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ABSTRACT Background and Objectives Pancreatic neuroendocrine tumors (pNETs) account for 1%–2% of pancreatic tumors, with an increasing incidence. The safety of concurrent pancreas‐liver resections remains uncertain. This study evaluated the national outcomes of concurrent pancreatectomy and liver‐directed surgery for pNETs. Methods ACS‐NSQIP (2019–2023) was queried for adult patients who underwent pancreatectomy for pNETs. Concurrent liver‐directed procedures were identified by CPT code and classified as hepatectomy or ablation alone; patients were grouped as isolated pancreatectomy, concurrent hepatectomy, or concurrent ablation alone. Pre‐, intra‐, and postoperative characteristics were compared using inferential statistics. Multivariable logistic regression identified predictors of 30‐day morbidity, readmission, reoperation, and mortality, with Firth penalized likelihood used for rare outcomes. Results Of 4794 patients, 4587 (95.7%) underwent isolated pancreatectomy, 172 (3.6%) underwent concurrent hepatectomy, and 35 (0.7%) underwent concurrent ablation alone. Concurrent hepatectomy was parenchymal‐sparing in 163 of 172 patients (94.8%); only nine patients underwent a major hepatectomy. Overall morbidity was similar across groups (38.8%, 45.9%, and 42.9%; p = 0.154), as was serious morbidity (28.7%, 27.9%, 22.9%; p = 0.730) and 30‐day mortality (1.0%, 0.6%, 0%). On multivariable analysis, neither concurrent hepatectomy (OR 1.02, 95% CI 0.71–1.48) nor concurrent ablation (OR 0.94, 95% CI 0.46–1.93) was associated with morbidity. Pancreatoduodenectomy was associated with morbidity (OR 2.38, 95% CI 2.05–2.76), reoperation (OR 2.16, 95% CI 1.52–3.08), and mortality (OR 2.50, 95% CI 1.39–4.50), and a minimally invasive approach was associated with lower morbidity (OR 0.69, 95% CI 0.60–0.80). Conclusions Concurrent liver‐directed surgery was not associated with an increase in 30‐day morbidity or mortality after pancreatectomy for pNETs. These findings support the safety of concurrent hepatic resection in appropriately selected pNET patients.

Abstract Treatment resistance and metastases occur in 10–20% of patients with invasive lobular carcinoma (ILC), the most common special histological subtype of breast cancer. ILC metastasizes to the ovary more frequently than no special type (NST) tumors, also known as invasive ductal carcinoma (IDC). To characterize the genomic landscape of breast cancer ovarian metastases, we analyzed 15,613 local breast cancers, 22,010 non-ovarian metastases, and 246 ovarian metastases sequenced using FoundationOne®CDx or FoundationOne® assays. Ovarian metastases had enriched CDH1 , PIK3CA , and TBX3 mutations and depleted TP53 and MYC alterations relative to local breast cancers, with additional depletion of ESR1 mutations compared to non-ovarian metastases. CDH1 mutations were less frequent in ovarian metastases (47%) than local ILC (81.3%), with reduced 16q loss (64% vs 84%), indicating that ovarian metastases also arise from non-ILC tumors. We extended these findings to a UPMC cohort of 27 ovarian metastases (13 ILC, 8 IDC, 6 mixed ductal-lobular carcinoma) with patient-matched primary tumors in most cases. In both cohorts, patients with ovarian metastases were significantly younger than those with other metastatic sites. In the UPMC cohort, the most frequent mutations were in PIK3CA , CDH1 , KMT2C , FOXA1 , and RUNX1 . Transcriptomic analysis identified upregulated G protein-coupled receptor (GPCR) pathways, including metabotropic glutamate receptor signaling. Functional studies showed that calcium-sensing receptor (CaSR), a GPCR overexpressed in ovarian metastases, drives MEK/ERK-dependent migration and F-actin reorganization in ILC cell lines, enhanced by estrogen and blocked by calcilytic, MEK, or anti- estrogen treatment. Our findings inform future therapeutic targeting of ovarian metastasis.

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.

Patients in the liso-cel plus ibrutinib cohort of the phase 1/2, open-label TRANSCEND CLL 004 study had relapsed/refractory chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and received liso-cel (50×106 [dose level (DL)1] or 100×106 [DL2] chimeric antigen receptor-positive T cells) with concurrent ibrutinib from enrollment through 90 days after liso-cel infusion or longer per investigator discretion. Primary end point was complete response/remission (CR)/CR with incomplete marrow recovery (CRi) by investigator assessment. Among 56 patients who received ibrutinib plus liso-cel (DL1, n=5; DL2, n=51), median (range) age was 64.5 years (44‒77), 98% had high-risk cytogenetics, 55% had progression on Bruton tyrosine kinase inhibitor and venetoclax failure, and median (range) number of prior therapies was 5 (1‒13). Median (range) follow-up was 24.8 months (3.1‒51.8). At DL2, CR/CRi rate was 45% (95% confidence interval [CI], 31‒60) and overall response rate was 86% (95% CI, 74‒94). Median (95% CI) duration of response was not reached (NR; 28.7‒NR) for patients with CR/CRi and 41.4 months (23.3‒NR) for all responders. Median (95% CI) progression-free survival was 31.4 months (20.1‒NR). In DL1+DL2, most common grade ≥3 treatment-emergent adverse events (TEAE) were neutropenia (52%) and anemia (41%). Cytokine release syndrome was reported in 80% of patients (grade 3, 4%; no grade 4/5), and neurological events in 41% (grade 3/4, 11%; no grade 5). Ibrutinib-related TEAEs were reported in 68% of patients (grade 3/4, 43%; no grade 5). Liso-cel plus ibrutinib demonstrated notable efficacy in patients with relapsed/refractory CLL/SLL with predictable and manageable safety. Clinicaltrials.gov: NCT03331198; NCT03435796.

Background High‐risk non‐muscle‐invasive bladder cancer (HRNMIBC) has a variable prognosis, managed predominantly by local surgical resection and intravesical Bacillus Calmette–Guérin (BCG), or radical cystectomy (RC). Current treatments are poorly tolerated, have supply limitations and often fail to control the disease. Treatments overcoming these limitations are needed to improve HRNMIBC outcomes. Many novel agents have been approved in recent years (including systemic pembrolizumab, nogapendekin alfa inbakicept‐pmln, N‐803), but long‐term efficacy is unknown. Given advanced bladder cancer findings, we believe direct intravesical administration of atezolizumab may aid with managing HRNMIBC or muscle‐invasive bladder cancer in patients who are ineligible for cisplatin‐based neoadjuvant chemotherapy. Study design The INtraVESical immunoTherapy (INVEST) trial is a UK‐based, open‐label, non‐randomised, single‐centre, Phase Ib dose escalation, window of opportunity study exploring atezolizumab administration via intravesical routes (passive instillation and direct injection [sub‐urothelial]) in patients with bladder cancer with all stages undergoing RC. For both routes, an initial dose confirmation stage will determine toxicity and recommended atezolizumab dosage, followed by a dose expansion stage to further evaluate safety and toxicity at the recommended dose. Endpoints We aim to investigate safety (primary) and preliminary activity (secondary) of intravesical atezolizumab delivered by passive instillation and direct injection into the tumour/bladder wall in patients with bladder urothelial cell carcinoma prior to RC. Primary endpoints include dose limiting toxicities and adverse events. Secondary endpoints include progression‐free survival, pathological complete response rate and treatment compliance. Exploratory endpoints include pharmacokinetic profile (assessed by serum and urine concentrations at prespecified timepoints), spatial analysis of atezolizumab distribution within RC tissue by imaging mass spectrometry and overall survival. Patients and Methods Atezolizumab will be administered intravesically by either passive instillation or direct injection into the tumour/bladder wall. Cohorts will receive either 600 mg or 1200 mg doses administered as a single dose or as multiple doses (weekly for 3–6 weeks). Trial Registration International Standard Randomised Controlled Trial Number: ISRCTN15842444 , registered 2 December 2022.

Most genetic variants associated with complex traits are hypothesized to regulate gene expression. To understand the genetics underlying gene expression variability, we characterized 14,324 RNA-sequencing samples from the Trans-Omics for Precision Medicine program and performed expression and splicing quantitative trait locus (e/sQTL) analyses in six tissues and cell types, including whole blood ( n = 6454) and lung ( n = 1291). We detected tens of thousands of secondary cis-e/sQTLs, showing that secondary cis-e/sQTL discovery remains unsaturated. We fine-mapped UK Biobank–derived genome-wide association study (GWAS) signals from 164 traits and identified e/sQTL colocalizations for 10,611 GWAS signals, including 7096 that colocalize with secondary e/sQTLs. Our results suggest that even larger e/sQTL analyses will uncover additional secondary e/sQTLs, further benefiting GWAS interpretation.

Background/Objectives: The PRO-CTCAE Average Composite Score (ACS), calculated as the mean of PRO-CTCAE composite scores, summarizes overall symptom and side effect burden. This study evaluated the test–retest reliability, responsiveness to change, known-groups validity, and sensitivity to group differences in the ACS. Methods: Analyses used the original PRO-CTCAE validation dataset, including lung (n = 174), breast (n = 222), and head and neck (n = 139) cancer cohorts, and data from the COMET-2 randomized phase III trial comparing cabozantinib (n = 53) and mitoxantrone–prednisone (n = 54) in men with previously treated prostate cancer. Test–retest reliability was assessed using intraclass correlation coefficients (ICCs) from two-way mixed-effects models for agreement. Responsiveness was evaluated by relating ACS change scores (Visit 1 minus follow-up Visit 2) to patient-reported global ratings of change (GRC; worsened, unchanged, or improved) using standardized response means (SRMs) and Jonckheere–Terpstra trend tests. Known-groups validity was examined by comparing mean ACS values between ECOG performance status groups (0–1 vs. 2–4). Sensitivity to treatment group differences was assessed using model-based area-under-the-curve (AUC) comparisons of longitudinal ACS trajectories. Results: Test–retest reliability was acceptable, with ICCs among GRC-defined stable patients of 0.80 (95% CI: 0.70–0.87) in lung cancer, 0.84 (95% CI: 0.77–0.89) in breast cancer, and 0.77 (95% CI: 0.63–0.86) in head and neck cancer; ICCs based on assessments completed one day apart ranged from 0.88 to 0.90. The ACS demonstrated responsiveness, with SRMs of 0.30/0.15/−0.37 (lung), 0.29/0.14/−0.40 (breast), and −0.01/−0.20/−0.56 (head/neck) for improved/no-change/worsened groups, respectively, and significant monotonic trends across GRC categories (all p < 0.01). Known-groups validity was supported by conceptually expected differences in ACS values across distinct levels of self-reported patient-reported physical functioning and ECOG performance status categories. Mean ACS values were lower among patients with good versus limited physical functioning (0.71 vs. 1.23 in lung cancer, 0.52 vs. 1.19 in breast cancer, and 0.69 vs. 1.29 in head and neck cancer) and among patients with ECOG PS 0–1 versus 2–4 (0.93 vs. 1.31, 0.74 vs. 1.22, and 0.90 vs. 1.06, respectively). In COMET-2, higher symptom burden was detected in the cabozantinib arm compared with the mitoxantrone–prednisone arm (AUC difference = 1.5, 95% CI: 0.2–2.8, p = 0.02). Conclusions: The ACS demonstrated acceptable test–retest reliability, responsiveness, and known-groups validity across multiple cancer populations. These findings support its use as a complementary summary measure of overall symptomatic adverse event burden alongside individual symptom-level analyses.

Abstract Improved understanding of how chimeric antigen receptor (CAR) and endogenous T‐cell phenotypes associate with progression‐free survival (PFS) is needed to individualize and improve immunotherapy outcomes in multiple myeloma (MM). We characterized and investigated the prognostic value of immune dynamics defined with multidimensional and computational flow cytometry in 258 bone marrow aspirates from 107 MM patients treated with idecabtagene vicleucel in the KarMMa trial. At screening, there was an association between longer PFS and increased percentages of PD1 + cytotoxic T cells and ICOS − TIGIT + Tregs. At Month 1 after infusion, the presence of >1% CAR‐T cells, a CD4/CD8 CAR‐T‐cell ratio >0.09, and greater abundance of non‐activated non‐cytolytic CAR‐T cells identified patients with longer PFS. Notably, 47 of the 115 endogenous T‐cell clusters were prognostic at the latest assessment performed after CAR‐T infusion. Lower percentages of ICOS + TIGIT − Tregs showed the strongest association with longer PFS. Altogether, this large dataset of dynamic immune profiling throughout treatment with anti‐B‐cell maturation antigen (anti‐BCMA) CAR‐T cells uncovered that the T‐cell composition prior to apheresis as well as CAR‐T and endogenous T‐cell phenotypes after infusion associates with PFS. These findings have potential for translation into routine laboratory practice for improved understanding of response and resistance to CAR‐T cells in relapsed/refractory MM.

Abstract Background This secondary analysis of a phase I clinical trial illustrates integrated summary and visualization of Common Terminology Criteria for Adverse Events (CTCAE) data and Patient-Reported Outcomes version of the CTCAE (PRO-CTCAE) data at baseline and through the first cycle of treatment for tolerability review during dose-cohort evaluation in a phase I trial. Methods This study uses data from a phase I clinical trial of patients with relapsed or refractory acute myeloid leukemia. Through iterative feedback from clinicians and statisticians, we developed a summary of cycle 1 PRO-CTCAE and CTCAE data for the first dose-level cohort. This summary is intended to demonstrate reporting that would be reviewed to inform a decision about proceeding to the next dose level in a dose escalation trial. Results Cycle 1 CTCAE and PRO-CTCAE data for 4 patients enrolled in the first dose cohort are summarized as narrative and tabular summaries and visualized using swimmer and butterfly plots. In this cohort, 3/4 (75%) patients had at least one CTCAE grade 3 or higher adverse event, and all 4 (100%) patients had at least one PRO-CTCAE composite score of 3 during cycle 1. All 4 (100%) patients had at least one symptom for which PRO-CTCAE suggested greater symptom burden than was reflected in CTCAE. Conclusions In this illustrative summary of a dose cohort, PRO-CTCAE complemented CTCAE reporting by capturing patient-reported symptomatic burden that was not always fully reflected by clinician-graded adverse events. Reviewing PRO-CTCAE and CTCAE data together during dose-cohort evaluation may enrich discussions on safety and tolerability in phase I trials.

Background: Hepatic stellate cells (HSCs) play a pivotal role in driving fibrosis during chronic liver injury. HSCs produce vast amounts of fibrotic proteins, causing endoplasmic reticulum (ER) stress and initiating the unfolded protein response (UPR). While the UPR is important for fibrogenesis, how signaling through UPR transducer Protein Kinase R-like ER Kinase (PERK) and its effectors impact HSC activation and fibrogenesis is unclear. Here, we sought to uncover the role of PERK and its effector GADD45A in liver fibrosis. Methods: PERK–GADD45A signaling was assessed in primary and immortalized HSCs treated with TGFβ, and mouse models of fibrosis. Genetic and pharmacological disruption of PERK or GADD45A was used to assess the role of PERK or GADD45A in HSC activation, proliferation, and fibrogenesis. HSC-specific Gadd45a -null mice were utilized to investigate the role of GADD45A on CCl 4 -induced fibrosis. Results: We found that TGFβ-induction of collagen I drives activation of PERK signaling in HSCs. Furthermore, loss or inhibition of PERK limits long-term HSC activation as illustrated by reduced levels of collagen I and fibronectin, impaired collagen I deposition, and reduced cell proliferation in vitro. Next, we show that PERK signaling induces expression of GADD45A during HSC activation, and loss of GADD45A disrupts HSC activation and expression of proliferation and cell-cycle-associated genes in immortalized and primary HSCs. Finally, HSC-specific GADD4Aa loss limits CCl 4 -driven fibrogenesis in vivo. Conclusion: PERK signaling is critical for HSC activation, and loss of the PERK downstream effector GADD45A limits fibrosis progression. Disruption of HSC activation and proliferation, coupled with dysregulation of cell-cycle-associated genes upon PERK or GADD45A loss, suggests that PERK–GADD45A signaling impacts multiple facets of HSC pathophysiology.