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e22006 Background: Metastasectomy is recommended for select pediatric patients with osteosarcoma with resectable pulmonary parenchymal metastases. It is unclear whether pulmonary metastasectomy confers the same benefit to patients with hilar or mediastinal lymph node metastases (LNM). This study aims to characterize pediatric patients with osteosarcoma with thoracic LNM and their outcomes compared to those with only pulmonary parenchymal metastasis. Methods: This is a retrospective cohort study of patients aged 0-21 with osteosarcoma metastatic to the lung who underwent pulmonary metastasectomy between 2000-2024. Patients were categorized into groups based on the presence or absence of LNM on imaging reviewed by pediatric surgeons and radiologists. Descriptive statistics and Wilcoxon rank sum, chi-square or Fisher’s exact tests evaluated differences between patients with and without LNM. Kaplan-Meier survival curves with log-rank tests evaluated the relationship between the presence of LNM and outcomes. The primary outcome was overall survival (OS) with secondary outcomes of recurrence-free survival (RFS) and disease-free survival (DFS). Results: 39 patients met inclusion criteria for this study, of which 13 (33%) had LNM (Table). Of the 13 patients with LNM, 8 (62%) had a pulmonary metastasectomy after their LNM diagnosis. Patients with LNM had poorer OS after first metastasectomy (log-rank p = .027), DFS after first metastasectomy (p = .018), and RFS after diagnosis (p = .039) than patients with pulmonary parenchymal metastasis without LNM. Patients who underwent metastasectomy after their LNM diagnosis had improved OS after LNM diagnosis than patients who did not undergo metastasectomy (pairwise log-rank test with Bonferroni correction p = .015). Conclusions: Pediatric patients with osteosarcoma metastatic to the lung with LNM had poorer OS, DFS, and RFS compared to patients without LNM. These results confirm the importance of attention to the presence of nodal involvement in patients with pulmonary metastatic osteosarcoma. Despite their poor prognosis, these results suggest a persistent survival benefit to surgical intervention. Total N = 39 No LMN N = 26 LMNN = 13 p Age 13.7 (9.5, 16.1) 13.9 (9.0, 15.9) 13.7 (10.7, 16.5) .777 Female 15 (38%) 10 (38%) 5 (38%) > .999 Histology Chondroblastic Osteoblastic Telangiectatic 11 (39%)16 (57%)1 (3.6%) 9 (50%)8 (44%)1 (5.6%) 2 (20%)8 (80%)0 (0%) .162 Primary tumor site Chest wall Femur Humerus Pelvis Radius Tibia 2 (5.1%)24 (62%)5 (13%)2 (5.1%)1 (2.6%)5 (13%) 2 (7.7%)14 (54%)3 (12%)2 (7.7%)1 (3.8%)4 (15%) 0 (0%)10 (77%)2 (15%)0 (0%)0 (0%)1 (7.7%) .821 Lung metastases present at time of diagnosis 20 (51%) 13 (50%) 7 (54%) .821 Treatment protocol AOST0331 AOST06P1 CCG 7921 P9754 30 (81%)2 (5.4%)4 (11%)1 (2.7%) 19 (79%)1 (4.2%)3 (13%)1 (4.2%) 11 (85%)1 (7.7%)1 (7.7%)0 (0%) > .999 Lung nodules removed during first metastasectomy 3 (2, 6) 3 (2, 5) 6 (1, 20) .567

3626 Background: For patients (pts) with dMMR stage III colon cancer, the addition of atezolizumab (atezo) to adjuvant 5-fluorouracil, leucovorin plus oxaliplatin (mFOLFOX6) significantly improved disease-free survival in ATOMIC (NCT02912559). Here we present HRQOL data. Methods: Pts with surgically resected stage III dMMR colon cancer were randomized (1:1) to receive mFOLFOX6 + atezo (840 mg IV q2 weeks) for 12 cycles (6 months [mo]) followed by atezo monotherapy for 13 cycles (12 mo total) versus mFOLFOX6 for 12 cycles. HRQOL was an exploratory endpoint measured using the FACT-C (includes FACT-G), FACT/GOG-NTX, EQ5D-5L, and PRO-CTCAE. Optional participation was by paper surveys at trial registration, prior to treatment cycles 4 and 7, and at 6, 12, and 36 mo after registration. Mean changes from baseline (BL) were compared between treatment arms using general linear mixed models (negative mean changes indicate worsening). At 6 mo, a two-sided 95% confidence interval excluding a difference of 1.9 points (FACT/GOG-NTX) and 6 points (FACT-C Trial Outcome Index [TOI]) favoring the mFOLFOX6 arm would indicate non-inferiority of the addition of atezo. Rates of side effect bother (FACT-G item GP5) and pt-reported adverse events (AEs) by PRO-CTCAE (composite scores, baseline adjusted) were compared using Fisher’s exact tests. Results: Of 712 randomized pts, 581 (285 atezo+mFOLFOX6; 296 mFOLFOX6) consented to participate in the survey. Pts completed 2398/3021 (79%) of expected surveys across all time points (1218/1489 [82%] atezo+mFOLFOX6; 1180/1532 [77%] mFOLFOX6). The difference in mean changes from BL between arms indicated non-inferiority of the addition of atezo at 6 mo (table); differences remained small at 12 and 36 mo. No significant differences in mean changes from BL between arms were found at 6, 12, or 36 mo for any scale. At 6 mo, 16% vs 20% of pts in each arm reported at least “quite a bit” of side effect bother (p=0.34), favoring atezo. Across cycles, atezo was associated with higher rates of pt-reported itchy skin (62% vs 48%), cough (53% vs 43%), and shortness of breath (51% vs 41%) [all p<0.05]. Conclusions: Addition of atezo to mFOLFOX6 slightly increases pt-reported AEs, but its effect on HRQOL is minimal and not clinically meaningful. Results support tolerability of atezo+mFOLFOX6 as standard of care adjuvant treatment for pts with dMMR stage III colon cancer. Support: UG1CA189823, U10CA180821, U10CA180882; Genentech, a member of the Roche group; https://acknowledgments.alliancefound.org. Clinical trial information: NCT02912559 . Scale Mo Mean change from BL – atezo+mFOLFOX6 Mean change from BL – mFOLFOX6 Diff (95% CI) FACT/GOG-NTX 6 -10.0 -10.6 0.6 (-0.8, 2.1) 12 -8.0 -9.4 1.4 (-0.2, 2.9) 36 -7.2 -6.9 -0.4 (-2.1, 1.4) FACT-C TOI 6 -4.1 -2.5 -1.6 (-3.7, 0.6) 12 2.1 1.8 0.3 (-1.9, 2.6) 36 0.7 1.8 -1.1 (-3.7, 1.5)

12007 Background: YAs with cancer, defined as those diagnosed prior to the age of 40, may experience greater symptom burden compared to those diagnosed at older ages. We evaluated the impact of an ePROM-triggered, CC-based, supportive care intervention on symptom burden in YAs with cancer. Methods: The Enhanced, Electronic Health Record-facilitated Cancer Symptom Control (E2C2) trial was a cluster-randomized, pragmatic trial (NCT03892967) that enrolled oncology patients seen at Mayo Clinic Rochester and within the Mayo Clinic Health System (sites in Minnesota and Wisconsin) between March 2019 and January 2023. Patients routinely reported the severity of six SPPADE symptoms (Sleep deficit, Pain, Physical function impairment, Anxiety, Depression, and Energy deficit/fatigue) on 11-point numerical rating scales. Symptom severity was classified as none to mild (0-3), moderate (4-6), or severe (7-10). Those with moderate or severe symptoms were offered symptom management education, while those with severe symptoms were also offered the option to work virtually with a symptom care manager. In this post hoc analysis, we examined the effects of the intervention on change in symptom scores among YAs and time to improvement to a mild/moderate level in those with at least one severe symptom. Results: Among 40,659 patients who responded to at least one survey, 2,598 were YAs and 38,061 were adults ≥ 40 years. Among YAs, 10.7%, 24.3%, and 65.1% were 18-24 years, 25-31 years, and 32-39 years, respectively. A greater proportion of YA patients were female (61.5% vs 57.0%), of a non-white race (12.4% vs 5.3%), living in an urban setting (65.7% vs 55.1%), single (36.4% vs 9.6%), on non-government insurance (78.1% vs 36.6%), employed (72.6% vs 37.4%), and had a Bachelor’s degree or greater (37.8% vs 28.3%, p < 0.001 for all). Fewer YA patients had metastatic disease compared to older patients (24.2% vs 35.2%, p < 0.001). Compared to a pre-intervention baseline, the mean change in symptom score for YA patients following the intervention demonstrated improvements in anxiety (-0.195) and depression (-0.168, p < 0.0001 for both), while physical function impairment worsened over the intervention period (0.101, p = 0.014). Compared to adults ≥ 40 years, YAs experienced greater intervention effects for management of depression ( p < 0.001), fatigue ( p = 0.01), pain ( p < 0.0001), and physical function impairment ( p < 0.0001). Among YAs with a severe symptom during the intervention period, median time to improvement to a mild/moderate level was longer for anxiety compared to those ≥ 40 years (3.5 vs 2.7 months, p = 0.009). Conclusions: Routine ePROM surveillance, coupled with CC-based symptom management, led to improvements in anxiety and depression among YAs with cancer, although, time to improvement was longer for anxiety compared to adults ≥ 40 years.

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.

Abstract Rationale American Indians and Alaska Native (AI/AN) people have the highest prevalence of tobacco use of any US racial or ethnic minoritized group, though this varies regionally. Smoking, and smoking-related cancers including lung cancer are more common in AI/AN people than non-Hispanic whites in the Pacific Northwest. Lung cancer screening (LCS) is effective but broadly under-utilized in AI/AN eligible adults. This study’s objective was to evaluate a AI/AN community co-designed patient navigation intervention to bridge community healthcare settings to a LDCT-capable LCS program. Methods We conducted a single-arm pilot study of the patient navigation intervention, grounded in community-based participatory research principles. The intervention was formalized in a living handbook, co-created with input from patients and providers at an AI/AN Urban Indian Organization and primary care clinic, Seattle Indian Health Board. Two community health workers served as navigators to deliver culturally sensitive support, link to shared decision-making with a nurse practitioner at the academic LCS program, coordinate transportation, interface with insurance and provide other barrier-directed activities. Patients eligible for LCS (n = 44) were recruited from the AI/AN clinic setting through on-site outreach. Enrolled participants completed pre-navigation surveys which assessed baseline knowledge, attitudes, experiences and barriers. Those who engaged with the central program completed an additional post-navigation survey (n = 15). Electronic health records were reviewed for all navigation and LCS-related data. Results Between July 2023 - November 2024, 44 participants were enrolled in the study. The median age of the participants was 65 (IQR 58-70), 66% reported current smoking, and 76% reported an annual household income &lt;$30,000. All participants reported at least one barrier that delayed care in the past 12 months. On review, two participants were up-to-date on LCS prior to enrollment. Within 6 months, 13 participants completed a shared decision-making appointment and 11 went forward with LDCT. On post-intervention surveys, barriers most commonly addressed were: scheduling (100%), transportation (80%), explaining LCS (80%) and cost/insurance (73%). Participants reported high acceptability, measured by Acceptability of Intervention Measure (AIM median 5.0, IQR 5-5) and patient satisfaction measured by Patient Navigation Satisfaction Measured-Instrument (PNS-I median 45, IQR 42-45). Conclusion A culturally tailored patient navigation program for LCS was feasible and highly acceptable among urban AI/AN adults. Navigation addressed multiple barriers and successfully connected some patient participants from a community clinic to tertiary screening centers for shared decision-making and/or screening. These findings support the effectiveness of academic-community partnered navigation to increase LCS uptake in AI/AN clinic settings. This abstract is funded by: ATS/ALA/Chest Foundation: Respiratory Health Equity Research Award (Triplette)

PURPOSE For patients with breast cancer undergoing breast conservation, escalating the dose (boost) of radiation to the lumpectomy cavity after whole-breast irradiation (WBI) reduces ipsilateral breast recurrence (IBR) but extends treatment duration. This phase III trial investigated whether boost delivery during WBI versus after WBI provides noninferior IBR and preserves cosmetic appearance. METHODS NRG/RTOG 1005 randomly assigned patients at higher risk for IBR after lumpectomy and axillary surgery to either a sequential boost of 12 Gy in six fractions(F) or 14 Gy in 7F after WBI of 50 Gy in 25F or 42.7 Gy in 16F (sequential arm) or a concurrent boost of 8 Gy in 15F of 0.53 Gy per day with WBI of 40 Gy in 15F (concurrent arm) using 3-dimensional conformal radiation therapy (RT) or intensity-modulated RT. Based on 1.59% 5-year IBR for the sequential arm, defining the noninferiority margin as a hazard ratio upper limit on the 90% CI of 2.12, 2,312 patients provide 80% power for noninferiority of IBR as first recurrence for the concurrent arm. Secondary end points included disease-free survival and overall survival, adverse events (AEs), and cosmetic outcomes. RESULTS Between May 24, 2011, and June 20, 2014, 2,354 patients were randomly assigned, with 2,255 eligible for analysis (sequential arm, n = 1,118; concurrent arm, n = 1,137). With median follow-up of 7.3 years, there were 56 IBR events; 5- and 7-year IBR were 2.1% and 2.2% on the sequential arm and 1.9% and 2.6% on the concurrent arm, respectively. The noninferiority criterion was met: HR (90% CI): 1.31 (0.84 to 2.04), P = .037. No differences were observed in AEs, cosmetic outcomes, or survival between arms. CONCLUSION Concurrent boost during WBI results in noninferior IBR compared with sequential boost without worsening toxicity or cosmetic outcomes and reduces overall treatment time.

Abstract Patients with extremely rare pathogenic variants pose unique challenges to current healthcare systems. Nano-rare mutations have been defined as mutations with a known prevalence of &lt;30 patients worldwide, but because of the small fraction of humans who have undergone genetic testing, neither the precise prevalence of individual mutations nor the total prevalence of patients with nano-rare mutations is known. n-Lorem is a non-profit founded in 2020 with the mission of equitably discovering, developing, and providing bespoke experimental antisense oligonucleotides (ASOs) for free, for life, to patients with nano-rare mutations that are amenable to ASO treatment. In this perspective, we provide an overview of the n-Lorem processes and systems, the characteristics of the first 329 patients who have applied for treatment for whom initial assessment was completed and suitability for ASO treatment determined, and a summary of the results of ASO treatment for patients treated to date. Detailed data on individual patients and the overall clinical safety and tolerability profiles of the ASOs for which there are clinical data are the subjects of other manuscripts.

Introduction: The objective of the study was to evaluate the prevalence of cardiovascular, renal, and hepatic biomarkers that fall outside guideline-based thresholds in adults with type 1 diabetes (T1D), and to identify demographic and clinical factors associated with these biomarkers. Methods: This observational study linked data on 2,923 adults with T1D from the T1D Exchange Registry and NorstellaLinQ’s laboratory data (2022–2023). Prevalence of biomarkers outside guideline-recommended thresholds was calculated. Generalized estimating equations (GEE) were used to model associations with age, sex, race/ethnicity, insurance, T1D duration, body mass index (BMI), and hemoglobin A1c (HbA1c), while accounting for within-subject correlation due to repeated measures. Results: Elevated low-density lipoprotein (LDL) cholesterol (≥70 mg/dL, above the recommended goal for individuals with diabetes at high risk for atherosclerotic cardiovascular disease) was common (80.2%), as were overweight (33.8%) and obesity (30.3%). Additional findings included high total cholesterol (≥200 mg/dL, 22.6%), low high-density lipoprotein (HDL) cholesterol (<40 mg/dL males, <50 mg/dL females, 13.4%), elevated urinary albumin-to-creatinine ratio (≥30 mg/g, 13.0%), reduced estimated glomerular filtration rate (<60 mL/min/1.73 m 2 , 6.2%), and elevated fibrosis-4 index (FIB-4) (≥1.3, 14.4%). In adjusted GEE models, higher HbA1c was significantly associated with increased odds of abnormal cardiovascular and renal biomarkers across most measures. Male sex and BMI were linked to lower HDL cholesterol, while older age was strongly associated with elevated FIB-4. Conclusion: Obesity and elevated LDL cholesterol are highly prevalent in adults with T1D, indicating substantial cardiometabolic risk. The lack of outcome trials in this population underscores the need for studies to evaluate strategies to improve weight and lipid management and thereby reduce cardiovascular and renal risk in adults with T1D.