Browse Articles

Real-world clinical impact and prognostic utility of circulating tumor DNA in stage I–IV non–small cell lung cancer.

e20091 Background: Circulating tumor DNA (ctDNA) is an established and widely used biomarker for detection of minimal residual disease (MRD) in non-small cell lung cancer (NSCLC). However, real-world data regarding its utilization, longitudinal interpretation, and impact on clinical management remains limited. Methods: We retrospectively analyzed 82 NSCLC patients undergoing serial ctDNA testing (≥3 tests). Clinical variables were compared by ctDNA status and stage using nonparametric tests. ctDNA trends were categorized as rising, stable positive, transient positive, or negative. Diagnostic performance for progression was assessed using sensitivity, specificity, PPV, and NPV with 95% CI. PFS and OS were estimated by Kaplan–Meier methods and compared using log-rank tests. Analyses were performed in R (v4.4.2). Results: The median age was 72 years and was predominantly male (54.9%), with adenocarcinoma histology (79.3%) and a non-acinar pattern (65.9%). ctDNA testing intensity differed by stage (p = 0.0309), with the highest median of 12.5 test per patient in stage III. In progressors, ctDNA-positive patients received more treatments (median 5 vs 3; p = 0.0205) and underwent more biopsies (median 2 vs 1; p = 4.63 × 10⁻⁵) than ctDNA-negative patients. The median lead time from ctDNA positivity to imaging-confirmed progression was 187 days (123.2–239.8). For detection of disease progression, ctDNA had a sensitivity of 0.58 (95% CI, 0.42–0.73), specificity of 0.89 (95% CI, 0.77–0.95), PPV of 0.81 (95% CI, 0.62–0.91), and NPV of 0.73 (95% CI, 0.60–0.83), with stage-specific performance reported in Table 1. Mutant Tumor Molecules per mL (MTM/ml) differed between true-positive (21.02 [2.43–123.89] and false positive cases 0.07 [0.06–0.07]; p = 0.001). For non rising and rising ctDNA, PFS at 24 and 48 months was 79.9% vs 20.0% and 68.0% vs 10.0% (log-rank p < 0.0001), while OS at 24 and 48 months was 96.6% vs 38.9% and 77.9% vs 25.9% (log-rank p < 0.0001), respectively. Conclusions: ctDNA provides stage-dependent diagnostic utility, with greater sensitivity and PPV in advanced disease and stronger NPV in early-stage disease. Low-level ctDNA positivity was more often associated with false-positive results, while rising ctDNA patterns were strongly associated with worse PFS and OS. ctDNA results impacts clinical management in regards biopsies and escalation of treatment. These findings support longitudinal ctDNA monitoring as a complementary diagnostic and therapeutic tool in NSCLC. Stage-stratified diagnostic performance of ctDNA. Stage Sensitivity Specificity PPV NPV I 0.50 (0.22–0.78) 0.88 (0.71–0.96) 0.57 (0.25–0.84) 0.85 (0.68–0.94) II 0.20 (0.04–0.62) 0.92 (0.65–0.99) 0.50 (0.09–0.91) 0.73 (0.48–0.89) III 0.64 (0.39–0.84) 0.75 (0.30–0.95) 0.90 (0.60–0.98) 0.38 (0.14–0.69) IV 0.78 (0.45–0.94) 1.00 (0.51–1.00) 1.00 (0.65–1.00) 0.67 (0.30–0.90)

Management of pancreatic metastases from renal cell carcinoma.

e16526 Background: The pancreas is a rare site of metastases, although metastatic renal cell carcinoma (mRCC) is the most commonly reported secondary tumor. It has been suggested that patients with pancreatic metastases (PM) have improved survival outcomes and more angiogenic driven biology than other metastatic sites although there is limited data in the literature concerning the management of these patients. The purpose of this study is to disclose the characterization and treatment outcomes of pancreatic metastases from RCC. Methods: Patients with recurrent RCC from previous radical surgery for localized tumor, presenting with < 3 metastatic lesions, treated at our hospital between 2005 and 2025, were retrospectively reviewed and statistically analyzed. Progression-free survival (PFS) and Overall Survival (OS) was assessed using Cox regression analysis comparing different therapeutic modalities. Results: 96 mRCC patients were identified, median age of 63 years. Twelve patients (12.5 %) within the cohort had pancreatic only metastases and underwent pancreatectomy followed by systemic therapy. The median time from index nephrectomy to pancreatectomy was 6 years. Median follow-up was 69.3 months. Patients with PM had a significantly greater interval from primary diagnosis to the date of first systemic treatment as compared to those without (median: 38 vs 9 months) (p,0.002). As expected, patients with PM in the overall population had improved OS from the primary diagnosis compared to non-PM [65 vs 29 months (HR 0.56, p,0.02)]. Similarly, PFS from diagnosis was significantly prolonged in those with PM (66 vs 26 months, HR 0.44, p,0.01). Post-pancreatectomy disease specific survival at 2- and 4-years were 87% and 76%. Interestingly, PM only patients who received either molecularly targeted therapies (single agent) or combinations with immunotherapy, have a significant improvement in survival compared to those without PM. Conclusions: The pancreas is frequently the only metastatic site from RCC with less aggressive features that may result in a more favorable patient prognosis. The study highlights the importance of multidisciplinary approach for patients with metachronous oligometastatic RCC. The OS period of these patients is long and both surgical and medical treatment resulted in good outcomes.

Genomic and biomarker landscape of MTAP deficiency in gastrointestinal cancers.

4175 Background: Genomic loss of MTAP and CDKN2A is frequently observed across cancers, with ongoing development of MTA-selective PRMT5 inhibitors aiming to achieve synthetic lethality in the setting of MTAP loss. However, the biomarker landscape of patients with gastrointestinal (GI) cancers and MTAP deficiency remains poorly defined, and whether subsets of GI cancers harbor non-genomic mechanisms of MTAP deficiency remains unknown. Methods: All GI cancer samples sequenced with MSK-IMPACT v7, a DNA-based next generation sequencing (NGS) panel with coverage for MTAP / CDKN2A were queried. MTAP and CDKN2A deletions (del) were defined by low read counts in coverage-based copy number analyses. Genomic and pathologic analyses were completed in tumors with high MTAP del prevalence: esophagogastric cancers (EGC), pancreatic adenocarcinoma (PDAC), pancreatic neuroendocrine tumors (PanNETs), and biliary tract cancers (BTCs). MTAP immunohistochemistry (IHC) was completed on PDAC, PanNET, small bowel NET, and BTC samples to investigate prevalence of MTAP protein loss. Results: Among 8346 GI cancer samples, MTAP del was identified in 456 (5.5%), co-occurring with CDKN2A del in 98.8% of cases, with 79.8% confirmed homozygous del by FACETS, and was associated with higher tumor purity compared to MTAP -intact samples (p < 0.001). MTAP del prevalence was 14.4% in esophageal squamous cell carcinoma (SCC), 5.9% in esophagogastric adenocarcinoma (EGA), 12.4% in PDAC, 7.4% in PanNET (grade 1 [G1]: 3.4%, G2: 4.3%, G3: 19.4%), 0% in small bowel NET, 10.2% in BTCs (including 11.5% in intrahepatic cholangiocarcinoma [iCCA]), and 0.7% in colorectal cancer. MTAP del was associated with wild-type (WT) KRAS amplifications (amp) in EGC, KRAS G12V and WT KRAS amp in PDAC, and KRAS mutations and FGFR2 fusions in iCCA. Among EGA, PDAC, and BTCs, MTAP del tumors were associated with higher fractions of genome altered (p < 0.001 for each) and rates of whole genome duplication (p < 0.001 for each). Among 463 samples profiled by MTAP IHC, MTAP deficiency was found in 29/93 (31%) PDAC, 3/33 (11%) BTC, 15/60 (25%) PanNETs, and 196/277 (71%) small bowel NETs. Analysis of MTAP deficiency and activity of standard systemic therapies, as well as metabolomic and epigenomic profiling of MTAP-deficient GI cancers are ongoing and will be presented. Conclusions: MTAP genomic del are recurrently identified across GI cancers, most notably in esophageal SCC, PDAC, G3 pancreatic NETs, and iCCA. MTAP del are associated with distinct genomic drivers across GI cancers and markers of chromosomal instability more broadly. We found evidence of discrepancy between MTAP loss by NGS and IHC across multiple GI cancers, most notably small bowel NETs, which demonstrate frequent MTAP IHC deficiency in complete absence of genomic loss, suggesting non-genomic mechanisms of MTAP silencing. These observations may help define the role for therapies targeting MTAP deficiency in GI cancers.

The impact of online CME on addressing clinical decision-making for immunotherapy in advanced squamous NSCLC.

e21002 Background: Immunotherapy (IO)-based regimens are foundational to the management of advanced squamous non-small cell lung cancer (NSCLC). Effective clinical application requires accurate interpretation of emerging trial data, integration of patient- and disease-specific considerations, and informed selection among available regimens. Given the multidisciplinary nature of NSCLC care, baseline understanding and practical readiness to apply immunotherapy data may vary across oncologists, pathologists, and pulmonologists. The objective of this study was to assess the educational impact of a single continuing medical education (CME) activity on clinicians’ recognition of the role of IO in advanced squamous NSCLC and treatment decisions. Methods: The educational intervention presented included an online, CME-certified video discussion between two expert faculty. Educational impact was assessed with repeated paired pre-/post-assessment study design, where individual participants served as their own control. Outcomes were analyzed by learning objective and stratified by specialty (oncologists, pathologists, and pulmonologists). A McNemar’s test assessed significant levels of changes reported with P values <.05 considered statistically significant. The activity launched September 2025; data were collected until January 2026. Results: Across specialties, participation in CME was associated with improvements in post-education performance (Table). Exploratory analyses demonstrated that frequency of clinical encounters with patients with advanced squamous NSCLC did not meaningfully influence baseline knowledge or degree of improvement. Conclusions: This analysis demonstrates variable baseline preparedness and distinct, specialty-specific educational needs related to IO use in advanced squamous NSCLC. While education improved understanding of clinical evidence and disease-specific considerations, gaps in translating data into regimen selection persisted for some audiences, reinforcing the need for ongoing, targeted educational strategies. Importantly, improvements were not dependent on patient volume or experience, suggesting that structured education can benefit clinicians regardless of prior exposure to this patient population. Learning Objective Oncologists (N = 35) (% Pre Correct, % Post Correct; P Value) Pulmonologists (N = 20) (% Pre Correct, % Post Correct; P Value) Pathologists (N = 43) (% Pre Correct, % Post Correct; P Value) Describe the clinical considerations associated with advanced squamous NSCLC 93%, 96%; NS 78%, 90%; NS 63%, 79%; <.01 Differentiate between key findings of immunotherapy use in advanced squamous NSCLC 61%, 77%; <.001 50%, 80%; <.01 48%, 64%; <.01 Articulate the rationale for selecting specific immunotherapy regimens for advanced squamous NSCLC 31%, 54%; <.01 5%, 15%; NS 7%, 9%; NS

Real-world analysis of pneumonitis risk after chemoradiation and durvalumab by chemotherapy regimen in NSCLC.

e20049 Background: Consolidation durvalumab after chemoradiation improves outcomes in patients with locally advanced NSCLC, but pneumonitis remains a clinically significant toxicity. The impact of taxane-based chemotherapy on pneumonitis risk and survival remains unclear. We evaluated this association in a real-world cohort of NSCLC patients treated with curative-intent chemoradiation and durvalumab. Methods: We conducted a single-center retrospective study of patients with NSCLC treated with concurrent chemoradiation followed by durvalumab, including unresectable and select oligometastatic cases treated with definitive intent between 2017-2025. Patients were grouped by receipt of taxane vs. non-taxane based chemotherapy. The primary endpoint was grade ≥2 pneumonitis. Multivariable analysis adjusted for treatment group, smoking status, nodal stage, delivered radiation dose, mean lung dose, and time from radiation completion to durvalumab initiation. Time to grade ≥2 pneumonitis was assessed using cumulative incidence methods, accounting for death as a competing risk. Overall survival (OS) was assessed with multivariable analysis adjusting for age, sex, smoking status, histology, delivered radiation dose, disease stage, and grade ≥2 pneumonitis. Results: A total of 289 patients were included (non-taxane n = 81; taxane n = 208). The median age was 65 years (range 39-87) in the non-taxane group and 70 years (42-86) in the taxane group. The majority of patients were male (58% in non-taxane vs 54% in taxane). Most patients were former smokers (62% vs 71%), with similar proportions of current smokers (23% in both groups). Histology differed between groups: squamous cell carcinoma was more common in the taxane group (45% vs 17%), whereas non-squamous histology was more frequent in the non-taxane group (64% vs 38%). Grade ≥2 pneumonitis occurred in 25% of non-taxane and 24% of taxane patients. On multivariable analysis, taxane use was not associated with pneumonitis risk (OR 1.00, 95% CI 0.54-1.90; p > 0.9). Being a former smoker (OR 2.20, 95% CI 1.07-4.91; p = 0.040) and increasing mean lung dose per 5 Gy (OR 1.74, 95% CI 1.23-2.55; p = 0.003) were independently associated with a higher risk of pneumonitis. Delivered radiation dose, nodal stage, and interval to durvalumab were not significant. Median OS for the cohort was 55 months (95% CI 34-76; p = 0.16), with no difference by treatment group. Taxane use was not significantly associated with OS on multivariable analysis (HR 1.31, 95% CI 0.83-2.08; p = 0.3). Conclusions: In this real-world cohort of patients treated with definitive chemoradiation and durvalumab, taxane-based chemotherapy was not associated with increased pneumonitis risk or worse survival. Mean lung dose and former smoking status were key predictors of pneumonitis, emphasizing the importance of radiation optimization and individualized risk assessment.

Distinct national mortality patterns in intrahepatic versus extrahepatic cholangiocarcinoma: A population-based study with future projections.

e16255 Background: Cholangiocarcinoma (CCA) presents a rising global health concern. United States mortality patterns differ substantially between intrahepatic (iCCA) and extrahepatic (eCCA) subtypes. These divergent trends are essential to understand for anticipating future disease burden and tailored resource allocation. This study analyzes U.S. national mortality trends for iCCA and eCCA from 1999–2023, with projections through 2030. Methods: A population-based analysis using CDC WONDER multiple-cause-of-death data (1999–2023) was conducted. AAMRs; per 100,000, 2000 U.S. standard population and total deaths were extracted for iCCA and eCCA using ICD-10 codes C22.1 and C24.0. Temporal trends were assessed with Joinpoint Regression to estimate APC with 95% CI. p-value < 0.05 was considered significant. Projections to 2030 used the ARIMA model using R Software Version 4.5.0. Subgroup analyses included sex, ethnicity, U.S. Census regions, urbanization status, and state-level distributions. Results: From 1999–2023, iCCA accounted for 132,830 deaths, with a mean AAMR of 2.88, projected to rise to 6.08 by 2040 (95% CI: 4.64 – 7.52). In contrast, eCCA caused 18,699 deaths, with AAMR declining from 0.53 in 1999 to 0.43 in 2023 and projected to reach 0.38 by 2040 (95% CI: 0.27–0.47). iCCA mortality rose significantly in both sexes (APC: females 3.54%, males 3.20%, 1999–2023). eCCA declined in both sexes until 2012; thereafter, males demonstrated a statistically significant rise (APC 4.92%, 95% CI: 3.37–8.97; p = 0.038, 2012–2021). Hispanic (APC 2.82%) and non-Hispanic (APC 3.42%) individuals showed persistent increases in iCCA mortality. eCCA initially declined across both groups but rose sharply among Hispanics from 2013–2021 (APC 9.69%) before declining again. Across racial groups, the largest increases occurred among White individuals for iCCA (APC 4.03%, 95% CI: 3.11–5.26, 1999–2019) and among Black individuals for eCCA (APC 12.34%, 95% CI: 2.66–29.01, 2012–2017). Highest mean AAMRs for iCCA were observed in the Northeast (3.13), Large Central Metro areas (2.92), and Rhode Island (3.77). For eCCA, lowest AAMRs occurred in the Midwest (0.47), non-core counties (0.456), and Vermont (0.58). Using ARIMA model time series analysis based on historic trends iCCA mortality is projected to exhibit consistent increase from 4.19 in 2023 to 4.89 by 2030 (95% CI: 4.67- 5.11) while eCCA mortality is expected to decline slightly and stabilize to 0.39 in 2030 with 95% CI spanning from 0.27 to 0.51, compared to the more precise growth trajectory of iCCA. Conclusions: U.S. mortality from iCCA continues to surge across nearly all demographic groups, whereas eCCA shows a predominantly downward trend with recent resurgence. These sharply diverging patterns underscore the urgent need for subtype-specific prevention, surveillance, and tailored therapeutic strategies.

Experiences, challenges, and enablers for promoting interprofessional education among medical students: A scoping review

Background Interprofessional education (IPE) has been commonly employed to facilitate preparation for collaborative practice among medical students. However, differences in IPE implementation and a lack of synthesis of student experiences continue to influence its integration into medical education. Methods The scoping review was conducted following the Arksey and O’Malley guidelines and was reported according to the PRISMA-ScR extension. Electronic databases such as PubMed, Scopus, and Web of Science were searched to include studies published between 2014 and 2024. The search yielded eight studies that met the inclusion criteria for this review. The results were synthesized to explore students’ experiences, challenges, and facilitators regarding IPE. Results The review found that medical students generally reported having a positive orientation towards collaborative practice and valued the opportunity to learn with others. However, understanding of professional roles was more inconsistent. Identified challenges included ambiguity of roles, hierarchy of professions, and constraints of time and organization. Enablers included integration into the curriculum, learning in practice, interaction and support. Conclusion IPE facilitates learning in collaborative practice, and its effectiveness relies on its development and implementation. Further consideration should be given to role clarification, learning, and integration in medical education programs. Future research should focus on the long-term effects of IPE on professional practice.

Blocking electron current in p-type SnO thin-film transistors to achieve compatibility with 385  <b>°</b> C back-end-of-line thermal budgets

Oxide thin-film transistors (TFTs) have shown great promise for monolithic 3D integration with silicon chips through back-end-of-line (BEOL) processes. While BEOL processing involves high-temperature (350–400 °C) thermal steps that are generally beneficial for n-type oxide TFTs, such conditions pose a critical challenge for p-type SnO TFTs, where high temperatures commonly induce high n-type conduction and pronounced degradation of the on/off current ratio. This study revealed that post-annealing at elevated temperatures induces the disproportionation of SnO into Sn0 and Sn4+ species, which contributes to the rise in electron current in SnO TFTs. To address this challenge, we first introduced Pt(O)/Pt electrodes with an Al2O3 interlayer to form Schottky drain contacts for blocking electron injection. More importantly, a submicrometer gate-to-drain (G–D) gap was designed to enhance electron depletion near the drain under negative drain bias, and simulations confirmed that the G–D gap modulates the electrostatic potential and carrier distribution. The combined strategy not only effectively suppressed ambipolar channel conduction after annealing at 385 °C but also reduced electron current by over three orders of magnitude without sacrificing the p-type on-current, underscoring the potential of p-type oxide TFTs for BEOL-compatible CMOS applications.

Development and characterization of lipid based solid dispersion of quassinoid enriched fraction of Simarouba glauca for enhanced lipid membrane permeability in MCF7 breast cancer cells

Multifunctional Neuromorphic Vision Enabled by Photo‐Regulated Radical

ABSTRACT Neuromorphic vision systems process information directly at the sensor front end, offering a promising hardware pathway for next‐generation machine vision. However, current implementations are typically restricted to single functions and rely on device mechanisms that limit scalability, uniformity and miniaturization, highlighting the need for multifunctional and integrable neuromorphic hardware. Herein, we introduce a photo‐regulated doping strategy enabled by galvinoxyl radicals (GX) as wavelength‐dependent bipolar dopants, in which radical‐mediated charge transfer enables wavelength‐dependent optical switching between excitatory and inhibitory responses within a single‐layer neuromorphic device. This mechanism supports high photoresponse and programmable synaptic dynamics, allowing the construction of a large‑scale (256 × 256) neuromorphic vision system that integrates dynamic motion detection, spatiotemporal memory, and contrast‐enhanced edge extraction. This work provides a potent hardware solution for complex dynamic scenarios, establishing a scalable pathway toward fully integrated, high‐performance neuromorphic vision system.

Effect of virtual reality environment complexity on tolerance and locomotor performance in healthy subjects

A novel synthetic melanin as a potential anticancer agent that induces apoptosis and cyclin D downregulation through distinct pathways

Preoperative combination radiotherapy (RT) and immune checkpoint inhibitor (ICI) in early-stage breast cancer: Influence of RT and ICI treatment sequencing (NCT04454528 post-hoc analysis).

615 Background: The anti-tumor immune effects of combination radiotherapy (RT) and immune checkpoint inhibitors (ICI) are synergistic. Optimal treatment sequencing, i.e. RT before ICI vs. RT after ICI, remains unclear. Assuming clinical equipoise, we conducted a phase 1b/2 multi-arm adaptive window of opportunity study to evaluate feasibility and treatment response after preoperative (preop) RT before ICI vs. RT after ICI vs. ICI alone. Methods: Participants with early-stage breast cancer planning for upfront surgery were eligible to enroll to receive a single preop intravenous dose of pembrolizumab (pembro, an ICI), 200 mg, either alone (Arm 3) or in combination with RT (single fraction, 7 Gy) given before (Arm 1) or after pembro (Arm 2). Primary outcome measures included 1) feasibility of administration of combination RT + pembro in a 21-day preoperative window, and 2) tumor response as measured by % tumor size change post-treatment, including the proportion achieving &gt; 30% tumor reduction (TΔ30). Secondary endpoints included pathologic response as measured by residual cancer burden (RCB). Study sample size was powered for proportion of participants with TΔ30. Assuming 40% of treated participants would achieve TΔ30 compared to untreated participants, 15 subjects would yield 80% power at α = 0.05. Comparison of proportions was performed using Chi-squared test. Results: Between 1/6/2021 and 1/28/2025, 30 participants enrolled and completed the preop regimen assignment. Median follow-up was 634 days (IQR 256 –1120 days). All participants proceeded to surgery without delay. There were no adverse events (AEs) ≥ grade 3. There was one grade 2 immune-related AE (hypothyroidism). The proportion of participants achieving TΔ30 was 8 of 14 (57.1%), 6 of 11 (54.5%) and 0 of 5 (0%) in Arms 1, 2, and 3 respectively. For TNBC, TΔ30 rate was 6 of 7 (85.7%), 4 of 6 (66.7%) and 0 of 4 (0%) in Arms 1, 2, and 3 respectively. Compared with Arm 3, overall TΔ30 rate was significantly higher for those treated in Arm 1 or 2, p = 0.0307 and p = 0.0433; and for TNBC, p = 0.0088 and 0.0454, respectively. TΔ30 rate was similar in those treated with RT before (Arm 1) or RT after (Arm 2) ICI. The proportion of participants with major pathologic response (MPR) defined as RCB class 0 or 1 (RCB 0/1) treated in Arms 1, 2, and 3 were 7 of 14 (50%), 1 of 10 (10%), and 0 of 4 (0%) overall and 4 of 7 (57%), 0 of 5 (0%), and 0 of 3 (0%) for TNBC, respectively. The proportion of participants with RCB 0/1 in Arm 1 was numerically and statistically higher than Arm 2 overall and for TNBC, p = 0.0448 and p = 0.0479, respectively. Conclusions: RT given before ICI is more effective than RT given after ICI and resulted in MPR in 57% of participants with TNBC. This chemotherapy-free preop regimen may possibly facilitate chemotherapy omission decision in those achieving MPR in future studies. Clinical trial information: NCT04454528 .

Generalizable cancer detection from ultra-low-pass whole-genome sequencing of cell-free DNA using a sequentially fine-tuned transformer framework.

10533 Background: Ultra-low-pass whole-genome sequencing (ULP-WGS) of cell-free DNA (cfDNA) provides a cost-effective approach for cancer screening, yet its clinical translation is constrained by extreme data sparsity and poor model generalizability, particularly in low-tumor fraction (TF) settings. Methods: We developed Fragmentia-AI WGS, a mutation-independent framework that leverages a transformer-based multiple-instance learning architecture with sequential fine-tuning across TF strata to extract latent cancer-associated signals from ULP-WGS data (~0.02× coverage, ~128k reads). Model performance and generalizability were evaluated across multiple independent cohorts, including a pan-cancer test cohort across 17 cancer types, a public online cohort sequenced on a different platform, and an analytical variability assessment cohort comprising samples processed under heterogeneous technical and pre-analytical conditions. Clinical relevance was further examined by associating prediction scores with progression-free survival (PFS) in patients with advanced non-small cell lung cancer receiving immunotherapy. Results: Sequential fine-tuning across all TF strata substantially improved performance in low-TF samples compared with high-TF-only training, yielding a 35.6% relative increase in AUC in the low-TF subgroup (from 0.652 to 0.884 in the validation cohort). In the independent test cohort, the model achieved an overall AUC of 0.930 (95% CI: 0.924 – 0.936), with consistently strong performance across TF levels (high TF: 0.984; medium TF: 0.958; low TF: 0.910) and across cancer types. External validation in the public cohort demonstrated robust cross-platform and cross-population generalizability (AUC: 0.929; sensitivity: 0.78; specificity: 0.92). Prediction scores remained stable across heterogeneous experimental conditions, supporting robustness to technical and pre-analytical variability. Notably, lower model prediction scores were independently associated with prolonged PFS (hazard ratio: 0.49, 95% CI: 0.31 – 0.77; p = 0.002) after adjusting for sex, age, clinical stage, and histologic subtype. Conclusions: Fragmentia-AI WGS enables robust and generalizable cancer detection as well as clinically meaningful risk stratification from ultra-sparse cfDNA sequencing, underscoring its potential for scalable and cost-effective liquid biopsy applications.

Age-dependent survival gradients and projected future disease burden in adult acute lymphocytic leukemia: A population-based SEER analysis.

e18542 Background: Outcomes in adult acute lymphocytic leukemia (ALL) remain heterogeneous and strongly influenced by age. However, population-level survival gradients across older age strata and the future burden of disease in an aging population remain incompletely characterized. We evaluated long-term survival patterns and projected disease burden in adult ALL using national registry data. Methods: We conducted a retrospective cohort study using the Surveillance, Epidemiology, and End Results (SEER) database including adults aged 50–89 years diagnosed with ALL between 2000 and 2022. Overall survival (OS) was estimated using Kaplan–Meier methods and compared across age and racial subgroups. Multivariable Cox proportional hazards regression was performed to identify independent predictors of mortality. Temporal trends in annual case counts were analyzed and projected through 2035 using time-series forecasting methods. Results: A total of 7,298 adult ALL patients were included. OS declined progressively with advancing age, demonstrating clear stepwise separation across age strata. Compared with patients aged 50–54 years, mortality risk increased incrementally across successive age groups, reaching more than fourfold higher risk among patients aged 85–89 years on multivariable analysis. Race-based survival differences were observed on unadjusted analysis; however, these differences were attenuated after adjustment for age and clinical factors. More recent year of diagnosis was independently associated with modest survival improvement, reflecting incremental therapeutic progress. Forecasting analysis projected a continued rise in adult ALL case burden through 2035, with widening uncertainty intervals over time, indicating sustained future healthcare impact. Conclusions: Adult ALL outcomes remain strongly age dependent, with sharply escalating mortality risk among older patients despite gradual therapeutic improvements. Projections indicate a sustained and growing disease burden in the United States. These findings highlight the urgent need for age-adapted treatment strategies, improved inclusion of older adults in clinical trials, and healthcare system preparedness to address the needs of an aging leukemia population.

Enhancing diverse participation in cancer clinical trials: Evaluating theory-based recruitment messaging and visual imagery preferences among underrepresented adults.

e24122 Background: Using multiple channels and theory-based recruitment messaging are strategies to enroll diverse audiences in cancer clinical trials (CCTs) and reducing sociodemographic health disparities. 1-7 Customizing recruitment content to participants, such as including race-concordant images (i.e., images that match participants race/ethnicity) and translating information to a community-level (i.e., message framing) is linked to positive health-seeking behavior among minorities and their intention to enroll in clinical trials. 8,9 Drawing on Communication Accommodation Theory and social identity theories, this paper evaluated recruitment channels used to successfully enroll underrepresented participants in CCTs, and preferences for race-concordant images and message framing. Methods: Social media ads, flyers, and postcards were used to recruit rural, African American/Black, and Hispanic adults interested in cancer prevention and screening. Participants ( N = 430, M = 40 years old, SD = 14.47, range 18-85) were recruited to the study with unique links to track the stimuli they viewed, and demographics were collected. Participants viewed one of four images and one of two motivational recruitment message frames. Specifically, given our interest in recruiting rural, African American/Black, and Hispanic populations to CCTs, three images were selected to feature each population, and a fourth Inclusive image featuring all three. Additionally, the person-centered message frame conveyed participating in research is motivated by one’s own benefit, whereas the other-centered frame conveyed motivation for other people’s benefit. Results: In social media ads, across a three-week campaign there were 2,653 clicks on recruitment stimuli ads, resulting in a 6.17% response rate of recruited and enrolled. Across all recruitment channels, enrolled participants engaged with the Inclusive (n = 202) and Black/African American (n = 130) recruitment stimuli the most. In the case of framing, person- (n = 174) and other-centered (n = 199) had similar engagement. Investigating within-race preferences, a chi-square analyses revealed Black/African American participants preference for Inclusive (n = 172) and Black/African American (n = 109) visuals over Hispanic (n = 13) and Rural (n = 17), X 2 (30, N = 419) = 194.94, p &lt; .001; as well as preference for other-centered (n = 180) vs person-centered (n = 129) framing, X 2 (30, N = 419) = 183.95, p &lt; .001. Conclusions: Our findings indicate that Black/African American participants are more likely to interact with race-concordant or sociodemographic inclusive stimuli, and a preference for other-oriented framing. To reduce health disparities in CCT participation, recruitment must avoid monolithic approaches and instead segment outreach by sociolinguistic and social identity factors.

Single-agent versus combination paradigms: A systematic review and meta-analysis of the immunotherapy clinical profile in metastatic renal cell carcinoma.

e16549 Background: Immunotherapy-based combinations are established as the first-line standard of care for metastatic renal cell carcinoma (mRCC) across major NCCN Guidelines and ESMO Guidelines. While these intensified regimens offer superior efficacy compared to historical monotherapies, they are associated with increased treatment-related toxicities and significant financial burden. The role of single-agent immunotherapy in patients with comorbidities or favorable-risk mRCC remains clinically controversial. This systematic review and meta-analysis evaluate the comparative safety and efficacy profiles of single-agent versus double-agent regimens in patients with mRCC. Methods: Following PRISMA guidelines, a systematic search was conducted across PubMed, Cochrane, Scopus, and ClinicalTrials.gov through October 2025 to retrieve 1,015 articles. Eight studies (including RCTs and cohorts) were selected. Data synthesis was performed using RevMan 5.4.1, employing a random-effects model to calculate Risk Ratios (RR) and Hazard Ratios (HR). Statistical significance was set at p &lt; 0.05. Results: A total of 3,018 patients were included (n = 1,546 receiving single-agent immunotherapy; n = 1,472 receiving doublet-regimens). Across the 8 included studies, nivolumab (n = 3) and bevacizumab (n = 4) were the primary intervention arms. The median age was 60 (55–65) years, with a male predominance and clear cell carcinoma as the primary histological subtype. Regarding safety, single-agent immunotherapy was associated with a significantly higher risk of ALT elevation (RR 2.48; 95% CI: 1.08–5.71; p = 0.03; I² = 0%) and proteinuria (RR 1.46; 95% CI: 1.04–2.05; p = 0.03; I² = 0%). Conversely, single-agent therapy was associated with a significantly lower risk of Grade 3–4 fatigue (RR 0.17; 95% CI: 0.05–0.60; p = 0.006; I² = 0%) and anemia (RR 0.33; 95% CI: 0.14–0.77; p = 0.01). No statistically significant differences were observed for overall adverse events, nausea, hyponatremia, hypertension, hematuria, fever, or diarrhea. In terms of efficacy, overall survival, objective response rate, and progression-free survival were comparable between the two groups. While heterogeneity for specific toxicities was low, overall heterogeneity across the included studies remained moderate to high. Conclusions: Single-agent immunotherapy demonstrates a comparable clinical profile to doublet regimens in mRCC. Despite increased risks of ALT elevation and proteinuria, monotherapy significantly mitigates Grade 3–4 fatigue and anemia. These findings suggest that monotherapy is a tailored strategy for patients prioritizing quality of life and the avoidance of hematological toxicities. However, high-quality RCTs are warranted to provide robust evidence for personalized treatment sequencing.

Lymphoma epidemiology in Syria: A 2024 analysis from the nation's primary oncology referral center.

e19042 Background: The ongoing conflict in Syria has significantly disrupted cancer surveillance, leading to a critical lack of contemporary epidemiological data on lymphomas. This study aims to characterize the demographic and clinical presentation of Hodgkin and non-Hodgkin lymphoma in the Syrian population. Methods: We conducted a retrospective, single-center analysis of all consecutive patients newly diagnosed with Hodgkin lymphoma (HL) or non-Hodgkin lymphoma (NHL) at Al-Bairouni University Hospital in 2024. This center functions as Syria's principal oncology referral facility, handling an estimated 65-70% of the nation's cases. Data on key demographic variables (age, sex, governorate of residence, and smoking history) were systematically collected. The study protocol received institutional ethical review board approval prior to initiation. Results: A total of 494 patients were diagnosed with lymphoma in 2024 (Table 1). Across this year, a consistent male predominance was observed 55.2%. The average age at diagnosis was 46.8 years, and 45.7% of patients were smokers. The highest patient loads originated from Damascus (14.1%) and Rural Damascus (16.3%), followed by the central governorates of Homs (8.7%) and Hama (12.1%). Notably, patients from more distant and underserved governorates such as Deir ez-Zor (7.4%), Aleppo (6.9%), and Al-Hasakeh with Raqqa (12.7%) accounted for a significant proportion of the Lymphoma presenting to our center. Several factors predicted advanced disease: smoking rates correlated with advanced stage (+0.43). males had 33% higher odds than females, and high-grade tumors had 2.32x higher odds. Conclusions: This study establishes the first national epidemiological profile of lymphoma in Syria. The high prevalence of both smoking and advanced-stage disease at diagnosis identifies two critical public health priorities: implementing robust tobacco control programs and improving pathways to early detection. These findings provide an essential evidence base to guide future clinical strategies and health policy in this conflict-affected setting. Diagnosis 2024 Cases Average Age Male Sex (%) Smokers (%) HL 193 37 51.8% 41.9 NHL 301 53 57.1% 48.1%

Cancer-related overall survival for patients on durvalumab for stage III unresectable non–small cell lung cancer with PD-L1 positive and negative tumors.

8026 Background: Durvalumab improves overall survival (OS) and progression free survival (PFS) when used as consolidation therapy for patients with stage III unresectable non-small cell lung cancer (UR-NSCLC) following chemoradiotherapy (CRT). However, it is uncertain if similar benefits are achieved for patients with PD-L1 positive (1% or greater) and negative (&lt;1%) tumors. We previously found no difference in OS, but no study has yet compared cancer-related overall survival (OS). Methods: Patients with stage III UR-NSCLC on durvalumab following CRT, at any Veterans Health Administration (VHA) facility, from 1/1/17 to 6/30/20, were included. Patients were followed from durvalumab initiation through the earliest of their last VHA visit, loss to follow up, death, or end of study (6/30/25). Electronic health record data were retrospectively collected to determine durvalumab treatment course, OS, and cancer-related OS—as determined by review of each patient’s chart and death certificate. Kaplan-Meier and Cox regression methods were used to compare cancer-related OS. Results: Of the 340 eligible patients, 221 (65%) had PD-L1 positive and 119 (35%) had PD-L1 negative tumors. Groups were similar in age, sex assigned at birth, White race, smoking status, marital status, Charlson score, ECOG 1+ status (78% overall), histology, stage, EGFR, and RAS mutations. Patients with PD-L1 positive and negative tumors had similar median (interquartile range [IQR]) number of durvalumab doses (15 [6-24] vs 13 [5-24], p=0.55), months of durvalumab (8 [3-12] vs 6 [2-12]), and months of follow-up (33 [12-69] vs 28 [11-63], p=0.22). OS was similar for patients with PD-L1 positive and negative tumors in a multivariate model accounting for ECOG 1+ status (HR 0.93, 95% CI 0.70-1.24). Likewise, cancer-related OS was similar in the multivariate model (HR 0.87, 95% CI 0.63-1.21). Median OS was 33.3 months (95% CI 29.8-47.3) for patients with PD-L1 positive tumors and 28.5 months (95% CI 21.6-39.7) for patients with PD-L1 negative tumors. Likewise, median cancer-related OS was 20.4 months (95% CI 16.0-25.4) for patients with PD-L1 positive tumors and 20.6 months (95% CI 15.4-28.5) for patients with PD-L1 negative tumors. The table depicts common causes of death. Conclusions: In this real-world study of VHA patients on durvalumab for stage III UR-NSCLC, OS and cancer-related OS were similar for those with PD-L1 positive and negative tumors. Cause of death. Cause of death PDL1+, n=221 PDL1-, n=119 P-value Disease progression 84% 77% 0.19 Bleeding event 4% 3% 0.75 Cardiac event 14% 14% 1.00 Infection/sepsis 19% 6% 0.01 Intracranial embolism/hemorrhage 2% 3% 0.67 Multiorgan failure 1% 2% 0.56 Thromboembolic event 2% 0% 0.30 Unknown 3% 4% 0.73 Other 9% 19% 0.03

A multicenter phase Ib/II trial of azacitidine, venetoclax, and ivosidenib in <i>IDH1</i> -mutated acute myeloid leukemia (AML).

6503 Background: Outcomes for patients with IDH1 mut AML have improved with the advent of targeted therapies. Two doublet regimens are approved for IDH1 mut AML: venetoclax (VEN) with a hypomethylating agent (HMA), and azacitidine (AZA) plus ivosidenib (IVO). Both regimens are effective, yet a substantial proportion of patients fail to respond or eventually relapse. Combining all three agents into a “triplet” regimen may improve outcomes. Herein, we report results from the fully enrolled newly diagnosed (ND) cohort of the multicenter phase Ib/II study of AZA+VEN+IVO for IDH1 mut AML (NCT03471260). Methods: Adults ≥18 years with ND IDH1 mut AML not eligible for standard induction chemotherapy and treated at the RP2D in the phase Ib or II cohorts were included. Patients received AZA 75 mg/m 2 days 1-7, VEN 400mg days 1-14, and IVO 500mg continuously starting C1D14. Dose attenuations in remission were permitted to minimize myelosuppression. The primary objectives were to determine the safety and overall response rate (ORR: CR + CRh + CRi + MLFS). Results: From November 2019 to October 2025, 40 patients with ND AML at four U.S. academic centers initiated treatment (Phase Ib: 9, Phase II: 31). The median age was 72 years (range, 51-80), and 26 patients (65%) were male. AML was classified as de novo in 21 (53%), therapy-related in 4 (10%), and secondary to antecedent myeloid neoplasm in 15 (38%). Six (15%) had received a prior HMA. The ORR was 95% (38/40) with 93% (37/40) achieving a composite CR (CRc; CR+CRh+CRi). The median number of cycles to best response was two (range, 1-7). Measurable residual disease (MRD) negativity by flow cytometry (sensitivity &lt;0.1%) was achieved in 92% (34/37) of CRc responders. With a median follow up of 35 months, median overall survival (OS) and duration of remission (DOR) were not reached. The 3-year OS was 79% (95% CI 64-96%). Three patients relapsed during follow-up with IDH1 -negative clones, and 18 patients (45%) transitioned to SCT. The 3-year DOR censored and not-censored at SCT was 82% (95% CI 68-98%) and 83% (95% CI 64-100%), respectively. Among the 22 patients who did not undergo SCT, the median number of cycles received is 14, with 10 patients (45%) remaining on study. Reasons for discontinuation included lack of response/relapse (n=5), development of another malignancy (n=2), adverse events (AEs; n=2), and patient preference (n=1). Non-hematologic AEs occurred in 32 patients (80%), with 12 (30%) experiencing grade ≥3 AEs. Most grade ≥3 AEs were infectious (n=7, 23%), although two patients each experienced grade ≥3 QTc prolongation, tumor lysis syndrome, and differentiation syndrome, all successfully managed with supportive care and/or with dose modifications. Conclusions: Triplet therapy with AZA+VEN+IVO demonstrates high MRD negative response rates, durable remissions, and comparable safety to doublet regimens in this multicenter study for patients with ND IDH1 mut AML. Clinical trial information: NCT03471260 .