Citations

Abstract Objective Advanced adrenocortical carcinoma (ACC) is treated with mitotane alone or combined with cytotoxic chemotherapy, yet outcomes remain poor and prognostic models in this setting are lacking. This study aimed to evaluate the prognostic value of clinical parameters in a large cohort of patients with advanced ACC undergoing systemic therapy. Methods Multicenter, international cohort study investigating 418 patients with advanced ACC (61.5% = women, median age = 52 years) from 11 centers. Patients received mitotane monotherapy (n = 161), etoposide + doxorubicin + cisplatin ± mitotane (n = 178), or second-line regimens (gemcitabine + capecitabine ± mitotane or temozolomide + mitotane, n = 79). Variables included age, cortisol excess, performance status (ECOG-PS), tumor burden, and neutrophil-to-lymphocyte ratio (NLR) at start of therapy. Outcomes were overall survival (OS), time to progression (TTP), and best objective response. Results Tumor burden, cortisol excess, ECOG-PS, and NLR ≥5 independently predicted shorter OS (hazard ratio [HR] 1.55-2.68). We developed an integrated ENSAT Risk Score for Advanced ACC combining these variables: tumor burden (0-2), cortisol excess (0/1), ECOG-PS (0-2), and NLR (0/1). A score >2 (poor-risk) was significantly associated with worse OS and TTP across all treatment groups (HRs for OS: 3.05-3.96; TTP: 2.53-3.08). It also predicted poorer response to mitotane (P < .01) and second-line therapies (P = .04). Conclusions The ENSAT Risk Score for Advanced ACC is a practical, prognostic tool for patients with advanced ACC receiving systemic therapy. Based on accessible clinical and biochemical markers, it can support treatment decisions and facilitate informed discussions in routine care.

PURPOSE This national study was undertaken to determine screening mammography rates among transgender and gender diverse (TGD) individuals. METHODS TGD individuals and cisgender women who qualified to receive screening mammography based on American College of Radiology guidelines were identified in the longitudinal OptumLabs Data Warehouse. The primary end point was the percentage of patients who had high rates of screening (>75% recommended screenings). Multivariable analyses were conducted in a matched population of transgender men to cisgender women to identify and adjust for factors associated with high adherence. Individuals were matched at a 1:4 ratio (transgender men: cisgender women) on age, race/ethnicity, year of enrollment in their health care plan, and duration of follow-up. RESULTS This study focused on 10,478 TGD individuals (3,778 transgender men; 1,294 transgender women; 5,406 with gender dysphoria not meeting other TGD criteria, NMOT) and 6,218,369 cisgender women. For transgender men, transgender women, individuals with gender dysphoria NMOT, and cisgender women, high mammography rates were observed in 41.1% (95% CI, 39.5 to 42.6), 7.4% (95% CI, 6.0 to 8.8), 11.9% (95% CI, 11.0 to 12.7), and 38.3% (95% CI, 38.3 to 38.4), respectively ( P < .0001). When transgender men were compared with 15,112 matched cisgender women, an age-based differential association was observed between sex and high mammography rates (interaction P = .0003); compared with cisgender women, transgender men appeared more likely to manifest high rates of screening at age 40-49 years (odds ratios [ORs], 1.38 [95% CI, 1.28 to 1.50]; P < .0001) and 50-59 years (OR, 1.57 [95% CI, 1.35 to 1.81]; P < .0001) but not in the older age groups. CONCLUSION The relatively high rates of screening mammography in cisgender women and transgender men suggest clinicians are offering mammography to individuals who are at average or high breast cancer risk, as compared with cisgender women, and not to transgender women at low risk.

Rationale: Neuromuscular blocking agents (NMBAs) show potential benefits on mortality and other complications of acute respiratory distress syndrome (ARDS) in adult patients. Evidence-based decisions and processes ensure appropriate use of neuromuscular blockade in adult patients with ARDS. Objectives: The objective of these guidelines was to develop evidence-based recommendations for the administration of NMBAs in critically ill adult patients with ARDS. Design: The American College of Critical Care Medicine Board convened a 21-member multidisciplinary panel of experts in critical care medicine, nursing, respiratory therapy, pharmacology, surgery, neurology, and anesthesiology. The panel included two expert methodologists specialized in developing evidence-based recommendations in alignment with the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) methodology. Conflict-of-interest policies were strictly followed during all phases of guidelines development including task force selection and voting. Methods: The panel members identified and formulated five Population, Intervention, Comparison, and Outcome questions. We conducted a systematic review for each question to identify the best available evidence, statistically analyzed the evidence, and assessed the certainty of the evidence using the GRADE methodology. We used the GRADE evidence-to-decision framework to formulate the recommendations. Results: The panel generated two conditional recommendations. One recommendation is to use NMBAs in adults with ARDS with Pa o 2 /F io 2 less than 150. For the other recommendations, there was equipoise in the recommendation for and against using titratable vs. fixed-dose NMBA dosing, a monitoring-based strategy for assessing depth of sedation and analgesia in adults with ARDS before initiating or while receiving neuromuscular blockade, and administration of NMBAs for patients who are proned, due to overall lack of evidence in critically ill patients and due to considerations of patient safety and experience concerns. Conclusions: These guidelines provide additional perspectives on the use of NMBA in patients with ARDS, recognizing that institutional and patient-specific considerations must help to guide the decision-making process.

Background Antitumor immune responses induced by oncolytic immunotherapy (OI) are often followed by upregulation of programmed death-ligand 1 (PD-L1). As such, the combination of OI with blockade of the programmed cell death protein-1 (PD-1)/PD-L1 axis has demonstrated therapeutic activity in preclinical and clinical trials. The purpose of this study is to understand further the immune-mediated mechanism of interaction between oncolytic viruses and anti-PD-1 therapy. Methods Tumor cells and immune cells (splenocytes) were cultured separately, or in co-culture with vusolimogene oderparepvec, an oncolytic herpes simplex virus expressing the fusogenic gibbon-ape leukemia virus-fusogenic membrane glycoprotein protein (GALV) and granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as RP1. Viral replication, interferon (IFN) responses and PD-L1 expression were analyzed using wild-type, IFNAR1, TNFAR1 and STING knockout splenocytes. In vivo studies evaluated immune cell infiltrates into the tumor following RP1 administration with anti-PD-1 therapy. Results RP1 replication was evident in tumor cells but not splenocytes. This was also accompanied by upregulated IFN expression in cultured splenocytes that was absent in cultured tumor cells. However, when these cell types were co-cultured, splenocytes mediated an interferon response to RP1 via STING that was transmitted to tumor cells in a non-touch-dependent manner. Tumor cells responded to these input signals via upregulation of cell surface major histocompatibility complex-I and PD-L1 through tumor intrinsic JAK-STAT signaling. In vivo, an IFN signature was observed following intratumoral injection of RP1, both in injected and non-injected tumors, which was further increased when combined with anti-PD-1 therapy. Marked upregulation of PD-L1 was observed in tumors injected with RP1 accompanied by the recruitment of CD11b+Ly6G+neutrophils into the tumor microenvironment, which stained positive for PD-L1. Conclusion Overall, the data demonstrate that RP1 remodels the tumor microenvironment through a combination of direct and indirect effects on both tumor and immune cells, resulting in an overall more inflamed phenotype.

Abstract Background Neuroendocrine tumors (NETs) are rare, heterogeneous neoplasms associated with prolonged survival and substantial symptom burden. However, patient-reported outcomes across NET subtypes remain poorly characterized, particularly in real-world settings. This study describes baseline health-related quality of life (HRQoL) and care experiences among patients with gastroenteropancreatic and lung NETs, examining differences by tumor site and time since diagnosis. Methods The Neuroendocrine Tumors–Patient Reported Outcomes study is a prospective, multi-institutional US cohort of adults (aged 18 years and older) with incident small intestinal, pancreatic, gastroenteropancreatic, or lung NETs diagnosed from January 2018 through September 2024, identified via a validated electronic medical record–based computable phenotype. Baseline surveys assessed HRQoL, symptoms, care experiences, and clinical characteristics using validated instruments. Descriptive statistics and standardized mean differences compared responses by NET site and time since diagnosis. Results Among 2367 participants (mean age = 57.8 years; 57.3% female), 1974 had gastroenteropancreatic NETs (659 small intestinal NET, 555 pancreatic NET) and 393 had lung NETs. Fatigue (mean = 33.0), insomnia (mean = 32.5), and diarrhea (mean = 25.7) were the most burdensome symptoms. Lung NET patients reported worse dyspnea (standardized mean difference = 0.58, P &lt; .001) and lower physical, role, and global QoL scores than those with gastroenteropancreatic NETs, while pancreatic NET patients reported better functioning. Diarrhea worsened over time, especially in small intestinal NETs. Most rated care highly (75.3%) but cited concerns about treatment side effects (80.4%), costs (60.7%), and travel burden (58.8%). Conclusions This large US cohort reveals persistent symptom burden and HRQoL variation by tumor site and disease duration, underscoring the need for longitudinal HRQoL assessment in NET care.

TPS277 Background: Recent advances in genomic sequencing have deepened our understanding of the molecular complexity of metastatic castration-resistant prostate cancer (mCRPC), revealing multiple actionable alterations that now inform biomarker-driven treatment strategies. Accordingly, germline and somatic tumor profiling is recommended for all patients with mCRPC. Beyond DNA aberrations, gene expression profiling can uncover additional therapeutic targets and pathway activations. The phase 2 PREDICT trial is leveraging both DNA and RNA alterations to guide rationally designed, biomarker-based therapeutic approaches for patients with mCRPC. Methods: This multi-center, multi-arm, biomarker-driven phase 2 umbrella trial is evaluating rationally selected therapies for patients with metastatic castration-resistant prostate cancer (mCRPC). The primary endpoint is objective response rate in patients with measurable disease, with secondary endpoints including radiographic progression-free survival, PSA response, time to first symptomatic skeletal event, overall survival, safety, and correlative biomarker analyses. Eligible patients must have progressive mCRPC of any histology, prior treatment with an androgen receptor pathway inhibitor (ARPI), and either prior or declined taxane chemotherapy, with both measurable and non-measurable disease permitted. Enrollment requires standard-of-care next-generation DNA sequencing from tissue or circulating tumor DNA performed in a CLIA-certified laboratory, and RNA-based allocation will use the CLIA-certified Caris MI Tumor Seek assay (whole exome and whole transcriptome sequencing) on tissue obtained within 12 months of study entry, with a real-time molecular tumor board reviewing results to confirm arm assignment. Patients with RB1 loss (DNA), an RB functional loss signature (RNA), or an NEPC signature (RNA) will receive the EZH1/2 inhibitor valemetostat; those with ≥2 of 3 tumor suppressor gene alterations (TP53, RB1, PTEN), FANC alterations (DNA), or SLFN11 overexpression (RNA) will receive cabazitaxel plus carboplatin; and those without study-defined alterations will receive physician’s choice of cabazitaxel, ARPI, or 177Lu-PSMA-617. The design permits incorporation of additional biomarker-defined arms, and up to 158 patients per arm (64 with measurable and 94 with non-measurable disease) will be accrued under a Simon two-stage minimax design, providing a one-sided type I error of 0.05 if the true response rate is 0.20 and 90% power if the response rate is 0.37 (Clinical trial information: NCT06632977). Clinical trial information: NCT06632977 .

476 Background: Lack of standardized reporting and collection of patient-reported outcomes (PROs) limits cross-trial comparisons of first-line IO-based regimens for mRCC. Prospectively collected real world data may fill this important knowledge gap. Pts with stable/improved QoL at 3 mo versus baseline have longer median OS than pts with worse/unobserved HRQoL versus baseline (Cella, 2024). Methods: ODYSSEY is a multi-site, prospective observational study of 468 US pts with mRCC. Pts must have mRCC (any histology), no prior systemic therapy (ST), and follow up at a PCORnet study site. Exclusion criteria include treatment for cancer except mRCC. Descriptive statistics are used to show PRO score changes from baseline. We evaluate longitudinal change from baseline in PRO scores using least squares mean (LSM). Minimally important differences (MID) are 3 points for FKSI-19 total score, 1 point for the FKSI-Disease Related Symptoms (DRS) subscale and 7 points for FACT-G. Higher score indicates better QOL. The primary objective is to determine patterns of change in QOL and symptom burden of pts with mRCC. Results: As of 10/1/25, 360 pts were managed with ST, including 266 pts on IO-based combinations: 35 cabozantinib + nivolumab (C+N), 49 lenvatinib + pembrolizumab (L+P), 40 axitinib + pembrolizumab (A+P), and 142 ipilimumab + nivolumab (I+N). Overall median follow-up is 12.1 mos (IQR 6, 24). Age, sex and race were similar across regimens. Prior nephrectomy (50%) was lower than in trials. C+N and L+P pts had less clear cell (56 and 65%) versus A+P and I+N pts (94 and 82%). A+P pts had more favorable IMDC risk (19%) and less poor risk (14%). Baseline QOL was variable across regimens, with L+P generally the lowest. Absolute changes in PROs from enrollment to mo 3 (early change) by regimen are shown in the Table. LSM change from baseline in FKSI-19 and FKSI-DRS favored IO-IO versus IO-TKI at 3 mos but not at 6 mos (not shown). Conclusions: While early change in PROs did not meet the MID threshold between the IO-TKI and I+N cohorts, different patterns of early change are apparent among specific IO-TKI regimens. IO-TKI regimens exhibited higher variation in early PRO change vs I+N. As the data matures, we will associate baseline PROs and early PRO changes with early death and other outcomes. Clinical trial information: NCT04919122 . 3 month change. Instrument C+N (N=35) L+P (N=49) A+P (N=40) All IO-TKI(N=124) I+N(N=142) FKSI-19, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.3 (11) 2.8 (13) -3.2 (12) -0.2 (12) 0.7 (10) Median (IQR) 1.4 (-7, 6) 5.0 (-7, 11) -1.0 (-14, 5) 1.4 (-10, 8) -0.3 (-5, 6) FKSI-DRS, N (%) 26 (74) 33 (67) 33 (83) 92 (74) 104 (73) Mean (SD) -0.8 (5) 1.5 (7) -1.8 (6) -0.3 (6) 0.8 (5) Median (IQR) -0.5 (-5, 3) 2.0 (-5, 5) -1.0 (-5, 3) 0.0 (-5, 4) 0.0 (-2, 4) FACT-G, N (%) 27 (77) 32 (65) 29 (73) 88 (71) 102 (72) Mean (SD) 2.1 (14) 5.2 (16) -3.5 (15) 1.4 (15) 0.3 (13) Median (IQR) 4.0 (-4, 10) 1.2 (-6, 13) -6.4 (-11, 4) 1.6 (-8, 10) 1.6 (-7, 8)

INTRODUCTION: Despite the widespread use of ursodeoxycholic acid (UDCA) in primary biliary cholangitis (PBC), many patients remain at risk of progression. Emerging data suggest that normalization of alkaline phosphatase (ALP) and total bilirubin (TB)—particularly when TB < 0.6 times the upper limit of normal (× ULN)—is associated with improved outcomes compared with ALP reduction to < 1.5 × ULN. This study investigated the association between ALP normalization in response to UDCA and long-term clinical outcomes in a real-world cohort of patients with PBC. METHODS: We compared complication-free survival in patients achieving an ALP > ULN and < 1.5 × ULN (adequate response) with those with an ALP ≤ ULN on UDCA monotherapy. Complication-free survival was defined as the absence of serious liver-related clinical events. Restricted mean survival time was used to quantify survival time gained. RESULTS: Patients achieving normal ALP and/or TB ≤ 0.6 × ULN demonstrated significantly improved complication-free survival compared with those with an adequate ALP response. Event-free survival was extended by 1.34 years (95% CI: 0.56, 2.11; P = 0.001) for ALP normalization alone, 3.7 years (95% CI: 3.11, 4.29; P < 0.001) for TB ≤ 0.6 × ULN, and 4.51 years (95% CI: 4.13, 4.88; P < 0.001) for those meeting both criteria. The risk of severe clinical events was reduced in patients achieving ALP normalization (hazard ratio [HR] 0.34; 95% CI: 0.15, 0.80; P = 0.01), TB ≤ 0.6 × ULN (HR 0.23; 95% CI: 0.09, 0.55; P = 0.001), or both (HR 0.14; 95% CI: 0.05, 0.38; P < 0.001). High-risk patients, defined by liver stiffness measurement ≥ 10 kPa or clinical, histological, or laboratory evidence of cirrhosis or portal hypertension, derived the greatest benefit. DISCUSSION: Achieving normal ALP and TB ≤ 0.6 × ULN is associated with significantly improved complication-free survival, particularly in high-risk patients. These findings highlight the potential of biochemical thresholds as a meaningful therapeutic goal in PBC management.

Abstract Introduction Combat casualty care requires standardized proficiency criteria to ensure readiness in austere environments, yet gaps persist in defining performance thresholds for critical trauma skills. The Combat Medical Skills Sustainment Consortium (CMSSC), a novel military-civilian collaboration, aimed to validate competency thresholds for 21 Department of Defense-identified trauma skills. Materials and Methods A prospective cohort study (2022-2025) enrolled 1,495 military and civilian personnel across five academic centers, stratified by experience (novice, intermediate, expert). Skills, including cricothyroidotomy, whole blood transfusion, and ultrasound-guided vascular access, were assessed using validated checklists in Role 2-congruent simulations. Statistical analysis compared checklist performance against participant experience with a priori checklist scores estimated at 40% (novices) and 90% (experts). Results Competency thresholds were established, ranging from 77% (mechanical ventilation) to 100% (handoff). Experts achieved 85%-98% proficiency across most skills, with novices at 34%-97%. A ceiling effect was observed for less complex skills consistent with the power law of practice. Conclusion The Combat Medical Skills Sustainment Consortium validated standardized assessment tools, with potential to address readiness gaps through military-civilian synergy. Findings support consortium-guided curriculum development and highlight the need for longitudinal skill decay studies. Impact This study sets a benchmark for trauma care skills assessment, facilitating rapid adoption across military and civilian settings.