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The impact of adjusting for c-Kit exon 11 mutation status when comparing prognostic models for gastrointestinal stromal tumors for prediction of recurrence.

e23510 Background: There is minimal data comparing the prognostic models (PM) developed to predict recurrence of Gastrointestinal stromal tumors (GIST). Current PM include tumor size, location, and mitotic index (MI) but lack genotypic data. This analysis compares the performance of the National Institute of Health, Armed Forces Institute of Pathology, and Memorial Sloan Kettering Cancer Center models for predicting tumor recurrence with and without adjustment for c-kit Exon 11 mutation status (MS). Methods: This is an IRB-approved single-institution retrospective analysis. Adults with GIST mentioned in their medical records from 2014 – 2025 at the authors’ institution were identified. 330 patients with documented biopsy-proven GIST were included. Data was collected by manual review. PM were evaluated using multivariate analysis, adjusting for surgical resection, systemic therapy, and c-Kit exon 11 MS. Predictive performance was measured by area under the curve (AUC) and receiver operating characteristics (ROC) analysis. Results: Mean age at diagnosis was 64.6 years (SD =13.1 years). 46.7 % of patients were male. Primary GIST was most common in the stomach (63.9%) and small bowel (23.6%). Primary tumors were an average of 6.5 cm (SD 5.6 cm) with a MI of 6.6/50 HFU (SD = 13.4 50/HFU). Patients received resection (80.9%) and first-line systemic therapy with imatinib (43.3%). Recurrence occurred in 17.9% of patients. 19.4% of patients completed genetic testing, of which 51.6% were c-Kit exon 11 mutation positive. The predictive performance of all PM was not statistically different with (p value = 0.16) or without (p value = 0.18) adjustment for c-Kit exon 11 MS (Table 1). However, adjusting for c-Kit exon 11 MS improved AUC for all PM. Conclusions: Adjusting PM for c-KIT exon 11 status improved the predictive performance of all PM, although the results were not significant. This study found no significant difference in the performance of PM that predict GIST recurrence, which aligns with the one other study on this topic. Lack of significance may be due to a small sample size, which also limited the multivariate analysis. Including genotypes in PM that predict GIST recurrence should be further explored with larger multi-center datasets that can adjust for multiple mutations. Multivariate analysis comparing prognostic models for gastrointestinal stromal tumors at predicting recurrence with and without adjustment for c-KIT exon 11 genotypes using receiver operating characteristic. Without c-Kit exon 11 AUC (95% Confidence Interval) P value NIH 0.86 (0.81,0.90) 0.18 AFIP 0.87 (0.82,0.91) MSKCC 0.89 (0.84,0.94) With c-Kit exon 11 genotype NIH 0.80 (0.67,0.93) 0.16 AFIP 0.84 (0.73,0.95) MSKCC 0.90 (0.80,0.99) NIH: National Institute of Health, AFIP: Armed Forces Institute of Pathology, MSKCC: Memorial Sloan Kettering Cancer Centre. AUC: Area under the curve.

Prognostic significance of pretreatment neutrophil-to-lymphocyte ratio in triple-negative breast cancer: A systematic review and meta-analysis.

e13121 Background: Triple-negative breast cancer (TNBC) lacks reliable prognostic biomarkers beyond standard clinical staging, limiting individualized risk stratification and treatment planning. The neutrophil-to-lymphocyte ratio (NLR), a readily available marker of systemic inflammation, has been proposed as a prognostic indicator in TNBC; however, existing evidence remains inconsistent. We performed an updated systematic review and meta-analysis to evaluate the prognostic value of pretreatment NLR in the contemporary treatment era. Methods: PubMed, Embase, Cochrane CENTRAL, and ClinicalTrials.gov were systematically searched from database inception through January 1, 2026, for randomized and observational studies reporting associations between pretreatment NLR and survival outcomes in TNBC. Two reviewers independently screened studies and extracted data with discrepancies resolved by consensus. Outcomes included overall survival (OS), disease-free survival (DFS), and progression-free survival (PFS). Hazard ratios (HRs) were pooled using random-effects models. Risk of bias was assessed using ROBINS-I tool. Prespecified subgroup and sensitivity analyses were performed based on NLR cut-off values, follow-up duration, geographic region, and risk of bias. Results: Twenty-three retrospective studies comprising 4,731 patients with TNBC were included. On multivariate analysis, elevated pretreatment NLR was independently associated with poorer OS (HR 2.21, 95% CI: 1.56–3.13) and DFS (HR 1.97, 95% CI: 1.65–2.37. Similar associations were observed on univariate analysis (OS: HR 1.70, 95% CI: 1.07–2.72; DFS: HR 1.84, 95% CI: 1.14–2.98). No statistically significant or consistent association was observed between NLR and PFS. Associations between high NLR and adverse OS and DFS remained robust across prespecified subgroup and sensitivity analyses, representing the largest contemporary synthesis of multivariable-adjusted outcomes in TNBC. Key pooled outcome associations are summarized in Table 1. Conclusions: Elevated pretreatment NLR is independently associated with worse OS and DFS in patients with TNBC, supporting its potential role as a low-cost tool for clinical risk stratification and treatment planning. Given its availability from routine blood tests, NLR may assist in identifying high-risk patients who could benefit from intensified surveillance or therapeutic strategies. Prospective validation in the modern chemo-immunotherapy era is warranted. Summary of pooled associations between pretreatment NLR and survival outcomes in TNBC. Outcome Studies (n) Interpretation Overall survival 14 Worse survival Disease-free survival 15 Worse survival Progression-free survival 3 Inconclusive

Trends and disparities in cerebrovascular disease–related mortality in patients with chronic lymphocytic leukemia: A retrospective analysis across two decades.

e18633 Background: Cerebrovascular disease (CVD) is an important cause of morbidity and mortality in patients with chronic lymphocytic leukemia (CLL), driven by aging, cancer-related inflammation, hypercoagulability, and treatment-associated vascular toxicity. National trends in CVD-related mortality among patients with CLL remain poorly characterized. Methods: This population-based cohort study analyzed CVD-related mortality trends among U.S. adults aged ≥55 years with CLL from 1999–2023 using CDC WONDER Multiple Cause of Death data. Deaths were identified using ICD-10 codes for CLL (C91.1) and cerebrovascular disease (I60–I69). Analyses were stratified by age, sex, race/ethnicity, census region, and urbanization. Age-adjusted mortality rates (AAMRs) were calculated using the 2000 U.S. standard population. Joinpoint regression was used to estimate annual percent change (APC) with 95% confidence intervals (CIs). Statistical significance was defined as P<0.05. Results: Between 1999 and 2023, 9,260 CVD-related deaths occurred among patients with CLL aged ≥55 years (54.3% male). Overall AAMRs declined from 1999–2016 (APC −3.4%; 95% CI −4.1 to −2.7; P<0.001) but increased from 2016–2023 (APC 7.9%; 95% CI 5.1 to 10.8; P<0.001), with similar trends in both sexes. Among adults aged 55–74 years, mortality declined from 1999–2017 (APC −4.7%; 95% CI −6.2 to −3.2) followed by a sharp increase from 2017–2023 (APC 13.6%; 95% CI 3.6 to 24.6; P=0.009). A similar pattern was observed in those aged ≥75 years, with declines until 2015 (APC −3.4%) and subsequent increases from 2016–2023 (APC 6.5%; 95% CI 4.3 to 8.8; P<0.001). The South exhibited the highest mortality burden, with rising AAMRs after 2016 (APC 9.1%; 95% CI 5.4 to 12.9; P<0.001) following earlier declines. Urban areas demonstrated the most pronounced recent increase, including a marked rise from 1999–2020 (APC 20.7%; 95% CI 0.02 to 45.8; P=0.05) after prolonged declines. Conclusions: CVD-related mortality among U.S. patients with CLL has increased substantially since 2016, particularly among older adults and residents of urban and Southern regions. These findings highlight a growing cardio-oncologic burden and underscore the need for improved vascular risk assessment, treatment monitoring, and preventive strategies in patients with CLL.

Health technology agencies' reimbursement decisions for cancer drugs across four high-income countries.

e23037 Background: For people with advanced cancer, alternative endpoints such as progression-free survival (PFS) often correlate poorly with meaningful outcomes including overall survival (OS) and quality of life (QOL). Health technology assessment (HTA) decisions may vary significantly between countries. As global regulators move towards convergence of drug approval decisions, it is important to understand how decisions for funding differ between jurisdictions, particularly for drugs without clear improvements in OS or QOL. Methods: We conducted a retrospective cohort study of trials used for FDA approval of cancer drugs to treat adult solid tumors from 2010 to 2021 with time-to-event endpoints. Trials were cross-referenced with HTA decisions in Canada, England, Australia, and Singapore. The unit of analysis was a drug-indication pair. The primary outcome was the HTA reimbursement decision across countries for FDA-approved drug-indication pairs, analysed according to the statistical significance of OS and PFS results. The secondary outcome was differences in time to HTA reimbursement decision across countries and by endpoint type and significance. Odds ratios (ORs) with 95% CIs were used to compare the odds of approval with Canada as the referent. Results: Of 141 FDA-approved drug-indication pairs, 66% (Canada), 69% (England and Australia), and 81% (Singapore) were given positive reimbursement decisions. Canada had the highest proportion of indications not submitted for evaluation (28%), followed by Australia (18%) and England (14%). Across all four jurisdictions, 60 indications (42%) were mutually approved, with an additional eight consistently not recommended for reimbursement or not submitted. Of 141 pairs, 79 had significant PFS and OS results, with similar recommendation rates. Singapore was significantly more likely than Canada to give a positive reimbursement decision for drugs demonstrating PFS benefit without OS improvement (OR for rejection 0.25, p=0.005). Mean decision delays versus the FDA were 16.1, 29.6, and 21.2 months in Canada, England, and Australia, respectively. Decision times did not differ by OS versus PFS benefit across countries. Conclusions: Regulatory decision-making differed substantially across the four publicly funded systems, reflecting heterogeneity in HTA priorities and governance. These findings underscore the limits to regulatory convergence, particularly in predicting downstream reimbursement outcomes. Approval timelines were not influenced by the presence of an OS benefit, suggesting that factors beyond endpoint significance and clinical benefit shape funding decisions.

Association of gut microbiota and peri-initiation proton pump inhibitor/antibiotic exposure with outcomes of atezolizumab-bevacizumab-carboplatin-paclitaxel regimen in patients with advanced non-squamous NSCLC: Prospective phase II study (K-TAIL-201).

8541 Background: Concomitant medications that alter gut microbiome composition, such as proton pump inhibitors (PPIs) and antibiotics, have been suggested as possible modifiers of immune checkpoint inhibitor outcomes; however, there is a paucity of prospective data with pre-specified exposure windows during atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) treatment. This study investigated the associations between peri-initiation PPI/antibiotic exposure and gut microbiota with clinical outcomes. Methods: K-TAIL-201 is a prospective, single-arm, phase II study (jRCT031200088) that enrolled Japanese patients with previously untreated advanced non-squamous non-small cell lung cancer (NSCLC) who received an induction ABCP regimen, followed by maintenance with atezolizumab plus bevacizumab. The primary endpoint was six-month progression-free survival (PFS) rate. PPI/antibiotic exposure was evaluated in two pre-specified windows: pre-treatment (up to 21 days before ABCP) and early on-treatment (the first 21 days of treatment). Longitudinal fecal samples were collected and analyzed using 16S rRNA gene sequencing. Exploratory analyses were conducted to investigate the relationships between exposure/microbiota features and outcomes. Results: Thirty-two patients were enrolled, with a median follow-up period of 20.6 months. The 6-month PFS rate was 59.4% (95% confidence interval (CI), 40.6–76.3), objective response rate was 50.0% (95% CI, 31.9–68.2), median PFS was 7.1 months (95% CI, 5.9–9.6), and the median overall survival (OS) was 24.3 months (95% CI, 18.7–not reached). Early on-treatment PPI exposure was associated with poorer outcomes, including shorter PFS (hazard ratio [HR] 7.07, p < 0.001) and OS (HR 5.66, p = 0.009), whereas pre-treatment PPI exposure was not associated with PFS of at least six months. Early on-treatment antibiotic exposure was associated with a lower 6-month PFS rate (21% versus 89%, p < 0.001), but showed no association with time-to-event PFS (HR 1.62, p = 0.41). Microbiota analyses revealed no significant differences in alpha or beta diversity by outcome or exposure group. However, Bifidobacterium was more frequently detected among responders. Conclusions: Early on-treatment (but not pre-treatment) PPI exposure is strongly associated with inferior PFS and OS in patients with advanced non-squamous NSCLC on ABCP regimen, supporting the clinical relevance of exposure timing. These findings suggest careful PPI use during the induction phase and warrant validation in larger prospective cohorts. Clinical trial information: 031200088.

Long-term survival, disparities, and future burden of multiple myeloma: A population-based analysis.

e19562 Background: Multiple myeloma is a chronic blood cancer in which patients often live for many years, yet the risk of death remains ongoing. While survival has improved over time, population-level studies that combine traditional survival analysis, advanced modeling techniques, and future burden projections are limited. Methods: We performed a population-based retrospective study using the Surveillance, Epidemiology, and End Results (SEER) database. Overall survival was evaluated using Kaplan–Meier analysis and Cox proportional hazards regression. Parametric survival modeling was conducted using Weibull regression to better characterize long-term mortality patterns. Machine-learning survival analysis was performed using random survival forests to assess the relative importance of clinical and demographic factors. Annual case counts were analyzed and projected through 2035 using time-series forecasting methods. Results: The study included 8,627 patients with multiple myeloma. Overall survival declined gradually over long-term follow-up, with approximately one-quarter to one-third of patients surviving at extended time points. Female patients experienced better survival than males. Significant survival differences were observed across racial groups, with Asian or Pacific Islander patients demonstrating the most favorable outcomes and American Indian or Alaska Native patients the poorest. In multivariable analyses, age, sex, race, and year of diagnosis were independently associated with survival. Parametric modeling closely mirrored non-parametric survival estimates and supported a time-dependent pattern of mortality. Machine-learning analysis identified year of diagnosis as the strongest predictor of survival, followed by age and race. Forecasting suggested that the burden of multiple myeloma will remain substantial through 2035. Conclusions: Multiple myeloma is associated with long-term survival but persistent mortality risk and ongoing demographic disparities. Combining traditional survival analysis with parametric and machine-learning approaches provides a more complete understanding of outcomes and highlights the sustained future burden of this disease, with important implications for clinical care and healthcare planning.

Informing optimal duration of adjuvant chemotherapy (ACT) in resected stage I-IV colorectal cancer (CRC) based on early circulating tumor DNA (ctDNA) dynamics.

3501 Background: While ACT is recommended by clinical guidelines for patients (pts) with high-risk stage II and stage III CRC, individual benefit varies significantly and appropriate ACT duration is debatable. Here, we evaluated whether on-ACT ctDNA dynamics can inform recurrence risk and benefit from continued ACT beyond 3 months (mo) in resected stage I-IV CRC. Methods: This analysis included 1,028 pts from the CIRCULATE-Japan GALAXY observational study who received ACT but no neoadjuvant chemotherapy, with >2 ctDNA results available within 6 mo post-surgery. Patients were divided into long-ACT (>3 mo, N = 651) and short-ACT cohort (< 3 mo, N = 377) cohorts. ctDNA was analyzed using a personalized, tumor-informed Signatera assay at two timepoints: a) pre-ACT (≥14 days post-surgery, before ACT), and b) post-3 mo from ACT (short cohort) or 3 mo ±45 days from ACT (long cohort). Disease-free survival (DFS) was measured from the date of surgery and compared between pts who received long vs short ACT, stratified by ctDNA dynamics. Subanalyses comparing ACT duration were landmarked at the second ctDNA timepoint. Results: Of the 1,028 pts (< 1%/17%/75%/7% stages I/II/III/IV), 44% were females; 81% had colon cancer and 19% rectal cancer. Median pt age was 66 (24-89) years. Median follow-up was 30.7 (4.9-55.8) mo. Median ACT duration was 5.7 mo in long-ACT and 2.5 mo in short-ACT cohorts. Pre-ACT sampling was a median of 14 and 20 days before ACT start for long- and short-ACT cohorts, respectively; post-3 mo sampling was a median of 112 days after ACT start for both cohorts. ctDNA dynamics from the pre-ACT to post-3 mo ACT timepoints revealed sustained negativity in 78.7% (N = 809) of pts, ctDNA clearance in 14.7% (N = 151), decreasing but detectable levels in 2.7% (N = 28), rising levels in 2.8% (N = 29), and newly detectable ctDNA on ACT in 1.1% (N = 11). No benefit of short vs long ACT duration was observed among pts with sustained ctDNA negativity (HR 0.71, p = 0.11) or ctDNA clearance (HR 1.06, p = 0.84). Similarly, pts with rising ctDNA experienced no benefit from longer ACT (HR 1.82, p = 0.18). Conversely, within the decreasing but detectable ctDNA subgroup, longer ACT was associated with improved DFS compared with short ACT median DFS 5.9 vs 1.7 mo; HR 3.64, p = 0.012), acknowledging that the analysis was limited by small cohort size and requires further investigation. Conclusions: ctDNA dynamics during ACT provide clinically meaningful stratification of recurrence risk and reveal heterogeneity in treatment benefit. Pts with ctDNA clearance or sustained negativity showed durable disease control and may not require longer ACT. Conversely, pts with partial molecular response showed directional benefit from longer ACT. Pts with molecular progression on ACT did not benefit from extended ACT, indicative of chemotherapy refractory disease and the need for alternative treatment regimens. Clinical trial information: R000044197.

A novel endoscopic sleeve en bloc resection for sinonasal mucosal melanoma: A propensity score–matched comparison with conventional endoscopic surgery.

e18150 Background: Sinonasal mucosal melanoma (SNMM) is a rare and aggressive malignancy for which complete surgical excision with negative margins remains the cornerstone of treatment, yet achieving en bloc resection through an endoscopic approach remains challenging because of complex anatomy and the skip-lesion growth pattern. Most endoscopic resections are performed piecemeal, potentially compromising margin control. We developed an endoscopic sleeve en bloc resection(ESER) technique to facilitate circumferential mucosal excision and improve oncologic completeness. This study evaluated the feasibility, safety, and preliminary oncologic outcomes of this approach compared with conventional endoscopic resection. Methods: Patients with T3N0M0 SNMM treated derived from a prospective single-arm study registered at the Chinese Clinical Trial Registry (ChiCTR2100046498) were included. Seven patients underwent ESER, and thirteen patients treated with conventional endoscopic resection were selected as matched controls using propensity score matching (PSM). Treatment modalities, surgical margin status, adverse events, recurrence, and survival outcomes were analyzed. Overall survival (OS) was the primary endpoint. Survival analyses were performed using Kaplan–Meier methods, log-rank tests, and inverse-probability weighting (IPW) to estimate the average treatment effect. Results: A total of 20 patients were analyzed (median age, 65 years; range, 39–79). Negative surgical margins were achieved in 85.7% of patients in the ESER group (n=7) and 76.9% in the conventional group (n=13). Most patients in both groups received multimodal therapy, including radiotherapy, chemotherapy, and immunotherapy. At a median follow-up of 5.5 months (range, 2–24) in the ESER group, no local recurrence, distant metastasis, or deaths were observed (OS 100%). In the conventional group, with a median follow-up of 29 months (range, 6–46), the 2-year OS was 59.8%, with three locoregional recurrences and three distant metastases. IPW analysis suggested a lower estimated risk of death with sleeve resection (ATE −0.275; p = 0.107), although the difference was not statistically significant. Treatment-related adverse events were predominantly Grade 1–2. No Grade 4 or 5 toxicities were observed. Grade 3 events were uncommon and included olfactory loss, chemotherapy-related leukopenia, and atrial fibrillation following combined therapy. Conclusions: ESER is a feasible and safe surgical approach for selected patients with SNMM, enabling true en bloc mucosal excision with acceptable morbidity. Preliminary results demonstrate favorable margin control and encouraging early oncologic outcomes. Longer follow-up and larger, multi-center studies are required to validate the long-term survival benefit and reproducibility of this technique. Clinical trial information: ChiCTR2100046498.

Azeliragon, a RAGE inhibitor, plus temozolomide and radiotherapy in patients with newly diagnosed glioblastoma: Final results from a dose-finding phase in the CAN-201 NDG trial.

2015 Background: Radiotherapy (RT) plus temozolomide (TMZ) is the standard of care for patients (pts) with newly diagnosed glioblastoma (GBM). However, most eventually progress. The RAGE receptor and its ligands may contribute to RT resistance in GBM by sustaining chronic pro-tumorigenic inflammation, enhancing DNA damage repair pathways, and promoting survival signaling in hypoxic and stressed tumor cells. Azeliragon, an extensively studied RAGE inhibitor in Alzheimer’s disease, may enhance overcome RT-TMZ resistance in newly diagnosed GBM. Methods: The CAN-201 NDG is an open-label, single-arm, phase Ib/II trial in Spain recruiting pts with newly diagnosed IDH-wildtype GBM. Pts received azeliragon in combination with standard RT-TMZ, followed by maintenance therapy with azeliragon. The trial consists of an initial dose-finding phase with a rolling six design and a subsequent expansion phase (up to 14 additional pts) at the recommended phase 2 dose (RP2D). The dose levels were 5 (L1), 10 (L2), 20 (L3), 30 (L4), and 50 (L5) mg/day. The primary objective was to determine the RP2D, defined as the dose for which <33% of pts experience dose-limiting toxicity (DLT) within 28 days of the initiation of dosing. Main secondary endpoints include progression-free survival (PFS), overall survival (OS), and changes in corticosteroid requirements. Pharmacokinetic and translational research is ongoing. Results: From Oct 2023 to May 2025, 33 pts were included across L1-L5 levels (6-8 pts per level). Median age was 56 years (range: 36-69). Most pts were male (66.7%), with ECOG 0-1 (93.9%), MGMT unmethylated (54.5%) and complete resection (45.5%). No DLTs occurred, and L5 (50 mg/day) was declared RP2D. One grade 3 maculopapular rash at L5 was the only serious adverse event related to azeliragon. Most common grade 3-4 toxicities were thrombocytopenia (21.2%) and lymphopenia (9.1%), all RT or TMZ-related. Most common possibly azeliragon-related AEs were asthenia (24.2%), nausea (21.2%), anorexia (9.1%), diarrhoea and dysgeusia (6.1% each), all grade 1-2. Median azeliragon treatment duration was 7.4 m (range: 2.7-21.1). Treatment ended due to disease progression (82.8%), toxicity (3.4%), and exitus (3.4%). Three pts at L5 remain on treatment. With median follow-up of 11 m (95% CI: 8.2-16.4), median PFS was 7.9 m (95% CI: 6.2-12.2) overall, 15.6 m (95% CI: 6.1-NR) and 6.7 m (95% CI: 5.0-10.9) for methylated and unmethylated MGMT, respectively. Median OS was not reached, 12m OS rate was 61.5% (95% CI: 4.4-85.3), with rates of 74.2% (95% CI: 52.4-100) and 51.1% (95% CI: 29.3-88.8) for methylated and unmethylated MGMT, respectively. Conclusions: Azeliragon at 50 mg/day in combination with standard RT / TMZ is safe, with no DLTs reported. More mature OS data will be presented. Further follow-up with a larger number of pts is required to assess preliminary efficacy. Clinical trial information: NCT05635734 .

Baseline visceral disease burden and treatment delivery factors association with outcomes after tumor-infiltrating lymphocyte therapy for metastatic melanoma.

e21521 Background: Outcomes following tumor-infiltrating lymphocyte (TIL) therapy vary in real-world practice, and accessible predictors are needed to inform patient selection and timing of referral. We evaluated whether baseline disease burden, metastatic distribution, and treatment delivery factors are associated with outcomes following TIL therapy. Methods: We retrospectively analyzed patients with metastatic melanoma treated with TIL therapy across Mayo Clinic sites (N = 27 infused). Baseline disease burden was characterized using AJCC metastatic stage and organ-specific involvement. A composite high visceral burden variable was defined as the presence of M1d disease and/or liver metastases. Bridging therapy use prior to infusion was recorded. Post-infusion IL-2 exposure was categorized as low (0-2 doses) vs. high (3-6 doses). Best overall response (BOR) was summarized using RECIST-based standard criteria. Overall survival (OS) and progression-free survival (PFS) were measured from TIL infusion and estimated using Kaplan–Meier methods with univariable Cox regression. Results: Median age at infusion was 62.0 years; 59.3% were male. Melanoma subtypes included cutaneous (81.5%) and mucosal (18.5%). Bridging therapy was used in 48.1%. Baseline metastatic stage was M1a/M1b in 18.5%, M1c in 63.0%, and M1d in 18.5%. Median follow up was 8.3 months. BOR included complete response (18.5%), partial response (37.0%), stable disease (22.2%), and progressive disease (22.2%), yielding an objective response rate of 55.6% and disease control rate of 77.8%. Patients with high visceral disease burden experienced inferior OS vs. those without high visceral burden (median 5.2 vs 13.4 months; HR 4.77, 95% CI 1.22–18.63; p = 0.014). Bridging therapy was not associated with OS or PFS. Higher post-infusion IL-2 exposure (seen in 77.8% of patients) was associated with improved OS (median 9.0 vs 3.7 months; HR 0.16, 95% CI 0.04–0.67, p = 0.005), likely reflecting early post-infusion clinical tolerance rather than a causal treatment effect. Median PFS for the cohort was 3.6 months and did not differ by IL-2 exposure ( p = 0.3), metastatic stage ( p = 0.8), bridging therapy ( p = 0.7), liver metastases ( p = 0.2), or LDH above upper limit of normal ( p = 0.1). Conclusions: The above findings are hypothesis generating and will support evaluation in larger cohort. In this real-world cohort of patients treated with TIL therapy, baseline visceral disease burden was strongly associated with survival outcomes, while bridging therapy did not compromise post-infusion efficacy among patients proceeding to infusion. Post-infusion IL-2 exposure correlated with OS and likely reflects early treatment tolerance. These readily available clinical features may inform patient counseling, referral timing, and sequencing decisions as TIL therapy enters broader clinical use.

Patient perspectives on delays in care for kidney stones: A qualitative analysis

Purpose Traditional insurance claims dataset analyses have exposed disparities in treatment delays for kidney stones along lines of socio-economic status, particularly among patients who are underinsured and/or racial/ethnic minorities. Analyzing patient experiences through qualitative semi-structured interviews allows for elucidation of common root causes leading to care delays in patients with kidney stones. Materials and methods 20 participants were recruited from a group of adult patients at a safety net hospital and academic medical center who had been referred for urological care after presenting to the Emergency Department for kidney stones. Patients were selected for semi-structured interviews if they failed to present to the urology clinic after 60 days of referral placement. Interviews were conducted in Spanish or English. Transcripts were coded and analyzed using thematic analysis. Results Of the 20 participants, the median age in years was 46 (range 22–72), 50% identified as female, 40% were White, 40% were Hispanic, 20% were Black, and 20% were Spanish-dominant. The median delay was 105 days. Thematic analysis identified patient-extrinsic obstacles in obtaining timely care in the form of care costs and skepticism from health care providers, such as perceptions of being drug-seeking or feigning pain. We further identified patient-intrinsic obstacles, such as gaps in understanding of the dangers of stone disease and difficulty navigating care coordination. Conclusions This study provides insights into multi-level factors that impact care delays for patients with kidney stone disease. Findings from this work deepen understanding of why patient experiences in care delays manifest along lines of socio-economic status and can inform future interventions to reduce disparities.

Orbital torque efficiency in NixFe1-x/Pt bilayers

Distinguished from spin torque dominantly determined by spin Hall angle of nonmagnetic metal, the generation and modulation of orbital torque strongly relies on the electronic structure, orbital magnetic moment, and spin–orbit coupling strength of the ferromagnetic material (FM). Here, the dependence of orbital torque generation on the FM is investigated by varying the composition in NixFe1-x/Pt bilayer systems. It is found that the torque efficiency varies non-monotonically with Ni concentration and peaks in pure Fe. Notably, Fe/Pt exhibits an order of magnitude higher orbital torque efficiency than other systems, which is enhanced by the specific bilayer combination. The long-range propagation observed in FM underscores a significant role of orbital Hall effect in torque generation. Using a diffusion model, we disentangle the spin and orbital contributions, and extract the characteristic diffusion lengths of Pt. Our work provides a viable material-engineering strategy for substantially improving orbital torque efficiency, contributing to the development of low-power orbitronic devices.

Recent advances in magnetic nanomaterials for clinical applications: A comprehensive review

A Cryoprotectant‐Compatible Nanoporous Platform for Stable and Scalable Delivery of Biopharmaceuticals (Adv. Mater. 33/2026)

Multi‐Energy‐State Covalent Organic Framework/Sulfur‐Vacancy‐Engineered Mn _0.2 Cd _0.8 S S‐Scheme Photocatalyst for Enhanced Light Harvesting and H ₂ O ₂ Generation

ABSTRACT Hydrogen peroxide (H 2 O 2 ) is an essential green oxidant with broad industrial relevance. Photocatalytic oxygen reduction reaction (ORR) offers a sustainable method for producing oxygen, yet its efficiency is limited by poor charge separation and severe carrier recombination. Single‐component photocatalysts suffer from sluggish carrier dynamics, while multi‐energy‐state systems frequently experience recombination at intermediate states. S‐scheme heterojunction engineering offers an effective strategy to address these challenges by regulating interfacial charge transfer while preserving strong redox potentials. Here, we report the construction of an S‐scheme photocatalyst by integrating a triazine‐based covalent organic framework (COF) with sulfur‐vacancy‐rich Mn 0.2 Cd 0.8 S (Sv‐MCS). This dual‐functional design preserves both the intrinsic n→π* electronic transitions of the COF and defect‐state absorption of Sv‐MCS, delivering an exceptional H 2 O 2 production rate of 5389.6 µmol·h −1 ·g −1 in pure water. Concurrently, the photostability of the catalyst is simultaneously enhanced. X‐ray absorption fine‐structural analysis confirms interfacial Cd–O coordination between Cd atoms and COF carbonyl groups. In situ spectroscopies combined with density functional theory elucidate a preferential two‐electron ORR pathway, while femtosecond transient absorption spectroscopy confirms suppressed carrier recombination enabled by synergistic S‐scheme charge transfer and interfacial chemical bonding. This work establishes design principles for multi‐energy‐state S‐scheme photocatalysts and advances solar‐driven H 2 O 2 production toward artificial photosynthesis.

Concurrent inflammatory, hemorheological and macrovascular responses to a 230-km ultramarathon: an exploratory study

Abstract To investigate the concurrent physiological response to extreme endurance exercise by examining inflammatory, hemorheological, endothelial, and vascular adaptations following an ultramarathon. Twelve runners (9 men/3 women; 48 ± 7 years) participating in a 230-km non-stop ultramarathon were assessed before and immediately after the race. Systemic inflammatory and oxidative stress markers, indices of red blood cell (RBC) aggregation and fibrinogen, plasma nitrite as a marker of nitric oxide (NO) bioavailability, and macrovascular hemodynamic parameters were measured. White blood cell count (WBC) ( p  < 0.001), interleukin (IL)-6 ( p  = 0.0002), IL-10 ( p  = 0.0002) and C-reactive protein (CRP) ( p  < 0.001) increased, while plasma free reactive oxygen species (ROS) ( p  = 0.0043) and total antioxidant capacity ( p  = 0.0041) decreased post-race. RBC aggregation increased ( p  = 0.0003) in concert with elevated fibrinogen ( p  < 0.0001). Plasma nitrite increased post-race ( p  = 0.0013). Macrovascular hemodynamics exhibited increased heart rate ( p  < 0.0001) with preserved pulse wave velocity (PWV; p  = 0.257) and central pressures. Wave reflection indices were altered, with reduced augmentation index (AIx; p  = 0.034), whereas heart rate–standardized AIx75 remained unchanged ( p  = 0.104), alongside an increase in diastolic reflection area (DRA; p  = 0.020) and divergent peripheral pressure responses. The ultramarathon was associated with pronounced inflammatory responses accompanied by increased fibrinogen-related RBC aggregation and elevated plasma nitrite concentrations, while macrovascular properties remained largely preserved. Together, these findings suggest that acute responses to extreme endurance exercise involve parallel inflammatory, hemorheological, endothelial, and macrovascular alterations, with cardiovascular adjustments primarily reflecting functional changes in peripheral vascular regulation rather than substantial changes in central arterial mechanical properties.

A dileucine motif in TMEM163 is essential for its binding with both AP-3 and BLOC-1 complex

A randomized phase III study of pembrolizumab versus pembrolizumab with carboplatin plus pemetrexed for locally advanced or metastatic nonsquamous non–small cell lung cancer with PD-L1 TPS ≥ 50%: LAPLACE-50.

8554 Background: For patients with advanced non-squamous non-small cell lung cancer (NSCLC) and high PD-L1 expression (TPS ≥50%), both pembrolizumab monotherapy and immune checkpoint inhibitor with platinum and pemetrexed combination chemotherapy are recognized as standard first-line therapies. However, direct head-to-head comparisons to determine the optimal strategy in this specific population are limited. We conducted a randomized phase III trial to compare these approaches. Methods: In this open-label, randomized phase III trial, previously untreated patients with advanced/metastatic non-squamous NSCLC and PD-L1 TPS ≥50% were randomized (1:1) to receive either pembrolizumab monotherapy (Arm A) or pembrolizumab plus carboplatin and pemetrexed (Arm B). The primary endpoint was progression-free survival (PFS) with a predefined non-inferiority margin of 1.25 for the hazard ratio (HR). Secondary endpoints included overall response rate (ORR), overall survival (OS), and safety. Due to slow accrual, the trial was terminated prematurely, and a final analysis was performed on the available cohort. Results: A total of 70 patients were randomized (Arm A, n=35; Arm B, n=35), and 69 patients were included in the full analysis set. Median PFS was 8.1 months in Arm A and 9.2 months in Arm B (HR 1.25; 90% CI, 0.77–2.04), and non-inferiority of pembrolizumab monotherapy was not demonstrated. ORR was 57.1% in Arm A and 73.5% in Arm B (odds ratio 0.49, 95% CI, 0.18–1.36; p=0.172). Median OS was 55.1 months in Arm A and 23.5 months in Arm B (HR 0.83, 95% CI, 0.42–1.63; p=0.663). Grade ≥3 hematologic toxicities were more frequent in Arm B. Serious adverse events occurred in 20.0% of patients in Arm A and 26.5% in Arm B. Conclusions: Although this trial was limited by early termination and did not statistically demonstrate the non-inferiority of pembrolizumab monotherapy in terms of PFS, the numerical OS favored the monotherapy group despite a lower ORR. These findings suggest that for patients with PD-L1 TPS ≥50%, pembrolizumab monotherapy remains a robust treatment option with a favorable safety profile, though the addition of chemotherapy may offer higher initial response rates. Clinical trial information: jRCTs031200078.

Platinum chemotherapy and oncolytic virotherapy as used to cooperatively sustain stem-like CD8⁺ T-cell immunity via type I interferon modulation.

e14545 Background: Durable antitumor immunity depends on the maintenance of stem-like CD8⁺ T cells capable of sustaining long-term effector responses. Oncolytic viruses (OVs) are potent immunomodulatory agents that reshape the tumor microenvironment and augment antitumor immunity. We hypothesized that platinum-based chemotherapy alters tumor-intrinsic type I interferon (IFN-I) signaling in a manner that can be functionally restored by OV therapy, thereby promoting the generation and persistence of stem-like CD8⁺ T cells. Methods: Tumor cells treated with platinum chemotherapy were evaluated in vitro for changes in IFN-I pathway activity, OV replication, and markers of immunogenic cell death (ICD). Syngeneic mouse tumor models were used to assess antitumor efficacy and immune remodeling following combination therapy. Tumor-infiltrating lymphocytes were analyzed by single-cell RNA sequencing and multiparameter flow cytometry to define CD8⁺ T-cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Platinum chemotherapy significantly suppressed tumor-intrinsic IFN-I signaling, while OV therapy restored antiviral responses, enhanced viral replication, and increased ICD in vitro. In vivo, the combination strategy resulted in superior tumor control and profound remodeling of the tumor immune microenvironment. The most pronounced immunologic effect was observed within the stem-like CD8⁺ T-cell compartment. Combination therapy induced a distinct population of TCF7⁺ ISG15^high NFATC1^low AP-1^low CD8⁺ T cells, characterized by restrained activation, enhanced persistence, and reduced propensity toward terminal exhaustion. In IRF7-deficient tumors, this stem-like CD8⁺ T-cell population failed to emerge and antitumor efficacy was significantly diminished, indicating that moderate tumor-intrinsic IFN-I signaling is required for this immune state. Conclusions: Tumor-intrinsic type I interferon signaling is a critical determinant of synergy between platinum chemotherapy and oncolytic virotherapy, enabling the maintenance of durable stem-like CD8⁺ T-cell immunity. These findings establish a mechanistic rationale for combining platinum chemotherapy, oncolytic viruses, and immune checkpoint blockade and support ongoing clinical translation. Clinical trial information: ChiCTR2500107607.

Indole alkaloid corynan isolated from <i>Petasites hybridus</i> as a potential antitumor agent.

e15158 Background: The aim of this study was to evaluate the antitumor activity of the alkaloid corynan, which we obtained, in silico and in vitro on H1299 and HT29 tumor cell lines. Methods: Corynan was extracted from the plant material Petasites hybridus using preparative chromatography. Its structure was confirmed by Nuclear Magnetic Resonance (NMR) as (2S,3R,12bS)-2,3-diethyl-12b-methyl-1,2,3,4,6,7,7a,12,12a,12b-decahydroindolo[2,3-a]quinolizine. Molecular docking of corynan with five receptors involved in carcinogenesis — EGFR, PDGFR, MET, MRP2, and NOX4—was performed using AutoDock Vina 4.0. PDB structures were imported into Discovery Studio Visualizer 4.0. AlphaFoldDB structures were already cleaned. These structures were optimized prior to docking using Chimera 1.6.2. The resulting .pdb files were validated using the PROCHECK server and aligned with the original structure. These files were used to prepare the grid in AutoDockTools-1.5.7. H1299 (non-small cell lung cancer) and HT29 (colorectal cancer) cells were cultured under standard conditions in MEM medium. Upon reaching 75-80% confluence, the medium was replaced with one containing corynan (128 µM concentration), and the cells were cultured for 72 hours. Cell viability was determined using a NanoEnTek JuliFl (Korea) counter in the presence of 0.4% trypan blue. The assessment of expression levels after treatment was performed by RT-PCR using a gene panel: CASP9, CASP7, CASP3, TP53, MDM2, BAX, BCL2, PTEN, ATM, MTCH1, CYCS, DIABLO, VDAC1. Results: Corynan demonstrated the highest affinity for the MET protein (-8.6 kcal/mol), followed by PDGFR (-7.2 kcal/mol), EGFR and MRP2 (-6.4 kcal/mol and -6.3 kcal/mol), and NOX4 (-5.9 kcal/mol). Corynan at a concentration of 128 µM and 72-hour exposure caused death in 60% of HT29 cells and 36% of H1299 cells. Under the same conditions, corinane caused a 22-fold increase in CASP9 expression in H1299 cells, and in HT29 cells, a 9.5-fold increase in CASP9 expression and a 12.5-fold increase in CASP7 expression. In HT29 cells, it caused an 82-fold increase in BAX expression and a 64-fold increase in MTCH1 expression. No statistically significant changes were observed in the expression of the other investigated genes. Conclusions: Molecular docking of corynan showed that it could be an effective inhibitor of the MET protein—a key factor in invasion and metastasis. The inhibition of viability in HT29 and H1299 cell lines in vitro and the changes in the expression of caspase genes, BAX , and MTCH1 suggest that corynan possesses antitumor activity and provides a basis for its further study.