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Non-melanoma skin cancer–related mortality in the United States: A 25-year CDC WONDER analysis.
9580 Background: Non-melanoma skin cancer (NMSC), including basal cell and squamous cell carcinoma, is the most common malignancy worldwide, with rising incidence due to ultraviolet exposure and aging populations. Analyzing two decades of CDC WONDER data provides insights into mortality disparities and geographic variation. Methods: Using the CDC WONDER database for adults aged ≥25, we analyzed age-adjusted and crude mortality rates (AAMRs and CMRs) per 100,000 for NMSC (ICD-10 C44.0 to C44.9) by year, sex, race/ethnicity, and geography. Joinpoint regression (version 5.4) estimated average annual percentage change (AAPC) and annual percentage change (APC) with 95% confidence interval (CIs). Results: From 1999–2023, NMSC caused 118,792 deaths (female: 36,921; male: 81,871), most occurring at the Decedent's home (37.7%). The AAMR rose 41% from 1.92 in 1999 to 2.72 in 2023 (AAPC: 1.55%; p<0.001), with significant increases in 2005–2019 (APC: 1.88, 95% CI: 1.45 to 2.30) and 2019–2023 (APC: 4.92, 95% CI: 2.78 to 7.09). Adults ≥65 had the highest CMR (8.59), rising 1.57% annually (p<0.001). Men consistently had higher AAMR about three times that of women in 1999 (3.24 vs. 1.03), and the gap remained in 2023 (4.35 vs. 1.50). Non-Hispanic (NH) Whites had the highest AAMR, rising 2.06% annually (p<0.001), while NH Asians or Pacific islanders had the lowest with a slight decline (-0.19%; p=0.81). Regionally, the West had the fastest rise in AAMR at 1.68% annually (p<0.001), while the Midwest had the slowest at 1.24% (p<0.001). Mortality in rural areas (AAMR: 2.35) rose faster (1.41%; p<0.001) than in urban populations (AAMR: 1.93; 0.80%). Oklahoma and West Virginia ranked highest in the top 90th percentile. Conclusions: Mortality from NMSC has risen in the United States over the past two decades. However, significant demographic and geographic disparities in mortality continue, emphasizing the need for equitable healthcare access and targeted interventions, particularly among males, NH Whites, and high-burden states and regions. Deaths and AAPC for trends related to non-melanoma skin cancer from 1999 to 2023. Variable Deaths AAPC (1999-2023) with CI Overall 118,792 1.55 (1.01 to 2.09) Male 81,871 1.29 (0.71 to 1.87) Female 36,921 1.54 (1.10 to 1.99) NH White 108,523 2.06 (1.54 to 2.60) NH Black 4,797 -0.67 (-1.74 to 0.40) Hispanic 3982 0.76 (0.48 to 2.02) NH Asians 1,105 -0.20 (-1.87 to 1.51) Midwest 25,260 1.25 (0.66 to 1.83) West 27,192 1.54 (1.03 to 2.05) South 46,442 1.64 (1.12 to 2.17) Northeast 19,898 1.69 (0.90 to 2.49)
Association between ctDNA kinetics and overall survival in patients with urothelial cancer.
e16574 Background: Circulating tumor DNA (ctDNA) dynamics have emerged as a promising biomarker of prognosis and therapeutic response in urothelial cancer (UC). However, the optimal approach to characterize the relationship between serial ctDNA changes and overall survival (OS) across various UC clinical disease states remains unclear. This study systematically evaluated multiple methods to describe ctDNA kinetics, including qualitative, quantitative, and data-driven machine learning (ML) strategies, to identify relationships between longitudinal ctDNA patterns and OS outcomes. Methods: We performed a single-institution retrospective cohort study of patients with UC, including variant histologies, with ≥2 tumor-informed ctDNA assays (Signatera) available. A 6-month landmark analysis was employed to minimize immortal time bias. Three ctDNA kinetic classification strategies were applied: (1) Qualitative—binary detectability patterns (clearance, conversion, persistent positive/negative); (2) Quantitative—percent change from baseline (major response ≥90% reduction, partial 30-89%, stable 0-29%, progressive ≥20% increase); (3) ML—unsupervised k-means clustering (k = 5) based on descriptive and kinetic ctDNA features. The primary endpoint was discrimination of OS from 6-month landmark using Harrell's C-index. Pairwise differences were tested via bootstrap resampling (500 iterations). Sensitivity analyses were performed stratified by treatment setting. Results: Among 215 evaluable patients, therapy settings included: neoadjuvant 38 (17.7%), adjuvant 51 (23.7%), metastatic 71 (33.0%), and no systemic therapy 85 (39.5 %). OS C-indices were: ML 0.902 (95% CI 0.855-0.934), Qualitative 0.883 (0.843-0.919), Quantitative 0.852 (0.818-0.899). Pairwise comparisons showed no significant differences (all p > 0.10). Subgroup analysis showed no statistically significant differences by treatment setting (all p > 0.10), although quantitative performance was numerically lower in metastatic setting (C-index 0.709 vs 0.799 qualitative; 0.839 ML), with a −0.13 difference relative to ML (95% CI −0.203–0.042; p = 0.376). Conclusions: All three ctDNA kinetic classification approaches demonstrated strong OS discrimination (C-index > 0.85) with no significant performance differences across treatment settings, which suggests that multiple analytic strategies may be suitable depending on clinical context. Larger, prospective studies are needed to define optimal approaches and establish context-specific thresholds.
Atrial fibrillation as an acute severity amplifier during cancer hospitalizations: A National Inpatient Sample analysis, 2018–2022.
e23098 Background: Atrial fibrillation (AF) is highly prevalent among patients with cancer and is frequently treated as a chronic comorbidity during hospitalization. Whether the presence of AF during cancer hospitalizations independently amplifies acute inpatient severity, critical care utilization, and mortality at a national level remains incompletely defined. Methods: A serial cross-sectional analysis was performed using adult hospitalizations with a principal diagnosis of malignancy in the 2018–2022 Healthcare Cost and Utilization Project National Inpatient Sample. AF/atrial flutter was identified using any-diagnosis ICD-10-CM code I48*. Outcomes included All Patient Refined Diagnosis Related Group (APR-DRG) severity of illness, extreme severity (APR-DRG level 4), in-hospital mortality, shock (R57*), mechanical ventilation, length of stay (LOS), and hospitalization cost. National estimates accounted for survey stratification, clustering, and discharge-level weighting. Survey-weighted multivariable regression adjusted for demographics, payer, ZIP-code income quartile, admission characteristics, cancer type, hospital characteristics, and year. Results: Among 961,848 unweighted cancer hospitalizations, representing 4,809,239 admissions nationally, AF was present in 11.9%. Hospitalizations with AF demonstrated substantially higher acuity compared with those without AF. Mean APR-DRG severity was higher (2.99 vs 2.50), and extreme severity occurred more frequently (5.19% vs 3.22%). In-hospital mortality was nearly doubled among AF-associated admissions (7.75% vs 3.93%). AF was also associated with higher rates of shock (2.83% vs 1.19%) and mechanical ventilation (4.97% vs 2.26%), longer LOS (8.23 vs 6.44 days), and greater hospitalization costs ($26,265 vs $22,365). After multivariable adjustment, AF remained independently associated with increased inpatient severity (APR-DRG severity β 0.38, 95% CI 0.36–0.39), extreme severity (odds ratio [OR] 1.79, 95% CI 1.72–1.86), in-hospital mortality (OR 1.75, 95% CI 1.70–1.80), shock (OR 2.34, 95% CI 2.23–2.44), and mechanical ventilation (OR 2.36, 95% CI 2.28–2.44). Conclusions: Atrial fibrillation occurring during cancer-related hospitalizations functions as an acute inpatient severity amplifier. The presence of AF as a comorbidity was independently associated with higher illness severity, ICU-level care, and mortality. These findings support reframing and prioritizing AF as a clinically actionable marker of inpatient decompensation rather than a chronic comorbidity, with implications for early risk stratification and escalation strategies in hospitalized oncology populations.
Health care utilization and management patterns of asymptomatic incidental pulmonary embolism in cancer patients.
e13562 Background: Asymptomatic incidental pulmonary embolism (iPE) is increasingly detected in cancer patients on routine imaging; however, the optimal management setting and real-world data on healthcare utilization remain poorly defined. Methods: We conducted a retrospective cohort pilot study of cancer patients with newly diagnosed iPE detected on routine imaging in the outpatient setting at MD Anderson Cancer Center. AI-assisted imaging review (Aidoc) identified CT scans with iPE from 9/29/2025 to 11/09/2025 and were manually confirmed. Asymptomatic iPE was defined as the absence of symptoms associated with PE such as chest pain, dyspnea, and cough. The primary endpoint was acute care utilization following diagnosis, defined as outpatient vs acute care setting (emergency department/urgent care/observation/inpatient). Secondary endpoints were time to anticoagulation (AC), time of radiologist notification, and 30-day clinical outcomes. Fisher’s exact and chi-squared tests were used to compare categorical variables. Results: Cancer patients with iPE (n = 153) were identified and 92% (n = 141) were asymptomatic (median age 64; 51% female, 51% gastrointestinal malignancy). Presence of symptoms was associated with management of iPE in the acute care setting (p < 0.001). Asymptomatic iPE patients were managed as outpatient (77%) or in the acute care setting (23%; emergency department 11%, urgent care 5%, observation 4%, inpatient 3%). BNP/Troponins (17%) and echocardiograms (11%) were obtained in patients, primarily in the acute care setting. iPE extent was categorized as distal (subsegmental, segmental; 87%) or proximal (central, lobar; 13%) but was not associated with acute care setting (p = 0.24). Radiologist notification of iPE occurred in the morning (8AM-12PM; 35%), afternoon (12PM-5PM; 43%), or after hours (5PM-8AM; 22%). Acute care management of asymptomatic iPE occurred in the morning (12%), afternoon (28%), and after hours (29%) (p = .096). AC was used in 97% (n = 137) of asymptomatic iPE patients. 12% of asymptomatic iPE patients were already on AC. AC was initiated within the same day of diagnosis in 70% and within two days in 94% of asymptomatic iPE patients. AC occurred within the same day in 66% outpatient vs 83% in the acute care patients (p = 0.11). Within 30 days, all cause mortality was 1% among outpatients compared with 6% in the acute care group, while recurrent VTE occurred in 2% vs 6%, respectively. Conclusions: In this pilot study, nearly one quarter of patients with asymptomatic iPE underwent acute care management. These results highlight substantial practice variation in the management of iPE and suggest further exploration of standardized outpatient pathways.
Identification of prognostically relevant residual tumor burden in glioblastoma after surgery: A comparative analysis of MR-based RANO resect classes vs [ <sup>18</sup> F]FET PET.
2068 Background: Accurate assessment of postoperative residual tumor burden is critical in IDH -wildtype glioblastoma. The MRI-based RANO resect classification stratifies patients according to postoperative contrast-enhancing and non-contrast enhancing tumor volume but may underestimate metabolically active residual disease. The additional prognostic value of postoperative [¹⁸F]FET PET beyond MRI is yet unclear. Methods: This retrospective bicentric study included 140 patients with newly diagnosed IDH -wildtype glioblastoma and evaluable postoperative MRI and [¹⁸F]FET PET. Residual tumor volumes were segmented on MRI and classified according to the RANO resect system. PET-derived residual metabolic tumor volumes were defined using PET RANO 1.0 criteria. Spatial agreement between MRI- and PET-based volumes was quantified using Dice coefficients. Associations with overall survival were analyzed using Cox regression. Incremental prognostic value of PET was assessed using an imaging-only model (contrast-enhanced T1 (T1CE) vs. T1CE + PET) and a fully adjusted model including clinical covariates. Results: PET-derived residual tumor volumes exceeded MRI-defined volumes and showed low spatial concordance with MRI (Dice coefficient: 0.01–0.25) across all RANO resect classes. Postoperative PET-, T1CE-, and T2/FLAIR-derived tumor volumes were each associated with overall survival. Increasing PET-derived residual tumor burden was associated with a continuous increase in mortality risk. In multivariable Cox regression, PET-derived residual tumor volume remained independently associated with overall survival (adjusted hazard ratio 1.021 per cm³, 95% CI 1.008–1.033; ** p = 0.0024). In the imaging-only model, addition of PET improved time-dependent discrimination between 6 and 24 months (ΔAUC(t) 0.03–0.07) and increased Harrell’s C (ΔC ≈ 0.03). In the fully adjusted model, PET provided significant non-redundant prognostic information (likelihood ratio test, * p = 0.0049). Conclusions: Postoperative [¹⁸F]FET PET identifies metabolically active residual tumor not adequately captured by MRI and provides additional prognostic information beyond MRI-based assessment. Integration of PET into postoperative evaluation may refine prognostic stratification in IDH-wildtype glioblastoma.
Soluble CD137 in health and disease: A systematic review and meta-analysis.
e14528 Background: Soluble CD137 (sCD137), produced by regulatory T cells, plays a critical role in immune response regulation. Its measured presence in serum highlights sCD137 as a potential biomarker for diagnosis and treatment monitoring across several conditions, including autoimmunity, cancer, and infectious diseases. However, inconsistent findings across studies call for a systematic review to clarify its clinical value. Methods: Following PRISMA guidelines, a comprehensive search across medical databases identified studies on sCD137 in healthy and diseased patients. Two researchers independently screened, extracted data, and assessed study quality. We conducted a random-effects meta-analysis to estimate the pooled standardized mean difference (SMD) between patient groups and healthy controls, as well as the change in sCD137 levels pre- and post-treatment. Meta-regression analysis was conducted to study the effect of age, geographical location, study design, and measurement technique on sCD137 levels. Results: A total of 47 articles and 4854 individuals were included in the analysis, encompassing a diverse range of study designs, diseases, and treatments. We found diseased patients exhibited higher levels of sCD137 than healthy controls (SMD: 1.08, 95% CI, 0.71 to 1.44). More specifically, elevations in sCD137 was more prominent in patients with infectious conditions (SMD: 1.78, 95% CI, 0.08 to 3.47) and gastrointestinal and genitourinary syndromes (SMD: 1.30, 95% CI, 0.12 to 2.48), while cancer (SMD: 0.79, 95% CI, 0.23 to 1.34) and autoimmune diseases (SMD: 0.73, 95% CI, 0.03 to 1.43) had lower magnitude elevations. Pre- and post-treatment analysis demonstrated that therapy reduced the levels of sCD137 in autoimmunity (SMD: -0.73, 95% CI, -1.24 to -0.23), whereas cancer therapies had the opposite effect (SMD: 1.14, 95% CI, 0.60 to 1.67). Age, geographical location, epidemiological design, or sCD137 measurement technique did not influence pooled estimations. Conclusions: Soluble CD137 emerges as a reliable biomarker for differentiating healthy individuals from diseased patients. In patients with cancer or autoimmune disease, longitudinal changes in sCD137 offer a valuable approach for tracking treatment responses. Given that sCD137 release reflects internal immunoregulatory pressures, disease and therapeutic contexts must be considered when making clinical interpretations.
RedTail: A next-generation systemic platform for tumor-localized expression of BiTEs and immune activation.
e14562 Background: RedTail is a next-generation gene therapy platform engineered for systemic delivery and highly selective tumor-specific payload expression. The platform uses a tumor-specific, extracellular enveloped vaccinia virus (EEV) expressing a chimeric form of CD55, providing resistance to complement and neutralizing antibodies and enabling systemic administration. The viral genome can be engineered to express immune activating payloads such as an IL-15 superagonist (IL-15 SA) and tumor-targeting bispecific T-cell engagers (BiTEs) for localized production within the tumor microenvironment (TME). Tumor selective viral amplification induces cancer cell lysis, infiltration of T cells, and the delivery of high concentrations of immunomodulatory payloads such as IL-15 SA directly into tumors, altering the composition of the TME and potentially overcoming long-standing challenges with T-cell engagement in solid tumors. Methods: RedTail EEVs were produced using selected host cell lines that provide protection against serum mediated inactivation. RedTail vectors engineered to express the IL-15 SA transgene and BiTEs were evaluated in vitro and in vivo to assess tumor localized expression of the payload and therapeutic efficacy. Results: Systemic administration of RedTail expressing IL15 SA resulted in selective tumor-localized viral replication and robust, IL-15 SA production—at levels comparable to locally delivered clinically validated IL-15 SA–Fc therapies—while remaining- undetectable in normal tissues. This effect was accompanied by marked increases in NK and CD8⁺ T cell infiltration and broad remodeling of immune -cell composition, observed only in tumor--bearing hosts, consistent with tumor-localized IL-15–mediated immune activation. Building on this platform, RedTail vectors were further engineered to coexpress tumor-localized BiTEs alongside IL-15 SA. Treatment of tumor cells in vitro resulted in efficient viral amplification, tumor cell lysis, and simultaneously high tumor-production of both IL-15 SA and BiTE payloads. In vivo , systemic administration of dual payload RedTail led to tumor--localized coexpression and generated robust therapeutic responses, demonstrating the platform’s capacity to deliver potent combinations of immune engaging agents to the TME, while minimizing serum payload exposure. Conclusions: The RedTail platform enables efficient systemic delivery and selective tumor targeting, transforming tumors into in situ bioreactors for localized therapeutic production. It drives tumor restricted amplification, immune-mediated tumor cell killing, and robust antitumor immune activation. Together, these features position RedTail as a next-generation platform capable of enhancing T cell recruitment, promoting IL-15–mediated expansion, and BiTEs-meditated redirection T cells for potent, tumor selective cytotoxicity.
Incidence and survival rates in pediatric and adolescent melanoma in the United States, 2001-2022.
9593 Background: Melanoma represents a significant malignancy in children, adolescents, and young adults. Recent trends in incidence and outcomes in this population have not been comprehensively characterized. We analyzed population-based data to evaluate temporal trends in melanoma incidence and survival among patients aged <40 years. Methods: Data from the North American Association of Central Cancer Registries (NAACR) and SEER registries (representing up to 76% of U.S. children, adolescents, and young adults) were analyzed for patients aged <40 years diagnosed between 2001-2022. Age-adjusted incidence rates per 1,000,000 were calculated and standardized to the 2000 U.S. population. Five-year relative survival rates were assessed for diagnoses from 2001-2020. Annual Percent Change (APC) and Average Annual Percent Change (AAPC) were calculated using Joinpoint Trend Analysis Software. Results: Melanoma incidence in patients aged <40 years demonstrated a consistent declining trend from 2001 to 2022. Incidence rates decreased from approximately 47-50 per 1,000,000 in the early 2000s to approximately 38 per 1,000,000 by 2022, representing approximately a 20% reduction over the study period. The decline was particularly notable after 2005, with a steady downward trajectory through 2022. Despite this declining incidence, 5-year relative survival rates remained consistently excellent throughout the entire study period at 95-97%, with a slight upward trend from approximately 95% in 2001 to approximately 97% in 2017-2020. Survival outcomes showed no statistically significant variation over time, remaining stable in the 95-97% range. Conclusions: This analysis reveals an encouraging 20% decline in melanoma incidence among children, adolescents, and young adults over two decades, likely reflecting the success of public health initiatives promoting sun protection, sunscreen use, and reduced indoor tanning. The sustained decrease in incidence, particularly among younger populations, suggests that prevention efforts have had measurable impact. Simultaneously, the consistently excellent 5-year relative survival rates exceeding 95% demonstrate the effectiveness of current diagnostic and therapeutic approaches for melanoma in this age group. The stable survival coupled with declining incidence represents a dual public health success, with both primary prevention reducing disease burden and clinical management maintaining excellent outcomes. These findings underscore the importance of continued emphasis on melanoma prevention strategies while supporting ongoing efforts to optimize early detection and treatment protocols in pediatric and young adult populations.
Treatment patterns and outcomes after metastatic recurrence following perioperative chemoimmunotherapy in triple-negative breast cancer (mTNBC).
e13131 Background: Data on the management and prognosis of metastatic recurrence after perioperative chemoimmunotherapy in TNBC are limited. Methods: We conducted a single-center cohort study to evaluate treatment patterns and clinical outcomes among patients with mTNBC who experienced distant recurrence after perioperative chemoimmunotherapy and were discussed at the multidisciplinary tumor board of the European Institute of Oncology (Milan) from Oct 2022 to Oct 2025. Endpoints were progression-free survival (PFS) and overall survival (OS), calculated from the start of first-line treatment. Results: A total of 62 patients were included. The median age at baseline was 48 years (IQR: 41-54) and 6% carried a germline BRCA pathogenic variant. 26% of patients did not complete the neoadjuvant phase of the KEYNOTE-522 regimen due to toxicity, comorbidity and/or disease progression; 92% had residual disease at surgery, 61% developed distant recurrence during perioperative treatment, and 94% within 1 year after its completion.First-line systemic therapy consisted primarly of antibody-drug conjugates (ADC, 57%), followed by chemotherapy (34%), chemo-immunotherapy (8%), and PARP inhibitors (1%).At a median follow-up of 10.5 months, 43 PFS events and 21 deaths were reported. The median PFS was 3.8 months (95%CI: 2.9-4.7), and was longer among patients treated with an ADC (4.6 vs. 3.1 months). The median OS was 18.9 months (95%CI: 4.4-23.3). Conclusions: Early distant recurrence following perioperative chemoimmunotherapy was associated with poor outcomes. The marked heterogeneity of postrecurrence treatment underscores the need for improved therapeutic strategies in this population.
Global burden of stomach cancer attributable to alcohol use (1990-2023): A comprehensive epidemiological analysis.
e16361 Background: Alcohol consumption is a Group 1 carcinogen by the International Agency for Research on Cancer, yet its attributable burden to stomach cancer (SC) remains understudied in global burden assessments. This systematic analysis leverages GBD 2023 data to quantify the evolving burden of alcohol-attributable SC from 1990-2023. Methods: Data were extracted from the GBD Study 2023 with comprehensive surveillance of incidence, mortality, disability-adjusted life years (DALYs), age-standardized incidence rates (ASIR), age-standardized death rates (ASDR), and age-standardized DALY rates (ASDR-DALY). Population-attributable fractions (PAF) for alcohol use were computed using comparative risk assessment frameworks, stratified by age, sex, sociodemographic index (SDI), and geographical regions. Results: In 2023, alcohol use was responsible for 178,000-195,000 incident SC cases globally (95% UI: 162,000-211,000), representing a PAF of 3.2-4.8%. Mortality attributable to alcohol-related SC reached 89,500-102,300 deaths annually (95% UI: 78,400-115,200), accounting for 3.4% of total SC mortality. DALYs attributable to alcohol consumption totaled 2.15-2.58 million (95% UI: 1.89-2.94 million), contributing 3.1% to global SC burden. ASIR revealed 2.45-2.89 per 100,000 person-years (95% UI), with males demonstrating 2.3-fold higher burden than females (male ASIR: 3.72-4.15 vs. female: 1.62-1.88 per 100,000). Conversely, ASDRs declined modestly by 8.3% (95% UI: -4.2 to -12.8%), reflecting improvements in diagnostic and treatment capacities. Regional stratification demonstrated that 67% of alcohol-attributable SC mortality occurred in East Asia, Central Asia, and South Asia, with Mongolia (ASDR: 3.24 per 100,000), Korea (2.15), and China (1.89) exhibiting highest burdens. Sociodemographic index analysis indicated inverse correlation between SDI and PAF, with low-SDI regions showing PAF of 5.2-6.1%, compared to high-SDI regions at 2.1-2.4%.Temporal analysis revealed two distinct epidemiological phases: Phase 1 (1990-2010) showed rising absolute cases (+32%) with declining age-standardized rates (-12.1%), reflecting competing forces of population growth and risk factor mitigation. Phase 2 (2010-2023) demonstrated accelerating absolute burden (+24.5%) with near-plateaued age-standardized improvements (-1.8% APC). Among alcohol-attributable cancers globally, SC represented 8.2% (95% UI: 6.8-9.6%) in 2023, ranking third after liver (27%) and esophageal cancers (24%). Conclusions: Alcohol use remains a significant but modifiable determinant of global SC burden, with 3.2-4.8% of all SC cases preventable through alcohol cessation. The 48.2% increase in absolute deaths from 1990-2023, coupled with persistent regional disparities, underscores urgent need for region-targeted alcohol reduction interventions in high-burden settings.
Turning clinically approved PARP inhibitors into immunotherapy sensitizers by reprogramming the tumor microenvironment in colorectal cancer.
e14552 Background: PARP1 promotes tumor survival through compensatory DNA-repair pathways and inflammatory signaling. While PARP inhibitors (PARPi) are most effective in BRCA-deficient tumors, their immunoregulatory roles remain poorly defined. Given the rarity of BRCA mutations and limited clinical outcome of PARPi in colorectal cancer (CRC), defining BRCA-independent immune regulatory role of PARP1 is critical. Understanding how PARPi modulates antitumor immunity and the key drivers of immune evasion may broaden the therapeutic utility of PARPi beyond DNA-repair-deficient tumors. Methods: We evaluated the PARPi, olaparib and talazoparib across three murine CRC models. Mice received escalating doses of PARPi, immune checkpoint blockade (anti-CTLA-4 or anti-PD-1), or combined PARPi and checkpoint blockade. Clinical scoring and tumor burden were assessed longitudinally. Tumor-infiltrating immune cells were phenotypically and functionally characterized, and cytokine production was quantified. Myeloid-derived suppressor cells (MDSCs) were isolated from tumor-bearing mice or generated ex vivo from human-derived bone marrow cells, then treated and evaluated after treatment in a co-culture system using a T-cell suppression assay. Results: PARP1 inhibition with low-to-moderate doses of olaparib significantly reduced tumor burden across CRC models, whereas higher doses were ineffective or even promoted tumor growth. Both olaparib and talazoparib impaired the activity of tumor-infiltrating MDSCs and T-reg cells by downregulating key immunosuppressive mediators, including Arg1, iNOS, and COX-2. Treated tumors exhibited increased CD8⁺ T-cell infiltration, and adoptive transfer of untreated MDSCs reversed the antitumor effects of PARP inhibition. Similarly, treatment with PARPi abrogated the suppressive activity of human-derived MDSCs in CFSE-based T-cell co-culture assays. Both inhibitors synergized with anti-PD-1 and anti-CTLA-4 therapy, resulting in complete tumor regression. Conclusions: PARP inhibition exerts dose-dependent immunoregulatory effects that reshape the CRC microenvironment by suppressing MDSC and T-reg functions while restoring antitumor T-cell responses. These findings reveal a previously underappreciated immune function of PARP1 and demonstrate that partial, rather than maximal, inhibition is optimal for antitumor immunity. The results support refining PARPi dosing strategies and clinical evaluation of PARP1-targeted therapies to enhance responsiveness to checkpoint blockade in CRC, with potential applicability across other gastrointestinal cancers. Overall, these data identify PARP1 as an immunoregulator and provide a compelling therapeutic rationale for clinical evaluation of PARPi in combination with PD-1 and CTLA-4 inhibitors to overcome immunotherapy resistance in CRC.
Inpatient outcomes of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy in the United States, 2018–2023.
e15605 Background: Cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) is a highly complex oncologic procedure historically concentrated at academic referral centers but increasingly performed in community settings. Contemporary national benchmarks describing inpatient outcomes and variation by hospital structural characteristics remain limited, limiting population-level insight into access, safety, and organization of CRS/HIPEC care. Methods: A retrospective, serial cross-sectional analysis was performed using the 2018–2023 Healthcare Cost and Utilization Project National Inpatient Sample. Adult hospitalizations with peritoneal carcinomatosis or primary peritoneal malignancy were identified using ICD-10-CM codes. CRS/HIPEC was ascertained using ICD-10-PCS procedure proxies for major gastrointestinal excision or resection with intraperitoneal chemotherapy. Outcomes included in-hospital mortality (primary), length of stay, and hospitalization cost estimated using cost-to-charge ratios. National estimates accounted for survey weighting and stratification. Secondary analyses evaluated outcomes by hospital teaching status and bed size. Survey-weighted regression models adjusted for demographics, payer, neighborhood income quartile, elective admission status, APR-DRG severity and risk of mortality, and calendar year. Results: In-hospital mortality following CRS/HIPEC demonstrated graded variation by hospital structural characteristics, instead of binary separation between academic and non-academic centers. Mortality was lowest at urban teaching hospitals (6.77%), modestly higher at urban non-teaching hospitals (8.25%), and substantially higher at rural hospitals (14.49%). A similar gradient was observed by bed size, with lower mortality at large hospitals (6.44%) compared with medium (8.36%) and small (8.72%) hospitals, indicating that the largest mortality differentials were in lower-resource settings. From 2018–2023, an estimated 58,320 CRS/HIPEC hospitalizations were identified nationally, increasing from 9,005 in 2018 to 10,655 in 2023, reflecting continued national adoption of CRS/HIPEC. Overall in-hospital mortality was 7.02% (95% CI, 6.50–7.58), with a mean length of stay of 13.08 days (95% CI, 12.75–13.40). Among hospitalizations with available cost-to-charge ratio data, mean hospitalization cost was $55,189. Conclusions: In this national inpatient analysis, CRS/HIPEC was associated with substantial mortality, prolonged length of stay, and high costs, with outcomes varying by hospital structural characteristics. The graded risk pattern suggests that resource context and rescue capacity may be more influential than academic designation alone.
The association of lymph node yield and survival after neoadjuvant immunotherapy for head and neck cancer: An NCDB analysis.
e18120 Background: Comprehensive lymph node resection is a quality measure previously associated with survival for head and neck squamous cell carcinoma (HNSCC); however, the prognostic significance of nodal yield after neoadjuvant immunotherapy is an important unanswered question for clinical management and trial development. This study evaluated the association of lymph node yield with overall survival (OS) among patients with HNSCC who underwent neoadjuvant immunotherapy. Methods: The US National Cancer Database (2004-2022) was queried for HNSCC patients who underwent neoadjuvant immunotherapy followed by surgical resection. 1:1 matched non-neoadjuvant controls were created using demographic variables, facility, stage, lymphovascular invasion, and year. Positive lymph node percentage (malignant lymph nodes/total lymph nodes resected) was assessed. Cox proportional hazard models identified prognosticators of five-year OS. Results: The study included 462 patients who received neoadjuvant immunotherapy and 462 matched controls. Median age was 60 years [IQR 53-67] and 74.5% were male. The majority (53.5%) had stage IV disease and received adjuvant radiation (72.7%). Compared to non-neoadjuvant controls, those who received neoadjuvant immunotherapy had more lymph nodes (median [IQR] 43 [31-60] vs 29 [18-45] P<0.001), but a similar percentage of positive nodes (2.5% [0.0%-7.1%] vs 3.1% [0.0%-8.8%], P=0.09). Total number of nodes removed did not predict survival in the neoadjuvant immunotherapy group. Positive lymph node percentage predicted 5-year OS, with every one-percent increase in positive lymph nodes resulting in increased hazard of death by 1.4% (HR: 1.014, 95% CI: 1.006, 1.023) and 1.6% (HR: 1.016, 95% CI: 1.010, 1.030) in unadjusted and adjusted models, respectively. Conclusions: In patients with head and neck cancer treated with neoadjuvant immunotherapy, lymph node yield is not associated with improved survival. Prospective studies are required to determine if typical quality metrics for lymph node yield apply to patients treated with neoadjuvant immunotherapy.
Adjuvant antibody-drug conjugate (ADC) eligibility and corresponding prognosis in HER2+ early breast cancer (eBC): A US-based real-world comparison of KATHERINE and DESTINY-Breast05 populations.
535 Background: The KATHERINE trial established adjuvant T-DM1 as standard of care (SoC) treatment for patients with HER2+ eBC and residual invasive disease (RD) following neoadjuvant therapy. Recently, DESTINY-Breast05 (DB-05) demonstrated reduced recurrence risk with T-DXd vs. T-DM1 in a high-risk subset. While KATHERINE included any RD, DB-05 restricted eligibility to high-risk patients (inoperable at presentation or ypN+ at surgery). In this analysis, we aim to estimate the prevalence and associated outcomes of patients with HER2+ eBC and RD meeting eligibility for DB-05 vs. KATHERINE in a US real-world setting. Methods: This retrospective cohort study utilized the nationwide Flatiron Health electronic health record-derived de-identified database. We included patients diagnosed with stage I–III HER2+ eBC (Jan 1, 2011–Sept 30, 2025) who completed pertuzumab-based neoadjuvant therapy and surgery. RD status was determined via pathology reports. KATHERINE eligibility required any RD in breast/axillary nodes. DB-05 eligibility required high-risk RD: operable at presentation with node-positive disease at surgery (ypN1–3; “DB-05-operable”) or inoperable at presentation (cT4 or cT1–3/cN2–3; “DB-05-inoperable”). Distant recurrence-free survival (DRFS) and overall survival (OS) were estimated at 3 years post-surgery. The analysis was conducted on complete cases only. Results: The cohort included 9561 patients with HER2+ eBC and RD after neoadjuvant therapy. Overall, 9447 (99%) met KATHERINE eligibility. Conversely, only 4567 (48%) met DB-05 high-risk criteria: 3241 (34%) DB-05-operable and 1326 (14%) DB-05-inoperable. DB-05-ineligible patients mostly presented with cT1–3/cN0–1 disease and had RD confined to the breast (ypN0). In the overall study population, with a median follow-up for DRFS of 44 months, 3-year DRFS and 3-year OS were 88% and 94%, respectively. Patients eligible only for KATHERINE (i.e. DB-05-ineligible) experienced relatively favorable outcomes, with a 3-year DRFS of 94% and 3-year OS of 97%; conversely, DB-05-eligible patients experienced a 3-year DRFS of 82% and 3-year OS of 91%. Within the DB-05-eligible population, the poorest outcomes were observed if patients had inoperable disease at baseline, with a 3-year DRFS of 73% and 3-year OS of 86%. Conclusions: Approximately half of the patients with RD did not meet DB-05 high-risk criteria yet would have been eligible for KATHERINE. While T-DXd may become a new option for high-risk patients, T-DM1 remains a SoC for those with operable disease at baseline and node-negative RD at surgery. As ADCs were not widely available for eBC during the study period, these outcomes do not reflect ADCs’ treatment effect, and modern 3-year DRFS may possibly exceed 94% for this population.
Connectome-sparing stereotactic radiosurgery: Results from the phase II COG-SRS trial.
2002 Background: Cognitive decline remains common after radiosurgery. The cognition-sparing stereotactic radiosurgery trial (COG-SRS, NCT04343157) evaluated a novel connectome-sparing SRS strategy leveraging advanced imaging to autosegment the cognitive connectome for individualized functional sparing. Methods: COG-SRS is a prospective, single-institution, phase II trial that enrolled adults (KPS≥70) treated with SRS for benign or malignant intracranial lesions from 06/2018-10/2025. Connectome structures (10 discrete eloquent bilateral white matter tracts [WMTs], corpus callosum, and hippocampi [HC]) were auto-segmented from pretreatment diffusion tensor imaging and structural MRI and assigned evidence-based dose constraints (single fraction Dmax WMT=12Gy, HC=8.4Gy, with 3-/5-fraction equivalent doses) during SRS planning. Neuropsychological testing assessed cognitive domains of memory, language, executive function, attention/processing speed, and fine motor control at baseline and 3 months post-SRS. Outcomes were summarized using normed T scores and analyzed with mixed effects models adjusting for baseline score and prespecified clinical covariates. In the brain metastases cohort, cognitive performance was also compared with historical controls treated with standard brain SRS on Alliance N0574/N107C using domain Z scores and baseline adjusted mixed effects models. Questionnaires assessed mood/QOL, and disease time to event endpoints were estimated by Kaplan Meier. Results: Ninety-two patients enrolled (mean age 57.8 years), including 82 (89%) with brain metastases. All plans met standard target coverage and organ-at-risk constraints while optimizing dose to the cognitive connectome, with 76% meeting predefined constraints for all 23 connectome structures. At 3 months, 74% of patients demonstrated stable-to-improved performance across all 5 cognitive domains, with no significant mean decline in any domain. Mean performance improved in executive function (+4.30 T; p=0.043) and language (+4.91 T; p=0.011). Compared with historical controls, COG-SRS demonstrated superior 3 month cognitive outcomes (global composite Z difference +0.38; p=0.001), with the most pronounced domain-level benefit in executive function (+0.71; p=0.009) and language (+0.35; p=0.010). Mood and QOL remained stable. Among patients with brain metastases (median followup 35.6 months), 1 year local control was 98.5%, freedom from distant intracranial failure 57.4%, and overall survival 66.7%. Conclusions: Connectome-sparing brain SRS is feasible, leveraging advanced MRI-based autosegmentation of patient-specific cognitive networks, and is associated with preserved early cognition at the cohort level with superior 3 month cognitive outcomes versus historical controls. Cognitive benefits were achieved without compromising oncologic control, supporting prospective randomized study. Clinical trial information: NCT04343157 .
Real-world brain metastasis outcomes with T-DXd versus tucatinib-based therapy in second-line HER2-positive metastatic breast cancer.
1051 Background: Brain metastases (BM) remain a major cause of morbidity and mortality in HER2+ metastatic breast cancer (MBC). HER2CLIMB established tucatinib/trastuzumab/capecitabine (TTC) as a standard regimen with CNS activity, including improved outcomes in patients (pts) with active BM. DESTINY-Breast12 further demonstrated clinically meaningful intracranial outcomes with trastuzumab deruxtecan (T-DXd) in pts with stable and active BM. However, real-world (RW) comparative estimates of incident BM risk and timing between these two regimens among pts without baseline BM are limited, particularly in the second-line (2L) setting. Methods: We conducted a retrospective cohort study using TriNetX, a federated electronic health record network. Eligible pts had HER2+ MBC previously treated with first-line THP (taxane + trastuzumab + pertuzumab) and were BM-free at index. To approximate a 2L comparison, index was the first dose of T-DXd or TTC; cohorts were mutually exclusive and prior T-DM1 exposure was excluded. Pts with documented BM prior to index were excluded. To reduce misclassification from occult baseline BM, a landmark sensitivity analysis excluded BM events within 60 days post-index. Cohorts were balanced using 1:1 propensity score matching (PSM) for age, comorbidity burden, and lines of treatment. Incident BM was compared using risk-based measures (risk difference, risk ratio [RR]) and time-to-event analyses (Kaplan–Meier [KM]; Cox [HR]; log-rank). OS was assessed from index to death using KM and Cox regression. Results: In the PSM cohorts (n=540 per arm; mean age 57.8±12.4 vs 59.2±12.3 years), median follow-up was 13.4 months. Incident BM occurred in 12.6% (68/540) with T-DXd vs 20.9% (113/540) with TTC, corresponding to an absolute risk difference of −8.3% (95% CI −13.34% to −2.90%; p=0.0015) and RR 0.62 (95% CI 0.46–0.83). 1-year BM-free survival probability was 72.65% with T-DXd vs 67.89% with TTC (log-rank p=0.03), with an HR of 0.72 (95% CI 0.54–0.97). Among pts who developed BM, TTC was associated with higher BM-associated healthcare encounter burden compared with T-DXd (mean 9.64 vs 5.20; p=0.03). CNS morbidity events were less frequent with T-DXd vs TTC, including seizures (4.77% vs 13.06%; OR 0.33, 95% CI 0.23–0.49; p<0.0001) and cerebral edema (5.47% vs 14.22%; OR 0.35, 95% CI 0.24–0.51; p<0.0001). OS did not differ significantly between T-DXd and TTC (HR 0.89, 95% CI 0.76–1.04; p=0.16). Conclusions: In HER2+ MBC pts without baseline BM following first-line THP, T-DXd was associated with significantly lower incident BM, delayed onset, and reduced CNS morbidity compared with TTC. These findings warrant validation using standardized CNS surveillance and may help inform treatment selection in pts at high risk for BM. BM outcomes in HER2+ MBC. T-DXd TTC Incident BM 12.6% 20.9% RR 0.62 (0.46–0.83) 1-year BM-free 72.65% 67.89% HR 0.72 (0.54–0.97)
Synergistic efficiency of methylene blue and carbon nanoparticles for sentinel lymph node biopsy in early breast cancer: A large-scale real-world cohort study of 1,355 patients.
583 Background: Sentinel lymph node biopsy (SLNB) using radioisotopes and fluorescence imaging is the gold standard but remains inaccessible in many resource-limited regions due to high costs and the lack of nuclear medicine infrastructure. Methylene blue (MB) is a globally available, low-cost tracer, but often lacks consistent nodal yield. This study evaluates a radiation-free, dual-tracer protocol combining MB with carbon nanoparticles (CN) to provide a highly accessible and reliable axillary staging method for diverse clinical settings. Methods: In this single-center retrospective cohort study, 1,355 female patients with cT1-2N0M0 breast cancer (May 2019 to December 2022) were stratified into the MB group (n=675) or the MB+CN group (n=680). Primary endpoints were the SLN detection rate and mean node retrieval (MNR). Sensitivity analyses adjusted for confounders, including Ki67 status, using multivariate regression. The goal was to determine if this dual-dye approach could match the reliability of high-cost methods without specialized equipment. Results: The MB+CN group achieved a comparable detection rate to MB alone (96.32% vs. 96.44%; P=0.905). Crucially, the dual-tracer protocol significantly increased the MNR (2.43±1.64 vs. 2.10±1.35; P<0.001). Adjusted linear regression confirmed a robust increase in node count (β=0.36, 95% CI: 0.19–0.52, P<0.001). Subgroup analysis demonstrated enhanced utility in aggressive molecular profiles, with significantly higher node retrieval in high-Ki67 (P=0.002), T2 stage (P=0.032), and ER-positive (P<0.001) cohorts. No significant differences in detection rates were observed across any clinicopathological subgroups. Conclusions: The MB+CN dual-tracer strategy significantly enhances nodal yield while maintaining high detection rates. By eliminating the need for radioactive tracers and expensive imaging hardware, this approach offers a precise, safe, and cost-effective SLNB solution. It is particularly suited for large-scale implementation in developing countries and rural healthcare systems, bridging the gap in breast cancer surgical standards globally. Comparison of SLNB outcomes between MB and MB+CN groups. Outcome MB Group (n=675) MB+CN Group (n=680) Univariate P Adjusted Estimate (95% CI) Multivariate P Detection Rate, % (n 1 /n) 96.44% (651/675) 96.32% (655/680) 0.905 OR: 0.83 (0.64–1.09) 0.182 Mean Node Retrieval (SD) 2.10 (1.35) 2.43 (1.64) <0.001 β: 0.36 (0.19–0.52) <0.001
Variants of uncertain significance and contralateral risk-reducing mastectomy in early-stage breast cancer across safety-net and private hospital settings.
10603 Background: Germline genetic testing informs surgical decisions in early-stage breast cancer. Guidelines recommend considering contralateral risk-reducing mastectomy (RRM) for patients with pathogenic or likely pathogenic variants in high-risk genes, but not for those with variants of uncertain significance (VUS). Despite this, VUS results may still affect surgical decisions. This study examines the impact of VUS on surgical decision-making across two university-affiliated settings: a safety-net hospital and a private hospital. Methods: We retrospectively reviewed patients with early-stage invasive breast cancer treated between 2012 and 2022 who underwent germline testing before surgery at both a safety-net and a private hospital. Patients with VUS were compared with genetically negative controls. Logistic regression was used to identify factors associated with RRM. Results: The cohort included 86 safety-net VUS patients, 115 safety-net controls, 102 private VUS patients, and 97 private controls. Table 1 highlights demographic differences between the hospitals. RRM was performed in 28 safety-net VUS patients (32.6%), 20 safety-net controls (17.4%), 37 private VUS patients (36.3%), and 45 private controls (46.4%). Stepwise regression analysis of the full cohort showed that treatment at the private hospital was independently associated with higher rates of RRM compared with the safety-net hospital, regardless of VUS status (OR 4.52, 95% CI 2.10 - 9.75, p < 0.001). Additional factors associated with higher RRM rates included higher tumor stage, higher tumor grade, and younger age at diagnosis. In hospital-specific analyses, VUS status did not influence RRM decisions at the private hospital. However, at the safety-net hospital, patients with VUS were more likely to undergo RRM than those with negative genetic testing (OR 2.38, 95% CI 1.09 - 5.21, p = 0.031). Conclusions: Surgical decision-making for RRM is influenced by multiple clinical and institutional factors. While VUS status did not affect surgical decisions at the private hospital, it was associated with increased RRM rates at the safety-net hospital. This finding suggests that differences in counseling practices and patient perceptions of genetic risk may exist within the safety-net setting, where patients may face more uncertainty about access to future care. Further studies are needed to better characterize these disparities and promote guideline-concordant care. Patient demographics by hospital. Safety-Net (n = 201) Private (n = 199) p-value Race/Ethnicity Non-Hispanic White 8 (4.0%) 116 (58.3%) < 0.001 Non-Hispanic Black 41 (20.4%) 39 (19.6%) Hispanic 141 (70.1%) 12 (6.0%) Other 11 (5.5%) 32 (16.1%) Language Spoken English 72 (35.8%) 199 (100%) < 0.001 Non-English 129 (64.2%) 0 (0%) Insurance Insured 62 (30.8%) 196 (98.5%) < 0.001 Uninsured 139 (69.2%) 3 (1.5%)
A systematic review and meta-analysis of artificial intelligence–assisted colon capsule endoscopy for colorectal polyp detection.
e15520 Background: Colorectal cancer remains a leading cause of cancer-related mortality worldwide, with early polyp detection crucial for prevention. Colon capsule endoscopy (CCE) offers a non-invasive alternative to traditional colonoscopy, but diagnostic accuracy is limited by the time-consuming image review and human error. Artificial intelligence (AI) has emerged as a promising tool to enhance CCE performance. This systematic review and meta-analysis aimed to evaluate the diagnostic accuracy of AI-assisted CCE for detecting colorectal polyps. Methods: We conducted a systematic review and diagnostic meta-analysis of studies evaluating AI-assisted CCE for colorectal polyp detection. Five studies published between 2020 and 2025 were included (Yamada 2020, Saraiva 2021, Gilabert 2022, Mascarenhas 2022, and Nadimi 2025). All employed retrospective designs using deep learning algorithms, primarily convolutional neural networks (CNNs), trained on CCE video frames. Primary outcomes were pooled sensitivity and specificity. Secondary outcomes included diagnostic accuracy, positive predictive value (PPV), negative predictive value (NPV), and area under the receiver operating characteristic curve (AUC). Random-effects models with the DerSimonian-Laird method were applied, and heterogeneity was assessed using the I² statistic. Results: Five studies comprising 3,897 polyp-positive frames were analyzed. The pooled sensitivity for AI-assisted CCE in detecting colorectal polyps was 93.44% (95% CI: 76.41%-98.43%), with high heterogeneity (I² = 98.1%). The pooled specificity was 94.63% (95% CI: 84.87%-98.22%, I² = 96.3%) based on four studies reporting this metric. Overall diagnostic accuracy was 94.97% (95% CI: 82.44%-98.70%, I² = 97.3%). Individual study sensitivities ranged from 79.0% (Yamada 2020) to 99.9% (Nadimi 2025), while specificities ranged from 79.2% (Saraiva 2021) to 99.4% (Nadimi 2025). Among studies reporting AUC values, performance ranged from 0.80 to 0.99. The high heterogeneity observed across all metrics suggests substantial variability in study populations, AI algorithms, and methodological approaches. Conclusions: AI-assisted CCE demonstrates excellent diagnostic performance for colorectal polyp detection, with pooled sensitivity and specificity both exceeding 93%. These findings suggest that AI integration can significantly enhance the diagnostic capabilities of CCE, potentially making it a viable alternative to conventional colonoscopy for colorectal cancer screening. High negative predictive values (86.8%-99.8%) indicate that AI-assisted CCE is effective at ruling out polyps when the test is negative, which is crucial for screening applications. Future research should focus on prospective validation studies and standardization of AI reporting to facilitate clinical implementation.
Histology-dependent survival and treatment benefit in primary tracheal cancer: A population-based analysis.
e23386 Background: Primary tracheal cancer is a rare thoracic malignancy representing only 0.1-0.4% of all malignancies. Evidence is largely limited to small institutional series, leaving uncertainty regarding prognostic stratification and optimal treatment across histologic subtypes. We conducted a population-based analysis to evaluate histology-specific treatment patterns and survival outcomes. Methods: We utilized the SEER database to identify adults with primary tracheal cancer (ICD-O-3 C33.9) between 2000 and 2022. Histologies were categorized as squamous cell carcinoma (SCC), adenoid cystic carcinoma (ACC), small cell carcinoma, or other subtypes. Treatments included surgery, radiation therapy, and chemotherapy. Overall survival (OS) was analyzed using the Kaplan-Meier method and compared using the log-rank test. Multivariable Cox proportional hazards models identified factors independently associated with OS. Sensitivity analyses included cancer-specific survival and interaction testing between histology and treatment modality. Results: Among 1,701 patients identified, the median age was 66 years, and 57.7% were male. Histologies included SCC (48.4%), ACC (16.9%), small cell carcinoma (4.4%), and other subtypes (30.3%). At diagnosis, 33.0% had localized disease, 27.1% regional disease, and 11.5% distant disease. Overall, 70.7% received radiation therapy, 27.9% chemotherapy, and approximately 20% underwent surgical resection. Median OS was 22 months, with a 5-year OS of 34.7%. Survival differed significantly by histology (p < 0.001), with a median OS of 130 months for ACC, 13 months for SCC, 7 months for small cell carcinoma, and 28 months for other histologies, demonstrating intermediate survival. In multivariable analysis, SCC (HR 2.49) and small cell carcinoma (HR 3.59) had higher mortality than ACC. Earlier stage was strongly associated with improved survival (localized vs distant: HR 0.38, 95% CI 0.30-0.47; p < 0.001). Surgical resection (HR 0.48, 95% CI 0.41-0.56; p < 0.001) and radiation therapy (HR 0.71, 95% CI 0.63-0.80; p < 0.001) were independently associated with improved OS, whereas chemotherapy was associated with worse survival (HR 1.29, 95% CI 1.15-1.45), consistent with confounding by indication. A significant histology radiation interaction was observed (p = 0.01), suggesting differential benefit across histologic subtypes. Results were consistent in cancer-specific survival analyses. Conclusions: Survival in primary tracheal cancer varies profoundly by histology and stage. ACC demonstrates markedly superior outcomes, and surgical resection, when feasible in appropriately selected individuals, is associated with improved survival. These findings support histology-driven risk stratification and strengthen the importance of referral to specialized centers for histology-informed multimodality care.