Citations

Abstract Newer approaches to control alloreactivity may produce similar transplant outcomes using HLA-mismatched donors vs HLA-matched unrelated donors (MUD). However, prospective comparisons are lacking. BMT CTN 1702 used a donor search prognosis score to assign patients to an 8/8 HLA MUD or the center’s preference of haploidentical related donors (HAPLO), mismatched unrelated donors (MMUD), or umbilical cord blood (UCB). Outcomes of MUD were compared to HAPLO, MMUD, and UCB transplantation after adjusting for covariates. Patients (n = 1179 [93% adults]) underwent transplantation with MUD (n = 772), HAPLO (n = 254), MMUD (n = 112), and UCB (n = 41) at a median of 3.7, 3.4, 3.9, and 3.8 months from enrollment. Posttransplant cyclophosphamide (PTCy) was used in 23.9%, 83.9%, 65.2%, and 0% of MUD, HAPLO, MMUD, and UCB. In multivariate analyses, compared to MUD, survival was lower for UCB (hazard ratio [HR], 2.65; P< .001) but not statistically different for HAPLO and MMUD (HRs, 1.08 and 1.18, respectively). Relapse risk was not significantly different by donor, but treatment-related mortality (HR, 3.31; P< .001) and disease-free survival (HR, 1.99; P = .002) were inferior for UCB but not different for HAPLO and MMUD than MUD. In patients who received PTCy, HAPLO and MMUD were associated with increased grade 3 or 4 acute graft-versus-host disease (GVHD; HR, 2.39 [P = .017] and 2.53 [P = .038], respectively) and chronic GVHD (HR, 1.71 for both; P = .028 and .080) than MUD, but other outcomes were not different. HAPLO or MMUD may be used to expedite transplantation when finding MUD is unlikely. This study was registered at www.clinicaltrials.gov as NCT03904134.

Chimeric antigen receptor (CAR) T cell therapy faces many challenges against solid tumors including T cell exhaustion and poor CAR durability. Here, we show that engaging the CAR T cell endogenous T cell receptor (TCR) using an oncolytic virus enhances CAR T cell functionality, durability, and therapy. Upon combination therapy of solid tumors with CAR T cells and vesicular stomatitis virus (VSV), a subpopulation of antiviral, TCR-primed CAR T cells was generated with enhanced effector functions, altered activation states, and differential gene and protein expression when compared to non–TCR-primed CAR T cells. Single-cell RNA sequencing showed clonal expansion of anti-VSV CAR T cells and enhancement of effector-associated genes with VSV-mediated CAR T cell expansion. CD4 T cells played a pivotal role in the development of these TCR-primed CAR T cells. These results provide a strong rationale both for a novel use of systemic oncolytic virotherapy and for directly exploiting the CAR T cell TCR to fine tune the CAR T cell phenotype and function.

Purpose: Neuroendocrine neoplasms (NENs) are increasingly recognized to have a hereditary predilection, yet the prevalence and clinical relevance of pathogenic germline variants (PGVs) in unselected patients with NEN remain poorly defined. This prospective, multicenter study aimed to evaluate the prevalence and clinical utility of PGVs through universal multigene panel testing in a diverse cohort of patients with NENs. Patients and Methods: Between 2018 and 2024, we enrolled unselected patients with NENs from 3 Mayo Clinic Cancer Centers. Germline genetic testing was performed using a next-generation sequencing panel of up to 84 cancer predisposition genes. Patients were not selected based on age, disease stage, ethnicity, or family history. Variants were classified as PGVs, variants of uncertain significance (VUS), or negative. Clinical and demographic data were analyzed descriptively. Results: Among 88 patients, PGVs were identified in 15.9% (n=14), most frequently in high- or moderate-penetrance genes including MEN1 , CHEK2 , MITF , and MUTYH . PGVs were most commonly found in pancreatic NENs [n=12/55 (21.8%)], followed by small bowel NENs [n=2/20 (10%)], with no PGVs detected in lung NENs. Mismatch repair (MMR) gene alterations were identified in 5.7% of patients, including 1 MLH1 PGV and 4 MSH2/MSH6 VUS, 2 of which demonstrated MMR deficiency by protein testing. VUS were reported in 34.1% of patients. Notably, 35.7% of PGV-positive patients did not meet current NCCN or ACMG testing criteria, and 53.9% had PGVs in genes outside of cancer-specific guideline recommendations. Conclusions: Universal germline testing in unselected patients with NEN identified clinically relevant PGVs in over 15% of cases. These findings support broader genetic testing approaches to guide treatment, enhance familial risk assessment, and inform cascade testing—regardless of traditional clinical selection criteria.

Background: Acetabular overcoverage (pincer morphology) has been suggested to be both a source of pain and dysfunction and potentially protective against osteoarthritic change. Purpose: To compare the minimum 5-year clinical outcomes of patients undergoing primary hip arthroscopic labral repair with a lateral center edge angle (LCEA) of ≥40° as compared with nondysplastic controls with an LCEA of 25° to 40°. Study Design: Cohort study; Level of evidence, 3. Methods: A retrospective review was performed to identify all patients who underwent primary hip arthroscopic labral repair between 2009 and 2019 at a single academic institution. Patients with an LCEA of ≥40° (pincer) were propensity-matched to nondysplastic controls with an LCEA of 25° to 40° on a 1-to-2 basis by sex, age, body mass index, and surgery year. Patient-reported outcome measures (PROMs)—including visual analog scale, Tegner activity score, modified Harris Hip Score, International Hip Outcome Tool (iHOT-12), and Hip Outcome Score were analyzed—as were reoperations and conversions to total hip arthroplasty (THA). Results: A total of 55 patients with pincer morphology (preoperative LCEA: 41.9°± 2.1°) were matched to 110 nondysplastic controls (LCEA: 31.2°± 4.1°), resulting in a total of 165 hips in 163 patients (67% women, mean age: 37.7 ± 9 years). Pincer patients were corrected to a mean postoperative LCEA of 38.7°± 4.1º ( P < .001), with 22 pincer patients having residual overcoverage; namely, a postoperative LCEA ≥40° (range, 40°-45.8°). There were no differences between cohorts regarding intraoperative characteristics—including femoral and acetabular Outerbridge grade—as well as capsulotomy type and the presence of capsular repair ( P ≥ .210). At a mean 8-year follow-up (range, 5.1-13.2), there was no difference in any postoperative PROMs between pincers and controls ( P ≥ .215) and no difference in PROMs between patients with residual overcoverage and pincer patients with a postoperatively normalized LCEA ( P ≥ .291). At final follow-up, 4 patients in the pincer cohort (7%) and 21 controls (19%) converted to THA ( P = .046). Conclusion: Patients with lateral acetabular overcoverage demonstrated similar and satisfactory postoperative PROMs at a minimum 5-year follow-up compared with propensity-matched nondysplastic controls, regardless of whether the LCEA was corrected to <40°. Of note, nondysplastic controls demonstrated a higher rate of conversion to THA, suggesting a potentially chondroprotective role for acetabular overcoverage.

LBA7000 Background: ~40% of DLBCL pts are not cured with first-line (1L) R-CHOP, underscoring a significant unmet need for more effective 1L regimens. Tafa (anti-CD19 mAb) + Len-R-CHOP in the phase 1b First-MIND study demonstrated safety and efficacy in pts with newly diagnosed disease. frontMIND, a phase 3, double-blind, placebo-controlled study, compared Tafa-Len-R-CHOP vs R-CHOP in pts with high-risk aggressive BCLs. Methods: Pts aged 18–80 y with newly diagnosed, high-intermediate/high-risk DLBCL or HGBL (IPI 3–5, aaIPI 2–3 if ≤60 y) and ECOG PS 0–2 were randomized 1:1 to Tafa-Len-R-CHOP or R-CHOP. Primary endpoint was investigator-assessed PFS; secondary endpoints included: EFS, OS, CR, ORR, safety. Results: At primary analysis (data cutoff Oct 20, 2025), 899 pts were randomized to Tafa-Len-R-CHOP (n=448) or R-CHOP (n=451); baseline characteristics were similar between arms. With a median follow-up of 35.2 mo, Tafa-Len-R-CHOP achieved a statistically significant improvement in PFS vs R-CHOP (HR 0.75 [95% CI: 0.59, 0.96]; P =0.019) in the overall population; in pts with centrally confirmed lymphoma subtypes (n=773), PFS HR was 0.68 (95% CI: 0.52, 0.88) and 24-mo PFS was 72.7% vs 62.2%. PFS benefit was observed with Tafa-Len-R-CHOP in both molecular COO subtypes, ABC and GCB (data will be presented). Tafa-Len-R-CHOP significantly improved EFS vs R-CHOP; CR and ORR were similar between arms and HR for OS was 0.85 (final OS planned at 5y) (Table). Any-grade TEAEs were similar in treatment arms (98.6% vs 97.1%); more grade ≥3 TEAEs occurred with Tafa-Len-R-CHOP vs R-CHOP (86.7% vs 76.1%). Discontinuations due to TEAEs occurred in 25.7% vs 17.9% and deaths due to TEAEs in 5.9% vs 3.8% of pts for Tafa-Len-R-CHOP vs R-CHOP. Overall, there were fewer deaths with Tafa-Len-R-CHOP vs R-CHOP (18.5% vs 21.7%). Conclusions: The primary endpoint of frontMIND was met; Tafa-Len-R-CHOP resulted in a significant 25% reduction in risk of disease progression or death compared with R-CHOP, with an 8.2% difference in 24-month PFS rate in the overall population and 10.5% difference in pts with centrally confirmed lymphoma subtypes. TEAEs were manageable and consistent with the expected safety profile. Tafa-Len-R-CHOP represents a potential new 1L standard of care for pts with both COO subtypes of high-risk DLBCL or HGBL. Clinical trial information: NCT04824092 . Efficacy outcomes by treatment arm.* Variable Tafa-Len-R-CHOP(n=448) R-CHOP(n=451) HR or OR(95% CI) P value PFS, # events (%) † 121 (27.0) 155 (34.4) 0.75 (0.59, 0.96) 0.019 PFS rate at 24 mo, % 71.1 62.9 − − PFS rate at 36 mo, % 67.3 60.7 − − EFS, # events (%) 154 (34.4) 191 (42.4) 0.79 (0.64, 0.97) 0.026 OS, # events (%) 82 (18.3) 95 (21.1) 0.85 (0.63, 1.14) 0.270 CR at EOT, n (%) 292 (65.2) 294 (65.2) 0.998 (0.76, 1.31) 0.987 ‡ ORR at EOT, n (%) 360 (80.4) 343 (76.1) 1.290 (0.94, 1.78) 0.120 ‡ *Investigator-assessed. † Progressive disease or death from any cause. ‡ Nominal P value.

Abstract Background Indocyanine green (ICG) fluorescence imaging is increasingly incorporated into robotic liver resections (RLR), yet clinical practice regarding timing, dosage, and staining techniques is divergent. Aims This international expert survey aimed to characterize current practices for ICG in RLR. Methods Experts in RLR were invited to participate based on surgical volume (experience of 50 RLR and 30 annual RLR). A 74-item questionnaire was developed following a literature search and reviewed by a steering committee. The survey addressed indications, timing, dosage, imaging technology, benefits, limitations, training, and future directions of ICG use. Responses collected between September and October 2025 were analyzed. Results Seventy experts from 19 countries completed the survey, corresponding to an 88% response rate. Centers performed a median of 180 annual liver resections, including 55 RLR. Most experts used ICG (96%) during RLR. Anatomical demarcation (91%), tumor localization (60%), and biliary anatomy assessment (60%) were the most frequent indications. 60% of experts use preoperative ICG, while intraoperative ICG is mainly administered for demarcation (67%) and biliary tract visualization (40%). Considerable heterogeneity exists in dosage, timing, and staining techniques, particularly in cirrhotic livers and for tumor localization. Only half of the experts had standard operating procedures, whereas 64% expressed the need for a higher degree of standardization. Reported benefits of ICG use included improved anatomical orientation, margin assessment, lesion detection, and support during complex resections. Perceived limitations included background fluorescence, tissue penetration and variable staining in diseased parenchyma. 80% anticipated improved outcomes with combined ICG and three-dimensional image-guidance. Conclusion ICG fluorescence is widely used in RLR and is an important cornerstone for precision-guided robotic liver surgery. Standardized clinical practice guidelines, structured training, and technological improvements in imaging and navigation systems are claimed to optimize its clinical use.

Background The pathophysiology of CS is complex and is associated with increased inflammation and impaired vascular tone. Corticosteroids are recommended in septic shock and have been proposed as a potential treatment for other types of shock. Objectives We sought to evaluate the clinical outcomes associated with early corticosteroid use in patients with cardiogenic shock (CS). Methods Using a nationally representative database including over 1000 hospitals, we identified adults ≥18 years of age admitted from 2015–2023 with a diagnosis of CS. Patients with adrenal insufficiency, chronic rheumatologic conditions, COVID-19 infection and acute COPD exacerbation were excluded. Using inverse probability treatment weighting (IPTW), we assessed for the association of receiving early corticosteroids (within the first 2 days of admission) versus no early corticosteroids and in-hospital mortality. Results Of the 167,721 identified patients with CS, the mean (SD) age was 65.5 (±15.2) years and 35.0% were women. A total of 13.2% received any corticosteroid within the first 2 days of admission. The most common corticosteroid was hydrocortisone (73.9%). Mortality for those receiving and not receiving early corticosteroids was 48.8% and 29.6% ( p < 0.001), respectively. After IPTW, early corticosteroid use remained associated with a 3.1% (95% confidence interval [CI]: 2.4% to 3.8%, p < 0.001) higher mortality. Among patients with CS and concomitant sepsis, 27.6% received early corticosteroids, which was similarly associated with a higher mortality (weighted mean 5.8% [95% CI: 4.6% to 7.0%, p < 0.001]). Conclusions Approximately 1 in 7 patients with CS received corticosteroids early during their admission, which was associated with higher in-hospital mortality.

ABSTRACT Purpose To explore the opioid decision‐making process of prescribers in primary care, surgery, and subspecialty pain management. Methods This was a multistage qualitative‐qualitative study with clinicians involved in opioid prescribing and management from a single healthcare organization with locations in Minnesota, Florida, Arizona, and Wisconsin. Clinicians in this study included physicians, nurse practitioners (NPs), and physician assistants (PAs) practicing in primary care, surgery, or pain medicine. The interview guide was organized in three domains of a conceptual model for opioid use: (1) prescriber characteristics, (2) patient characteristics, and (3) practice environment characteristics. Individual interviews ( N = 20) were performed first, and data were summarized using a rapid template‐based approach. Subsequently, focus groups (FGs) ( N = 4) were conducted with an additional 21 clinicians to confirm and explore interview results. Data from interviews and FGs were analyzed using a common codebook. Results Findings were organized as decision factors into the three domains. Factors in the prescriber domain included characteristics such as formal pain management training, as well as factors that influenced knowledge and beliefs (e.g., advice from or observation of supervising clinicians and expert colleagues). Decision factors in the patient domain included patient pain etiology, comorbid medical or mental health conditions, and demographic characteristics. Clinicians' perceptions of these factors, such as viewing older age as having lesser risk for opioid misuse, influenced prescribing decisions. Clinicians also described challenges associated with “legacy patients” whose therapy was previously managed by a different clinician. Primary care clinicians, in particular, expressed difficulties managing post‐surgical or trauma‐related pain after care transition. Relevant decision factors reported by prescribers in the practice environment domain included guidelines and practice oversight. Most participants reported practicing in an environment that promoted conservative opioid use and having access to standardized institutional guidelines that reduced perceived decision‐making burden. Clinicians described how they used prescribing guidelines to help them communicate with patients about opioid use and prescribing decisions. Conclusions Intersecting prescriber, patient, and practice environment factors shape opioid analgesic prescribing decisions. Available resources in the practice environment, including peer input and institutional guidelines, may support clinician decision‐making and conversations with patients at the point of care, including in cases where patients have complex histories or personal characteristics that influence decision making.

PURPOSE In immunoglobulin light chain (AL) amyloidosis, amyloid fibrils cause organ dysfunction. Anselamimab, a monoclonal antibody, selectively binds to amyloid fibrils, accelerating their clearance. METHODS Newly diagnosed patients with European modification of Mayo 2004 stage IIIa or IIIb AL amyloidosis were randomly assigned to receive anselamimab or placebo with cyclophosphamide, bortezomib, and dexamethasone (with or without daratumumab). The primary end point was a hierarchical composite of time to all-cause mortality (ACM) and frequency of cardiovascular hospitalizations (CVHs), analyzed using the Finkelstein-Schoenfeld test and win ratio estimation. RESULTS Among 406 randomly assigned patients, the primary end point win ratio for anselamimab versus placebo was 1.11 (95% CI, 0.83, 1.50; P = .332) and the hazard ratio (HR) for ACM was 0.80 (95% CI, 0.57, 1.13; P = .290). CVH rates in the anselamimab and placebo groups were 0.59 (95% CI, 0.42, 0.83) and 0.89 (95% CI, 0.55, 1.43), respectively ( P = .145). Among patients with kappa isotype (n = 72), the win ratio was 2.06 (95% CI, 0.98, 4.31; P = .100) and anselamimab reduced ACM by 62% versus placebo (HR, 0.38; 95% CI, 0.17 to 0.86; nominal P = .012), and CVH by 71% (IRR, 0.29; 95% CI, 0.10 to 0.87; nominal P = .028) with improvements in Kansas City Cardiomyopathy Questionnaire-Overall Score. There was no clinical benefit observed in the lambda population. Anselamimab was generally well-tolerated; safety data were comparable between treatment arms overall. CONCLUSION Treatment with anselamimab, an antifibril antibody used alongside antiplasma cell dyscrasia therapy, while not meeting the primary end point in the overall population, significantly improved ACM and CVH in patients with kappa AL, potentially offering a new therapeutic option for this isotype.