of FUS in the context of neuropathic pain. Studies were retrieved from PubMed using keyword combinations "focused ultrasound" and "neuropathic pain," with no restrictions on country of origin. Studies published in English from inception to December 2024 were considered. Eligible studies were limited to those involving animal models or in vitro cell models relevant to neuropathic pain. Clinical studies, review articles, editorials, and studies unrelated to neuropathic mechanisms were excluded. RESULTS:A total of 28 preclinical studies were identified, all employing either animal or cell-based models of neuropathic pain. Across various nerve injury models, both high-intensity (HIFU) and low-intensity focused ultrasound (LIFU) were associated with behavioral improvements indicative of pain reduction, partial restoration of nerve function, and modulation of inflammatory cytokine profiles. Although the precise mechanisms remain to be fully elucidated, current evidence suggests that FUS may exert its effects through thermal, mechanical, and neuromodulatory pathways, including modulation of inhibitory neurotransmission, suppression of neuroinflammation, and regulation of ionic homeostasis. CONCLUSIONS:Preclinical studies indicate that FUS may alleviate neuropathic pain via thermal, mechanical, and neuromodulatory mechanisms. However, clinical translation remains uncertain, highlighting the need for further investigation in human models.

Supplementary Table 4. Cox regression analysis of CGGA cohorts.

Glioblastoma (GBM), a highly aggressive brain tumor, thrives in hypoxic environments. Tumor-derived exosomes are key drivers of glioma progression, facilitating tumor growth, immune evasion, angiogenesis, and therapy resistance. Acrolein, a toxic byproduct produced under hypoxic conditions, causes DNA damage, inflammation, and mitochondrial dysfunction and potentiates oxidative stress. Elevated acrolein levels and associated DNA damage are linked to poor GBM prognosis. This study aims to uncover the role of acrolein in GBM progression through exosome-mediated pathways and the associated molecular mechanisms. We found that acrolein production under hypoxia promotes GBM cell malignant behaviors, such as migration and spheroid formation, by downregulating NCAM1 via autocrine and paracrine signaling of miR-30a-5p. Inhibiting the miR-30a-5p/NCAM1 axis reverses the tumor-promoting effects of acrolein treatment. Analysis of tumor samples from GL261 tumor-bearing mice and patients with glioma showed that decreased NCAM1 levels in glioma tissues correlate with elevated acrolein expression. In samples of patients with GBM, lower NCAM1 levels are associated with a worse prognosis. This study suggests that targeting the miR-30a-5p/NCAM1 axis could be a potential therapeutic strategy for GBM.

Background and Objective:Primary Intracranial DICER1-Mutant Sarcoma (PIDMS) is a rare brain tumor with limited data available on its clinical presentation, treatment, and prognosis. This review aimed to analyze the literature on PIDMS, focusing on its presenting features, imaging findings, genetic profiling, surgical treatment, and outcomes. Methodology:Our systematic review was conducted following the Preferred Reporting Items for Systematic Review and Meta-Analyses (PRISMA) guidelines. PubMed and Google Scholar were searched to identify the studies published between 2000 and 2024. Only the studies with biopsy-proven PIDMS cases were included. Studies on animals, metastatic, and extracranial sarcomas were excluded. The Joanna Briggs Institute (JBI) critical appraisal tools were used for the quality assessment. Results:Eight studies comprising 10 patients met the inclusion criteria. Five of the cases (50%) occurred in the pediatric group, while five (50%) in the adult age group (mean age: 15.91 ± 17.71 years). Six patients (60%) were males, and the most common symptoms included headaches and seizures. The frontal and frontoparietal lobes were the most common tumor locations, and the molecular profiling in all 10 cases revealed DICER1 mutation. Gross total resection (GTR) was achieved in 50% of the cases. The mean follow-up duration was 17.5 months, and seven patients underwent combined adjuvant treatment with radiotherapy and chemotherapy. Five patients (50%) had stable disease after undergoing surgical resection and adjuvant therapy. Conclusion:PIDMS is an aggressive neoplasm with non-specific clinical features overlapping with other brain tumours. Extensive genetic profiling and large-scale clinical trials are needed to develop optimized treatment protocols.