Citations

11059 Background: Payments from the drug industry to oncologists are common and influence physicians’ prescribing decisions. However, whether payments affect the likelihood that patients receive optimal cancer treatment has not been assessed. Methods: This was a population-based cohort study. We used fee-for-service Medicare claims to identify patients with incident cancer diagnosis (new cancer diagnosis code after >= 1 year with no cancer diagnosis codes) from 2014-2020. We used National Comprehensive Cancer Network (NCCN) Guidelines to identify treatment scenarios (e.g., metastatic melanoma, stage III colon adjuvant therapy) with variation in the clinical benefit among recommended treatment options. The patient cohort corresponding to each scenario was identified using claims. We used NCCN Guidelines to identify the “optimal” treatment for each scenario (defined as the designated “preferred” treatment, with NCCN Evidence Blocks scores used for tiebreaks) at each time point across the study period. The primary outcome was whether a patient received the treatment that was, as of their diagnosis date, the optimal treatment for their cancer (vs. any non-optimal treatment). The primary exposure[s] were whether a patient’s medical oncologist received personal (“general”) payments (source: linked Open Payments data) related to 1) optimal treatment or 2) any non-optimal treatment, during the year prior to the patient’s cancer diagnosis. We fit Poisson-family generalized estimating equations, with physician-level clustering and adjustment for scenario, year, and patient characteristics, to estimate the relative risk (RR) of optimal treatment. Results: There were 14 clinical scenarios comprising 15,835 patients. There were 3,429 (21.7%) patients whose oncologist received payment for the optimal treatment, 4,891 (30.9%) for non-optimal payments, and 1,993 (12.6%) to both payment types. Oncologist receipt of payment for optimal treatment was associated with a greater likelihood (RR=1.07, 95%CI:1.01-1.13), and payment for non-optimal treatment was associated with lower likelihood (RR= 0.94, 95%CI:0.89-0.98) of patients receiving optimal treatment. Associations became stronger as payment dollar value increased; for optimal payments ≥$10,000, RR=1.26 (95%CI:1.02-1.57), and for non-optimal payments ≥$10,000, RR=0.70 (95%CI: 0.49-1.00). An estimated 41.6% of unexposed patients received optimal treatment; versus 52.6%, 29.3%, and 33.8% among patients exposed to ≥$10,000 of payments for optimal treatment only, ≥$10,000 non-optimal payments only, and ≥$10,000 of both payment types, respectively. Conclusions: Industry payments related to the optimal cancer treatment were associated with increased use of the optimal treatment. However, payments related to non-optimal treatments were more common and were associated with decreased use of optimal treatment.

Background: Despite the growing clinical relevance of obesity in the context of multiligament knee injuries, there remains a paucity of data evaluating patient-reported outcomes in this population. Purpose: To compare clinical and functional outcomes, including postoperative patient-reported outcome measures (PROMs) and complication/revision rates, of multiligament knee reconstruction (MLKR) in individuals with a body mass index (BMI) >30 kg/m 2 versus <30 kg/m 2 at a minimum 2-year follow-up. Study Design: Case series; Level of evidence, 4. Methods: A retrospective review was performed to identify all patients who underwent MLKR between 2001 and 2022 at a single institution. Patients with a BMI >30 kg/m 2 were propensity-matched to patients with a BMI <30 kg/m 2 on a 1:1 basis by age, sex, laterality, and Schenck classification (knee dislocation). Medical records were reviewed for patient characteristics, time to surgery, year of surgery, number and type of ligament interventions, graft choice, single versus staged reconstruction, and concomitant injuries. Postoperative clinical examination findings and PROMs for each cohort, including visual analog scale score, Tegner activity scale score, Lysholm score, and International Knee Documentation Committee (IKDC) subjective score, were analyzed and compared. Postoperative complication and revision rates were evaluated and compared. Results: Of 158 patients, 79 patients with a BMI <30 kg/m 2 (mean age, 31.0 ± 11.5 years; mean BMI, 25.8 ± 3.0 kg/m 2 ) were matched to 79 patients with a BMI >30 kg/m 2 (mean age, 32.8 ± 9.5 years; mean BMI, 37.1 ± 5.8 kg/m 2 ). There were no significant differences between cohorts regarding age, sex, laterality, and Schenck classification ( P ≥ .100); however, patients in the BMI >30 kg/m 2 group had greater numbers of posterior cruciate ligament reconstruction. The mean follow-up was 7.5 ± 4.8 years for the BMI <30 kg/m 2 cohort and 7.2 ± 4.8 years for the BMI >30 kg/m 2 cohort ( P = .229). Patients with a lower BMI (<30 kg/m 2 ) had significantly better postoperative mean IKDC (79.3 ± 18.7 vs 67.9 ± 21.2; P = .004), Lysholm (85.1 ± 17.1 vs 75.7 ± 21.0; P = .007), and Tegner (5.1 ± 2.0 vs 4.4 ± 1.7; P = .041) scores. The BMI >30 kg/m 2 group also had significantly more postoperative complications ( P = .028). However, there was no significant difference between the 2 cohorts in terms of reoperation rate or conversion to total knee arthroplasty ( P ≥ .189). Conclusion: Patients who undergo MLKR and have a BMI >30 kg/m 2 demonstrate significantly decreased postoperative PROMs when compared to patients with a BMI <30 kg/m 2 . Increasing BMI significantly increased the incidence of complication rates after MLKR.

Abstract TRIM29 (Tripartite Motif-Containing Protein 29), also known as ATDC (Ataxia-Telangiectasia Group D-Complementing Protein), is an E3 ubiquitin ligase frequently upregulated in muscle-invasive bladder cancer (MIBC). We have previously shown that TRIM29 overexpression in a genetically engineered mouse model (GEMM) is sufficient to drive development of MIBC. We have also shown that TRIM29 is enriched in basal bladder cancer subtypes and is part of a TP63-regulated program that promotes migration and invasive progression. Prior studies suggest that Keratin 5/14 (K5+/K14+) expressing basal-stem progenitor cells in the urothelium are the cells of origin for MIBC in mice. However, whether Trim29 expression in these basal urothelial cells is required for MIBC development has not been established. In this study, we find that Trim29 expression in K5+ basal cells is linked to the inflammatory response and is critical for bladder tumor formation and invasive progression. We show that urothelial TRIM29 expression is enhanced during inflammation in humans and under inflammatory and genotoxic stress in mice. Knockout (KO) of Trim29 in the K5+ basal urothelium of a GEMM exposed to a bladder-specific chemical carcinogen blocked MIBC development. Further, urothelial Trim29 KO enriches immune cell recruitment to the bladder and upregulates STING and inflammatory signaling in mouse and human bladder cancers. These data reveal a critical role for TRIM29 in immunomodulation of the bladder tumor microenvironment (TME), which may act in concert with pro-migratory basal gene programs to expedite MIBC development.

Abstract The use of chimeric antigen receptor (CAR) T-cell therapy is increasing for adult B-cell acute lymphoblastic leukemia (B-ALL), with 3 CD19 CAR T-cell products commercially available. Several key clinical questions related to best practices for CAR T-cell administration in this population exist, and limited prospective randomized trials have been conducted to fill these knowledge gaps. Thus, to help guide clinical practice, we conducted a modified Delphi study to develop and validate consensus recommendations on the administration of commercially available CAR T-cell therapy for adults with B-ALL. Consensus panelists (n = 9) included principal investigators (PIs) from Real World Outcomes Collaborative of CAR T-Cell Therapy in Adult ALL (ROCCA) consortium sites and were selected based on expertise and CAR T-cell center volume. Final panel consensus recommendations were distributed for rating by the remaining PIs from ROCCA consortium sites, which served as the validation group (n = 27). Consensus topics included patient selection, bridging and pre–CAR T-cell leukemia staging, lymphodepletion, and CAR T-cell treatment setting, specific toxicity prevention and management, post–CAR T-cell response assessment and disease monitoring, and the role of consolidation and/or maintenance therapies after CAR T-cell therapy. Initially, 58 recommendation statements were evaluated for consensus. After 2 panel meetings, a total of 34 statements achieved consensus rating among the expert panel. After rating by the validation group, all but 1 recommendation statement continued to meet consensus, for a total of 33 consensus recommendation statements on the administration of CAR T-cell therapy in adult B-ALL.

Expert consensus recommendations from 21 academic centers were established for appropriate radiography utilization at 12 potentially low-yield anatomic sites through a multidisciplinary process endorsed by six major American medical societies.

Introduction Lynch syndrome (LS) is a hereditary cancer syndrome that increases risk for colorectal and other cancers. We hypothesize that vaccines against tumor-associated antigens CEA, MUC1, and brachyury, simultaneously delivered in an adenovirus serotype-5 vector (Tri-Ad5) combined with the immune-enhancing IL-15 receptor superagonist nogapendekin-alfa-inbakicept (NAI) will reduce the incidence of colorectal neoplasms in LS carriers. Methods In this ongoing phase IIB double-blind placebo-controlled trial, two open-label safety phases (SPs) assessed safety of Tri-Ad5 alone (SP1, n=10) and with added NAI (SP2, n=10). A randomized controlled trial (RCT) follows the SPs. After baseline colonoscopy, vaccine dosing occurs at weeks 0, 4 and 8; Tri-Ad5 alone in SP1 and Tri-Ad5 plus NAI in SP2, with identical boosters at Week 52. The RCT phase participants (n=138) were randomized to receive Tri-Ad5 plus NAI or placebo. All participants complete colonoscopy at Weeks 52 and 104 for assessment of the primary endpoint: cumulative colorectal neoplasm incidence. Secondary endpoints include safety, tolerability, and immunogenicity. Results All 20 SP participants (median age 57.5 (range 42–75), 70% female, 15% minority) received all prime and booster series. SP1 participants reported 139 adverse events (AEs) and SP2 participants reported 178. AEs were predominantly grade 1; no treatment-related serious adverse events (SAEs) occurred. The most common treatment-related AEs were reactogenic events including grade 3 rash (without skin necrosis or breakdown) at NAI injection site (100% of SP2 participants). The RCT phase (n=138) recently completed accrual. Discussion In LS carriers without active cancer, the combination of Tri-Ad5 + NAI was well-tolerated; the RCT phase is ongoing. Clinical Trial Registration https://clinicaltrials.gov/study/ , identifier NCT05419011.

Abstract Rationale Sleep is an important dimension of COPD symptomology. Poor self-reported sleep quality has been independently associated with increased exacerbation risk and worse quality of life. There is limited evidence around the longitudinal sleep quality of patients with smoking-related lung disease. Methods Using the SPIROMICS longitudinal cohort of heavy smokers, we used group-based trajectory modeling to understand sleep quality over time as measured by serial retests of the Pittsburgh Sleep Quality Index (PSQI). We considered all participants of Black or Non-Hispanic White race who completed the PSQI in Visits 1-4, a span of 3 years. We considered race, gender, and social environmental exposures as time-stable risk factors for trajectory group membership. We adjusted for age, lung function, mood symptoms and self-reported COPD symptom severity were considered as time-varying factors. We selected the number of trajectory groups by minimizing Bayesian Information Criteria and polynomial order by maximizing the significance of exponential terms. For quality assurance we calculated average posterior probability of correct group assignment. Calculations were performed by complete case analysis and multiple imputation with chained equations. Results We analyzed 2,838 participants yielding 76,153 usable observations. Overall, 39.2% of participants had complete observations for all variables of interest at every measured visit, and 60.8% had at least one relevant observation missing. The largest single source of missingness in our dataset was the comorbidity count, for which 44% of participants had a missing observation. We identified two major trajectory groups. In one group, the PSQI was persistently high with little variation over time, containing 77.7% of the overall study population. The second group had low PSQI at baseline but experienced wide fluctuation over time. Risk factors for persistently poor sleep included female gender, Black race, and more adverse social conditions at either the neighborhood or individual level (Table). The average posterior probability of correct group assignment was 94.6% among the Low Variable group and 89.5% among the Persistent High group. Results were similar by complete case and imputed analysis, save that BMI did not independently predict group membership in the latter. Conclusion Historically underserved groups are at long term risk for poor sleep outcomes in smoking-related lung disease, even among those who are highly motivated and participate in clinical research. More work is needed to ensure equitable access to sleep medicine in order to improve the quality of care in COPD. This abstract is funded by: Nina Ireland Program for Lung Health

Abstract Oligodendroglioma is a primary central nervous system tumor classified by the presence of isocitrate dehydrogenase (IDH) mutations and codeletion of 1p/19q. Here we describe the generation of an IDH-mutant 1p/19q-codeleted oligodendroglioma mouse model using in utero electroporation. We identified IDH1 R132H , PIK3CA E545K , Cic KO , Fubp1 KO and Cdkn2a KO as the optimal combination (termed Oligo Cdkn2a ) to drive fully penetrant tumors that histologically resemble human grade II/III IDH-mutant, 1p/19q-codeleted oligodendroglioma. Replacing Cdkn2a with Trp53 loss in this mouse model shifted tumor histology towards high grade astrocytoma. Oligo Cdkn2a tumors displayed metabolic and transcriptional changes associated with IDH and CIC mutations, and single cell sequencing identified a bias towards oligodendrocyte differentiation compared to an IDH wild-type glioblastoma mouse model. Oligo Cdkn2a tumors represent the first mouse model system to recapitulate the genetic, histological and transcriptional features of human IDH-mutant 1p/19q-codeleted oligodendrogliomas, offering a platform to further dissect tumor biology and test new therapeutic strategies.

Importance Standard adjuvant therapy for human papillomavirus–associated oropharyngeal squamous cell carcinoma (HPV-OPSCC) is radiation therapy 60 Gy with or without cisplatin delivered in 30 fractions during 6 weeks. A phase 3 randomized clinical trial demonstrated decreased toxic effects and improved patient-reported outcomes with de-escalated adjuvant radiation therapy (DART) compared with standard therapy; however, outcomes for patients treated in the clinical practice setting following trial adoption remain unknown. Objective To compare characteristics and oncologic outcomes of patients treated with DART during clinical trials (on study) and in clinical practice settings (off study) and report progression-free survival (PFS) by risk category. Design, Setting, and Participants This retrospective cohort study included patients treated with DART in the MC1273 and MC1675 trials and in clinical practice after study completion at a multisite tertiary care center. Patients with surgically resectable HPV-OPSCC who underwent margin-negative resection between August 20, 2013, and March 21, 2023, and were treated with DART were included in the analysis. Those with prior head and neck cancer, pT0 or pT4 disease, unknown HPV status, metastatic disease at presentation, synchronous primary tumors, induction chemotherapy, or treatment at an outside institution were excluded. Data were analyzed from July 1, 2024, to July 18, 2025. Interventions DART consisting of 30 to 36 Gy in 1.5- to 1.8-Gy fractions twice daily with docetaxel 15 mg/m 2 on days 1 and 8. Main Outcomes and Measures Progression-free survival as measured via Kaplan-Meier analysis. Results A total of 282 patients were included in the analysis: 176 (62.4%) in the on-study group and 106 (37.6%) in the off-study group (252 [89.4%] male; mean [SD] age, 59.1 [9.3] years). Both groups were predominantly male (157 [89.2%] and 95 [89.6%], respectively) and consisted mostly of never smokers (118 [67.0%] and 62 [58.5%], respectively). Pathologic features were similar between groups except for nodal stage (pN1: 155 [88.1%] on study vs 102 [96.2%] off study; pN2: 21 [11.9%] on study vs 4 [3.8%] off study; P = .02). The median follow-up times were 5.2 years (95% CI, 5.2-5.8 years) in the on-study group and 2.2 years (95% CI, 1.9-2.4 years) in the off-study group. Two-year PFS was similar (93% [95% CI, 88%-97%] on study vs 93% [95% CI, 88%-99%] off study). For patients with pN1 and no extranodal extension (ENE), 2- and 5-year PFS were 97% (95% CI, 93%-100%) and 96% (95% CI, 92%-100%), respectively. Patients with pN1 and ENE had a 2- and 5-year PFS of 93% (95% CI, 89%-98%) and 87% (95% CI, 81%-94%), respectively. Conclusions and Relevance In this retrospective cohort study of patients receiving DART on and off study, oncologic outcomes were similar between the 2 groups. Fewer patients with pN2 received DART off study, given the interim results of MC1675. Patients with pN1 and no ENE treated with DART had excellent 2- and 5-year PFS, supporting DART as a compelling treatment option in well-selected patients. An additional study that is currently underway will evaluate biomarker risk-stratified treatment of patients with pN1 and ENE receiving DART.

PURPOSE We tested the hypothesis that adding metastasis-directed therapy (MDT) to standard-of-care (SOC) systemic therapy improves progression-free survival (PFS) among patients with oligometastatic disease. METHODS EXTEND was a multicenter randomized phase II trial. Patients with 1-5 metastases were randomly assigned to MDT + SOC versus SOC in one of the six baskets (breast, pancreas, kidney, two prostate baskets, and an other basket) with basket-specific stratification and powering. PFS, the primary end point, was prespecified in the per-protocol set within each basket, across all baskets, and across all baskets excluding the prostate baskets. Exploratory end points included circulating tumor DNA (ctDNA) and immune profiling. RESULTS From 2018 through 2023, 521 patients were screened, 350 were randomly assigned, and 334 were analyzed per protocol (MDT + SOC, n = 166; SOC, n = 168). Radiotherapy was used as MDT for 98% of metastases (370/379). Overall, after a median follow-up of 53 months, PFS was improved with MDT + SOC (hazard ratio [HR], 0.54 [95% CI, 0.41 to 0.72], P < .001). Similarly, PFS was improved when excluding the prostate baskets (HR, 0.60 [95% CI, 0.40 to 0.89]). Within each basket, PFS superiority was identified for the pancreas, prostate, and other baskets, whereas the breast and kidney baskets were inconclusive. At enrollment, detectable ctDNA correlated with shorter PFS and survival; by contrast, ctDNA clearance 3 months postenrollment correlated with improved survival. MDT + SOC-induced systemic immune activation was most pronounced among baskets demonstrating PFS superiority. CONCLUSION The phase II EXTEND trial supports the addition of MDT to SOC for oligometastatic disease. Histology-specific efficacy signals were identified for phase III testing. Translational insights suggest the potential for optimizing the definition of oligometastasis using ctDNA and point to systemic immune responses as a possible mechanism of benefit from MDT.