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Objective: To evaluate factors associated with the conversion of robotic-assisted partial nephrectomy (RAPN) to open partial nephrectomy (OPN) and radical nephrectomy (RN). Methods: We retrospectively reviewed 775 consecutive RAPNs from a single surgeon. Perioperative factors were evaluated for association with RAPN conversion such as Mayo Adhesive Probability (MAP) score, length of stay (LOS), and operative time (OT). A logistic regression model was utilized to evaluate factors associated with conversion and reported as odds ratio (OR) with 95% confidence intervals. Continuous and categorical variables were analyzed through the Wilcoxon rank-sum and chi-square tests. Results: Thirty-two (4.1%) patients had a conversion including 19 (2.5%) to OPN and 13 (1.7%) to RN. OPN conversions were related to bleeding ( n = 7), inability to dissect perinephric fat ( n = 4), liver retraction ( n = 1), and failure to secure renal hilum/progress ( n = 7). In contrast, conversions to RN were due to tumor involvement of the renal vein ( n = 3) or ureter ( n = 5) and inability to achieve negative margins ( n = 5). Patients in the conversion cohort were more likely to have larger tumor size (3.7 vs 2.8 cm; p < 0.001) and higher MAP score (3.0 vs 2.0; p = 0.04). Median LOS was higher in the conversion group (3.0 vs 2.0 days; p = 0.003). Conversions were associated with postoperative complications (28.1% vs 13.7%; p = 0.023). After adjusting tumor size in our regression model, longer OT and dissection time were statistically higher in the conversion group (OR = 2.19 [1.50–3.21]; p < 0.001 and OR = 2.67 [1.82–3.94]; p < 0.001, respectively). Conclusions: Larger tumor size and higher MAP score were associated with conversions during RAPN. Conversions were associated with higher LOS, longer OT, and postoperative complications.

Urinary urea is a key biomarker for tracking protein oxidation and nitrogen balance. A persistent analytical limitation is that conventional total-nitrogen assays do not deconvolute urinary urea from urinary ammonia, and direct measurement still requires capital-intensive clinical analyzers. Here, we implement and independently validate two cost-effective methods that resolve urinary urea by pairing the presence and absence of urease: Method 1 is a urease-coupled potentiometric assay using an ammonium ion-selective electrode (ISE method); Method 2 is a microplate Berthelot–salicylate colorimetric assay employing a repurposed consumer-grade aquarium ammonia test kit (API®) (API method). Each method was validated against the Roche Cobas C311 clinical analyzer (ISE for urinary ammonia and API for urinary urea) in healthy adult volunteers (n = 10 each), and API–ISE were then compared head-to-head for urinary urea. ISE vs. Cobas yielded R2 = 0.967, slope 95% CI [0.867, 1.173], and Bland–Altman bias of −1.02 mM (95% LoA [−7.40, +5.36] mM). API vs. Cobas yielded R2 = 0.973, slope 95% CI [0.790, 1.039], and bias of −1.55 mM (95% LoA [−11.56, +8.46] mM). API–ISE urinary urea comparison confirmed mutual agreement (R2 = 0.9976, slope 95% CI [0.946, 1.024]; bias of +3.47 mM; 95% LoA [−14.60, +21.53] mM), with mean recoveries near 100% (API: 100.7 ± 2.9%; ISE: 100.6 ± 5.4%; 20–350 mM). Both methods agreed with the clinical analyzer, supporting their potential for decentralized, resource-limited testing; clinical and point-of-care validations are needed.

Importance Although adding immune checkpoint inhibitors to neoadjuvant chemotherapy improves outcomes in high-risk early-stage breast cancer, opportunities remain to further enhance response. Dual checkpoint blockade offers a potential strategy to further enhance efficacy. Objective To evaluate the combination of anti−programmed cell death 1 protein (PD-1) cemiplimab and anti−lymphocyte activation gene 3 (LAG-3) added to neoadjuvant therapy in ERBB2 -negative early-stage, high-risk breast cancer. Design, Setting, and Participants The I-SPY2 (Investigation of Serial Studies to Predict Your Therapeutic Response With Imaging and Molecular Analysis 2) is an ongoing randomized clinical platform trial being conducted at multiple US clinical sites including patients with early-stage (II or III) ERBB2 -negative, high-risk breast cancer. Participants, continuously enrolled since 2010, were adaptively randomized from February 2, 2020, to December 9, 2021, to one of several experimental neoadjuvant therapies or control groups based on receptor subtypes defined by hormone receptor (HR), ERBB2 status, and MammaPrint (Agendia Inc) molecular risk, categorized as high (MP1) or ultrahigh (MP2). Data were analyzed from January 1, 2022, to August 5, 2025. Interventions Both groups received weekly paclitaxel for 12 weeks, then doxorubicin and cyclophosphamide followed by surgery; concomitant with paclitaxel, the intervention group also received 4 doses of cemiplimab and fianlimab (PCF) every 3 weeks. Main Outcomes and Measures Pathologic complete response (pCR). Treatments graduated when they achieved 85% bayesian probability of success in a subtype-specific phase 3 trial. Pathway-specific biomarkers were assessed for response prediction. Results A total of 78 participants (mean [SD] age, 47 [39-54] years) were randomized to the intervention group, with 350 participants (mean [SD] age, 48 [39-57] years) randomized to the historical control population. PCF graduated in all clinical signatures, with pCR rates vs control of 44% (95% CI, 34%-53%) vs 21% (95% CI, 17%-25%) in all ERBB2 , 53% (95% CI, 39%-67%) vs 29% (95% CI, 22%-36%) in triple-negative, and 36% (95% CI, 23%-49%) vs 14% (95% CI, 9%-19%) in HR-positive and ERBB2 -negative disease. Among the total participants, 16 (21%) experienced adrenal insufficiency, including hypophysitis (11% grade 3 or 4), mostly occurring after immunotherapy completion. PCF was found to be highly effective in the subset of patients with immune signature positive status (ImPrint positive). Conclusions and Relevance In this randomized clinical trial, the combination of PD-1 and anti−LAG-3 inhibition with standard NAC was effective in early-stage ERBB2 -negative breast cancer, particularly in patients displaying a positive ImPrint immune signature. These results warrant further definitive trials. Trial Registration ClinicalTrials.gov Identifier: NCT01042379

Abstract Objectives This study used both researcher and patient perspectives to identify high-priority research questions related to clinical reasoning. Methods This study integrates findings from two previously published research prioritization exercises aimed at advancing the science of diagnostic safety, focusing on questions relevant to clinical reasoning. In Study 1 (April 2019), 97 researchers submitted 177 unique research questions that could be useful “to reduce patient harm in the diagnosis process”. In Study 2 (November 2019), 41 patients/caregivers/advocates submitted 84 unique research questions on the same topic. In an in-person meeting, a subset of these participants identified 81 of these questions as high-priority (51 from Study 1; 30 from Study 2). For the current study, five investigators identified questions that focused on clinical reasoning, first independently and then by consensus. They then categorized the clinical reasoning questions into inductively identified themes. Results Twenty-nine of the 81 high-priority research questions addressed clinical reasoning and were categorized into 5 themes: understanding clinical reasoning and cognition (12 questions), decision support/technology (6 questions), team-based decision making (5 questions), how to learn from cases/scenarios (3 questions), and patient engagement (3 questions). Questions addressed a range of basic/foundational science and clinical applications, and involved individuals, teams, and/or systems. Conclusions Identification of high-priority clinical reasoning research questions can help medical educators, clinicians, researchers, and funders catalyze research and discovery of interventions to improve clinical reasoning and ultimately improve patient outcomes.

ABSTRACT Surgery after response to first‐line chemoimmunotherapy may offer a potential curative option for patients with locally advanced biliary tract cancer (BTC) initially considered unresectable. However, robust real‐world evidence in this setting remains limited. We retrospectively analyzed patients with locally advanced BTC treated with first‐line cisplatin, gemcitabine, and durvalumab (CGD) across 55 centers in 12 countries. Endpoints included overall survival (OS), progression‐free survival (PFS), disease‐free survival (DFS) among resected patients, objective response rate (ORR), and the prognostic impact of surgery. A multivariable logistic regression model was developed to predict surgical conversion using baseline clinical and laboratory variables. Among 1358 screened patients, 219 had locally advanced disease and were included in the analysis. Median follow‐up was 14.5 months. ORR was 34.6%, with median PFS and OS of 10.0 and 20.7 months, respectively. Twenty‐four patients (10.9%) underwent surgical resection after systemic therapy. Median OS was 22.5 months in resected patients versus 19.9 months in those who did not undergo surgery. Median DFS after resection was 15.8 months. Pathological lymph node involvement was independently associated with shorter DFS. Larger baseline tumor size correlated with higher odds of radiological response but not with OS. An exploratory elastic‐net model retained four baseline variables and showed moderate discriminative ability for surgical conversion, with an apparent AUC of 0.72 and an optimism‐corrected AUC of 0.65. First‐line CGD enabled secondary resection in approximately 11% of patients with locally advanced BTC. A simple baseline model may support patient selection for conversion surgery, although prospective validation is needed.

Stem cell-derived β (SC-β) cells are a promising therapy for type 1 diabetes (T1D), but their long-term efficacy is limited by immune-mediated graft rejection. Platelet-derived exosome product (PEP) has emerged as a novel immunomodulatory agent, although its effect on SC-β cell xenograft rejection remains unclear. Here, we evaluated PEP in stimulated human peripheral blood mononuclear cells (PBMCs) and in an immunocompetent mouse model of SC-β cell transplantation under the kidney capsule. Immune-related gene expression was assessed by quantitative PCR, immune cell infiltration by immunofluorescence, and graft function by circulating human insulin. In vitro, PEP reduced NK-cell-associated gene expression, including NK1.1, EOMES, and KLRK1, and increased IL-10 expression. In vivo, untreated SC-β cell xenografts showed progressive immune infiltration and loss of detectable human insulin by day 14, whereas PEP-treated grafts retained detectable insulin through day 14 across co-transplantation, pretreatment, and systemic administration strategies. PEP co-transplantation delayed, but did not prevent, xenograft rejection, with graft loss observed by day 21. This delay was associated with reduced NK1.1+ cell infiltration and lower expression of selected inflammatory and rejection-associated markers, including NK1.1, Nos2, and Nlrp3. These findings suggest that PEP modulates graft-associated immune responses and may serve as an adjunct immunomodulatory strategy for stem cell-based therapies for type 1 diabetes. Further studies are needed to evaluate sustained graft durability, safety, and translational efficacy.

Background: Noninvasive tests are well validated in metabolic dysfunction–associated steatotic liver disease, but evidence in metabolic dysfunction and alcohol-associated liver disease (MetALD) and alcohol-associated liver disease (ALD) is limited. We evaluated noninvasive test–based clinical care pathways for fibrosis risk stratification in MetALD and ALD. Methods: This is a multinational, multicenter, cross-sectional study across 35 centers in 16 countries (2013–2025), including adults with MetALD or ALD. Fibrosis was assessed by liver biopsy and/or vibration-controlled transient elastography (VCTE). In biopsy-proven participants, we analyzed the sequential pathway (Fibrosis-4 [FIB-4] first, followed by VCTE for indeterminate FIB-4) to identify advanced fibrosis (≥F3). Diagnostic accuracy was assessed using the AUC. Results: Among 893 participants (41.3% MetALD and 58.7% ALD), the median age was 52 [43.0–61.0] years, and 79.4% were male. The estimated prevalence of advanced fibrosis was 45% (32.2% in MetALD and 54.0% in ALD). Participants with MetALD had a more dysmetabolic profile but lower fibrosis stages than ALD. Among biopsy-proven participants, FIB-4 AUC was 0.720, and VCTE AUC was 0.833. FIB-4 performed better in MetALD than ALD (AUC 0.773 vs. 0.540), while VCTE accuracy was similar across groups. In the sequential pathways, the false-negative rate for advanced fibrosis (misclassified as low risk) was 6.8% (4.9% MetALD and 11.3% ALD). Conclusions: In biopsy-proven patients, FIB-4 performance was acceptable in MetALD but substantially weaker in ALD. The standard 2-step pathway performed adequately in MetALD but missed a clinically meaningful proportion of advanced fibrosis in ALD.

Abstract Introduction We have shown that combining CAR T cells with oncolytic viruses (OVs) generates a subpopulation of highly cytotoxic CAR T cells that can mediate long-term solid tumor therapy. Methods To profile these CAR T cells, we used C57BL/6 mice bearing B16F10 tumors expressing EGFRviii, treated with anti-EGFRviii CAR T cells and the OV vesicular stomatitis virus (VSV). TCR signaling in CAR T cells was investigated using the novel Tocky transgenic mouse model, which reports T cell activation over time using an unstable fluorescent protein reporter of Nr4a3. We further investigated CAR T phenotypes using CyTOF and scRNA-Seq. Results Using an MHC I tetramer for the dominant VSV epitope VSV N52-59, we found that 20-50% of transfused CAR T adopted TCR specificity against VSV N (referred to as TCR-primed), indicating significant in vivo expansion. Ex vivo, these TCR-primed CAR T produced increased levels of granzyme B and IFNγ over tetramer-negative CAR T against either TCR or CAR targets. However, TCR-primed CAR T cells were notably less activated via Nr4a3 as compared to non-TCR-primed CAR T. CyTOF and scRNA-Seq analyses demonstrated a hypereffector phenotype among TCR-primed CAR, with increased expression of T-bet, CD44, granzyme B, IFNγ, and perforin. TCR sequencing revealed hyperexpansion of VSV N-specific CAR T cells and little overlap in clonotypes between CAR T co-treated with PBS versus VSV. These TCR-primed CAR T cells exhibited a CD4-helped phenotype with increased expression of chemotactic and migratory transcripts. When CAR T and OV were administered with antibody-mediated CD4 depletion, the TCR-primed CAR population was significantly diminished, emphasizing the importance of the immune triad for CAR T expansion. Conclusion Overall, CAR T cells that undergo endogenous anti-viral TCR priming and signaling adopt a unique phenotype that promotes their expansion and cytotoxic function. Interactions with CD4 T cells appear to be integral for the generation of this subpopulation of CD8 CAR T cells. Funding Source NIH Topic Categories Tumor Immunology: Checkpoints, Prevention, and Treatment (TIPT)

Although structured reporting of adverse events related to medical therapies is a critical aspect of clinical trials, the current practice fails to capture postoperative complications accurately or systematically, which precludes our ability to fully assess the impact of the risks of surgical interventions on oncologic outcomes. The incorporation of standardized, procedure‐specific definitions and severity classifications for postoperative complications into adverse event reporting in trials conducted through the National Clinical Trials Network is proposed.

Background Compassionate extubations (CEs) can be categorized as stressful clinical events that have potential to trigger a second victim response. The Second Victim Experience and Support Tool-Revised (SVEST-R) is a survey used by healthcare organizations to evaluate second victim experiences of their staff. The purpose of this study was to quantify the level of agreement among respiratory therapists (RTs) who participate in CEs resulting in the perception of being a second victim, as well as various desired forms of support. Methods The study employed a cross-sectional, non-experimental survey design. The SVEST-R was disseminated via an anonymous electronic survey posted to a private social media site for RTs. Data analysis included descriptive statistics for demographic variables, exploratory factor analysis, measures of reliability for the SVEST-R instrument, and comparison of responses across demographic variables. Results There were 146 survey responses. The majority of respondents were female (92%), between the ages of 25–40 (49%), had between 11 and 20 years of RT experience (27%), and practiced primarily in adult critical care (87%). Up to 51.4% of the sample reported that physical distress had occurred due to participation in CEs. The majority of respondents (80.8%) agree that colleague support is present. There was general agreement that supervisor (>60%) and organization (>50%) support are present. Perception of professional self-efficacy was preserved, and resilience remained high for the majority of RTs in this sample. There was general disagreement that involvement in CEs resulted in absenteeism from work or turnover intentions. The most frequently desired form of support was a peaceful location to recover and recompose after the event (85.8%). Conclusions RTs experience marginal yet meaningful distress as a result of participating in CEs. Respondents desire more opportunities to exist in terms of institutional support. Participating in CEs rarely impacts perceptions of self-efficacy. Respondents identify as resilient and feel the experiences with CEs have promoted professional growth.