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OBJECTIVE The aim of this study was to evaluate freedom from tumor progression and clinical outcomes in older adults with small- to medium-sized vestibular schwannoma (VS) managed by observation versus stereotactic radiosurgery (SRS) to better inform optimal management in this patient population. METHODS In this international multicenter study, patients aged ≥ 60 years with Koos grade I or II VS managed by observation or SRS were retrospectively reviewed. Propensity score matching was conducted using patient characteristics, tumor size, and hearing assessments. Outcome measures of freedom from tumor progression, serviceable hearing preservation (SHP), and neurological function (tinnitus, vestibulopathy, House-Brackmann grade, and trigeminal nerve function) were assessed for both groups. RESULTS The observation and SRS groups each comprised 51 matched patients (median age 68 years for both). Ipsilateral serviceable hearing was observed at presentation for 35 patients in each group. The median follow-up duration was 39 months in the observation group versus 27 months in the SRS group (p = 0.5). Tumor progression was significantly lower with SRS than with observation (2% vs 52.9%, p < 0.001). The rate of 5-year freedom from tumor progression was 100% in the SRS group versus 43% (95% CI 29%–64%) in the observation group. The rate of 10-year freedom from tumor progression was 90% (95% CI 73%–100%) in the SRS group versus 20% (95% CI 8.5%–49%) in the observation group. At the last follow-up, hearing loss occurred in 42.9% of the observation group and 51.4% of those who underwent SRS (p = 0.5). The 3-year SHP rate was 68% (95% CI 53%–88%) versus 65% (95% CI 49%–85%) (p = 0.8), and the 5-year SHP rate was 53% in both groups (95% CI 36%–78% in the observation group and 95% CI 35%–79% in the SRS group, p = 0.8). The composite endpoint of tumor progression and/or worsened neurological outcome, including hearing loss, tinnitus, vestibulopathy, facial nerve dysfunction (House-Brackmann grade), or trigeminal dysfunction, demonstrated a significantly lower rate in the SRS group (17.6%) compared with the observation group (66.7%) (p < 0.001). CONCLUSIONS SRS in older patients for management of Koos grade I or II VS resulted in significantly superior rates of freedom from tumor progression, comparable hearing preservation rates, and significantly higher rates of favorable overall radiographic and neurological outcomes than observation alone. Compared with observation, SRS might be the preferred management option in this patient population.

Abstract The growing availability of large-scale biomarker datasets has allowed data-driven methods to characterize Alzheimer’s disease biological heterogeneity. However, most prior studies have focused on cohorts of late-onset amnestic cases, leaving early-onset Alzheimer’s disease underexplored. We aimed to characterize tau-PET-based subtypes through a robust data-driven approach in the Longitudinal Early-Onset Alzheimer’s Disease Study. Baseline [18F]Flortaucipir PET scans from 365 amyloid-PET-positive participants with sporadic early-onset Alzheimer’s disease were quantified in the left and right medial temporal, lateral temporal, occipital, parietal, and frontal cortices. Tau PET values were z-scored against 85 amyloid-PET-negative cognitively normal age-matched participants and fitted into Subtype and Stage Inference (SuStaIn)—an unsupervised clustering algorithm that simultaneously models subtypes and progression from cross-sectional data. The derived subtypes were subsequently characterized by baseline and longitudinal clinical, cognitive, MRI, tau and amyloid PET features. We identified three tau-PET-based subtypes: on average, Subtype 1/Typical (n = 144, 40%) showed a predominant bilateral temporoparietal pattern typical of Alzheimer’s disease. Subtype 2/Left temporal (n = 111, 31%) showed predominant left temporal binding. Subtype 3/Posterior (n = 104, 29%) showed early and permeating occipitoparietal involvement. Subtypes did not differ in demographics or global amyloid burden, but were relatively more enriched for specific clinical presentations: S1/Typical for amnestic presentations, S2/Left Temporal for primary progressive aphasia, and S3/Posterior for posterior cortical atrophy. Baseline tau PET subtypes aligned with cortical atrophy patterns and domain-specific cognitive impairment. When follow-up tau PET scans were fitted to SuStaIn trained on baseline data, 85.6% (n = 172/201) of participants retained the same subtype classification, indicating subtype temporal stability, and progressed within subtypes by 0.56 ± 0.70 SuStaIn stage/year. Longitudinal voxel-wise linear mixed-effects modelling revealed tau accumulation patterns for each subtype in regions relatively spared at baseline: occipital lobe accumulation predominated in S1/Typical, bilateral frontal and right temporal in S2/Left Temporal, and bilateral frontotemporal lobes in S3/Posterior. All subtypes showed longitudinal increases in Clinical Dementia Rating-Sum of Boxes, but with slower worsening in S3/Posterior compared with the other subtypes. Our findings reveal robust subtypes in sporadic early-onset Alzheimer’s disease characterized by distinct spatiotemporal tau patterns that parallel differences in clinical presentations and trajectories of neurodegeneration. These subtypes extend beyond traditional clinical syndromes and support a more nuanced framework for individualized prognosis and care. Incorporating tau PET subtyping into clinical trial design could enable more targeted therapeutic approaches for this younger population.

Abstract Background Older adults remain underrepresented in prospective trials of immunotherapy for advanced lung cancer. To estimate pembrolizumab adverse events, we conducted a multicenter, nonrandomized, open-label phase 2 trial of oncologist-choice first-line pembrolizumab with or without chemotherapy for older adults with advanced lung adenocarcinoma. Methods Alliance for Clinical Trials in Oncology A171901 enrolled patients aged 70 years and older with stage IV or recurrent lung adenocarcinoma starting oncologist’s choice of first-line pembrolizumab with or without carboplatin and pemetrexed. The primary endpoint was the proportion of patients experiencing a solicited grade 3 or greater adverse event within 6 months. Secondary endpoints included overall survival, quality of life, and association of a geriatric assessment toxicity risk score with severe adverse events. Results Among 95 evaluable patients, 43 (45.3%) received pembrolizumab and 52 (54.7%) received pembrolizumab plus chemotherapy. Median age was 77 years (range = 70-92 years); 11.6% had an E Performance Status of 2 or higher. During 6 months of treatment, 25.6% (95% CI = 13.5% to 41.2%) experienced a solicited grade 3 or greater adverse event in the monotherapy group and 42.3% (95% CI = 28.7% to 56.8%) in the combination group. Median overall survival was 16.4 months (95% CI = 10.1 to not estimable) with monotherapy and 29.9 months (95% CI = 16.4 to not estimable) with combination therapy. Quality of life worsened during treatment. The geriatric assessment toxicity risk score was not associated with severe adverse events with pembrolizumab with or without chemotherapy. Conclusions Older adults with advanced lung adenocarcinoma receiving pembrolizumab with or without chemotherapy had comparable adverse event rates to those in prior registration trials that excluded medically frail patients. These findings can inform shared decision making and support inclusion of older adults in future trials. Clinical Trial NCT04533451 (https://clinicaltrials.gov/study/NCT04533451)

Abstract Background Meningiomas exhibit clinical heterogeneity. Radiotherapy (RT) remains the only adjuvant therapy, but tumor-control is variable, and biomarkers are limited. NRG/RTOG-0539 is the first prospective phase 2 trial to stratify meningioma patients for adjuvant RT based on clinical risk. Here, we apply modern molecular tools to this cohort and identify correlates of RT response. Methods Tumor tissue from 100 RTOG-0539 patients was profiled using DNA methylation arrays, RNA sequencing, and whole-exome sequencing. Recurrence scores, Molecular Groups, gene expression, and copy number alterations were compared across clinical groups and between RT responders and non-responders; non-response was defined as progression or death within 3 years. Results Modern grading criteria, including brain invasion, TERT mutation, CDKN2A/B deletion, and 1p/1q status, would reclassify 10% of tumors and alter treatment group assignment in 7%. Non-responders to RT exhibited more frequent 1p and 14q loss, and more copy number alterations. Transcriptomic and epigenetic profiling revealed immune-related signatures in responders and cell cycle–related pathways in non-responders, several of which overlapped with targets of vorinostat, a histone deacetylase inhibitor previously validated in aggressive meningioma models. The Proliferative Molecular Group was an independent predictor of post-RT recurrence in multivariable analysis, outperforming WHO grade. Conclusion Multi-omic analysis of the NRG/RTOG-0539 cohort shows that updated WHO grading criteria, incorporating molecular and cytogenetic features, improve risk stratification. However, molecular classification, particularly the Proliferative group, remains an independent and stronger predictor of RT response. These findings support integrating molecular biomarkers alongside modern grading frameworks to guide treatment and trial design in meningioma. Clinical Trial Information NCT00895622.

The NCCN Guidelines for Prostate Cancer include recommendations for staging and risk assessment after a prostate cancer diagnosis and for the care of patients with localized, regional, recurrent, and metastatic disease. These NCCN Guidelines Insights summarize the panel’s discussions on select 2026 updates to the guidelines regarding nonmetastatic disease: the elimination of the very-low-risk group, updates to the Principles of Active Surveillance, and caution in the use of focal therapy in newly diagnosed patients.

BACKGROUND AND OBJECTIVES: Craniopharyngiomas are complex intracranial tumors that pose significant challenges in surgical management. We aimed to develop risk-stratified surgical outcome benchmarks for adult patients undergoing endoscopic craniopharyngioma resection by using the Registry of Adenomas of the Pituitary and Related Disorders database to facilitate comparisons across institutions and guide clinical decision-making. METHODS: A retrospective cohort of adult patients (18 years and older) with craniopharyngioma undergoing a first-time endoscopic transnasal surgery across 14 academic centers in the United States was analyzed using data collected from 2011 to 2024. Patients were stratified into low-risk and high-risk cohorts based on criteria including age, body mass index, selected tumor characteristics (size, infundibular relationship, intraventricular extension), and previous radiation. Surgical outcomes were analyzed, and benchmarking ranges were defined using the established methodology. RESULTS: The overall cohort included 318 patients with a mean age of 50 years. Upon benchmarking analysis (50th-75th percentile performance), low-risk patients (n = 136) had a median length of stay of 4.0 to 6.0 days, 90-day readmission rates of 15.5% to 22.2%, skilled nursing facility discharge rates of <1.0%, postoperative cerebrospinal fluid leak incidence of <1.0% to 14.3%, gross total resection rates of 50.0% to 60.8%, new postoperative arginine vasopressin deficiency rates of 33.3% to 50.0%, and tumor progression/recurrence rates of <1.0% to 18.3% over a median follow-up period of 27.0 (IQR 10.5-56.5) months. Benchmarking ranges were proposed for each outcome to facilitate cross-institutional comparisons. CONCLUSION: Establishing surgical outcome benchmarks for adult patients undergoing craniopharyngioma resection using data from the Registry of Adenomas of the Pituitary and Related Disorders provides a framework for assessing surgical performance and guiding clinical decision-making. Benchmark ranges can inform institutional quality improvement efforts, perioperative risk stratification, and patient counseling regarding expected postoperative outcomes.

~80% of kidney stones (KS) are composed of calcium oxalate and small increases in urinary oxalate significantly enhance the stone risk. We previously discovered Oxalobacter formigenes (Of)-derived secreted factors which stimulate oxalate transport by human intestinal Caco2-BBE (C2) cells and reduce urinary oxalate excretion in hyperoxaluric mice by enhancing colonic oxalate secretion (JASN, 2017). The small Sel1-like protein-derived peptides (P8 and P9) were identified as the major Of-derived factors (AJP Cell Physiol, 2023), acting via the oxalate transporters SLC26A6 (A6) and SLC26A2 (A2). P8/9-induced stimulation of oxalate transport in C2 cells is likely PKA-dependent based on studies using the PKA inhibitor H89. Enhancing gut oxalate secretion with subsequent fecal excretion represents a novel therapeutic pathway for getting rid of body oxalate. Building on these findings, the study objective is to test the hypothesis that the observed regulation is indeed PKA-mediated, through mechanisms potentially involving other signaling pathways and/or altering A6 total and/or surface protein expression. To provide further evidence that it is PKA-dependent, we successfully identified the binding mode of P8/9 bound to PKA using molecular docking (ZDOCK). The regulatory subunit of PKA binds two cyclic AMPs and P8/P9 are predicted to interact at the cyclic AMP binding site according to our PKA-peptide modeling studies. To directly confirm the role of PKA, we used siRNA to knockdown its α catalytic subunit (PKA-α) in C2 cells. PKA-α mRNA expression is reduced by >90% as assessed by qPCR. Importantly, siRNA knockdown of PKA-α completely abolished P8/P9-induced stimulation of 14C-oxalate uptake by C2 cells in pilot studies, confirming the role of PKA in P8/9-mediated stimulatory regulation of intestinal oxalate transport. To identify the signaling pathways potentially upstream and/or downstream of PKA we used relatively selective pharmacological inhibitors. Interestingly, the stimulatory effects of P9 on 14C-oxalate uptake by C2 cells are significantly blocked by the ERK1/2 inhibitor U0126 (~90%), the PI3K inhibitor LY294002 (~84%), and the p38 inhibitor SB 202190 (~73%), while the general tyrosine kinase inhibitor genistein has no effect. Inhibitors alone did not affect baseline transport. These results support the involvement of the MAPK ERK1/2, PI3K, and p38 in the signaling pathways regulating intestinal oxalate transport by P8/9. We used immunoblotting and surface biotinylation studies to evaluate whether P8/9 stimulates oxalate transport in C2 cells by increasing its total and/or surface protein expression. P8/9 peptides did not affect A6 total and surface protein expression levels in preliminary studies. We could not assess A2 total and surface protein expression due to lack of good working antibodies. In view of our previous findings that the observed regulation is due to P9-induced increase in Vmax and reduction in Km, and since P8/9 did not affect A6 surface protein expression, it is likely possible that the observed stimulation is due to mechanisms including P8/9-induced enhanced A6 transport activity resulting from an increase in the intrinsic activity of the preexisting A6 membrane transporters. We conclude that P8/9 stimulates intestinal oxalate transport in C2 cells via signaling pathways including PKA, ERK1/2, PI3K, and p38 and through mechanisms including P8/9-induced enhanced A6 transport activity. Having the P8/9-PKA bound conformation determined, we plan to optimize P8/P9 into small molecule like drugs with better stability and clinical translational potential in terms of stimulating intestinal oxalate secretion, leading to reduced plasma and urinary oxalate levels. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: Exogenous and endogenous polyamines are critical for gastrointestinal (GI) barrier integrity, of which putrescine, spermidine and spermine are most well studied. Our recent work shows n-acetylputrescine, a putrescine derivative, correlates with increased intestinal permeability and loss of microbial diversity. Despite this, bacterial mechanisms of n-acetylputrescine production or direct effects on barrier integrity are unknown. Aim: Determine the role of microbiota in shaping n-acetylputrescine abundance and the effect on barrier integrity. Methods: N-acetylputrescine effects on barrier were assessed both in vitro using Caco-2 and ex vivo in Ussing using colonic strips from conventional mice. Germ-free (GF) mice were monocolonized with wild-type E. coli (SK929) or E.coli SK930 (2-weeks, n=4mice/group), strains given by Dr. Shin Kurihara. E. coli SK930 is deficient in SpeC, SpeF and SpeB, genes generating putrescine, required for n-acetylputrescine production. Untargeted metabolomics (Metabolon) was performed on fecal pellets. Targeted isotope tracing with [13C6, 15N4]-arginine delivered via enema was done to track bacterial production of n-acetylputrescine by Fusobacterium varium, a known producer, in vivo with isotopolog labeling measured by LC/HRMS. Results: In vitro n-acetylputrescine (100mM) addition to Caco-2 monolayers caused significant barrier disruption compared to controls (%Baseline TER, 13.7±6.7 vs 102.8±9.4, 3h postexposure, n=3 p=0.0002), not seen at lower (10mM) concentration. N-acetylputrescine caused increased flux of 300Da fluorescein (12.6±2.0 vs 6.0±0.2 mg/mL, n=3 p=0.004) and 4kDa FITC-Dextran flux on Ussing compared to untreated controls (999±94 vs 562±121 ng/hr/cm2, n=3 p= 0.01). Mutant E. coli SK930 monocolonized mice had similar fecal n-acetylputrescine to GF animals. In contrast, wild type E. coli SK929 monocolonization led to significantly greater n-acetylputrescine (5-fold, FDR< 0.001) compared to SK930, indicating a bulk of n-acetylputrescine production is driven by bacterial mechanisms. Pathway enrichment analysis predicted decreased spermidine and spermine biosynthesis in SK930 monocolonization, indicative of impaired polyamine metabolism, compared to SK929 (FDR< 0.01). Targeted metabolomics on fecal pellets showed a shift in the production of isotopolog [13C1, 15N0]-N-acetylputrescine to increased isotopolog [13C4, 15N2]-N-acetylputrescine concentration after monocolonization with F. varium compared to GF mice (5.9±5.0 vs. 2.1±3.6 pg/mg stool, n=3mice/group p=0.05) suggesting microbiota driven shifts in n-acetylputrescine metabolism. Conclusion: Luminal n-acetylputrescine production and profile is driven by bacteria in the GI tract. Concentration dependent effects of n-acetylputrescine suggest insufficient regulation by intestinal microbiota can lead to accumulation of n-acetylputrescine and the intestinal barrier disruption seen in human studies. Ongoing studies aim to identify bacterial taxa critical for n-acetylputrescine suppression, the mechanisms involved, and impact on GI health. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Elevated intratumoral interstitial fluid pressure (IFP) can negatively impact the efficacy of neoadjuvant chemotherapy (NAC) of breast cancer. This study aims to predict breast cancer pathological complete response (pCR) to NAC based on IFP measures by 3-D subharmonic-aided pressure estimation (SHAPE). SHAPE uses the inverse linear relationship between hydrostatic pressure and subharmonic signal magnitude from intravascular ultrasound contrast agents. Thirty-eight breast cancer patients undergoing NAC from three clinical sites were enrolled for this study. SHAPE data were collected for each subject at 0%, 10%, and 30% of NAC completion using a Logiq E9 system (GE HeathCare) equipped with an RSP6-16D probe. The contrast agent used was Definity (Lantheus Medical Imaging). The subharmonic signal gradients between tumor and adjacent normal tissue were calculated and compared with patient pathological response outcome using t-test and receiver operating characteristic (ROC) curve analysis. Pressure gradients between pCR (15 patients) and non-pCR (23 patients) groups were significantly different at 0 (p = 0.02), 10 (p = 0.03), and 30% (p = 0.0003) completion of NAC. Area under the curve values of 0.69, 0.77, and 0.86 were achieved at 0%, 10%, and 30% of NAC completion, respectively. Overall, SHAPE pressure gradients may aid prediction of NAC pathological response in breast cancer patients.