Ashutosh Kumar Tewari

Key Points: Afferent vagus nerve stimulation (aVNS) suppressed maladaptive renal sympathetic nerve activity after ischemic injury by engaging kidney-associated vagal–autonomic circuits identified by transsynaptic tracing. Full renoprotection by aVNS required an intact spleen, revealing an integrated vagal–renal–splenic neuroimmune reflex aVNS protected kidney function, whether delivered as preconditioning before injury or 72 hours after ischemia-reperfusion injury, defining a clinically therapeutic window. Background: AKI is associated with maladaptive increases in renal sympathetic nerve activity (RSNA) and frequently progresses to CKD. Neuromodulatory strategies that suppress sympathetic outflow may provide therapeutic benefit. We tested whether afferent vagus nerve stimulation (aVNS) mitigates ischemic AKI by modulating RSNA through central autonomic circuits and splenic neuroimmune signaling. Methods: Retrograde transsynaptic pseudorabies virus tracing was used to identify neural pathways linking the kidney to vagal sensory circuits in C57BL/6J mice. RSNA, arterial pressure, and heart rate were recorded during intermittent aVNS. Bilateral renal ischemia-reperfusion injury was used to assess therapeutic efficacy. Mechanistic studies included subdiaphragmatic vagotomy, renal denervation controls, splenectomy, ganglionic blockade, and c-Fos mapping. Results: Pseudorabies virus tracing identified polysynaptic pathways linking the kidney to nodose ganglia, dorsal root ganglia, and central autonomic nuclei, with controls supporting tracer specificity. aVNS produced frequency-dependent and sustained suppression of RSNA. In ischemia-reperfusion injury, aVNS attenuated RSNA surges, preserved GFR, reduced tubular injury markers including neutrophil gelatinase–associated lipocalin and kidney injury molecule-1, and limited fibrosis. Protection was observed with both preconditioning and delayed treatment, including stimulation initiated up to 72 hours after injury. Ganglionic blockade abolished acute aVNS responses. Splenectomy eliminated the full RSNA-lowering and renoprotective effects of aVNS, while aVNS reduced systemic norepinephrine and altered splenic signaling. Conclusions: aVNS engages kidney-associated vagal–autonomic pathways that suppress RSNA and require splenic signaling for full renoprotection after ischemic AKI.

Background/Objectives: Active surveillance (AS) is the recommended management strategy for localized, early-stage prostate cancer. Despite promising cancer-specific outcomes, up to one-third of men discontinue AS and undergo radical prostatectomy without evidence of disease progression, often because of stress, anxiety, uncertainty, and unmet supportive care needs. Evidence-based psychosocial interventions tailored to men on AS are lacking. We aimed to: (1) adapt the Stress Management and Resilience Training (SMART) program to address the unique psychosocial and supportive care needs of men with prostate cancer on AS (SMART-AS), and (2) evaluate the feasibility and acceptability of SMART-AS. Methods: Following the Assessment, Decision, Adaptation, Production, Topical Experts, Integration, Training, Testing (ADAPT-ITT) framework, we adapted SMART for men with prostate cancer on AS (SMART-AS) informed by our prior qualitative study and expert input. Next, we conducted a single-arm pilot feasibility study at one large urban academic medical center. Participants attended eight weekly 90-minute telehealth group SMART-AS sessions. Feasibility and acceptability were evaluated one-week post-intervention. Results: Based on our prior qualitative study and expert input, core SMART-AS components included content targeting stress, anxiety, communication, and self-management. In total, 30 participants were enrolled in the pilot feasibility study and completed baseline assessments (mean age = 71 years, standard deviation = 8.3); 26/30 (86.7%) completed six out of eight SMART-AS sessions, and 17/30 (56.7%) completed post-intervention assessments. Nearly all (16/17, 94.1%) reported that they would recommend SMART-AS to others. Most agreed that SMART-AS helped them talk to clinicians (13/17, 76.5%), reduced anxiety (13/17, 76.5%), enhanced coping skills for AS challenges (15/17, 88.2%), and supported self-care (15/17, 88.2%). Nearly two-thirds (11/17, 64.7%) reported SMART-AS helped them continue AS as a management strategy. Conclusions: This pilot study provides preliminary evidence supporting the feasibility and acceptability of SMART-AS among men with prostate cancer on AS. Participants reported perceived improvements in anxiety, coping, communication with clinicians, and self-management. Findings support further evaluation in a randomized controlled trial.

Background and Objective: Positive surgical margins (PSMs) remain a major challenge during radical prostatectomy, particularly in patients with high-risk prostate cancer (HR-PCa), where extracapsular extension, multifocal disease, and aggressive tumor biology substantially increase the likelihood of incomplete resection. In this setting, PSMs are strongly associated with early biochemical recurrence and frequently prompt adjuvant or salvage treatments, potentially exposing patients to overtreatment and added morbidity. Materials and Methods: To review and critically appraise established and emerging intraoperative technologies for surgical margin assessment during radical prostatectomy, with a specific focus on their potential role and relevance in patients with HR-PCa. Evidence Acquisition: A non-systematic literature review was performed using Pubmed, MEDLINE, Web of Science, and Google Scholar, focusing on preoperative, intraoperative ex vivo, and intraoperative in vivo technologies for margin assessment. Emphasis was placed on techniques with potential applicability to HR-PCa, where real-time intraoperative decision-making is particularly consequential. Evidence Synthesis: Preoperative tools, including multiparametric MRI, PSMA-PET imaging, and predictive nomograms, aid surgical planning but show limited sensitivity for microscopic extracapsular extension, especially in high-risk disease. Intraoperative frozen section analysis reduces positive surgical margin rates while enabling selective nerve-sparing (defined as a side-specific, risk-adapted preservation strategy); however, its widespread adoption is constrained by substantial logistical and resource requirements, and robust oncological outcome data in high-risk populations remain limited. Novel ex vivo approaches, such as fluorescence confocal microscopy and specimen-based PSMA PET/CT imaging, offer rapid whole-gland or targeted margin assessment with reduced dependency on dedicated pathology workflows. In parallel, emerging in vivo technologies, particularly PSMA-targeted near-infrared-fluorescence-guided surgery, enable real-time detection of residual tumor and facilitate selective re-resection, representing a biology-driven approach that may be especially suited to HR-PCa. Conclusions: In high-risk prostate cancer, intraoperative margin assessment technologies may extend beyond functional preservation and play a central role in optimizing oncological radicality and multimodal treatment sequencing. While NeuroSAFE remains the reference standard, PSMA-based ex vivo and in vivo technologies are particularly promising in HR-PCa due to their ability to integrate tumor biology into surgical decision-making. Prospective studies focusing on high-risk-specific oncological and patient-reported outcomes are needed before widespread clinical implementation.

Purpose We systematically reviewed the long-term outcomes of untreated prostate cancer across different risk categories to inform treatment decisions and active surveillance protocols. This comprehensive analysis synthesizes long-term progression data across tumor staging and grading systems. Materials and methods We conducted a systematic literature search of PubMed, EMBASE, and Cochrane databases (1990–2025) for studies reporting ≥10-year outcomes in untreated or conservatively managed prostate cancer patients. Eligible studies included observational cohorts, population registries, and meta-analyses. Primary endpoints included prostate cancer-specific mortality, metastatic progression, and competing mortality. Results Fifteen major studies encompassing 43,127 patients (median follow-up 15–30 years) demonstrated heterogeneous progression patterns. Ten-year prostate cancer-specific survival ranged from >95% for Gleason 6 tumors to <60% for Gleason 8–10 disease. Grade Group 1 tumors showed <5% metastatic risk over 15–20 years, while Grade Groups 4–5 exhibited rapid progression with median disease-specific survival <5 years. Across all risk groups, disease progression accelerated markedly after 15 years. Men diagnosed after age 75 faced substantial competing mortality (~57–60% 10-year non-cancer mortality), regardless of tumor grade. Conclusions Tumor grade is the strongest prognostic factor in the natural history of untreated prostate cancer. Low-grade disease often remains indolent for 15–20 years, whereas high-grade tumors frequently progress to lethal disease within a few years, warranting early intervention. These findings support contemporary active surveillance protocols for low-risk patients and inform evidence-based treatment decisions for higher-risk disease. Summary with methodological context:

Background: MRI-based radiomics has shown promise in men with prostate cancer (PCa); however, successful clinical implementation is contingent upon on reproducible measurements. Purpose: We assessed the reproducibility of radiomics features extracted from bi-parametric prostate MRI (bpMRI) in prostate lesions and non-tumoral prostate tissue in men with PCa undergoing active surveillance (AS). Methods: This retrospective study included 47 men with biopsy-proven PCa undergoing AS (mean 68.9 ± 8.2 years, mean PSA density [PSAD] 0.08 ± 0.03 ng/mL/mL) who underwent two bpMRI approximately 12 months apart (range, 10–14 months; December 2018 to April 2020). The reproducibility of radiomics measurements was assessed using the same MRI platform (3T Skyra, Siemens Healthineers; inter-platform) (n = 37), different MRI vendors (Skyra, Siemens Healthineers; 3T Discovery MR750, GE Healthcare; inter-platform) (n = 10), and between observers (n = 10). Shape/1st-/2nd-order radiomics features were extracted from regions of interest on axial T2-weighted (T2-WI), diffusion-weighted imaging (DWI, b1600), and apparent diffusion coefficient (ADC) maps on prostate lesions, non-tumoral peripheral zones (PZs), and transition zones (TZs) using software. Reproducibility was evaluated by calculating the intraclass correlation coefficient (ICC) and coefficient of variation (CV). Associations of clinical variables and prostate volume were assessed. Results: PCa diagnoses included Gleason grade groups 1 (n = 46) and 2 (n = 1)]. Thirty-seven lesions (mean size 0.9 ± 0.4 cm) in 31 patients had PI-RADS v2.1 scores of 2 (n = 3)/3 (n = 12)/4 (n = 21)/5 (n = 1); 16 patients demonstrated diffuse PI-RADS 2 changes. Lesion radiomics features from T2-WI yielded a high proportion of good/moderate ICCs (intra-platform, 77.8%; inter-platform, 56.5%), whereas most DWI/ADC features yielded poor reproducibility. Similar results were observed for non-tumoral PZ/TZ. Intra-platform CVs were lowest for T2-WI lesion features (13.6%) and background PZ/TZ (p > 0.05). Higher reproducibility (ICC > 0.5) was associated with larger prostate volume (intra-platform diagnostic odds ratio [DOR] = 2.58, 95% confidence interval [95%CI], 1.35–3.80, p = 0.01; inter-platform DOR = 3.48, 95%CI 1.79–5.17, p = 0.01) and older age (inter-platform DOR = 5.30, 95%CI 3.75–6.85, p < 0.01). Conclusions: Radiomics measurements from T2-WI demonstrated better intra-/inter-platform reproducibility than DWI/ADC for prostate lesions and non-tumoral tissue. Patient factors (larger prostate volumes and older age) influence radiomics stability. The optimization of diffusion-based radiomics features is needed to improve reproducibility given the essential role of DWI in prostate MRI.

ChatGPT Health was launched in January 2026 as OpenAI’s consumer health tool and has reached millions of users. Here we conducted a structured stress test of triage recommendations using 60 clinician-authored vignettes across 21 clinical domains under 16 factorial conditions, yielding 960 total responses. Performance followed an inverted U-shaped pattern, with the most dangerous failures concentrated at clinical extremes—nonurgent presentations (35%) and emergency conditions (48%). Among gold-standard emergencies, the system undertriaged 52% of cases, directing patients with diabetic ketoacidosis or impending respiratory failure to 24–48 h evaluation rather than the emergency department, while correctly triaging classical emergencies such as stroke and anaphylaxis. When family or friends minimized symptoms, indicating anchoring bias, triage recommendations shifted significantly in edge cases (odds ratio = 11.7, 95% confidence interval = 3.7–36.6), with the majority of shifts toward less urgent care. Crisis-intervention messages activated unpredictably across suicidal ideation presentations, occurring more frequently when patients described no specific method than when they did. Patient race, sex and barriers to care did not show significant effects, although confidence intervals did not exclude clinically meaningful differences. These findings reveal missed high-risk emergencies and inconsistent activation of crisis safeguards, raising safety concerns that warrant prospective validation before consumer-scale deployment of artificial intelligence triage systems.

Purpose: The limited resolution of standard transrectal ultrasound (TRUS) has made it difficult to perform biopsies of the prostate bed in cases of suspected local recurrence following radical prostatectomy. The aim of this study was to benchmark the performance of using high resolution micro‐ultrasound (microUS) in place of standard TRUS for performing post‐prostatectomy biopsies. Materials and Methods: We conducted a retrospective review of pathology reports from January 2013 to October 2024, identifying patients who underwent biopsies of the prostate bed for suspected local recurrence after radical prostate. Sensitivity and specificity were compared for biopsies performed using standard TRUS. A biopsy was deemed diagnostic if it revealed prostate tissue (cancerous or benign) or non‐prostatic tissue when a previously suspicious lesion was no longer detectable on subsequent imaging. The ground truth for local recurrence was defined by biochemical recurrence (prostate‐specific antigen [PSA] ≥ 0.2 ng/mL in two consecutive measurements) accompanied by reproducible findings in the prostate bed on MRI and/or PET. Results: Of the 24 patients included, 10 (42%) underwent microUS‐guided biopsy and 14 (58%) underwent TRUS‐guided biopsy. The median PSA levels at biopsy for the microUS and TRUS cohorts were 0.39 ng/mL (range 0.39–6.40) and 0.45 ng/mL (range 0.20–30.82), respectively. The median lesion sizes on MRI were 0.9 cm (IQR 0.7–1.8) for microUS and 2.5 cm (IQR 1.2–6) for TRUS. MicroUS demonstrated a sensitivity of 89% (95% CI: 52–100), compared with 43% (95% CI: 18–71) for TRUS. Specificity could not be reliably assessed, as only one recurrence‐negative patient was available in the microUS group and none in the TRUS group. Conclusion: MicroUS‐guided transrectal biopsies appear to offer superior diagnostic performance in detecting local recurrences following radical prostatectomy compared to standard TRUS‐guided biopsy. Further study is needed to confirm our findings and to evaluate the performance of microUS‐guided biopsies independently of pre‐biopsy imaging results.

Lineage plasticity, a critical hallmark of cancer progression, enables tumor cells to evade inhibition of primary oncogenic pathways through histologic transformation. This adaptive process, driven by stemness-associated features and epigenetic reprogramming, poses significant challenges in treatment. Using non–small cell lung cancer and prostate cancer as models, we examine the utility of tissue and liquid biopsies in detecting histologic transformations and tailoring treatments to specific subtypes, which has profound clinical implications, potentially improving outcomes in patients with advanced, therapy-resistant disease. We also discuss emerging therapeutic strategies, including novel molecular targets, and address ongoing clinical challenges in managing treatment-emergent histologic transformation. Significance: The advent of highly effective molecularly targeted therapies results in increased recognition of treatment-emergent histologic transformation. This review not only summarizes current evidence on diagnosis and management of lineage plasticity but also explores therapeutic strategies under study, outlining a framework for clinical translation and successful drug development.