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PubMed2026

Insights from changes in NDEV biomarkers of metabolism: effects of PPARγ and GLP1 receptor agonists on brain metabolism.

BACKGROUND: Insulin resistance (IR) is implicated in central nervous system disorders, including depression and Alzheimer's disease (AD). METHODS: We analyzed biological samples from two cohorts of clinical trial participants: (1) participants with unremitted depression after six months of treatment as usual who received pioglitazone (PPARγ agonist, N = 12) or placebo and (2) middle-aged participants at genetic risk for AD who received liraglutide (glucagon-like peptide 1 [GLP1] receptor agonist, N = 15) or placebo. These cohorts, which previously showed treatment-related improvements in peripheral IR, were used to assess the effects of pioglitazone and liraglutide on CNS insulin signaling using neuron-derived extracellular vesicles (NDEVs) as biomarkers. We utilized biological samples to measure biomarkers of IR in NDEVs. Eleven Akt-mTOR pathway proteins were measured before and after 12 weeks of treatment in both groups. RESULTS: Participants who received pioglitazone experienced broader changes, with significant increases in GSK3β (Ser9), mTOR (Ser2448), and RPS6 (Ser235/Ser236; all P ≤ .02) compared with placebo, and 77% of participants showed mTOR (Ser2448) response. Participants who received liraglutide demonstrated significantly increased NDEV-associated phosphorylated Akt (Ser473) and mTOR (Ser2448; P = .04 and P = .025, respectively) compared with placebo, with 40% and 30% of participants in the liraglutide group showing biomarker response in both Akt (Ser473) and mTOR (Ser2448), respectively. These effects appeared relatively independent from changes in fasting plasma insulin and glucose concentration at 120-minutes during the oral glucose tolerance test. DISCUSSION: Our findings demonstrate CNS-specific biomarker responses to both PPARγ agonists and GLP1 receptor agonists.

Humans↗

PubMed2026

Continuous Intrathecal Infusion of Nivolumab in Advanced Melanoma With Concomitant Leptomeningeal Disease: Efficacy, Safety, and Pharmacokinetics.

BACKGROUND AND OBJECTIVES: Prognosis of melanoma with leptomeningeal disease (LMD) is poor (median overall survival of 5.1 months). Intrathecal (IT) nivolumab appears safe, although its efficacy remains uncertain. We investigated the feasibility, safety, and efficacy of continuous IT nivolumab. METHODS: This was a retrospective analysis of 11 melanoma patients with progressive LMD (MelBase; NCT02828202) treated as part of the patients' care with continuous IT nivolumab administered through spinal (n = 10) or ventricular catheter (n = 1). RESULTS: Patients (5 women, median age 52) with Eastern Cooperative Oncology Group ≤1 (except for 1) and stable extracranial disease (except for 4) were treated over a median duration of 1.5 months and followed for 2.5 months. Seven presented symptomatic LMD. Primary tumors were mostly cutaneous (n = 8) and BRAF-mutated (n = 10). All patients had progressed on systemic immunotherapy; 7 had received brain radiotherapy (whole brain radiotherapy [n = 3]; stereotactic radiosurgery [n = 4]). Concomitant therapies included corticosteroids >10 mg (n = 5), intravenous nivolumab (first 3 months of IT therapy, n = 1), and targeted therapies (n = 7). The median overall survival was 2.5 months, with 3 patients surviving for more than a year. Reversible treatment-related adverse events occurred in 5 patients: meningoencephalitis (grade 3, n = 1), intracranial hemorrhage (grade 1, n = 1), intracranial hypotension (grade 2, n = 2; grade 1, n = 1). Baseline levels of nivolumab in the cerebrospinal fluid (CSF) were <2 µg/mL, even among patients with plasma detection. CSF concentrations of nivolumab at steady state varied from 36 to 97 µg/mL, with clearances of 4.3-15.7 mL/h. Next-generation sequencing identified CSF genomic profiles correlating with clinical progression in 4 patients. CONCLUSION: These findings warrant further trials on IT nivolumab.

Humans↗

PubMed2026

Proteomic Signatures Related to Physical Activity Are Associated with Risks of Future Disease.

PURPOSE: Physical activity (PA) can lower the risk of developing chronic diseases. However, few studies have examined the proteomic signatures linked to PA, and the role of these signatures in the connection between PA levels and future disease risk remains unclear. This study aimed to investigate whether proteomic signatures indicative of PA are associated with the risk of developing common chronic diseases and to explore their role as statistical links in the relationship between PA levels and disease development. METHODS: We used data from a subcohort of UK Biobank participants. PA intensity data were collected from accelerometers worn by each participant. Plasma proteomics results were obtained through Olink analysis. The risks of developing each primary chronic disease were evaluated for types of PA and their associated proteomic signatures, adjusting for age, sex, ethnicity, socioeconomic status, lifestyle factors, and key measurement time-lag covariates. RESULTS: Based on the UK Biobank, we identified significant differences among the proteomic signatures of accelerometer-measured light PA, moderate-to-vigorous PA, and total PA. The main enriched pathways of these proteomic signatures included cell adhesion, cell migration, and immune response. Higher levels of accelerometer-measured PA and their associated proteomic signatures correlated with a lower risk of developing cardiometabolic disorders, cancers, psychological or neurological disorders, and respiratory diseases. CONCLUSIONS: Our findings show that PA and PA-related proteomic signatures are statistically associated with lower risks of chronic diseases. Further analyses identified proteins that were correlated with both PA and disease risk. These results need to be confirmed through longitudinal studies involving diverse populations.

Humans↗

PubMed2025

Genetic analysis of IFNG-AS1 implicates opposite effects to Leishmania guyanensis-cutaneous leishmaniasis: rs4913269 confers protection while rs7134599 enhances susceptibility and correlates with high plasma IL-4 and IL-10 levels.

BACKGROUND: The long non-coding RNA interferon gamma antisense-1 (IFNGAS-1) is essential for Th1 lineage specific expression of IFNG. IFN-γ is a key component cytokine in host immune response against intracellular pathogens like Leishmania. We investigated the association of two genetic variants of IFNGAS-1, rs4913269 and rs7134599, with susceptibility or protection to Leishmania guyanensis- induced cutaneous leishmaniasis (Lg-CL). METHODS: A case-control study involving 1,714 individuals (855 Lg-CL and 859 healthy controls) was conducted in the state of Amazonas, Brazil. Genotyping of rs4913269 and rs7134599 were performed using direct nucleotide sequencing and polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP), respectively. Plasma cytokines concentrations (IL-10, IL-12p70, IL-4, IL-1β and TNF-α) were quantified using multiplex Luminex platform. Logistic regression, linkage disequilibrium (LD), and haplotype analyses were applied to assess genetic associations and cytokine correlations. RESULTS: Individuals with the rs4913269 G/G genotype had a 46% reduced risk of developing Lg-CL, (OR adjusted for age and sex [ORadj] = 0.54; 95% CI 0.39-0.75; Pvadj = 0.0001). Carriers of the rs7134599 A/A genotype had a 130% increased risk of progression to Lg- CL (ORadj = 2.3; 95% CI, 1.6-3.4; P = 0.0001). The rs7134599 A/G genotype also showed a 52% increased risk compared to GG genotype (ORadj = 1.52, 95%CI 1.22-1.89; Pvadj = 0.0002). The rs4913269 G/G genotype was associated with lower levels of IL-10 (P = 0.05) and IL-12p70 (P = 0.009) compared to the C/C genotype. Conversely, the rs7134599 AA genotypes were correlated with higher levels of TNF-α, IL-4, IL-10 and IL-1β in comparison to the GG genotype. LD revealed independent segregation of the variants. CONCLUSIONS: The IFNG-AS1 variants rs4913269 and rs7134599 exert opposing effects on Lg-CL risk and modulate key cytokines involved in disease pathogenesis. These findings underscore the regulatory role in immune responses and increase our understanding of the immunogenetic basis of CL and support the potential IFNG-AS1 as a biomarker for susceptibility.

Humans↗

PubMed2024

Identification of breast cancer-associated PIK3CA H1047R mutation in blood circulation using an asymmetric PCR assay.

PURPOSE: To establish a highly sensitive and specific approach for the detection of circulating PIK3CA H1047R mutation in breast cancer (BC) patients and to investigate the association between the prevalence of PIK3CA H1047R mutation and clinical presentations. METHODS: A proper blocker was designed in an allele-specific manner and optimized for PCR-based identification of the PIK3CA H1047R mutation. The established technique was validated in cell-free DNA samples from 196 recruited BC patients. RESULTS: The allele-specific PCR assay with a properly designed blocker was able to detect the H1047R mutant variant with 0.01%. By applying the newly established assay, 62 cases (31.6% of the total recruited cases) were found to carry a blood-circulating H1047R mutant. Wherein, the detected mutant rates increased with disease stages from 2/18 (11.1%) of stage I to 17/71 (23.9%) of stage II, 20/53 (37.7%) of stage III, and 23/31 (42.6%) of stage IV (p = 0.025), respectively. Higher frequencies of H1047R mutation were associated with late-stage (p = 0.033) or recurrence (p = 0.045) or metastatic patients (p = 0.049) as well as radiation-treated human epidermal growth factor receptor 2 (HER2) positive BC (p = 0.004). PIK3CA mutant carriers were frequently observed in patients under the age of 50 who had liver-metastasized or brain metastases or lymph node-invaded (p < 0.05). CONCLUSION: A novel allele-specific PCR assay with high sensitivity was established successfully for the detection of the PIK3CA H1047R mutation in clinical practice.

Humans↗

PubMed2024

Genomic variants associated with type 2 diabetes mellitus among Filipinos.

Type 2 diabetes mellitus leads to debilitating complications that affect the quality of life of many Filipinos. Genetic variability contributes to 30% to 70% of T2DM risk. Determining genomic variants related to type 2 diabetes mellitus susceptibility can lead to early detection to prevent complications. However, interethnic variability in risk and genetic susceptibility exists. This study aimed to identify variants associated with type 2 diabetes mellitus among Filipinos using a case-control design frequency matched for age and sex. A comparison was made between 66 unrelated Filipino adults with type 2 diabetes mellitus and 121 without. Genotyping was done using a candidate gene approach on genetic variants of type 2 diabetes mellitus and its complications involving allelic association and genotypic association studies with correction for multiple testing. Nine (9) significant variants, mostly involved in glucose and energy metabolism, associated with type 2 diabetes mellitus in Filipinos were found. Notably, a CDKAL1 variant (rs7766070) confers the highest level of risk while rs7119 (HMG20A) and rs708272 (CETP) have high risk allele frequencies in this population at 0.77 and 0.66, respectively, making them potentially good markers for type 2 diabetes mellitus screening. The data generated can be valuable in developing genetic risk prediction models for type 2 diabetes mellitus to diagnose and prevent the condition among Filipinos.

Humans↗

PubMed2025

Genetic influence on choroidal vascularity index.

PURPOSE: To investigate the heritability of genetic influence on macular choroidal vascularity index (CVI). METHODS: Total choroidal area (TCA), luminal area (LA), and CVI was measured using horizontal scan of spectral-domain optical coherence tomography with enhanced depth imaging in the 373 healthy twin participants. Characteristics of the participants were investigated, including age, sex, axial length, hypertension, diabetes, drinking habits, and smoking status. Univariate and subsequent multivariate regression analyses were performed to evaluate the associations of these factors with TCA, LA, and CVI. RESULTS: Patients who were older and had a higher intraocular pressure, higher diastolic blood pressure, and lower pulse pressure showed associations with lower CVI (p<0.001, p = 0.014, p = 0.005, and p = 0.015, respectively). The covariate-adjusted heritability (±standard error) of the CVI was 0.716 ± 0.091, and the heritabilities of the TCA and LA were 0.691 ± 0.089 and 0.634 ± 0.100, respectively. CONCLUSION: The TCA, LA, and CVI are highly heritable.

Humans↗

PubMed2026

Dysregulation of the serum and IgG N-glycome in decompensated cirrhosis and its association with Model for End-Stage Liver Disease-Sodium (MELD-Na).

BACKGROUND AND AIMS: N-glycans modulate glycoprotein structure and function and are altered during chronic inflammation. We sought to define the extent of serum and IgG N-glycan disruption in patients with decompensated liver cirrhosis from alcohol-related liver disease (ALD), primary sclerosing cholangitis (PSC), and ALD-related hepatocellular carcinoma (HCC). Finally, we aimed to examine whether serum and IgG glycosylation is associated with changes in Model for End-stage Liver Disease-Sodium (MELD-Na) scores, a clinical marker used to prioritise liver transplantation. METHODS: Serum samples were obtained from patients with ALD (n = 17), PSC (n = 7), ALD-related HCC (n = 4), and healthy controls (n = 10). N-glycans were released, fluorescently labelled, and profiled by hydrophilic interaction ultra performance liquid chromatography (HILIC-UPLC). Chromatograms were integrated into 46 and 23 glycan peaks for serum and IgG respectively. These peaks and their associated glycosylation traits were statistically compared with healthy controls using age- and sex-adjusted linear regression models. RESULTS: In serum, decompensated cirrhosis shows statistically significant shifts toward less complex, agalactosylated and asialylated biantennary glycans, accompanied by significant losses of highly branched, galactosylated and sialylated structures. IgG mirrored this pattern, which is characteristic of a pro-inflammatory signature, with increased agalactosylation and bisected glycan levels, along with reduced levels of digalactosylated and sialylated species. N-glycan profiles showed significant associations with MELD-Na scores, indicating that inflammatory processes in decompensated liver cirrhosis continue to reshape serum glycoproteins. CONCLUSION: Decompensated liver cirrhosis shows profound remodelling of serum and IgG N-glycans. These data establish a reference framework for terminal glycomic disruption in liver disease and highlight the potential value of incorporating glycosylation analysis into broader assessments of liver disease progression.

Humans↗

PubMed2024

Molecular Analysis of Persistent and Recurrent Barrett's Esophagus in the Setting of Endoscopic Therapy.

INTRODUCTION: Early neoplastic progression of Barrett's esophagus (BE) is often treated with endoscopic therapy. Although effective, some patients are refractory to therapy or recur after apparent eradication of the BE. The goal of this study was to determine whether genomic alterations within the treated BE may be associated with persistent or recurrent disease. METHODS: We performed DNA sequencing on pre-treatment esophageal samples from 45 patients who were successfully treated by endoscopic therapy and did not recur as well as pre-treatment and post-treatment samples from 40 patients who had persistent neoplasia and 21 patients who had recurrent neoplasia. The genomic alterations were compared between groups. RESULTS: The genomic landscape was similar between all groups. Patients with persistent disease were more likely to have pre-treatment alterations involving the receptor tyrosine kinase pathway ( P = 0.01), amplifications of oncogenes ( P = 0.01), and deletions of tumor suppressor genes ( P = 0.02). These associations were no longer significant after adjusting for patient age and BE length. More than half of patients with persistent (52.5%) or recurrent (57.2%) disease showed pre-treatment and post-treatment samples that shared at least 50% of their driver mutations. DISCUSSION: Pre-treatment samples were genomically similar between those who responded to endoscopic therapy and those who had persistent or recurrent disease, suggesting there is not a strong genomic component to treatment response. Although it was expected to find shared driver mutations in pre-treatment and post-treatment samples in patients with persistent disease, the finding that an equal number of patients with recurrent disease also showed this relation suggests that many recurrences represent undetected minimal residual disease.

Humans↗

PubMed2026

A Web-Based, Pedometer-Mediated Intervention Increases Amount and Intensity of Physical Activity in COPD: A Randomized Controlled Trial.

INTRODUCTION: Ground-based walking training is an aerobic exercise used in supervised pulmonary rehabilitation (PR). Physical activity (PA) interventions typically promote step counts, but it is unclear whether community-based walking intensity can be targeted as aerobic exercise. This randomized controlled trial evaluated a web-based, pedometer-mediated PA intervention designed to increase walking amount and intensity. MATERIAL AND METHODS: Participants with COPD who had never enrolled in PR were randomized 1:1 to control or intervention. The intervention included individualized step-count goals, iterative feedback, educational content, and an online community forum. The Fitbit Inspire Heart Rate objectively monitored daily step counts. Participants were instructed to achieve step-count goals with as many steps of moderate-intensity as possible guided by a modified Borg rating of 4-5 for dyspnea. The primary outcome was change in PA measured as average daily step count at 12 weeks. Aerobic intensity was assessed by the Rapid Assessment of PA Questionnaire which uses self-reported moderate or vigorous PA to categorize responders as underactive or active. Linear mixed-effects models (PROC MIXED, SAS v9.4), adjusting for group, time, group*time, FEV1%predicted, enrollment season, and study modality (eg, in-person, virtual, hybrid), assessed between-group change. RESULTS: Participants (57 intervention, 52 control) were 97% male, mean age 73±7 years, and baseline FEV1 73±23% predicted. Baseline daily steps were 4,222±1,929 (intervention) and 4,851±2,637 (control). Intervention participants increased average daily steps by 1,410 steps/day more than controls (p=0.005). The intervention group showed greater transitions from underactive to active intensity (between-group: p=0.025), with 20 (41%) moving to active status (within-group: p=0.001). CONCLUSION: Technology-mediated community-based walking increased PA amount and intensity. These findings support further evaluation of this intervention as a potential option for ground-based walking training with objective measurement of exercise intensity.

Humans↗

PubMed2026

User Engagement and Feature Preferences in an AI-Powered mHealth Intervention for Diabetes Prevention: Secondary Analysis of a Randomized Controlled Trial.

BACKGROUND: Prediabetes is highly prevalent and increasing globally, yet lifestyle interventions remain underused. AI-driven mobile health (mHealth) tools can help scale diabetes prevention efforts, but the key factors driving their success are not well understood. OBJECTIVE: This post hoc secondary analysis of a randomized controlled trial (RCT) aimed to characterize the most valued features and the role of user engagement in outcomes of a fully automated mHealth intervention for diabetes prevention. METHODS: Data from 151 participants with prediabetes and overweight or obesity who were assigned to an AI-based diabetes prevention program (Sweetch) in a parent RCT (NCT05056376) were analyzed. Engagement (defined as the total number of days the app was used) was categorized into tertiles (low, medium, and high). Baseline characteristics were compared across engagement groups using ANOVA, Kruskal-Wallis, and chi-square tests, and regression models assessed the association between engagement and achievement of diabetes risk reduction outcomes (≥5% weight loss, ≥4% weight loss with ≥150 min/week of physical activity, or ≥0.2 percentage point reduction in hemoglobin A1c [HbA1c] at 12 months). Perceived usefulness of intervention features was surveyed at 12 months. RESULTS: Median engagement was 98 (IQR 34-232) days. Older age (P<.001) and lower baseline BMI (P=.04) were significantly associated with higher engagement. Compared with low engagement, high engagement was associated with greater odds of achieving the composite diabetes risk reduction outcome (odds ratio [OR] 2.59, 95% CI 1.11-6.01; P=.03), ≥5% weight loss (OR 3.31, 95% CI 1.16-9.42; P=.03), and ≥0.2 percentage point reduction in HbA1c (OR 3.57, 95% CI 1.19-10.75; P=.02). Participants most frequently rated weight tracking, physical activity tracking, and the digital body weight scale as the features that were most helpful for achieving their health goals. CONCLUSIONS: Higher engagement with an AI-driven intervention requiring no human intervention was associated with improved diabetes risk reduction. Contrary to concerns about lower digital literacy, older adults engaged with the intervention more than younger adults. Features related to weight and physical activity tracking were most valued by patients in the program. TRIAL REGISTRATION: ClinicalTrials.gov NCT05056376; https://clinicaltrials.gov/study/NCT05056376.

Humans↗

PubMed2026

Emerging trends in invasive Streptococcus dysgalactiae subsp. equisimilis infections in Denmark, 2014 to 2024: a nationwide genomic and registry-based study.

BACKGROUNDIncreasing incidence rates of invasive Streptococcus dysgalactiae subspecies equisimilis (iSDSE) have been detected worldwide.AIMWe aimed to investigate iSDSE infection incidence rates in Denmark during 2014-2024, and characterise the genomic population structure of a subset of iSDSE isolates and their antimicrobial resistance (AMR).METHODSUsing national register data, we estimated overall and sex-/age-stratified iSDSE incidences during 2014-2024, by retrospectively identifying cases of invasive infections with group C and G streptococci or S. dysgalactiae (including specified as subspecies equisimilis). From the voluntary national beta-haemolytic streptococci laboratory surveillance system, whole-genome-sequenced isolates from August 2020-September 2022 were used to investigate the iSDSE genomic population structure. Susceptibility to penicillin, erythromycin and clindamycin was determined and AMR genes identified.RESULTSDuring 2014-2024, iSDSE incidence rates increased significantly (linear trend analysis p < 0.001) with mean annual incidence ranging between 10.3 and 16.4 per 100,000, peaking in 2023. Incidence was higher in males, increasing with older age. Nearly 75% of the 1,223 iSDSE isolates belonged to four of 14 genetic clusters. Sequence types (STs) ST20 and ST17 were most prevalent, while emm-type stG62647, a variant associated internationally with higher virulence, dominated. All isolates were phenotypically susceptible to penicillin but approximately 10% were respectively erythromycin and clindamycin resistant. High erythromycin resistance prevalence (57%; 39/68), coinciding with gene ermA, occurred in one genetic cluster.CONCLUSIONThe findings illustrate the need for national registry-based surveillance to detect epidemiological changes and potential outbreaks. Further, continuous genomic surveillance can monitor the occurrence and expansion of genetic clades and AMR genes.

Denmark↗

PubMed2026

Genomic Analysis and Clinical Correlation of Non-Small Cell Lung Cancer with Special Reference to Brain Metastasis.

BACKGROUND: Next-generation sequencing (NGS) has improved genomic analysis depth in precision oncology. This study analyzed genomic biomarker testing in stage IV NSCLC, focusing on brain metastasis and clinicopathological correlations. OBJECTIVE: To study molecular markers and clinicopathological correlations in stage IV NSCLC patients, with and without brain metastasis. METHODS: A total of 169 stage IV NSCLC patients were studied from April 2023 to May 2025. Demographic data, clinical presentations, and mutation analyses were assessed using NGS on tissue blocks or liquid biopsies. RESULTS: Among 169 patients, 41.42% (n = 70) had brain metastasis (NSCLC-BM), while 58.58% (n = 99) had no brain metastasis (mNSCLC). Median ages were 51.5 and 56 years, respectively. Adenocarcinoma comprised 95.27% (n = 161) of cases. The cerebral hemisphere was the most common intracranial metastatic site, while skeletal involvement was the most common extracranial site. Headache was the predominant neurological symptom. EGFR mutations were the most common overall. EGFR > TP53 > ALK > other mutations were observed in NSCLC-BM, while EGFR > TP53 > KRAS > other mutations were seen in mNSCLC. Mutation analysis stratified by smoking history (χ²(1) = 1.347, p = 0.245) and sex (χ²(1) = 0.0302, p = 0.862) was not statistically significant. The benefit of gefitinib plus chemotherapy in EGFR exon 19 and exon 21 L858R mutations was greater in mNSCLC (log-rank χ²(1) = 10.813, p = 0.001) than in NSCLC-BM (log-rank χ²(1) = 3.100, p = 0.078). Median survival was 11 months (95% CI: 7.506-14.494) for NSCLC-BM versus 21 months (95% CI: 8.365-33.635) for mNSCLC, with a statistically significant difference (log-rank χ²(1) = 8.639, p = 0.003). CONCLUSION: NSCLC-BM showed higher genomic biomarker enrichment (80% vs. 68.68%) but poorer outcomes than mNSCLC. EGFR was the most common targetable mutation, followed by ALK in NSCLC-BM and KRAS in mNSCLC.

Humans↗

PubMed2026

Extent of resection as an independent predictor of survival for patients with glioblastoma as defined by the new WHO 2021 classification.

OBJECTIVE: Extent of resection (EOR) has previously been demonstrated to have an impact on survival in patients with glioblastoma (GBM). However, with the World Health Organization (WHO) 2021 reclassification of GBMs based on IDH-mutation status, patients with "IDH-mutant GBMs," who typically survive long term, were reclassified as WHO grade 4 IDH-mutant astrocytomas and removed from the GBM taxonomy. Therefore, it is unknown whether the previously reported impact of resection on survival was a false-positive result due to the inclusion of the less aggressive IDH-mutant tumors in previous datasets. This study aimed to determine the extent to which EOR remains an independent predictor of survival in patients with WHO 2021 GBM after the reclassification of IDH-mutant grade 4 astrocytomas. METHODS: All cases of GBM tumors (based on the pre-2021 GBM classification) that were newly diagnosed between 2005 and 2021 were identified in our institutional database and subsequently reclassified based on the updated WHO 2021 criteria using IDH status. Multivariable statistical analyses of demographic information, survival time, and EOR based on volumetric MRI were performed to determine the independent predictors of survival for the whole group of patients and for IDH-wildtype GBM patients exclusively. Additional analyses were performed to identify an EOR threshold for improvement in survival. RESULTS: Of the 523 tumors classified as GBM based on the pre-2021 taxonomy, 52 (9.9%) cases were reclassified as WHO grade 4 IDH-mutant astrocytomas, and the median survival of patients in this group was 7.9 years, whereas median survival of the IDH-wildtype GBM patients was 1.4 years. Multivariate analyses of the whole group demonstrated that IDH-mutant astrocytomas were associated with reduced hazard of death. In both the whole group (n = 523) and in IDH-wildtype GBMs (n = 471), higher EOR of the contrast-enhancing (CE) tumor was associated with reduced hazard of death, whereas older age or male sex was associated with increased hazard of death. Because most patients (90%) had high EOR values (> 81%), a statistically meaningful EOR threshold could not be established. CONCLUSIONS: These analyses demonstrated that EOR of the CE tumor is an independent predictor of survival and that greater EOR is associated with improved survival in WHO 2021 IDH-wildtype GBMs even after excluding grade 4 IDH-mutant astrocytomas. However, an absolute EOR threshold below which resection did not improve survival could not be established, raising concerns about prior cutoff assessments.

Humans↗

PubMed2026

Evaluation of the clinical and mechanistic role of MCM2 expression in the prediction of meningioma recurrence after radiotherapy.

OBJECTIVE: Postoperative radiotherapy is an effective treatment for meningiomas; however, treatment response varies among patients. In addition, practical methods for predicting tumor recurrence after radiotherapy have not been well established. Minichromosome maintenance protein 2 (MCM2), a key regulator of DNA replication licensing, was recently implicated in highly proliferative molecular subtypes of meningioma. In this study, the authors evaluated whether MCM2 immunohistochemical expression predicts response to radiotherapy in patients with meningiomas. METHODS: The authors retrospectively analyzed the records of patients with WHO grade 1-3 meningiomas treated with resection followed by radiotherapy at a single institution between July 2003 and November 2023. The MCM2 labeling index was assessed immunohistochemically, and patients were stratified into MCM2-high and -low groups using a cutoff of 35%. Progression-free survival (PFS) was defined as the interval from the completion of radiation therapy to postoperative radiological tumor recurrence or regrowth. Patients who showed no progression were censored at their last follow-up. PFS was estimated using Kaplan-Meier analysis and subsequently evaluated with Cox proportional hazards models. To further investigate the biological mechanisms associated with MCM2 expression, comprehensive transcriptomic analyses, including gene set enrichment analysis, was performed to elucidate the molecular processes that occur within MCM2-high tumors. RESULTS: The study population included 15 men (42%) and 21 women (58%), with a mean age of 63 years. Ten tumors (28%) were classified as MCM2-high meningiomas and 26 (72%) as MCM2-low meningiomas. High MCM2 expression was significantly associated with WHO grades 2-3 histology and higher Ki-67 labeling indices. During a median follow-up of 2.52 years, tumor progression after radiotherapy occurred in 47% of the patients. High MCM2 expression (HR 8.34, p = 0.03) was significantly associated with shorter PFS and remained an independent predictor of recurrence after adjustment for WHO grade, tumor size, and Ki-67 labeling index. Transcriptomic analyses of MCM2-high tumors revealed upregulation of cell proliferation-related pathways, accompanied by increased signaling through the E2F8-CHEK1 axis associated with radiation resistance and suppression of the TNF-α signaling pathway implicated in radiosensitivity. CONCLUSIONS: In meningiomas, high MCM2 expression is associated with early recurrence following radiotherapy. The study findings suggest that this association is driven by diverse biological mechanisms related to cell cycle regulation and radioresistance. Immunohistochemical assessment of MCM2 expression may serve as a practical and accessible biomarker for risk stratification and may support the future development of individualized postoperative radiotherapy strategies.

Humans↗

PubMed2026

Paramedian supracerebellar transtentorial approach for Yaşargil T2 tentorial incisura meningiomas.

OBJECTIVE: Tentorial incisura meningiomas, particularly those arising from the middle incisural region (Yaşargil T2), are surgically challenging because of their deep location and compression of critical neurovascular structures. These lesions typically have supratentorial or infratentorial extension but can also extend across both compartments. Although approach selection is often guided by the dominant compartment of tumor extension, for lesions with supratentorial-dominant extension, the optimal approach remains controversial, and a standardized strategy has not been established. Authors of this study evaluated the feasibility and outcomes of the paramedian supracerebellar transtentorial (PST) approach for Yaşargil T2 tentorial incisura meningiomas with a supratentorial-dominant or combined extension. METHODS: The authors retrospectively reviewed data from consecutive patients with radiographic and intraoperative findings consistent with a Yaşargil T2 tentorial incisura lesion treated via the PST approach from September 2005 through December 2025. Patients were placed in a semisitting position whenever feasible and in a semilateral position when semisitting was contraindicated. Collected data included demographics, tumor extension patterns, extent of resection on postoperative MRI, neurological outcomes, histopathology, rate of recurrence, and follow-up. RESULTS: Six patients, 1 male and 5 female, with an overall mean age of 43 years, underwent resection via the PST approach. Four lesions had predominantly supratentorial extension, and 2 had combined supra- and infratentorial growth, with no cases of isolated infratentorial extension. Five patients had been placed in the semisitting position and 1 in a semilateral position because of a cardiac contraindication to the semisitting position. No new permanent neurological deficits were observed. Postoperative MRI showed Simpson grade I resection in all 6 patients. The mean follow-up was 8.6 years. Histopathological analysis revealed 3 WHO grade 1 meningiomas, 1 WHO grade 2 meningioma (clear cell), and 2 solitary fibrous tumors (meningioma mimics). These diagnoses were evaluated according to the 2021 WHO classification. CONCLUSIONS: In this consecutive series, the PST approach was a viable single-corridor strategy for Yaşargil T2 tentorial incisura lesions, including supratentorial-dominant tumors, achieving Simpson grade I resection with no permanent neurological deficits. By providing early devascularization at the tentorial attachment and a gravity-assisted, retractorless working corridor with favorable deep venous visualization, the PST approach challenges compartment dominance as the primary determinant of approach selection.

Humans↗

PubMed2026

Efficacy and Safety of Durvalumab plus Tremelimumab for Unresectable Hepatocellular Carcinoma: A Real-World Multicenter Observational Study.

Introduction: Durvalumab plus tremelimumab (Durva/Treme) improved survival in the HIMALAYA trial for unresectable hepatocellular carcinoma (HCC), but real-world evidence remains limited. This study aimed to evaluate clinical outcomes of Durva/Treme in routine practice. Methods: This retrospective multicenter study included patients with unresectable or advanced HCC who received Durva/Treme through the Expanded Access Program in Thailand between August 2023 and November 2025. Treatment outcomes and adverse events (AEs) were analyzed and descriptively compared with the HIMALAYA trial. Results: Fifty patients were included; median age was 62 years and 80% were male. Etiologies included hepatitis B (44%), hepatitis C (30%), and nonviral liver disease (26%). Most patients had Child-Pugh A (92%), while 24% had macrovascular invasion, including five with Vp4 portal vein involvement. The objective response rate (ORR) and disease control rate (DCR) were 12% and 60%, respectively. Among 43 patients meeting HIMALAYA eligibility criteria, ORR and DCR were 12% and 56%, respectively. With a median follow-up of 28.9 months, median progression-free survival (mPFS) and overall survival (mOS) were 4.6 and 10.5 months in the overall cohort, and 6.9 and 14.0 months in the HIMALAYA-eligible subgroup. Any-grade AEs occurred in 76% of patients, with grade ≥ 3 AEs in 24%. Hepatitis was the most common toxicity (48% overall; 14% grade ≥ 3). Conclusions: Durva/Treme demonstrated clinically meaningful activity with manageable toxicity in unresectable HCC. Outcomes among HIMALAYA-eligible patients were broadly consistent with the pivotal trial, supporting the feasibility of this regimen in routine clinical practice.

Aged↗

PubMed2026

Differentiating tuberculous pleurisy from pulmonary tuberculosis using mNGS: a multicenter cohort analysis.

BACKGROUND: Tuberculous pleurisy (TBP), a major extrapulmonary form of tuberculosis, is characterized by a paucibacillary state that makes diagnosis challenging. Metagenomic next-generation sequencing (mNGS) has emerged as a promising approach for MTB detection; however, its discriminatory value between TBP and pulmonary tuberculosis (PTB) among mNGS-confirmed cases, and its integration with clinical features for differential diagnosis, remain insufficiently defined. METHODS: This multicenter retrospective cohort included hospitalized patients with MTB-positive mNGS results from January 2020 to January 2025. As only mNGS-positive cases were included, overall mNGS diagnostic sensitivity cannot be estimated. Twelve TBP patients were matched 1:2 with twenty-four PTB patients by age and sex; patients with immunosuppressive conditions were excluded prior to matching. Clinical, laboratory, mNGS, and conventional TB test data were collected. Logistic regression and ROC analyses were performed. RESULTS: Conventional tests showed limited sensitivity in TBP despite universal mNGS positivity. MTB read counts were similar between groups (median 1976.5 vs. 990.0, P = 0.920). Pleural-derived specimens predominated in TBP (41.7% vs. 4.2%, P = 0.007). CRP demonstrated the highest individual discriminatory value (AUC = 0.658, P = 0.131), though no single predictor reached significance. A combined model (cough, fever, CRP, WBC) showed modest non-significant improvement (AUC = 0.722, overall P = 0.359; sensitivity 66.7%, specificity 83.3%). Given EPV ≈ 3, all findings are exploratory only. No significant prognostic predictors were identified in TBP; a non-significant trend toward lower lymphocyte counts was observed in patients with unfavorable outcomes (0.60 vs. 1.10 ×109/L, P = 0.115). CONCLUSIONS: Among mNGS-confirmed cases, MTB read counts were comparable between TBP and PTB. No single parameter reliably distinguished the two; a combined clinical model showed modest improvement but requires prospective validation in larger cohorts. Integrating mNGS with systematic clinical evaluation remains essential for accurate TB diagnosis.

Humans↗