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Background Grade group 5 (GG5) prostate cancer (PCa) carries a less favorable prognosis after standard-of-care (SOC) therapy, necessitating novel therapeutic approaches. High-dose rate brachytherapy (HDRBT) and androgen deprivation therapy (ADT) may modulate immune response in GG5 PCa, particularly in tumors with increased immune content. This study evaluated whether the addition of nivolumab to SOC was associated with improved disease control in patients with high-volume GG5 PCa, including those with oligometastatic disease. Methods In this non-randomized phase II trial, 31 patients with localized or oligometastatic GG5 PCa and >30% positive biopsy cores were evaluated between September 2018 and April 2021. Patients received four doses of nivolumab (240 mg every 2 weeks) beginning 4 weeks prior to HDRBT, alongside ADT, HDRBT, and external beam radiation. The primary endpoint was to evaluate whether the 2-year freedom from biochemical recurrence (FFBR) rate would exceed a prespecified historical control rate of 75%. Results Among the 31 patients, the median follow-up was 38.8 months (IQR 31.0–46.5 months). The addition of nivolumab to SOC RT with ADT was associated with a 2-year FFBR rate of 90.3% (95% CI 74.3% to 98.0%) (median FFBR not reached), exceeding the prespecified historical control rate of 75% (one-sided p value from binomial test=0.024). Definitive and probable nivolumab-related toxicity included 6.3% acute grade 2 and 6.3% acute grade 3 adverse events (AEs), with no grade 4+ AEs observed. A higher Decipher immunosuppression score at diagnosis correlated with early pathologic response (p=0.005) and was independently associated with time to metastatic failure (p=0.044). Conclusions Nivolumab combined with SOC was associated with encouraging FFBR in this high-risk GG5 PCa population and may represent a promising therapeutic intensification strategy. The Decipher immunosuppression score may serve as a predictive biomarker for response. These findings warrant further investigation in randomized trials.

Abstract Purpose: Circulating tumor fraction estimate (ctFE) is a machine learning–derived composite metric of circulating tumor DNA (ctDNA) burden. We hypothesized that pre-treatment and early on-treatment ctFE could robustly risk-stratify patients with locally advanced (LA) and oligometastatic non–small cell lung cancer (NSCLC) treated with radiotherapy (RT). Experimental Design: In a prospective phase II clinical trial (NCT03916419), 26 patients with unresectable stage IIB to IIIC NSCLC received magnetic resonance (MR)-guided hypofractionated chemoradiotherapy (chemoRT) followed by immunotherapy. Plasma ctDNA was profiled at baseline and mid-treatment (days 10–14) to derive ctFE and maximum variant allele frequency (Max VAF). A burden-based ctFE threshold derived from baseline samples was applied unchanged to mid-treatment samples and validated in two external cohorts: LA NSCLC treated with chemoRT (LA-RW; n = 94) and oligometastatic NSCLC treated with RT (OM-RW; n = 309). Results: Pre- and mid-treatment ctFE burden strongly stratified overall survival (OS) and progression-free survival (PFS), outperforming Max VAF and ctFE detectability. The baseline ctFE was prognostic for OS (HR 5.93, P = 0.005) and PFS (HR 11.08, P < 0.001) and remained significant at mid-treatment (OS: HR 7.08; PFS: HR 12.06; both P < 0.001). Early ctFE dynamics defined three molecular response groups with OS separation (median OS 60.8 vs. 13.0 vs. 2.9 months; P < 0.001). ctFE remained associated with survival in both validation cohorts. Conclusions: Early ctFE derived from a clinically available, tumor-naïve ctDNA assay enables noninvasive risk stratification in LA and oligometastatic NSCLC treated with RT, supporting its use as a practical biomarker for precision treatment adaptation.

Background: Given the faster onset and shorter duration of action of ultra-rapid insulin lispro-aabc (URLi, Lyumjev™ insulin), compared with insulin lispro (a rapid-acting insulin [RAI]), the present study investigated the safety and glycemic outcomes of MiniMed™ 780G advanced hybrid closed-loop (AHCL) use with URLi in youths and adults with T1D. Methods: This 19-site, single-arm, clinical trial enrolled children and adolescents (aged 7–17 years) and adults (aged 18–80 years) with T1D who underwent a run-in period (∼2 weeks) using open loop or automated basal only with an RAI (aspart or lispro), followed by a 3-month study period using URLi with AHCL (AHCL + URLi). End-of-study glycemic metrics and A1c were compared to predefined thresholds and to data from baseline/run-in. Use of recommended optimal settings (ROS, 100 mg/dL glucose target with an active insulin time [AIT] of 2 h) was also assessed. Results: In an intention-to-treat population ( N = 101 pediatric and N = 110 adult participants), percentage of time in range (%TIR) during the last ∼6 weeks of the study period was significantly greater than the predefined thresholds for both the pediatric and adult participants. A1c was unchanged in the pediatric cohort but significantly reduced in the adult cohort (from 7.4 ± 0.9% to 6.9 ± 0.6% [ P < 0.001]). Compared with run-in, study period %TIR and percentage of time in tight target range (%TITR) were significantly increased (pediatric mean %TIRΔ [17.4%] and %TITRΔ [16.0%], respectively, and adult mean %TIRΔ [10.6%] and %TITRΔ [11.6%], respectively; P < 0.001 for all). Additionally, % time above range for both groups was significantly reduced. Use of ROS allowed more participants to achieve recommended glycemic targets. There were no severe hypoglycemia or diabetic ketoacidosis events. Most caregivers agreed that mealtime versus premeal URLi delivery simplified pediatric meal management. Conclusions: Similar to previous studies investigating automated URLi delivery, URLi use in the MiniMed™ 780G system was safe, and glycemic outcomes were favorable for pediatric and adult participants.

We report correlative circulating tumor DNA (ctDNA) analyses from TRANSFORM (ClinicalTrials.gov identifier: NCT03575351 ) evaluating lisocabtagene maraleucel (liso-cel) versus standard of care (salvage immunochemotherapy, high-dose chemotherapy, autologous stem cell transplantation [ASCT]) in second-line large B-cell lymphoma (LBCL). ctDNA association with efficacy was investigated at predefined time points (random assignment, day 43, day 64, and day 126 [3 months after liso-cel, approximately 2 months after ASCT]) for 136 patients using ultrasensitive PhasED-Seq. ctDNA clearance (measurable residual disease [MRD] neg ) predicted longer event-free survival (EFS) at all time points in both arms, with significantly more liso-cel–treated patients achieving MRD neg . Liso-cel demonstrated superior outcomes versus ASCT, including longer EFS, progression-free survival (PFS), and duration of response among patients in complete response (CR) and MRD neg . ctDNA re-emergence in patients with CR after ASCT confirmed its potential in predicting relapse. MRD neg remained significantly associated with EFS after adjusting for positron emission tomography (PET) response, while interaction testing revealed a significant interaction between PET status and treatment arm for EFS. Liso-cel achieved deeper, more durable molecular clearance by ctDNA, consistent with superior EFS and PFS versus ASCT for second-line LBCL treatment. ctDNA-MRD provided prognostic value beyond PET, supporting its role as a complementary biomarker for treatment response and relapse prediction.

Abstract Pancreatic cancer disproportionately affects Black individuals in the United States, but they have limited representation in genetic studies of pancreatic ductal adenocarcinoma (PDAC). To address this gap, we performed admixture mapping and genome-wide association analysis (GWAS) in genetically inferred African ancestry individuals (1,030 cases and 889 controls). Admixture mapping identified three regions with a significantly higher proportion of African ancestry in cases compared to controls (5q33.3, 10p1, 22q12.3). GWAS identified a genome-wide significant association at 5p15.33 ( CLPTM1L , rs383009:T>C, T Allele Frequency=0.51, OR:1.45, P value=1.24×10 -8 ), a locus previously associated with PDAC. Known loci at 5p15.33, 7q32.3, 8q24.21 and 7q25.1 also replicated (P value <0.01). Multi-ancestral fine-mapping identified two potential causal SNPs (rs3830069 and rs2735940) at 5p15.33. Collectively these findings identified novel PDAC risk loci and expanded our understanding of this deadly cancer in underrepresented populations, emphasizing the multifactorial nature of PDAC risk including inherited genetic and non-genetic factors. Statement of Significance To understand how genetic variation contributes to PDAC risk in Black people in North American, we studied individuals of genetically-inferred African ancestry. We identified novel risk loci and differences in the contribution of known loci. This demonstrates that ancestry-informed genetic analyses improve our understanding of PDAC risk and enhances discovery.

Introduction Approximately 50% of patients with uveal melanoma develop metastatic disease, most commonly involving the liver, and prognosis remains poor. Immunoembolization (IE) is an established liver-directed therapy for patients with liver-dominant metastatic uveal melanoma (mUM), though comparative data with other regional therapies remain limited. We present a single-center retrospective analysis of IE in hepatic mUM and compare outcomes with those reported in the Phase 3 FOCUS trial evaluating melphalan via percutaneous hepatic perfusion. Methods All patients with liver-dominant mUM treated with IE between 2010 and 2023 at our institution were included. Clinical records were reviewed for demographics, tumor characteristics, treatment details, and outcomes. The primary endpoint was disease control rate (DCR), defined as complete response (CR), partial response (PR), or stable disease (SD). Secondary endpoints included progression-free survival (PFS) and overall survival (OS), with subgroup analyses based on prior systemic therapy exposure. Descriptive statistics were used for analysis. Results Forty-three patients (62.8% female; median age 62 years; all Caucasian) underwent 249 IE procedures (mean 5.8 procedures per patient) over a median treatment duration of 9.1 months. Choroidal primaries accounted for 95.3% of cases, and 90.7% had liver-only metastases. The overall DCR was 27.9% (CR 4.7%, PR 20.9%, SD 2.3%), while 62.8% experienced disease progression. Median PFS was 0.85 months, and median OS was 32.7 months. One- and two-year OS rates were 69.8% and 55.8%, respectively. In subgroup analysis, patients who had received prior systemic therapy (n=12) demonstrated improved outcomes compared with treatment-naïve patients, with longer median PFS (29.9 vs. 7.2 months) and higher 2-year OS (60.0% vs. 47.0%). Compared with outcomes reported in the FOCUS trial, IE demonstrated shorter median PFS (0.85 vs. 9.0 months) and lower DCR (27.9% vs. 73.6%), but longer median OS (32.7 vs. 20.5 months). Discussion IE produced overall survival outcomes comparable to hepatic melphalan delivery despite lower radiographic response rates. Notably, patients previously treated with systemic therapy experienced improved outcomes, suggesting a potential sequencing effect. These findings support IE as a viable liver-directed therapy for liver-dominant mUM. Prospective, multicenter trials are warranted to clarify optimal sequencing strategies and enhance therapeutic outcomes.

Abstract Background Accurate assessment of left ventricular outflow tract (LVOT) gradients is critical for hypertrophic cardiomyopathy (HCM) management, yet Doppler-based measurements are technically demanding and require expertise. Objective To develop a multi-view deep learning model capable of classifying LVOT obstruction (> 20mmHg) using routine 2D echocardiographic windows without reliance on Doppler imaging. Methods We trained and externally validated a cross-attention-based video-to-video fusion framework that integrated EchoPrime-derived video representations from three standard transthoracic echocardiographic views to classify LVOT gradients. Results Training was performed on a derivation cohort (N = 1833) from a tertiary care system in the United States, with model performance evaluated on an internal held-out test set (N = 275) and a Korean external validation cohort (N = 46). Single-view baselines showed limited discrimination (external AUROCs 0.47–0.70). Conversely, domain-specific foundational model (EchoPrime) achieved superior single-view performance (AUROCs 0.75–0.80 internal; 0.79–0.83 external), highlighting the importance of echo-specific pretraining and temporal modeling. The proposed multi-view fusion further enhanced predictive performance, with the late fusion model reaching an AUROC of 0.84 on the external cohort with significant population-shift. Conclusions These results suggest LVOT physiology is encoded in routine 2D imaging and can be leveraged for clinically relevant gradient classification without Doppler input- proposed AI-guided strategy demonstrates substantial cost savings compared with the screen-all approach. By integrating complementary spatial-temporal information across multiple views, our approach generalizes robustly across populations and may enable real-time decision support, extend LVOT assessment to portable or resource-limited settings, and complement Doppler-based evaluation for longitudinal HCM management.

Morel-Lavallee lesions (MLLs) are traumatic closed degloving injuries with operative intervention (OI), especially excisional debridement, remaining the mainstay of treatment. However, high-quality evidence describing operative techniques and outcomes remains limited. This study aimed to characterize current OI practices and associated outcomes, especially among patients undergoing excisional debridement, hypothesizing an increased risk of wound complications with this approach for MLLs. Methods This prospective (2021-2024), multicenter, observational study was conducted across 15 trauma centers and included patients diagnosed with MLL who underwent OI. The association between operative technique (eg, excisional debridement) and the primary outcome of wound complications was evaluated. Wound complications were defined as cellulitis, deep wound infection, skin necrosis, necrotizing soft tissue infection (NSTI), and/or organized hematoma. Results Of 88 MLL patients undergoing OI, 36 (40.9%) had excisional debridement, with 4 (11.1%) limited excision to skin, 20 (55.6%) extended to subcutaneous tissue, and 12 (33.3%) down to muscle. Excisional debridement had higher rates of skin necrosis (22.2% vs. 1.9%, P = .002). Although overall rates of wound complications were statistically similar between cohorts (33.3% vs. 17.3%, P = .098), univariate analysis demonstrated excisional debridement had increased risk of wound complications (OR 2.52, CI 1.07-5.97, P = .035). Conclusion This prospective multicenter study over three years demonstrated that a fifth of MLLs undergoing excisional debridement developed postoperative skin necrosis. Excisional debridement also had a more than two-fold increased risk of wound complications compared to other OIs. These findings underscore the importance of investigating alternative operative techniques, such as incision and drainage or minimally invasive debridement methods.