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Metabolic and inflammatory marker elevations and associations with hormone therapy usage in prostate cancer patients of the All of Us Research Program cohort.
5031 Background: The development of cardiovascular disease (CVD) involves an interplay of inflammatory and metabolic factors. While hormone therapy (HT) is associated with increased CVD risk in prostate cancer (PCa) patients, the underlying mechanism remains unclear. Prior studies suggest an association between hypogonadism and systemic inflammation, but the specific effect of HT is poorly understood. Utilizing the All of Us Research Program, we investigated the effects of HT on metabolic and inflammatory markers. Methods: Our study examined All of Us participants who were diagnosed with PCa and were either treated or not treated with HT (GnRH agonists, GnRH antagonists, and/or anti-androgens), as well as those who received HT for non-PCa indications. We used ANCOVA to evaluate the effect of HT on metabolic and inflammatory labs after adjusting for pre-PCa baseline values. Among HT-treated PCa patients without prior CVD (myocardial infarction, stroke, or heart failure), we used Gray's test to compare CVD time-to-event between participants with and without elevated inflammatory labs (CRP > 10, ESR > 20, or Ferritin > 300) after HT treatment. In the non-PCa cohort, paired T-tests compared pre-HT and post-HT values. Results: The study included 7124 participants with PCa (1480 with HT; 5644 controls) and 2683 participants without PCa who received HT. After adjustment for baseline values, HT usage was associated with increased HgbA1c (P<0.001), HDL (P<0.001), triglycerides (P<0.001), ESR (P=0.006), CRP (P=0.009), and ferritin (P=0.006). Similar trends were seen in the non-PCa cohort (Table). In our survival analysis, HT-treated PCa patients with elevated inflammatory labs had higher CVD risk (P<0.001). Conclusions: Our study demonstrated associations between HT usage and metabolic dysregulation, while also suggesting a pro-inflammatory effect of HT in PCa patients. These trends reinforce prior studies and were similar among those without PCa, suggesting a drug-class effect. Our study also observed an increased risk of CVD among HT-treated PCa patients with elevated inflammatory labs. Future research should explore the role of HT associated inflammation in CVD, as well as identify targets for risk mitigation. Lab HT Treatment EMM (SE) No HT TreatmentEMM (SE) P-value(ANCOVA) Non-PCa Pre-HTMean Non-PCa Post-HTMean P-Value (Paired T-test) HgbA1c (%) 6.34 (0.04) 6.15 (0.02) P< 0.001 5.8 6.0 P<0.001 LDL (mg/dL) 102 (1.10) 101 (0.55) P= 0.71 103.0 107.6 P<0.001 HDL (mg/dL) 52.0 (0.17) 49.7 (0.33) P< 0.001 55.0 55.9 P= 0.02 Triglycerides (mg/dL) 136 (2.33) 127 (1.18) P< 0.001 117.5 124.1 P= 0.001 CRP (mg/L) 45.7 (8.81) 24.9 (4.61) P= 0.009 19.8 23.3 P= 0.45 ESR (mm/hr) 28.0 (2.27) 21.8 (1.19) P= 0.006 27.1 30.2 P= 0.02 Ferritin (ng/mL) 303 (55.8) 267 (34.2) P= 0.006 195.7 338.6 P= 0.02 EMM= Estimated Marginal Mean, SE = Standard Error.
Interpretable machine learning for overall survival prediction in vulvar cancer: SEER-based development and external validation in a Chinese multicenter cohort.
e17651 Background: Vulvar cancer is a rare gynecologic malignancy, and accurate prognostic tools for avoiding under- or over-surveillance remain limited. We developed and externally validated an explainable machine learning model to predict overall survival (OS) in patients with vulvar cancer. Methods: We identified 12,764 patients from the SEER database (2004–2021) and an external Chinese multicenter cohort (n = 361; 2003–2023). Candidate predictors were selected in the training set using univariable and multivariable Cox regression. Five predictive models—Cox proportional hazards model (CoxPH), random survival forest (RSF), extreme gradient boosting (XGBoost), support vector machine (SVM), and Light Gradient Boosting Machine (LightGBM)—were developed using the training set. Model performance was evaluated using the C-index, time-dependent AUROC at 1, 3, and 5 years, Brier score, calibration curves, and decision curve analysis (DCA). Model interpretability was assessed using SHapley Additive exPlanations (SHAP) to provide transparent, patient-level explanations of key drivers of predicted risk. Results: Among the five models, RSF achieved the best overall performance, with a C‐index of 0.7502 in the internal validation set and 0.7500 in the external validation set. The 1‐, 3‐, and 5‐year AUROCs were 0.830, 0.817, and 0.810 in the internal validation set, and 0.770, 0.813, and 0.787 in the external validation set. SHAP interpretation identified age, FIGO stage, and lymph node involvement as the leading contributors to OS prediction. Conclusions: We developed and externally validated an explainable RSF-based OS prediction model for vulvar cancer using a large population-based dataset and a multicenter Chinese cohort. The model showed robust discrimination, calibration, and potential clinical utility, supporting individualized risk stratification and follow-up planning.
First-in-human trial of BH-30643, a novel macrocyclic, non-covalent, mutant-selective OMNI-EGFR inhibitor, in <i>EGFR</i> -mutant ( <i>EGFR</i> m) NSCLC.
3014 Background: Macrocyclic next-generation tyrosine kinase inhibitors (TKIs) have transformed outcomes in ALK- and ROS1-positive NSCLC; such creatively designed medicines are similarly needed to improve outcomes in EGFR-mutant NSCLC. Using a novel, mutant-selective macrocyclic structure, BH-30643 was designed for super-potency against driver EGFRm, largely sparing wildtype (WT) EGFR, and with unique invulnerability to resistance from C797S with or without T790M. Here we report emerging first-in-human dose-escalation data from the SOLARA trial (NCT06706076). Methods: Phase 1 dose escalation used a BOIN design with backfill at potentially efficacious doses. Expansion cohorts targeted populations of interest. Patients (pts) had advanced NSCLC with EGFR and/or HER2 mutations detected on local testing (tissue or plasma). Measurable disease was required; asymptomatic untreated brain metastases (BM) were permitted. Objectives included safety, PK, and RECIST response rate (ORR). Plasma NGS was performed at baseline and on treatment. Results: As of 01/05/2026, 72 pts enrolled into dose escalation and backfill across 7 dose levels at a total daily dose of 20mg -160mg, median age 62, 44% Asian, 65% with history of BM, median of 3 prior lines of treatment (range 1-12). EGFR mutations included classical (38 pts), exon20ins (14 pts) and other/atypical (18 pts) or HER2 mutations (2 pts). Plasma exposures at doses of 40mg BID and above achieved > 10x coverage over target EC90 and exceeded exposure levels of most contemporary EGFR TKIs. Common TRAE ( > 10%) were WT EGFR-associated, including diarrhea (38%), rash (28%), fatigue (15%), stomatitis (13%), and were predominantly grade 1. Bilirubin elevation was seen in 26 pts (36%) related to off-target UGT1A1 inhibition (Gilbert’s-like). Grade 3 TRAE were seen in 15 pts (18%), most commonly bilirubin (8/15); DLTs included bilirubin increase and mucositis, occurring at doses ≥ 60mg BID. No pneumonitis was observed. Responses were observed across diverse EGFRm subsets, including in CNS. Including expansion pts, 28 pts enrolled with C797S on their most recent informative molecular testing (6 with concurrent MET+ or KRAS+), with 23 still on therapy. Of 17 with on-treatment scans, partial responses (confirmed or ongoing) were seen in 10 (59%); ORR was comparable with (50%) or without (66%) T790M. Of 9 pts with baseline C797S detected in ctDNA (3 with T790M), 7 had > 99% reduction of C797S VAF on treatment. Conclusions: Leveraging a novel macrocyclic scaffold, BH-30643 is the first TKI monotherapy to demonstrate clinical responses against C797S both with or without T790M. High plasma exposures combined with super-potency, CNS activity, and favorable safety offers potential for deep and durable EGFR inhibition. Enrollment into backfill and expansion cohorts is ongoing to better characterize activity in both TKI-naïve and resistant pts. Clinical trial information: NCT06706076 .
Mammography utilization and male breast cancer in BRCA1/2 carriers.
10563 Background: Males with pathogenic germline variants in BRCA1 /2 (BRCA+) have a 1-10% lifetime risk of developing breast cancer (MBC). NCCN guidelines recommend that BRCA+ males consider annual mammograms. We have prior shown low rates of mammography uptake in an academic cohort from Penn Medicine (PM). We sought to validate these findings about mammography in a national veteran (VA) cohort and to investigate the clinical characteristics of BRCA+ compared to nonBRCA+ MBC. Methods: We performed a retrospective analysis of 327 BRCA+ male veterans with no prior history of MBC. The electronic health record was reviewed to determine indication for and results of mammography episodes. A mammography episode was defined as all breast imaging studies obtained for asymptomatic screening or for symptoms within six months. The first mammogram episode identified was referred to as the “initial” mammogram and all other mammography episodes were “subsequent”. To determine BI-RADS PPV, data for 85 PM and 68 VA BRCA+ males were combined and compared to 1819 nonBRCA+ males. To determine clinical characteristics of MBC, data for 30 PM and 18 VA BRCA+ MBC were combined and compared to 104 PM and 122 VA nonBRCA+ MBC. Results: Sixty-eight (20%) of VA BRCA+ males underwent an initial mammogram, 57% of which were ordered for screening. Among patients ≥50 without mammography, 31% of individuals had no discussion documented and 66% had a shared decision-making discussion against screening with an ordering provider. BI-RADS 4 and 5 findings occurred in six and five mammograms, respectively. MBC was diagnosed in 13% (9/68) after initial and 13% (3/23) after subsequent mammography pooled VA and PM data showed that 95% (21/22) of MBC diagnoses in BRCA+ males were after a symptom-prompted mammogram. BI-RADS 4 PPV was higher in BRCA+ compared to non-BRCA+ men (75% vs 5%, p < 0.0001), and BI-RADS 5 PPV was similar (100% vs 67%, p = 0.0661). In an expanded cohort of 48 BRCA+ MBC compared to 226 nonBRCA+ MBC, median (IQR) age of diagnosis was 66 (56-73) vs 66 (59-74) (p = 0.52). The majority of BRCA+ and nonBRCA+ MBC were ER+Her2- (85% and 90%, respectively, p = 0.70). Among those with Oncotype testing, 93% BRCA+ BC had intermediate or high-risk recurrence scores compared to 50% of non-BRCA+ (p = 0.002). However, BRCA+ and nonBRCA+ male patients had similar rates of node positivity (40% vs 41%, p = 0.87) and progression to metastatic disease (19% vs 16%, p = 0.67). Conclusions: Analysis of a Veteran cohort of BRCA+ males confirms low rates of mammography as we prior reported in an academic cohort. Counseling and SDM were inconsistently documented, highlighting gaps in guideline implementation. Both BRCA+ and nonBRCA+ MBC were nearly always diagnosed based on symptoms. Both BRCA+ and nonBRCA+ MBC were often node-positive and nearly 20% progressed to metastatic disease. These characteristics suggest the need for prospective evaluation of mammography in high-risk males to reduce rates of advanced disease.
Demographic and clinical patterns of basosquamous carcinoma: An NCDB analysis.
e21548 Background: Basosquamous carcinoma (BSC) is a rare cutaneous malignancy with histopathologic features of both basal and squamous cell carcinoma, accounting for 1.2–2.7% of basal cell carcinomas. BSC exhibits higher recurrence and metastasis rates than either subtype alone, reflecting its potential for aggressive clinical behavior. Clinical management is challenged by limited population-level data and reliance on small institutional series, highlighting the need for broader epidemiologic characterization of this tumor. To address this, the National Cancer Database (NCDB) was analyzed to reveal demographic, socioeconomic, and clinical patterns among patients diagnosed with BSC in the United States. Methods: A retrospective cohort study of the NCDB identified confirmed cases of BSC diagnosed from 2004–2020 (ICD-O-3 code 8094). Demographic and clinical variables (age, sex, race, ethnicity, primary site, stage, urban/rural residence, income, insurance status, facility type, treatment, and survival) were summarized using descriptive statistics, and incidence trends were assessed via regression analysis. Results: A total of 413 patients were diagnosed with BSC from 2004–2020. Incidence was stable over the study period (R² = 0.97). The mean age at diagnosis was 67.8 years (SD = 14.3, range = 16–90 years), and the cohort was predominantly female (74.8%), White (87.2%), and non-Hispanic (90.3%). Most patients were Medicare-insured (55.9%) and treated at community (40.1%) or academic (35.4%) facilities. Patients primarily resided in metropolitan areas (85.2%) and were in the highest income quartile (≥$74,063; 36.0%). The most common primary sites were the vulva (37.0%), anal canal (12.3%), and anus (11.4%). Stage I disease predominated (36.3%), and mean tumor size was 34 mm. Surgery was the primary treatment (70.0%), with negative margins achieved in 55.0% of those cases. Radiation was administered in 34.9% and chemotherapy in 30.5% of cases. Two-, five-, and ten-year survival rates were 83.1%, 66.6%, and 44.1%, respectively, with mean survival of 114 months. Conclusions: To our knowledge, this is the first NCDB analysis of BSC, addressing an important gap in national epidemiologic data for this malignancy. BSC primarily affects older, non-Hispanic White females, is treated at community or academic centers, and typically presents at an early stage. Although HPV is a known driver of squamous cell carcinoma, no evidence currently links HPV to BSC, despite the anogenital distribution observed. Socioeconomic patterns, including the concentration of patients in metropolitan areas and the highest income quartile, may reflect structural factors affecting disease recognition and access to specialized care. Further research is needed to clarify how demographic and socioeconomic factors shape diagnosis, treatment patterns, and long-term outcomes in this rare but clinically significant malignancy.
Malnutrition as associated with high-risk airway failure phenotypes in hospitalized head and neck cancer: A national, site-specific analysis.
e23172 Background: Malnutrition is common in patients with head and neck cancer (HNC) and is associated with adverse outcomes, yet its role in acute airway failure is poorly characterized. Prior studies focus on mortality or length of stay without isolating airway-specific endpoints or accounting for tumor site heterogeneity. This study evaluated whether malnutrition independently increases the risk of acute airway compromise and defines inpatient airway risk phenotypes across HNC subsites. Methods: A retrospective, survey-weighted analysis of the National Inpatient Sample (NIS), 2016 to 2023, was performed, including adults hospitalized with HNC identified using ICD-10-CM codes C00 to C14 and C30 to C32. Tumors were categorized by first-hit anatomic site. Malnutrition was defined using a narrow definition (E43, E44, E46) and a broad sensitivity definition (E43, E44, E46, R64). Palliative admissions (Z51.5) were excluded. Primary outcomes were airway failure proxies, mechanical ventilation and tracheostomy. Secondary outcomes included shock, in-hospital mortality, length of stay (LOS), and hospitalization cost. Survey-weighted logistic, linear, and gamma-log models adjusted for demographics, payer, socioeconomic status, admission characteristics, hospital factors, tumor site, comorbidity burden, and year. Results: Among 112,495 HNC hospitalizations (weighted national estimate approximately 562,000), 29.0% met the narrow malnutrition definition. Malnutrition was independently associated with mechanical ventilation (OR 1.32, 95% CI 1.13 to 1.53), tracheostomy creation (OR 1.58, 95% CI 1.36 to 1.84), and in-hospital mortality (OR 1.29, 95% CI 1.04 to 1.60). Adjusted absolute risk differences included increases in mechanical ventilation of 2.07% (95% CI 1.64 to 2.49), tracheostomy of 6.21% (95% CI 5.61 to 6.81), mortality of 0.85% (95% CI 0.61 to 1.09), and shock of 0.60% (95% CI 0.40 to 0.81). Mortality varied by airway phenotype, from 1.34% (95% CI 1.26 to 1.42) without airway intervention to 22.18% (95% CI 20.89 to 23.54) with mechanical ventilation alone. LOS increased stepwise from 5.5 days (95% CI 5.46 to 5.55) to 18.7 days (95% CI 18.1 to 19.3) with combined mechanical ventilation and tracheostomy. Malnutrition was associated with approximately 35% higher hospitalization costs (gamma-log coefficient 0.30, 95% CI 0.27 to 0.34), with mean costs ranging from $21,387 to $86,519. Results were consistent using the broad malnutrition definition, with highest baseline airway risk in laryngeal and hypopharyngeal cancers. Conclusions: Malnutrition is an independent determinant of acute airway failure, mortality, and healthcare utilization in hospitalized patients with HNC. Distinct airway failure phenotypes are defined by malnutrition, with large absolute differences in mortality, LOS, and cost, supporting early nutritional risk stratification.
The influence of COVID-19 severity on the local lung hormonal profile in patients with non-small cell lung cancer.
e20047 Background: Lung cancer is a leading cause of cancer-related mortality, with pronounced sex differences. The COVID-19 pandemic, which has sex-specific characteristics, highlights the role of sex hormones in the immune response. Since lungs are a hormone-sensitive organ that expresses receptors for a range of hormones, the level of the hormones in normal and abnormal lung tissue in the context of previous COVID-19 requires further investigation. The aim of the research was to investigate the influence of previous COVID-19 of varying severity on the levels of sex hormones and cortisol in the lung tissue of patients with non-small cell lung cancer (NSCLC). Methods: The study included 60 patients (mean age 59.1±2.9 years) with stage I-IIIA NSCLC and a history of SARS-CoV-2 infection. Based on infection severity, two groups were formed: main (n=30, severe infection requiring hospitalization) and control (n=30, asymptomatic/mild infection), comparable in age and sex. Concentrations of estradiol (E2), testosterone (T), progesterone (P4), and cortisol were measured in lung tumor and adjacent normal resection margin tissue using ELISA. Statistical analysis used Student's t-test and Mann-Whitney U-test; only significant differences (p<0.05) are reported. Results: Severe COVID-19 leads to significant changes in the hormonal background in the resection line tissue, especially in women: there were an increase in the levels of E2 (1.7 times), P4 (4.1 times), and cortisol (1.5 times), while the levels of T decreased (1.3 times) compared to the control group. In the main group of men, the levels of T and P4 increased in the resection line tissue (1.8 times), while the levels of E2 and cortisol did not change. The effect of severe COVID-19 on tumor tissue parameters was less pronounced: in patients of both sexes in the main group, the E2 level was significantly higher by an average of 1.7 times, and in women, the cortisol content also increased by 1.8 times, compared to the control values. Conclusions: Result obtained indicates that the key target for hormonal changes induced by severe COVID-19 in patients with NSCLC is not so much the tumor as the relatively healthy lung tissue. This may indicate a systemic influence of the infectious disease on the hormonal homeostasis of the entire organ. The increased vulnerability of women (hyperestrogenism, hypercortisolemia) suggests an increased risk of more aggressive NSCLC, as estrogen stimulates proliferation as well as cortisol suppresses immunity. The data obtained suggest that COVID-19, by modulating the hormonal environment in the lungs, may affect the course and prognosis of lung cancer, which requires further study in the context of disease risks, response to therapy, and long-term outcomes.
The role of NECTIN4 in shaping the tumor microenvironment and potentiating the efficacy of immunotherapy in bladder cancer.
4574 Background: The EV-302 trial established enfortumab vedotin plus pembrolizumab (EV/P) as first-line therapy for metastatic urothelial carcinoma (UC). Although EV/P is administered without NECTIN4 testing based on the assumption of uniform NECTIN4 expression, real-world data have identified NECTIN4-low tumors associated with inferior responses to EV, highlighting the need for NECTIN4-based precision therapy. We aimed to define the molecular and immunologic roles of NECTIN4, identify predictive biomarkers of EV/P outcomes, and explore rational therapeutic strategies for NECTIN4-low UCs. Methods: We performed multi-omics analyses of 817 UC cases integrating whole-exome sequencing, RNA-seq, multiplex immunofluorescence, and spatial single-cell profiling (CODEX). We evaluated associations among NECTIN4 status, molecular subtype, tumor microenvironment (TME), survival, and response to immune checkpoint inhibitors. Basal bladder cancer (BC) cell lines and orthotopic MB49 bladder cancer models with NECTIN4 overexpression (OE) or control were used to assess tumor biology and therapeutic response. Results: Clustering by NECTIN4 H-score and molecular subtype revealed that basal/squamous (Ba/Sq) muscle-invasive BCs with low NECTIN4 had significantly worse survival outcomes than NECTIN4-high tumors in both our cohort (P=0.001) and the IMvigor210 trial (P=0.019). In vitro, NECTIN4 OE in basal BC cells suppressed proliferation and migration through downregulation of inflammation-related signaling pathways. CIBERSORTx and EcoTyper analysis of RNA-seq data indicated a more immune-inflamed TME in NECTIN4-high Ba/Sq tumors. Spatial single-cell profiling showed increased CD8+ T cells, particularly CD8+/TIGIT+ cells, in NECTIN4-high Ba/Sq UCs. Moreover, in orthotopic mouse models, NECTIN4-OE tumors exhibited reduced growth and increased CD8+ T-cell infiltration. Clinically, NECTIN4-high Ba/Sq tumors showed higher objective response rate (ORR) to pembrolizumab/avelumab than NECTIN4-low tumors (55.5% vs 0%, P=0.002) in our cohort; in IMvigor210, NECTIN4-high Ba/Sq patients also had superior ORR (38.5% vs 15.6%, P=0.025). Additionally, in orthotopic mouse models, EV/P showed limited efficacy in NECTIN4-low tumors, whereas NECTIN4-OE tumors responded well. Transcriptomic analyses identified histone deacetylases (HDAC) as potential targets in NECTIN4-low tumors; accordingly, HDAC inhibitors demonstrated greater efficacy in NECTIN4-low basal BCs in vitro and vivo. Conclusions: NECTIN4 influences tumor progression and shapes the TME, thereby impacting immunotherapy efficacy. NECTIN4 is a potential predictive biomarker for survival and for outcomes with immunotherapy and EV/P in Ba/Sq UCs. NECTIN4-low Ba/Sq tumors may require alternative strategies, and HDAC inhibition represents a rational therapeutic approach for NECTIN4-low Ba/Sq UC patients.
Cardiotoxicity diagnoses and inpatient outcomes in principal breast cancer hospitalizations: National Inpatient Sample, 2018–2023.
e24036 Background: Cardiotoxicity diagnoses are increasingly recognized among patients with cancer, yet national data describing their association with inpatient severity, mortality, and resource utilization during breast cancer hospitalizations remains limited. Methods: A retrospective cross-sectional analysis of the 2018–2023 National Inpatient Sample was performed. Adult hospitalizations with a principal diagnosis of breast cancer (ICD-10-CM C50*) were included. Cardiotoxicity was defined by the presence of myocarditis (I40*), cardiomyopathy or heart failure (I42*/I50*), or arrhythmia (I47–I49*) in any diagnosis position. Outcomes included in-hospital mortality (primary), shock (R57*), mechanical ventilation (ICD-10-PCS 5A1935Z/5A1945Z/5A1955Z), extreme APR-DRG severity, length of stay (LOS), and hospitalization cost. Costs were derived using hospital-specific cost-to-charge ratios. National estimates accounted for NIS stratification, clustering, and discharge-level weighting. Multivariable survey-weighted logistic and linear regression models compared outcomes by cardiotoxicity status, adjusting for age, sex, year, race, payer, ZIP-code income quartile, elective admission, and hospital teaching status and region. Sensitivity analyses restricted cardiotoxicity to secondary diagnosis positions (DX2–DX40). Results: Among 32,672 unweighted principal breast cancer hospitalizations (weighted N = 163,360), cardiotoxicity was present in 11.7% (weighted n = 19,050). Crude mortality was higher among hospitalizations with cardiotoxicity compared with those without (6.77% vs 2.93%), as were shock (1.55% vs 0.45%) and mechanical ventilation (1.68% vs 0.59%). In adjusted analyses, cardiotoxicity was independently associated with increased odds of extreme severity (OR 2.92, 95% CI 2.29–3.71), in-hospital mortality (OR 1.54, 95% CI 1.28–1.85), shock (OR 2.65, 95% CI 1.74–4.05), and mechanical ventilation (OR 2.69, 95% CI 1.88–3.87). Cardiotoxicity was also associated with longer LOS (+1.11 days, 95% CI 0.86–1.36) and higher adjusted hospitalization cost (+$1,714, 95% CI $642–$2,786). Associations persisted in sensitivity analyses restricted to secondary diagnoses, including mortality (OR 2.41, 95% CI 2.08–2.78) and mechanical ventilation (OR 2.87, 95% CI 2.15–3.82). Conclusions: In nationally representative hospitalization-level data, cardiotoxicity diagnoses were common among principal breast cancer admissions and were independently associated with greater inpatient severity, mortality, critical care utilization, LOS, and costs. These findings identify cardiotoxicity as a high-risk inpatient phenotype with important implications for resource utilization and inpatient care pathways.
Evidence-linked complementary care AI supporting standard oncology: Real-world outcomes in pancreatic, HNSCC, and prostate cancer.
e23381 Background: Complementary care may improve oncology treatment tolerance but often lacks rigorous safeguards. We developed an evidence-linked AI system generating individualized supportive protocols (micronutrients aligned with DNA damage response) under strict "No evidence → No claim" constraints. This system integrates with standard-of-care (SoC) to enhance safety and auditability. Methods: We established a prospective registry (N = 23; data cutoff 01/07/2026) with structured clinical/SoC data capture. This retrospective analysis of de-identified secondary data was deemed exempt by Advarra IRB (Protocol BTBC-2026-00; Ref Pro00092368). AI logic selected supportive products by matching micronutrient mechanisms to DNA damage pathways within safety constraints. The AI platform employed a locked prompt sequence (Extract → Validate → Transform → Analyze → Narrate) to construct an evidence ledger comprising verified data (Level 1) and derived outcomes (Level 2). Outcomes were compared between adherence levels (0/1/2) using covariate-adjusted Restricted Mean Survival Time (RMST) truncated at 12 months. RMST regression utilized pseudo-observations (R package pseudo) adjusting for age, gender, stage, and time-to-entry. Immediate non-cancer deaths in non-adherent patients were excluded to prevent bias. Toxicity metrics were assessed via multivariable regression; missing data used complete-case analysis. Results: Among 23 patients (Full Adherence n = 17; Lower Adherence n = 6), higher adherence was associated with superior outcomes: Mean planned dose intensity (PDI) was 18.3% higher (95% CI: 10.5 to 26.1, estimated) 55% reduction in treatment interruptions (IRR 0.45) 9.2 fewer grade ≥2 adverse event days per patient (95% CI: -13.5 to -4.9) 85% faster resolution of adverse events (HR 1.85) 48% fewer unplanned acute-care visits (IRR 0.52) 88% of patients reported stable or improved quality of life In the covariate-adjusted RMST analysis truncated at 12 months, each level increase in adherence (0 to 1 to 2) yielded +1.55 months of survival; full adherence (Level 2) was associated with a +3.1-month survival gain compared to non-adherence (Level 0) after adjusting for age, gender, stage, and time-to-entry. Although the survival trend was positive (p = 0.088), statistical significance was limited by sample size. CBR increased from 47.4% (low) to 95.5% (full). No safety events were attributed to the protocol. Conclusions: An AI-driven complementary care system demonstrated reductions in adverse events and acute-care visits, improved chemotherapy dose delivery, and suggestive survival benefits (+3.1 months in full adherence; p = 0.088). This structured, evidence-based approach ensures auditability. A larger prospective, multi-site validation is recommended to confirm these findings and explore subgroup-specific effects.
Network meta-analysis of first-line therapies for unresectable HER2-negative gastric/gastroesophageal junction adenocarcinoma: Efficacy and safety of novel combinations versus standard chemoimmunotherapy.
e16045 Background: For patients with unresectable HER2-negative advanced gastric or gastroesophageal junction adenocarcinoma, first-line chemotherapy alone provides limited benefit. Combining novel agents—including immune checkpoint inhibitors (ICIs), adoptive cell therapy (ACT), and targeted therapies—with chemotherapy may improve outcomes. This network meta-analysis (PROSPERO: CRD420251058622) comprehensively compares the efficacy and safety of these emerging first-line regimens. Methods: We systematically searched PubMed, EMBASE, the Cochrane Library, and conference abstracts (Jan 2013–Aug 2025) for randomized controlled trials evaluating first-line systemic treatments. A frequentist random-effects network meta-analysis was performed to synthesize evidence on overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs). Results: Twenty-nine trials (14,318 patients, 18 regimens) were included. ACT combined with triplet chemotherapy ranked highest for improving PFS (P-score: 0.94) and ORR (SUCRA: 91.1), and showed a significant OS benefit over doublet chemotherapy (HR 1.49, 95% CI 1.06–2.09). Adding a PD-1 inhibitor to doublet chemotherapy significantly improved both OS and PFS. Bispecific antibodies demonstrated considerable efficacy: PD-1/CTLA-4 bispecific antibody plus doublet chemotherapy ranked first for OS (P-score: 0.86) and third for PFS (P-score: 0.88); PD-L1/TGF-β bispecific antibody plus doublet chemotherapy ranked second for OS (P-score: 0.86) and third for ORR (SUCRA: 82.9). MET inhibitor plus triplet chemotherapy ranked second for PFS (P-score: 0.89) and ORR (SUCRA: 87.6) and third for OS (P-score: 0.86). Other targeted agents (anti-EGFR, anti-VEGF, TKIs) combined with chemotherapy did not confer significant survival advantages. All chemotherapy-based combinations increased the risk of grade ≥3 TRAEs versus doublet chemotherapy, with safety profiles consistent with known toxicity patterns and no new safety signals. Conclusions: Beyond standard chemoimmunotherapy, ACT-based combinations and bispecific antibody regimens show meaningful survival benefits with acceptable toxicity. This is the first network meta-analysis to evaluate the clinical applicability of ACT and bispecific antibodies in the first-line setting for advanced gastric cancer. These findings support the consideration of novel immunotherapeutic combinations and may inform future trial design.
Stomatitis as a harbinger of harm: Long-term mortality and multiorgan adverse events associated with immune-related stomatitis in checkpoint inhibitor-treated melanoma—A propensity score–matched cohort study.
e21600 Background: Immune checkpoint inhibitors (ICIs) have revolutionized treatment for advanced malignant melanoma, but immune-related adverse events (irAEs) such as stomatitis may impact long-term outcomes. The association between stomatitis and subsequent morbidity, including mortality and systemic irAEs, remains underexplored. To evaluate the long-term effects of stomatitis on mortality and other adverse outcomes in melanoma patients receiving ICIs. Methods: Retrospective cohort study using the TriNetX federated database (deprecated COVID-19 Research Network, 88 healthcare organizations). Patients aged ≥18 years with malignant melanoma (ICD-10-CM C43) receiving ICIs (pembrolizumab, nivolumab, or ipilimumab) were divided into cohorts with (n = 1,719) and without (n = 22,228) stomatitis (ICD-10-CM K12). Propensity score matching (PSM) balanced cohorts on demographics, BMI, ECOG score, and comorbidities, yielding 1,708 patients per group. Exposures included-Stomatitis during ICI therapy. Main Outcomes and Measures--Primary outcome: all-cause mortality. Secondary outcomes: respiratory diseases, dysphagia, malaise/fatigue, trismus, fever, circulatory/respiratory symptoms, endocrine/metabolic diseases, circulatory diseases, and digestive diseases. Analyses included risk ratios (RRs), odds ratios (ORs), hazard ratios (HRs) from Kaplan-Meier survival, and mean instances, starting 1 day post-index event (first ICI administration). Results: After PSM, the stomatitis cohort had a higher mortality risk (37.3% vs 31.4%; RR, 0.842 [95% CI, 0.765-0.926]; HR, 0.829 [95% CI, 0.737-0.933]; P = 0.002 for log-rank). Respiratory diseases were more common (53.3% vs 43.3%; RR, 0.813 [95% CI, 0.721-0.917]; P = 0.001; HR, 0.711 [95% CI, 0.600-0.842]; P < 0.001). Dysphagia instances were higher (mean 2.913 vs 2.121; P = 0.023), though risk was borderline (11.2% vs 9.1%; RR, 0.806 [95% CI, 0.648-1.003]; P = 0.053). Circulatory/respiratory symptoms (49.2% vs 42.3%; RR, 0.860 [95% CI, 0.758-0.975]; P = 0.020) and circulatory diseases (59.5% vs 51.5%; RR, 0.866 [95% CI, 0.757-0.990]; P = 0.041; HR, 0.690 [95% CI, 0.562-0.847]; P < 0.001) were elevated in the stomatitis group. No significant differences for malaise/fatigue, trismus, fever, endocrine, or digestive diseases. Conclusions: Stomatitis during ICI therapy for melanoma is associated with increased long-term mortality and select irAEs, particularly respiratory and circulatory complications. These findings suggest stomatitis may signal broader immune dysregulation, warranting closer monitoring.
Impact of prophylactic cyclophosphamide on ALC and delayed neurotoxicity after cilta-cel.
7543 Background: Delayed neurotoxicity (DNT) after ciltacabtagene autoleucel (cilta-cel) is associated with severe morbidity and mortality occurring in 10-15% of patients. A high post-infusion peak absolute lymphocyte count (ALCpeak ≥3x10 9 /L; ALC hi ) is correlated with an increased risk of DNT (25-30%). We previously examined prophylactic dexamethasone (PPX DEX) administered for 3 days when ALC hi was reached and found no reduction in ALC expansion, DNT incidence or severity. Here, we report the use of prophylactic cyclophosphamide (PPX CTX) on ALC kinetics and DNT. Methods: We conducted a retrospective analysis of patients (pts) treated with cilta-cel at Mayo Clinic (09-12/2025; n =60). Pts with ALC hi received CTX 500 mg IV/PO once (n = 22). Outcomes and ALC kinetics including ALCpeak, ALC D28 (ALC D28 ), and area under the curve D1-D28 (ALC AUC ) were compared with PPX DEX cohort (12/2024-08/2025; n =50) and a historical cohort without PPX (04/2022-11/2024; n =116). Results: Pre-lymphodepletion (LD) demographics were similar across historical ALC hi , PPX DEX, and PPX CTX groups. Pre-LD CRP was higher in the historical ALC hi cohort; however, baseline ferritin, CRS, and ICANS, and disease burden did not differ significantly between groups. There were no statistically significant differences in time to ALCpeak or ALC kinetics among the 3 cohorts. Among pts with ALC < 3×10⁹/L treated during the PPX CTX study period, 2 developed cranial nerve palsy (IEC-CNP; 2/38, 5%). Both presented with unilateral facial nerve palsy and were treated with corticosteroids. One pt resolved symptoms by one month, while the second had persistent symptoms at 2 weeks and remains on follow-up. Among ALC hi patients in the PPX CTX cohort, DNT occurred in 4/22 pts (18%), including 1 case of IEC-CNP (5%) and 3 with parkinsonism (IEC-PKS, 14%). Within the PPX CTX cohort, baseline characteristics and post-infusion CRS or laboratory parameters did not differ between patients with and without DNT. Among patients who developed DNT, ALC kinetics were similar across PPX CTX, PPX DEX, and historical cohorts. PPX CTX was well tolerated, with 2 cases of grade 1 nausea reported. The incidence of DNT did not differ significantly between the PPX DEX (14/61, 23%) and PPX CTX (4/22, 18%) cohorts. However, DNT presentations in the PPX CTX cohort appeared milder and were responsive to treatment. Two of three patients (67%) presented with mild symptoms (one with dynamic dysphasia; second with flat affect) that responded to DEX. A third patient presented with typical parkinsonian features (hypomimia, bradykinesia, rigidity) and demonstrated clinical improvement following high-dose CTX. Conclusions: PPX CTX was well tolerated. While it did not significantly impact ALC expansion kinetics or DNT rates, first few cases of IEC-PKS suggest that the presentation may be milder and amenable to less toxic treatment. Larger cohorts are needed to refine optimal prophylactic strategies.
Analysis of circulating small extracellular vesicle-associated miRNA in head and neck squamous cell carcinoma (HNSCC): Biomarker discovery in pre-operative neoadjuvant nivolumab.
2577 Background: Standard treatment options for HNSCC include chemotherapy, radiation, surgery, and immunotherapy. Immune Checkpoint Inhibitors (ICI) are safe and improve survival in platinum-refractory and metastatic HNSCCs. Further studies are needed to efficiently stratify patients who may benefit from ICIs. MYC-V1 is a family of oncogenes, induced by MYC signaling, that is negatively correlated with response to ICI in HPV+ HNSCC. Non-invasive Biomarkers (NiBs) identifying patients with low MYC-V1 expression may aid in predicting response to ICIs. Small extracellular vesicles (sEVs) are membrane-bound mediators of intercell communication that are present in circulation, serving as a promising source of NiBs. The Let-7 family of tumor suppressors are negative regulators of the MYC-V1 gene family and exhibit low expression in HNSCC compared to healthy controls. Let-7 family members, such as Let-7d and Let-7c, may play a role in ICI responsiveness via PD-L1 and MYC mRNA degradation, respectively. Here, we analyze the miRNA profile of sEVs from patients enrolled in a randomized Phase I clinical trial undergoing Neoadjuvant Nivolumab therapy. (NCT03238365). Methods: Plasma was collected before and after treatment (N=24) with ICI. 12 patients were included and stratified based on HPV status (6 HPV-, 6 HPV+) and pathologic treatment response (pTR) (6 Responders [R], 6 Nonresponders [NR]). pTR >20% of tumor surface area as graded by two pathologists was R; 0% was NR. sEVs were isolated via immunoprecipitation targeting tetraspanins CD63/9/81. miRNA was isolated and NGS was performed. Analysis was performed using Python and Biomni. Log2FC (FC) compared expression levels between groups and a False Discovery Rate (FDR) <.05 was significant. Results: 189 miRNAs were detected in HNSCC sEVs. Analysis comparing HPV+ R vs NR revealed 48 miRNAs with significantly different levels between these pretreatment groups. 47 were more abundant in R; 1 was less abundant. miRNAs found at higher levels in HPV+ R include the Let-7 family. Let-7d was most abundant (FC: 2.26, FDR 0.04), with a family (Let-7a,b,d,f,g,i) FC range of 1.63-2.26 (FDR 0.03-0.05). Following treatment with ICI, HPV+ patients had increased Let-7c levels (FC 4.71, FDR 0.02) compared to pretreatment. Analysis of HPV– R vs NR showed 0 miRNA that met statistical significance. Conclusions: Here, we show that ICI-responsive HPV+ HNSCC is associated with high levels of circulating, sEV-contained Let-7 family members and that Let-7c is increased in response to ICI in those same patients. We propose that a MYC-V1-suppresive, PD-L1-destabilizing mechanism may be present in patients with higher than average Let-7 expression, conferring sensitivity to ICI, and that sEV-associated Let-7 levels may serve as NiBs to identify these patients as favorable ICI candidates prior to treatment.
Population-based prediction of cardiovascular mortality in gynecologic cancer survivors using machine learning (RISKHEART).
5518 Background: General-population cardiovascular disease (CVD) risk scores underperform in cancer survivors by failing to capture treatment-related cardiotoxicity. Gynecologic cancer survivors constitute a distinct phenotype defined by older age and heterogeneous therapies. RISKHEART is an oncology-specific, survivorship-oriented model for individualized cardiovascular risk stratification. Methods: Women with primary gynecologic malignancies diagnosed between 2000 and 2020 were identified from the SEER program. Predictors included demographics (age, race, marital status) and SEER-available treatment variables (surgery, radiation, and chemotherapy [yes/no]). Model performance was evaluated using AUC, and explainability was assessed via SHAP. Results: The study included 104,384 women with gynecologic cancer. CVD-specific death occurred in 4,962 patients, with cumulative incidence rates of 2.44% at 5 years and 4.75% at 10 years. Affected patients were significantly older at diagnosis than those without CVD death (mean age, 75.0 vs 62.5 years; P < .001). CVD mortality differed by marital status and race (both P < .001), with widowed patients accounting for a higher proportion of CVD deaths (37.3% vs 17.7%). Endometrial cancer accounted for most CVD deaths (58.2%), whereas ovarian cancer was underrepresented among CVDs deaths relative to its prevalence in the overall cohort (15.1% vs 27.8%). In the independent testing cohort, the RISKHEART model demonstrated good discrimination for 10-year cardiovascular mortality (AUC, 0.786). For 5-year cardiovascular mortality, discrimination was slightly higher (AUC, 0.796), with sensitivity of 0.73 and specificity of 0.74. For the 5-year cardiovascular mortality model, discrimination remained elevated across 2000-2009 (AUC, 0.805) and 2010-2020 (AUC, 0.784). Explainability analyses identified age at diagnosis as the dominant predictor of cardiovascular death, with treatment-related variables contributing more prominently to short-term risk and sociodemographic factors increasing in relative importance over longer follow-up. Conclusions: In this large population-based cohort of gynecologic cancer survivors, the RISKHEART ML model demonstrated clinically meaningful discrimination for predicting CVD-specific mortality. This approach may support individualized CVD risk stratification and inform survivorship care.
Prediction of progression in MGUS using transformer-based survival time-series modeling.
7518 Background: Monoclonal gammopathy of undetermined significance (MGUS) is common, yet only a minority progress to malignant plasma-cell disorders. Mayo risk stratification uses baseline factors and is commonly implemented/validated in a Cox proportional hazards (CoxPH) framework, which may miss prognostic longitudinal patterns. Methods: We assembled 15,158 MGUS patients with longitudinal laboratory data and progression outcomes (smoldering multiple myeloma, multiple myeloma, AL amyloidosis, or Waldenström macroglobulinemia). We compared a Mayo-factor Cox proportional hazards (CoxPH) baseline versus STRaTS, a transformer-based survival model, to predict progression risk at 3-, 5-, and 10-year horizons. STRaTS leveraged longitudinal trajectories of routine labs including hemoglobin, platelets, differential counts (neutrophils/lymphocytes/monocytes), immunoglobulins (IgG/IgA/IgM), free light chains (kappa/lambda), M-spike, and creatinine. To minimize bias, we used laboratory results collected from 1–3 years after diagnosis and started follow-up at year 3; patients progressing before year 3 or lacking follow-up beyond year 3 were excluded. A total of 7,305 patients met eligibility and were split into train/validation/test cohorts of 4,383/1,461/1,461. Discrimination was assessed by concordance index (C-index). Clinical operating performance was evaluated on a held-out test cohort by comparing sensitivity and specificity at the same proportion of patients selected for intensified surveillance (same workload). Results: Among MGUS patients with complete baseline Mayo factors(N=3,388), Kaplan–Meier–estimated 3-/5-/10-year cumulative progression risk was 0.1/0.4/3.4% (Low), 3.0/4.3/7.9% (Low-Intermediate), 4.4/6.4/14.1% (High-Intermediate), and 8.9/12.5/16.9% (High). On a held-out test cohort, STRaTS demonstrated superior discrimination versus the Mayo-factor CoxPH (C-index 0.75 vs 0.538; p<0.0001). Both models were trained and evaluated on identical train/test splits. At the same surveillance workload, STRaTS achieved higher sensitivity with comparable specificity; when 40.3% of patients were selected for closer surveillance, 3-year sensitivity was 81.0% for STRaTS versus 47.6% for CoxPH (Table). Conclusions: Among MGUS patients who remain progression-free at 3 years, transformer-based survival modeling of longitudinal laboratory trajectories provides more accurate individualized conditional progression risk estimates and improved workload-matched identification of progressors compared with the conventional Mayo/Cox approach. Sensitivity/specificity (%). Operating Point Flagged % STRaTS Sens / Spec (%) CoxPH Sens / Spec (%) Int+High, 3y 40.3 81.0 / 58.5 47.6 / 58.9 Int+High, 5y 40.3 81.2 / 60.4 46.9 / 58.8 Int+High, 10y 40.3 25.0 / 56.3 23.8 / 58.7 Two-Group High (≥2 factors), 5y 5.6 37.4 / 93.4 35.4 / 93.1
Real-world outcomes and circulating tumor DNA (ctDNA) dynamics in patients (pts) with microsatellite instability–high (MSI-H) metastatic colorectal cancer (CRC) treated with immune checkpoint inhibitors (ICI).
3516 Background: ICIs produce durable benefit in MSI-H CRC, yet optimal treatment duration and monitoring strategies remain unclear. ctDNA enables minimally invasive assessment of molecular response during and after ICI. We evaluated real-world treatment patterns, outcomes, and longitudinal ctDNA dynamics in pts with MSI-H CRC treated with ICI. Methods: Pts with MSI-H mCRC treated with first-line ICI were identified from Natera’s Real-World Database with linked longitudinal ctDNA results (Signatera, Natera, Inc.) and commercial claims data (Forian’s Hybrid data ecosystem, CHRONOS). Overall survival (OS) was estimated using available mortality data (Veritas Data Research, Fact of Death Mortality Data Index). ctDNA status was assessed pre-ICI when available and longitudinally following ICI initiation. Outcomes included OS and time to next trmt (TTNT); ctDNA dynamics following ICI discontinuation were descriptively evaluated. Results: Among 559 pts treated with first line ICI (pembrolizumab [70.1%], ipilimumab+nivolumab [15.7%], and nivolumab [11.8%]), the median duration of ICI was 266 days. Baseline (pre-ICI) ctDNA results were available for 180 pts, including 38% who were treated with chemotherapy, and most pts (71.7%, 129/180) were ctDNA-positive (ctDNA(+)) prior to ICI initiation. Of these, 89.9% (116/129) had ctDNA-timepoints after the start of ICI, and 81.0% (94/116) achieved anytime ctDNA clearance (from ctDNA(+) to negative), while 19.0% (22/116) remained ctDNA(+). ctDNA(+) at anytime after the start of ICI (HR: 8.0, p < 0.0001) or on first result after the start of ICI (HR: 3.4, p < 0.0001) was associated with inferior OS compared ctDNA-negativity (ctDNA(-)) at these time points. Among pts whose first post-ICI test was ctDNA(+), 32% switched treatments, with a median TTNT of 302 days, compared to only 6.6% of pts (median TTNT 683 days) whose first post-ICI test was ctDNA(-). First post-ICI ctDNA status was associated with longer ICI duration (median 192 days for ctDNA(+) vs 303 days for ctDNA(-)), and ctDNA(+) was predictive of inferior OS (HR: 4.9; p < 0.001). ctDNA after the end of ICI was available for 392 patients; it was persistently negative in 77.2% (303/392), persistently positive in 12.8% (50/392), cleared after the end of ICI (positive to persistently negative) in 4.1%, and the remaining 5.9% had variable patterns (e.g. positive to negative to positive). Conclusions: In this large real-world cohort of MSI-H mCRC treated with ICI, longitudinal ctDNA dynamics strongly correlated with treatment durability, time to subsequent therapy, and OS. These findings support further evaluation of ctDNA to inform treatment duration and surveillance strategies in MSI-H mCRC.
Real-world impact of first immunotherapy infusion timing on outcomes in locally advanced non-small cell lung cancer.
8071 Background: Emerging evidence suggests that earlier time-of-day (ToD) infusion of immune checkpoint inhibitors (ICIs) is associated with improved progression-free survival (PFS) and overall survival (OS) in patients with advanced non-small cell lung cancer (NSCLC). Although the timing of the initial infusion may be particularly influential, its impact on outcomes in earlier stages of NSCLC remains unclear. We investigated the association between first ICI infusion ToD and clinical outcomes in a racially and ethnically diverse population with locally advanced NSCLC. Methods: We conducted a retrospective cohort study of patients with locally advanced NSCLC treated with definitive chemoradiation followed by consolidation durvalumab between 2018-2025. Patient demographics, smoking status, ECOG performance status, PD-L1 tumor proportion score (TPS), lung cancer stage and histology, disease volume (DV), mean heart dose, and clinical outcomes were all obtained using chart review. Neighborhood distress was classified using patient zip codes and the Distress Communities Index. ICI administration timing was categorized into quartiles: ≤11:20 AM, 11:20 AM-12:32 PM, 12:32 PM-13:48 PM, >13:48 PM. Kaplan Meier methods and cox proportional hazards models, adjusted for major patient factors, were used to evaluate OS and PFS. Results: Among 109 eligible patients (median age 69.5 years), 55% were male, 42% were Non-Hispanic Black, 30% were Hispanic, 64% resided in distressed ZIP codes. Patients receiving ICIs in the latest ToD quartile (>13:48) had a significantly shorter PFS compared to those treated in the earliest quartile (≤11:20) in both univariate (HR 2.10, p=0.024) and multivariate analysis (HR 3.32, p=.0.0057). A non-significant trend towards inferior OS was also observed with later ToD administration. Higher DV (HR 1.09 per 10 mL, p=0.029) and mean heart dose (HR 1.86, p=0.03) were independently associated with worse OS. Conclusions: In this real-world study of a diverse population with locally advanced NSCLC, later ToD ICI administration (>13:48) was associated with a significantly shorter PFS and a trend towards worsened OS. These findings suggest that the timing of ICI delivery may influence outcomes in locally advanced NSCLC, consistent with prior observations in metastatic disease, and highlight the need for prospective trials to validate the impact of infusion timing on survival and clarify the underlying circadian mechanisms contributing to these differences. Multivariable Cox regression analysis. OS PFS HR 95% CI p-value HR 95% CI p-value ToD of First Infusion ≤11:20 - - - - - - 11:20-12:32 1.53 0.57,4.10 0.40 1.68 0.75,3.80 0.21 12:32-13:48 0.48 0.15,1.59 0.23 1.30 0.53,3.16 0.57 >13:48 1.66 0.62,4.45 0.31 3.32 1.39,7.92 0.007 Mean Heart Dose (Gy) 1.86 1.06,3.26 0.030 1.54 0.98,2.42 0.060 Disease Volume (mL) 1.09 per 10 mL 1.01,1.17 0.029 1.03 per 10 mL 0.97,1.09 0.29
Effect of statins on outcomes in renal cell carcinoma patients undergoing immune checkpoint inhibitor therapy: A retrospective US cohort study.
e16553 Background: Immune checkpoint inhibitors (ICI) have transformed the treatment of renal cell carcinoma (RCC). Statins possess pleiotropic anti-tumor effects, including anti-inflammatory and immunomodulatory properties that may influence ICI efficacy and toxicity. However, real-world data evaluating their impact on outcomes in RCC are limited. Methods: We conducted a retrospective cohort study using the TriNetX database, including adults (≥18 years) with RCC treated with ICIs. Patients were categorized by statin exposure during ICI therapy. Cohorts were 1:1 propensity score–matched (PSM) for age, sex, race, comorbidities, and concomitant medications. Outcomes over a 3-year follow-up period included overall mortality, immune-related adverse events (irAEs), and major adverse cardiovascular events (MACE). Cox proportional hazards models and Kaplan–Meier survival analyses were performed. Results: A total of 6,162 patients without statin exposure and 4,633 with statin exposure met eligibility criteria. After 1:1 PSM, 2,787 patients were included in each cohort. Baseline characteristics were statistically similar (p > 0.05) (Table 1). After a 3-year follow-up period, statin use was associated with significantly increased survival (63.1% vs. 49%; p < 0.01). There was decreased risk of mortality in this cohort (28% vs. 36%; hazard ratio [HR] = 0.63, 95% CI 0.57-0.69). Median overall survival was not reached in the statin cohort compared with 1,074 days in the non-statin cohort. Statin exposure increased the risk of select irAEs such as colitis/enteritis (10.9% vs 6.0%; HR = 1.58, 95% CI 1.31–1.90), rash (12.5% vs 8.9%; HR = 1.23, 95% CI 1.04–1.44), and thyroiditis/hypophysitis/adrenal insufficiency (9.9% vs 6.9%; HR = 1.27, 95% CI 1.05–1.52). MACE occurred more frequently among statin users (32.2% vs 18.9%; HR = 1.58, 95% CI 1.42–1.76). No significant differences were observed for immune-mediated hepatitis, pneumonitis, or diabetes mellitus. Conclusions: In this large, real-world study of RCC patients on ICIs, statin use was associated with improved overall survival but was associated with higher risks of select irAEs and MACE. Further prospective studies are needed to validate causality and identify patients most likely to derive net benefit from concomitant statin therapy during ICI treatment. Baseline characteristics of the two cohorts after propensity score–matching. Characteristic RCC without Statins(N = 2,787) RCC with Statins(N = 2,787) P value Age at index [mean ± SD (years)] 65.3 ± 10.7 65.2 ± 9.8 0.681 Sex Female, n (%) 787 (28.2) 818 (29.4) 0.359 Male, n (%) 2,000 (71.8) 1,969 (70.6) 0.359 Race White, n (%) 2,168 (77.8) 2,156 (77.4) 0.700 Hispanic, n (%) 219 (7.9) 220 (7.9) 0.960 Black or African American, n (%) 171 (6.1) 166 (6.0) 0.779
Perioperative chemotherapy in patients with grade 2 or 3 appendiceal cancer undergoing cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC): A real-world data analysis.
e15522 Background: CRS with HIPEC is an established option for selected appendiceal cancers with peritoneal metastases. Current guidelines recommend neoadjuvant chemotherapy for high-grade disease and consideration of adjuvant therapy. However, recent studies have shown conflicting results regarding perioperative chemotherapy on overall survival (OS) and progression-free survival (PFS), with mixed signals suggesting both benefit and harm. In this study, we aim to investigate the effect of perioperative chemotherapy in AJCC grade 2 or 3 appendiceal cancers undergoing CRS/HIPEC. Methods: We performed a retrospective review of all grade 2 or 3 appendiceal cancer cases from a prospectively collected database of CRS/HIPEC cases performed at the University of Pittsburgh Medical Center between May 2001 and November 2024. Perioperative chemotherapy was defined as any chemotherapy given within 3 months before or after CRS/HIPEC procedures. Patient characteristics including age, gender, peritoneal cancer index (PCI) score, and completeness of cytoreduction (CC) score were collected. Survival analyses were performed using Kaplan-Meier analysis and Cox proportional hazards model. Results: A total of 340 patients were included and divided into two groups: no perioperative chemotherapy (i.e., NPC group, n = 128) and perioperative chemotherapy (i.e., PC group, n = 212) groups. No significant difference in baseline characteristics was found between the two groups. We found that NPC group had significantly better OS and PFS compared to PC group (OS univariate HR 0.68, 95%CI 0.50-0.92, p = 0.013; OS multivariate HR 0.51, 95%CI 0.37-0.71, p < 0.001; PFS univariate HR 0.69, 95%CI 0.51-0.92, p = 0.013; PFS multivariate HR 0.55, 95%CI 0.41-0.75, p < 0.001). In subgroup analyses, NPC group showed trends toward better OS and PFS in both PCI < = 20 and PCI > 20 PCI score subgroups (PCI < = 20 OS: HR 0.65, 95%CI 0.42-1.01, p = 0.055; PCI > 20 OS: HR 0.71, 95%CI 0.46-1.09, p = 0.12; PCI < = 20 PFS: HR 0.69, 95%CI 0.47-1.03, p = 0.067; PCI > 20 PFS: HR 0.69, 95%CI 0.44-1.09, p = 0.11). NPC group showed significantly better PFS in both CC-0 and CC > = 1 CC-score subgroups (CC-0: HR 0.62, 95%CI 0.41-0.92, p = 0.018; CC > = 1: HR 0.49, 95%CI 0.30-0.78, p = 0.003), and trend towards better OS in CC-0 and significantly better OS in CC > = 1 subgroup (CC-0: HR 0.66, 95%CI 0.42-1.04, p = 0.074; CC > = 1: HR 0.45, 95%CI 0.29-0.70, p < 0.001). Conclusions: In this real-world data analysis of grade 2 or 3 appendiceal cancer patients undergoing CRS/HIPEC, perioperative chemotherapy was associated with worse outcomes in both univariate and multivariate analyses. These findings complement recent studies questioning the combined benefit of systemic therapy and CRS/HIPEC in this population and underscore the need for prospective trials to further investigate this question.