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<i>ESR1</i> hotspot–specific chemotherapy resistance patterns in metastatic breast cancer identified by ctDNA analysis.

e13009 Background: ESR 1 mutations are established drivers of endocrine resistance in ER+ metastatic breast cancer (MBC), yet their relevance to chemotherapy resistance remains unclear. Building on our prior work showing circulating tumor DNA (ctDNA) ESR1 monitoring is prognostic in MBC (ASCO 2025 #1042; AACR 2025 #3613), we investigated whether baseline ctDNA ESR 1 hotspots are associated with agent-specific and broad chemotherapy resistance to inform risk stratification and treatment sequencing. Methods: This study included 158 ER + MBC patients (IRB: NU16B06) treated at Robert H. Lurie Cancer Center. Baseline ctDNA was analyzed by Guardant 360 NGS panel. Two clinically motivated analyses were applied to patients with ESR 1 mutations: (1) ESR 1 hotspot mutations were categorized as classic hotspots (D538G, Y537S/Y537N, E380Q) versus non-classic hotspots (L536H, L536R, L536P, K362N, K520K, V392I), and their association with chemotherapy resistance; and (2) very broad resistance was defined a priori as resistance to ≥5 chemotherapeutic agents. Associations were tested using two-sided Fisher’s exact test with odds ratios reported. Results: ESR1 mutations were identified in 10 hotspots among 40 of 158 patients, including 8 E380Q (mean 6.3%), 12 Y537S (mean 5.6%), 13 D538G (mean 11.9%), 1 V392I (0.1%), 1 Y537N (1.7%), 1 L536P (3.4%), 1 L536R (11.0%), 1 L536H (23.9%), 1 K520K (0.6%) and 1 K362 (15.8%). The cases sensitive vs resistant to chemotherapy drugs are as follows: Doxorubicin (22 vs 18), Epirubicin (33 vs 7), Pegylated Liposomal doxorubicin (37 vs 3), Carboplatin (25 vs 15), Paclitaxel (21 vs 19), Docetaxel (23 vs 17), Vinorelbine (29 vs 11) , Ixabepilone (34 vs 6), Eribulin (32 vs 8), Capecitabine (17 vs 23), Cyclophosphamide (16 vs 24), Gemcitabine (36 vs 4), and Abraxane (35 vs 5). Among 40 patients, vinorelbine resistance was more frequent in those harboring non-classic ESR 1 hotspots compared with classic hotspots (66.7% [4/6] vs 20.6% [7/34]; OR 7.71, P = 0.0385). When chemotherapy resistance burden was evaluated, very broad resistance (≥5 agents) was observed in 8/40 (20%) patients, and was absent in D538G cases (0/13, 0%) compared with non-D538G cases (8/27, 29.6%; P = 0.0373), suggesting a distinct resistance spectrum. These findings suggest ESR 1 hotspot mutation information may help identify patients at risk for specific agent resistance and early multi-line chemotherapy failure. Conclusions: Our findings indicate that baseline ctDNA ESR 1 hotspot heterogeneity is associated with distinct chemotherapy resistance patterns. Non-classic ESR 1 hotspots were enriched for vinorelbine resistance, whereas D538G was inversely associated with an extreme multi-drug resistance phenotype (≥5 agents), suggesting ESR 1 hotspots may serve as a clinically relevant biomarker for chemotherapy resistance spectrum, supporting prospective validation and biomarker-guided treatment strategies.

Genitourinary safety of SGLT2 inhibitors in patients with cancer and type 2 diabetes: A real-world analysis.

e23089 Background: Sodium–glucose cotransporter-2 (SGLT2) inhibitors are increasingly used for glycemic and cardiovascular benefits; however, concerns persist regarding genitourinary infections, particularly in vulnerable populations such as patients with cancer and diabetes. Real-world data evaluating the safety of SGLT2 inhibitors in this population remain limited. We evaluated the association between SGLT2 inhibitor use and genitourinary infection risk among cancer patients with type 2 diabetes. Methods: We conducted a retrospective cohort study using the TriNetX federated research network. Adult patients (≥18 years) with malignant neoplasms and type 2 diabetes mellitus were identified. Patients were stratified based on exposure to SGLT2 inhibitors and compared with cancer patients with diabetes not receiving SGLT2 inhibitors. Primary outcomes included urinary tract infection (UTI) and cystitis, identified using ICD-10 diagnostic codes. Analyses included unadjusted comparisons, 1:1 propensity score matching (PSM), and a Cox proportional hazards model as a sensitivity analysis to assess time to first UTI within one year following index exposure. Results: A total of 7,485 patients were included (7,137 without SGLT2 inhibitors and 348 with SGLT2 inhibitors). In unadjusted analyses, crude rates of UTI and cystitis were numerically higher in the SGLT2 inhibitor cohort. After 1:1 propensity score matching (312 patients per cohort), baseline characteristics were well balanced. The incidence of UTI was identical between matched cohorts (6.41% vs 6.41%, p = 1.00), with no significant differences observed for cystitis or acute cystitis. In a Cox proportional hazards sensitivity analysis, SGLT2 inhibitor use was associated with a significantly lower hazard of UTI compared with no SGLT2 inhibitor exposure (hazard ratio 0.68, 95% confidence interval 0.52–0.89; p = 0.0048). Conclusions: In this large real-world cohort of cancer patients with diabetes, SGLT2 inhibitor use was not associated with an increased risk of genitourinary infections. Propensity-matched analyses demonstrated no difference in absolute infection risk, while time-to-event analysis suggested a lower hazard of UTI among patients receiving SGLT2 inhibitors. These findings support the genitourinary safety of SGLT2 inhibitors in cancer patients with diabetes and may inform clinical decision-making in this high risk population.

Sequential or concurrent immunotherapy with locoregional radiotherapy in de novo metastatic nasopharyngeal carcinoma.

2622 Background: First-line chemotherapy combined with immunotherapy (CT-IO), followed by selective locoregional radiotherapy (LRRT), has emerged as the mainstay treatment for de novo metastatic nasopharyngeal carcinoma (dmNPC). However, the efficacy of adding concurrent immunotherapy to LRRT remains controversial. Methods: This study enrolled patients with dmNPC who received platinum-based chemotherapy, anti–PD-1 immunotherapy, and definitive LRRT. Survival outcomes were assessed using a 12-month landmark analysis to minimize immortal time bias. Inverse probability of treatment weighting (IPTW) was employed to balance baseline characteristics between the CCRT+IO (LRRT with concurrent immunotherapy) and CCRT-IO (LRRT without concurrent immunotherapy) groups. Recursive partitioning analysis (RPA) utilizing baseline and post-CT-IO factors was applied to stratify patients into low- or high-risk groups to evaluate the benefit of concurrent IO. Absolute lymphocyte count (ALC) was monitored during and up to 6 months post-LRRT. Results: A total of 238 patients were included (185 receiving concurrent IO and 53 without). In the IPTW-adjusted Kaplan-Meier analysis at the 12-month landmark, the addition of concurrent IO was associated with significantly inferior progression-free survival (PFS) (Hazard Ratio [HR]: 3.189; 95% CI, 1.352–7.524; p = 0.008). The "Sandwich" mode—comprising 4-6 cycles of induction CT-IO, followed by LRRT, and subsequent IO maintenance—yielded the optimal survival outcomes (HR: 0.288; 95% CI, 0.106–0.786; p = 0.015). An RPA model incorporating five prognostic factors (the number of metastatic lesions, pretreatment LDH level, post-CT-IO Epstein-Barr virus DNA, and radiological response post-CT-IO) stratified patients into two risk subgroups. Low-risk patients derived no clinical benefit from concurrent IO (p = 0.134), whereas high-risk patients exhibited significantly worse 12-month landmark adjusted PFS (p = 0.031). Notably, subgroup analysis showed that patients with persistent radiation-induced lymphocytopenia at 3 months post-RT demonstrated the most unfavorable survival outcomes after concurrent immunotherapy (p &lt; 0.001). Conclusions: DmNPC patients receiving first-line CT-IO followed by LRRT did not benefit from concurrent immunotherapy during RT, particularly those identified as high-risk by the prognostic model and those with persistent lymphocytopenia at 3 months post-RT.

ISABELA: A phase 2 study of isatuximab, belantamab mafodotin, pomalidomide, and dexamethasone in relapsed/refractory multiple myeloma.

7562 Background: Combination therapies form the backbone of multiple myeloma (MM) care, and therapies targeting BCMA are now a cornerstone of treatment. We evaluated ISABELA, a phase 2 study that combines an established regimen of isatuximab (isa), pomalidomide (pom), and dexamethasone (dex) with the recently approved anti-BCMA antibody drug conjugate belantamab mafodotin (belamaf) in relapsed/refractory (RR) MM. Methods: ISABELA is an investigator-initiated study (NCT05922501) enrolling up to 50 patients (pts) with RRMM who have received at least 1 prior line of therapy including lenalidomide and a proteasome inhibitor. We gave belamaf 1.9 mg/kg iv q8 weeks; isa 10 mg/kg iv weekly for cycle 1 and then days 1 and 15 for cycle 2 onward; pom 4 mg on days 1-21, and dex 40 mg weekly divided over two days. Each cycle was 28 days. Treatment was until progression or unacceptable toxicity. Results: At data cutoff, the trial had enrolled 17 pts with a median follow-up of 9.6 months. Median age was 72 (range 55-91); 65% were male. ISS at study entry: I (59%), II (24%), III (18%). Median number of prior regimens was 2 (range 1-12). All pts were refractory to their last line of therapy and were previously treated with lenalidomide and a proteasome inhibitor. Prior therapies included pom (59%), bortezomib (82%), carfilzomib (41%), ixazomib (35%), CD38 antibody (59%) [daratumumab, 59%; isa 12%], and auto SCT (24%). Prior exposure to newer therapies included drugs that target BCMA (24%) [teclistamab 6%, elranatamab 18%, CAR T-cells 12%]; GPRC5D (12%) [talquetamab]; and cereblon (29%) [mezigdomide, 29%; cemsidomide, 12%]. Soft tissue plasmacytomas were present in 18%. The overall response rate (ORR) was 86% (12/14, not evaluable (NE) 3), ≥VGPR 43%, CR 7%, and 16-month PFS was 73% (95% CI 0.5-1). In CD38-antibody-naïve patients, ORR was 84% (5/6, NE 1) and 16-month PFS was 67% (95% CI 0.38-1). In triple-class exposed (BCMA naïve) pts, ORR was 75% (3/4, NE 2), and 12-month-PFS was 86% (95% CI 0.63-1). In quad-class exposed pts (including BCMA) (N=4), ORR was 100% and 12-month PFS was 75% (95% CI 0.43-1). Grade 3-4 hematologic adverse events (AEs) included neutropenia (53%), thrombocytopenia (29%), and anemia (12%). Common non-hematologic AEs (all; grade 3-4) included blurred vision (65%; 6%); fatigue (65%; 0%); hypertension (59%; 6%); diarrhea (53%; 0%); and AST/ALT increase (47%; 6%). Infections occurred in 35% with no grade ≥3 events. Ocular AEs by keratopathy visual acuity scale included grade 1 (14%), grade 2 (29%), grade 3 (36%). No patients discontinued treatment for AEs or ocular toxicity. Conclusions: This is the first report in RRMM for the combination of belamaf with a CD38 monoclonal antibody. The ISABELA regimen shows promising preliminary activity in RRMM with an ORR of 86% and 16-month PFS of 73%, including quad-class-exposed pts treated with anti-BCMA therapy, with manageable, reversible AEs. Clinical trial information: NCT05922501 .

Improving post-discharge appointment coordination for hospitalized cancer patients utilizing inpatient patient service coordinators.

e13561 Background: Hospitalized cancer patients often require complex post-discharge care, including oncology follow-up, imaging, and laboratory testing. Failure to schedule these appointments prior to discharge may delay care, increase patient and caregiver burden, and contribute to fragmented care transitions that may increase readmission risk. As part of a broader hospital throughput initiative, we implemented a multidisciplinary quality improvement project to improve post-discharge appointment coordination on an inpatient oncology unit caring for melanoma, sarcoma and gastrointestinal medical oncology patients. Methods: The project occurred between March 1-31, 2025. The intervention included electronic health record (EHR) modifications to identify post-discharge orders, training inpatient patient service coordinators (PSCs) to directly schedule or transfer discharge-related orders through a dedicated work queue, and provider education to promote timely order entry using the discharge navigator. An EHR-embedded dashboard was developed to enable real-time monitoring of scheduling performance by unit, service, and provider. The primary outcome measure was the proportion of post-discharge orders scheduled prior to discharge. Results: During the study period, 44 patients were discharged and the median length of stay on the pilot unit was 7 days. Among 99 post-discharge orders placed in the scheduling work queue, 80.8% (n = 80) were scheduled prior to discharge, representing an improvement from a baseline average of 57%.The majority of orders were laboratory testing (n =52, 52.5 %), clinic follow-up (n =38, 38.4%), imaging (n =3, 3%), and other (n =6, 6.1%). Among scheduled orders, 40.4% (n =41) were scheduled directly by inpatient PSCs, with the remainder transferred to outpatient scheduling teams. Real-time dashboard access supported sustained performance through targeted feedback. Conclusions: A scheduling model incorporating inpatient PSCs supported by EHR optimization and real-time performance monitoring substantially improved post-discharge appointment coordination for hospitalized cancer patients. Based on early success, this model is now being expanded across the institution. The ongoing effort aims to improve the reliability of care transitions, with the potential to decrease delays in oncology follow-up and help reduce avoidable hospital readmissions.

The efficacy and safety of neoadjuvant toripalimab combined with temozolomide in resectable stage III melanoma: A prospective, single-center, phase 2 trial.

9562 Background: Neoadjuvant immune checkpoint inhibitors (ICIs) have demonstrated efficacy in resectable cutaneous melanoma and are recommended by current guidelines. Nevertheless, the clinical benefit of combining ICIs with chemotherapy as neoadjuvant setting in Chinese patients remains to be established. This study is being conducted to explore the efficacy and safety of neoadjuvant toripalimab combined with temozolomide in resectable stage III melanoma. Methods: This is a prospective, single-center, single-arm clinical trial (ClinicalTrials.gov identifier: NCT05827770). Patients with resectable stage IIIB-IIID acral or cutaneous melanoma and an ECOG performance status of 0-1 were enrolled and received two cycles of neoadjuvant temozolomide 200 mg/m² plus toripalimab 240 mg every 3 weeks, followed by radical surgery. The primary endpoint was the pathologic response rate (pRR). Secondary endpoints included objective response rate (ORR), disease control rate (DCR), recurrence-free survival (RFS), overall survival (OS) and safety. Results: As of December 2025, 20 eligible patients with resectable stage IIIB-IIID melanoma were enrolled, with 14 (70%) acral, 5 (25%) cutaneous and 1 (5%) of unknown primary. Of 20 patients underwent surgery, nine achieved pRR (45%), including 3 with near pathologic complete response (near pCR) and 6 with partial pathologic response (pPR). Radiological assessment showed partial response in 5 patients, stable disease in 12 patients, and progressive disease in 3 patients, yielding an objective response rate of 25% (5/20) and a disease control rate of 85% (17/20) according to RECIST criteria. With a median follow-up of 12 months, 8 recurrence-free survival events had been observed; the median RFS and OS had not yet been reached. Notably, one patient who attained near pCR remained relapse free for 27 months. No new safety signals were observed with the combination therapy. We further performed single-cell-resolution spatial transcriptomics and single-cell RNA sequencing in the current cohort. Integrative multi-omics analyses identified a T cell-excluded tumor microenvironment preferentially associated with non-response. Leveraging these features, we robustly distinguished immunotherapy responders from non-responders. Conclusions: This study demonstrates the preliminary efficacy and tolerability of toripalimab combined with temozolomide in the neoadjuvant treatment of patients with resectable stage IIIB-IIID acral and cutaneous melanoma. Given the fact that ICIs alone has limited response rate in acral melanoma, further studies are warranted. Clinical trial information: NCT05827770 . Treatment outcomes. Pathologic Response Eligible patients (%)N=20 Radiological Response Eligible patients (%)N=20 Near pCR 3 (15) PR 5 (25) pPR 6 (30) SD 12 (60) pNR 11 (55) PD 3 (15) pRR (pCR+Near pCR+pPR) 9 (45) ORR (CR+PR) 5 (25) DCR (CR+PR+SD) 17 (85)

The role of tyrosine kinase inhibitors as a post-hematopoietic stem cell transplant maintenance therapy for pediatric acute leukemia.

e22003 Background: Hematopoietic stem cell transplantation (HSCT) is a critical component of care for pediatric acute leukemia patients. Relapse following HSCT is a leading cause of transplant failure, emphasizing the need for effective post-transplant maintenance therapy. Tyrosine kinase inhibitors (TKIs) block the signaling pathways essential for leukemic cell growth and proliferation, and they are clinically useful for treating a wide variety of cancers. This systematic review aims to evaluate the role of tyrosine kinase inhibitors as a post-HSCT maintenance therapy in pediatric acute leukemia. Methods: The authors conducted a literature search of the PubMed, Cochrane, Web of Science, and VHL libraries according to PRISMA guidelines. All original studies were included if they were relevant to the research question and fit the eligibility criteria. Quality assessment for observational studies was done using STROBE and for case reports was done using CARE. Risk of bias for observational studies was assessed using ROBINS-I. Results: The initial search identified 765 articles, and after filtration, the final number included was 16. TKIs were used in patients with chromosomal alterations that result in fusion proteins with constitutively active tyrosine kinase activity in order to prevent relapse, particularly in high-risk patients with positive minimal residual disease (MRD). The specific TKI was chosen based on disease status and molecular profiling. Imatinib, dasatinib, and ponatinib were frequently used for Philadelphia-chromosome-positive acute lymphoblastic leukemia to target the BCR-ABL fusion kinase. Sorafenib was often used for FLT3-ITD-positive acute myeloid leukemia to target the FLT3 kinase. The duration of maintenance ranged from 10 months to 3 years, with dosage dependent on the specific drug and tolerability. Reported side effects included cytopenia, liver dysfunction, and skin conditions, but TKIs were found to be generally well-tolerated in this population. Overall, TKIs were an effective and well-tolerated maintenance therapy for preventing relapse in pediatric patients post-HSCT, with many patients achieving MRD negativity and sustaining complete remission. However, duration and safety need to be further studied in the pediatric population to develop standardized treatment regimens. Conclusions: TKIs can serve as targeted post-HSCT maintenance therapy in select pediatric acute leukemia patients, particularly those with high-risk, mutation-driven disease. Molecular profiling and MRD monitoring are central to clinical decision-making, guiding agent selection, timing, and mutation-directed therapy adjustments. These findings support the individualized use of TKIs to reduce relapse risk following HSCT, while highlighting the need for prospective studies to define standardized treatment strategies.

Assessing responses to UGN-102 across EORTC recurrence score groups in patients with recurrent low-grade intermediate-risk NMIBC (ENVISION trial).

4601 Background: The ENVISION phase 3 study (NCT05243550) treated patients with recurrent low-grade intermediate-risk non-muscle-invasive bladder cancer (LG-IR-NMIBC) with UGN-102, a reverse thermal hydrogel administered intravesically containing 75 mg mitomycin. Complete response (CR) rate at 3 months was 79.6% (95% confidence interval [CI]: 73.9, 84.5) with a 72.2% (95% CI: 64.1, 78.8) probability of remaining in response 24 months later. The European Organization for Research and Treatment of Cancer (EORTC) recurrence score tables provide estimates of recurrence based on baseline prognostic factors. We conducted a post-hoc analysis of CR and duration of response (DoR) by EORTC recurrence score subgroup. Methods: 240 patients with recurrent LG-IR-NMIBC received ≥1 dose of UGN-102. CR was assessed at 3 months using cystoscopy, urine cytology testing, and for-cause biopsy. Patients achieving CR entered the follow-up period and are being assessed for recurrence or progression for up to 5 years. CR at 3 months and probability of maintaining CR at 24 months in patients with EORTC recurrence scores of 1–4, 5–9, and 10–17 were calculated. DoR was calculated using the Kaplan–Meier (KM) estimation method. Results: The median (range) EORTC recurrence score was 7 (2–13). CR rate at 3 months was 83.9%, 81.2%, and 60.0% for patients with recurrence scores of 1–4 (n=31), 5–9 (n=191), and 10–17 (n=15), respectively. Of the patients with CR at 3 months, 26.9%, 23.9%, and 33.3% (for recurrence scores of 1–4, 5–9, and 10–17) experienced recurrence of LG disease, progression (either in stage or grade), or death by 24 months. The KM estimate of median DoR was not estimable for any group due to the low event rates. Conclusions: UGN-102 demonstrated robust complete response rates across all EORTC recurrence score subgroups, including patients with higher baseline recurrence risk. The majority of patients remained recurrence-free at 24 months. Despite the post-hoc design and small subgroup sizes, these findings suggest UGN-102 provides durable and clinically meaningful disease control in recurrent LG-IR-NMIBC. Clinical trial information: NCT05243550 . EORTC recurrence score group 1–4 N=31 5–9 N=191 10–17 (N=15) CR at 3 months, n (%) 26/31 (83.9) 155/191 (81.2) 9/15 (60.0) CRR (95% CI) 83.9 (66.3, 94.5) 81.2 (74.9, 86.4) 60.0 (32.3, 83.7) Recurrence 24 months a , n (%)Recurrence of LG diseaseProgressionDeath 7/26 (26.9)5/26 (19.2)02/26 (7.7) 37/155 (23.9)27/155 (17.4)7/155 (4.5)3/155 (1.9) 3/9 (33.3)3/9 (33.3)00 Probability of remaining in response at 24 months, %, 95% CI b 67.4 (43.2, 83.1) 73.7 (64.6, 80.8) 66.7 (28.2, 87.8) Median duration of follow up, months, 95% CI c 23.29 (23.03, 23.92) 23.72 (23.66, 23.92) 23.90 (23.72, NE) a 24 months after 3-month CR. b Calculated using the KM method, with Brookmeyer–Crowley CIs. c Estimated using reverse KM method. CI, confidence interval; CRR, complete response rate.

Recurrence risk prediction using a large, multi-site observational dataset of patients with early breast cancer, including early-onset disease.

547 Background: Accurate risk stratification in early breast cancer (eBC) is critical to guide adjuvant treatment intensity. In HR+/HER2- stage I-III disease, clinicians use clinical and genomic information to estimate recurrence risk, yet a comprehensive, real-world predictive model that synthesizes these inputs after curative-intent surgery is not established in routine practice. We developed a multimodal predictive survival model in a large, eBC cohort to predict recurrence-free survival (RFS) after surgery and derive risk groups to inform treatment escalation or de-escalation. Methods: This study used the US-based EHR-derived deidentified Flatiron Health Research Database (data cutoff: Sep 30, 2025). The cohort consisted of patients (pts) diagnosed with HR+/HER2- stage I-III eBC between Jan 1, 2016, and Jan 1, 2023, who received surgery and no neoadjuvant therapy. An Extreme Gradient Boosting (XGBoost) model was developed using 10-fold cross-validation, reserving 20% for testing, predicted time from surgery to recurrence or death. SHapley Additive exPlanations (SHAP) analysis was used to rank feature importance. Pts were classified into 3 risk groups by prediction percentile, and RFS by group was plotted in the test set using the Kaplan-Meier method. A second XGBoost model identified predictors specific to pts diagnosed with early onset (EO) eBC (age ≤ 45 yrs). Results: 158,111 pts qualified for the cohort, and the model C-index was 0.76. Top features that contributed to increased predicted hazard include age, higher tumor grade, higher stage, higher OncotypeDx score, longer time from diagnosis to surgery, ECOG score ≥2, and smoking history. Higher socioeconomic status (SES) decreased predicted hazard. Age had a non-linear association with predicted hazard; risk was elevated among pts &lt;35 and &gt;71, with lowest prediction occurring at ages 46-51. The median RFS in the high-risk group was 8.5 yrs (IQR, 8.2-8.8) and was not reached in the medium and low-risk groups. In the early onset subgroup of 12,196 pts, the C-index was 0.71. Top features in the EO model that contributed to increased hazard also included higher tumor grade and stage, and younger age. Importance of race and Ki67 percent staining (PS) superseded that of ECOG and SES in the EO model. Pts of Black or African American race and pts with Ki67 PS ≥20% had higher predicted hazard. Conclusions: This analysis elucidated key predictors of RFS following surgery in pts with eBC, specifically in non-neoadjuvant–treated pts at higher risk for recurrence, and illustrated predictors that vary in younger pts. Predictors from this large, representative dataset are aligned with known associations with recurrence risk. These findings suggest real-world data models may complement established tools guiding adjuvant treatment intensity, though external validation and prospective evaluation are needed.

Electronic nicotine delivery systems versus combustible cigarettes: A systematic review and meta-analysis of biomarkers of harm from randomized controlled trials.

e22520 Background: Electronic nicotine delivery systems (ENDS) advertised harm reduction, yet their long-term oncologic and toxic safety remains uncertain. While eliminating combustion reduces many toxicants, ENDS aerosols still deliver nicotine and residual carcinogens capable of DNA damage and inflammation. Randomized evidence on how switching from cigarettes to ENDS affects validated biomarkers of harm is limited; therefore, we conducted a systematic review and meta-analysis of RCTs assessing changes in established tobacco related biomarkers of harm among adults switching to ENDS versus continued smoking controls. Methods: RCTs published through October 2025 were identified in PubMed, Scopus, Web of Science, Cochrane Library, and ClinicalTrials.gov. Eligible trials reported pre- and post-intervention changes in blood, urine, or exhaled breath biomarkers among ENDS users and continued smoking. Two reviewers independently performed study selection, data extraction, and risk of bias assessment RoB 2. Within-arm effects were calculated as standardized mean change with raw score standardization (SMCR): (X̄-post − X̄-pre)/SD-pre. Between-arm SMCR differences, SMCRDs (ENDS SMCR - continued smoking SMCR), were pooled using random effects inverse variance meta-analysis. Heterogeneity, meta regression, and subgroup analyses were performed. Results: ENDS substitution was associated with insignificant reductions in urinary NNAL (7 trials; SMCRD = −0.43, 95% CI: −1.05 to 0.19; I² = 99.8%), urinary 3-hydroxypropyl mercapturic acid or 3-HPMA (6 trials; SMCRD = −2.84, 95% CI: −6.79 to 1.10; I² = 99.8%), urinary S-phenyl mercapturic acid or SPMA (6 trials; SMCRD = −1.09, 95% CI: −3.15 to 0.96; I² = 99.8%), and exhaled CO or COHb (8 trials; SMCRD = −3.83, 95% CI: −9.89 to 2.23; I²=99.7%). ENDS substitution insignificantly increased blood Cotinine (5 trials; SMCRD = 0.49, 95% CI: −0.10 to 1.09; I²=94.8%). All tests for subgroup differences in SMCRs between ENDS and continued smoking were insignificant (p &gt; 0.05). Meta-regression identified follow-up duration as a significant moderator of the SPMA SMCRD (p &lt; 0.001). A significant reduction in SPMA was observed only at short follow-up, including trials with follow-up &lt;1 month (5 trials; SMCRD = −1.59, 95% CI: −1.89 to −1.28) and a 5-day subgroup (4 trials) showing a pooled SMCRD of −2.14 (95% CI: −3.54 to −0.74; I² = 41.2%). Conclusions: Switching ENDS did not consistently reduce biomarkers of toxicant exposure; although SPMA showed short-term decreases that were dependent on follow-up duration. Our conclusions are limited by high heterogeneity, limited trials, follow-up, and variability in ENDS products, biomarkers, and adherence. Longer term randomized and outcome based studies are needed to determine whether these exposure patterns translate into meaningful reduced risk.

Atrial fibrillation in hematologic malignancies: A systematic review and meta-analysis.

e24018 Background: Atrial fibrillation (AF) affects approximately 1-2% of the general adult population, with incidence rates around 5-7 per 1,000 person-years, and sharp increases in advanced age. Among patients with cancer, AF is increasingly recognized and may be particularly prevalent in those with hematologic malignancies due to systemic inflammation, shared cardiovascular risk factors, and exposure to potentially arrhythmogenic therapies. In this population, AF further complicates management given competing risks of thrombosis and bleeding, yet the burden of AF has not been systematically quantified. Methods: We conducted a systematic review and meta-analysis of observational studies reporting the incidence and/or prevalence of AF among adults with hematologic malignancies. PubMed and Embase were searched from database inception through January 24, 2026, in accordance with PRISMA guidelines. Eligible studies included cohort, registry-based, or population-based designs reporting AF incidence or prevalence. Studies limited to peri-operative or post-procedural AF, pediatric populations, or AF reported solely as an adverse effect of a specific anticancer therapy were excluded. Random-effects models were used to pool prevalence and incidence estimates. Subgroup analyses and meta-regression were performed to explore sources of heterogeneity. Results: Twelve studies involving 949,304 patients were included in the prevalence analysis, yielding a pooled AF prevalence of 10.6% (95% CI, 7.6-14.6; I² = 99.9%), substantially higher than estimates reported in the general population. Prevalence was highest among patients with lymphoma (17.1%) and chronic lymphocytic leukemia (16.6%). Seven studies reporting 4,764 AF events over 299,818 person-years were included in the incidence analysis, resulting in a pooled incidence rate of 12.18 per 1,000 person-years (95% CI, 8.35-16.00; I² = 99.2%). The highest incidence rates were observed in lymphoma and multiple myeloma. Meta-regression identified older age, male sex, and geographic region as significant contributors to heterogeneity. Conclusions: AF is frequent among patients with hematologic malignancies, with incidence and prevalence markedly higher than in the general population and substantial variation across disease subtypes. These findings underscore the significant cardio-oncology burden of AF in this high-risk group and highlight the need for improved risk stratification, surveillance strategies, and prospective studies to inform optimal management.

Nanotechnology-enabled nose-to-brain delivery: Promising strategies for targeting neurological disorders

Economic Low‐Carbon Chemical Production via Paired Electrolysis of Carbon Monoxide (CO) and 5‐hydroxymethylfurfural (HMF)

ABSTRACT Paired electrolysis of CO 2 and biomass‐derived alcohols, such as 5‑hydroxymethylfurfural (HMF) and glycerol, offers a sustainable approach for co‐producing valuable chemicals, but suffers from poor cathode‐anode compatibility and limited economic feasibility. Herein, we show that replacing CO 2 with carbon monoxide (CO) and adopting a catholyte‐layer electrolyzer design jointly enhance the operational stability of alcohol‐paired electrolysis by preventing HCO 3 − formation and suppressing inter‑electrode mass exchange. Within this platform, HMF oxidation is identified as the optimal anodic partner compared with glycerol oxidation, because it exhibits negligible product crossover and the oxidation kinetics of its intermediates consistently outpace those of the oxygen evolution reaction. Consequently, the paired electrolysis of CO and HMF in a membrane‐electrode assembly electrolyzer incorporating a catholyte‐layer enabled efficient and stable co‑production of ethylene and 2,5‑furandicarboxylic acid (FDCA), both key plastic monomers derived from CO 2 and biomass, respectively. Techno‐economic and environmental assessment indicate that the CO‐HMF pairing outperforms all tested combination of CO 2 or CO‐HMF or glycerol and approaches the production cost and carbon emission to petroleum‐derived terephthalic acid. These results demonstrate CO electrolysis coupled with HMF oxidation as a cost‐effective and climate‐conscious strategy for sustainable chemical production.

A randomized, open-label, phase 3 study of ZL-1310, a DLL3 antibody-drug conjugate (ADC), compared to investigator’s choice therapy in participants with relapsed small cell lung cancer (DLLEVATE).

TPS8136 Background: Small Cell Lung Cancer (SCLC) is a neuroendocrine tumor with high proliferation rate, early metastasis and poor prognosis. DLL3 is a validated target for neuroendocrine tumor and is highly expressed in SCLC. ZL-1310 is a novel antibody-drug conjugate (ADC) that employs the TMALIN (Tumor Microenvironment Activable LINker-payload) platform, an anti-DLL3 monoclonal antibody linked to a topoisomerase I inhibitor payload via a protease-cleavable linker. ZL-1310 has demonstrated encouraging systemic efficacy in heavily pre-treated ES-SCLC and showed intracranial activities. Methods: DLLEVATE is a randomized, open-label phase III study to further evaluate the efficacy and safety of ZL-1310 compared to investigator's choice of locally approved and available single agent therapy (ICT). This multi-country Phase III study (NCT07218146) enrolls adults with Extensive Stage (ES)-SCLC patients (pts) who have progressed after platinum-based first-line (1L) therapy or after tarlatamab as second-line (2L) therapy. Those with stable or asymptomatic BM are eligible (including those with no prior brain radiotherapy). The eligible pts are randomized at 1:1 according to presence/absence of brain metastasis, sensitivity to prior chemotherapy and with/without prior tarlatamab. ZL-1310 is given intravenously every 3 weeks until disease progression or unacceptable toxicity. Systemic efficacy is assessed by investigators using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1. Intracranial efficacy is assessed by blind independent radiologists using Modified Criteria for Radiographic Response Assessment in Neuro-Oncology (mRANO). The study has one interim analysis based on Objective Response Rate (ORR) assessed by Blind Independent Review Committee (BIRC) and the primary analysis based on Overall Survival (OS). Enrollment is underway, and is planned at ~250 sites across several continents. Clinical trial information: NCT07218146 .

An NCDB analysis on the demographic, treatment, and survival of nonkeratinizing small cell squamous cell carcinoma.

e20147 Background: Nonkeratinizing small cell squamous cell carcinoma (NSCSCC), ICD-O-3 code-8073, is a malignant epithelial neoplasm composed of small, basaloid-appearing squamous cells with high nuclear-to-cytoplasmic ratios and minimal cytoplasmic keratinization, lacking keratin pearl formation, retaining immunohistochemical evidence of squamous differentiation, and not exhibiting neuroendocrine features. Despite NSCSCC’s rarity, it accounts for 5% of all squamous cell carcinomas (SCC). Given NSCSCC’s rarity, evaluating diagnostic trends may provide important insights into its epidemiology. Therefore, the National Cancer Database (NCDB) was analyzed to characterize demographic factors among patients diagnosed with NSCSCC. Methods: A retrospective cohort study using the 2004–2020 NCDB identified patients with histologically confirmed NSCSCC (N = 934). Demographic and clinical variables including age, sex, race, household income, survival rate, and treatment method—were summarized using descriptive statistics, and incidence trends were evaluated using regression analyses. Results: Between 2004 and 2020, 934 patients with SCNSCC were identified in the NCDB with a decreasing incidence (R2 = 0.33). The majority of patients are female (60.3%), with the racial breakdown as follows: 84.5% White, 11.3% Black, and 4.2% Other. The mean age at diagnosis is 64.6 years (SD = 0.442). Median household income for each patient is measured through the respective data for their zip code of residence, said data is then further categorized as quartiles based on equally proportioned income ranges among all US zip codes; 21.1% of patients are in Q1 ( &lt; $46,277), 23.9% in Q2 ($46,227 - $57,856), 25.1% in Q3 ($57,857 - $74,062), and 29.9% in Q4 ($74,063 or more). The most frequently observed primary sites is the upper lobe of the lung (27.7%), with the mean tumor size being 44.94mm (SD = 4.08). The majority of patients (62.5%) did not receive surgical procedures at the primary site, for those that did the vast majority (79.9%) had no residual tumor as the surgical margin; additional primary treatment methods include, 49.3% received at least chemotherapy, 51.5% had radiation, 0.5% had hormone therapy, and 1.2% had immunotherapy. The 2-, 5-, and 10-year survival rates are 52.5%, 37.0%, and 26.3%, respectively, with a mean survival time of 70.209 months (SD = 3.127). Conclusions: To our knowledge, this is the first NCDB analysis addressing SCNSCC, thus addressing a significant knowledge gap on the topic. This analysis shows that SCNSCC mainly affects the elderly, with surgery, chemotherapy, and radiation being the common treatments, consistent with previous published work on SCC, the broader category that includes SCNSCC. To better understand how demographic and socioeconomic factorsinfluence diagnosis, treatment, and survival in SCNSCC, further research is needed.

Evaluating the efficacy and mechanisms of action of seriniquinone against pediatric neuroblastoma.

e15125 Background: Children diagnosed with neuroblastoma face poor prognosis despite aggressive multimodal therapies, highlighting the urgent need for effective and targeted treatments. Natural products derived from microbial sources like marine actinomycetes are promising novel anticancer agents. Seriniquinone, a quinone-based compound originally isolated from a Serinicoccus species, has demonstrated potent anticancer activity across a variety of tumor types via targeting dermcidin, a peptide associated with cancer cell survival and proliferation, inducing autophagocytosis followed by apoptosis. Given its unique mechanism of action and prior efficacy, we hypothesize that seriniquinone may represent a novel and selective therapeutic option for pediatric neuroblastoma. Methods: Techniques used included neuroblastoma cell culture and quantification, CCK-8 viability assays, and Western Blot analysis. Synthetic seriniquinone was tested by preparing MYCN-amplified and non-amplified neuroblastoma cell lines for treatment with increasing concentrations of seriniquinone. Treated cells were analyzed vy CCK-8 viaiblity assays and Western blots analysis of whole cell lysates to evaluate protein expression changes due to the effect of seriniquinone on intraceullar markers and markers of apoptosis such as PARP and Caspase-3. Results: Treatment of various MYCN-amplified and non-amplified neuroblastoma cell lines shows that Seriniquinone inhibits cell growth and viability in a concentration-dependent manner, with observed cell rounding, detachment and death compared to the healthy monolayers in the control cells. Seriniquinone treatment also resulted in decreased expression of dermcidin and MYCN and induction of apoptosis compared to control cells. Conclusions: Our results support the efficacy of seriniquinone as a potent therapeutic agent with efficacy against pediatric neuroblastoma cells, with further studies planned to confirm the efficacy and mechanisms of action. Ultimately, we hope these findings lay the groundwork for further preclinical validation and support future clinical investigation, including the potential for translation into early phase clinical trials.

Impact of leukocytosis on outcomes in patients with myelofibrosis: A propensity-matched analysis.

e18608 Background: Myelofibrosis (MF) is a myeloproliferative neoplasm (MPN) that is characterized by bone marrow fibrosis and inefficient hematopoiesis, leading to extramedullary hematopoiesis. Leukocytosis, a common disease manifestation and a minor criterion for the diagnosis of MF, has been associated with poorer clinical outcomes. This study evaluates the long term impact of leukocytosis on clinical outcomes at different time points in the real-world population of patients with MF. Methods: We conducted a retrospective cohort study using de-identified EHR data from the TriNetX Global Federated Health Research Network. Adults (≥18 years) with myelofibrosis were identified using ICD-10 and ICD-O-3 codes and stratified into leukocytosis (WBC ≥25.0 ×10³/µL; L+) and non-leukocytosis (L−) cohorts at the index diagnosis. Patients with prior or current hematopoietic stem cell transplantation were excluded. Cohorts were propensity score–matched 1:1 for demographics, comorbidities, and baseline laboratory values. Outcomes at 1, 3, and 5 years included all-cause mortality, pulmonary embolism, venous thromboembolism, and transformation to acute myeloid leukemia, with hazard ratios estimated using Cox proportional hazards models. Results: After matching, 13237 patients with MF were identified, of whom 52.12% were male, and 47.8% were female. The mean age in L+ and L- was 66.5 +/- 16.6 years and 68.1 +/- 15.5 years, respectively. The mean hemoglobin in L+ was 10.9+/- 2.8 g/dL, and in L- was 12.9+/- 2.3 g/dL. The mean platelet count in L+ was 303.4+/- 294.9 and in L- was 239.5+/- 151.4 ×10³/µL. HR for all-cause mortality in L+ when compared to L- at years 1, 3, and 5 were statistically significant at 4.079 (95% CI 3.691-4.508), 3.215 (95% CI 2.982-3.466), and 2.787 (95% CI 2.608-2.978), respectively, with log-rank p &lt; 0.01. The HR for PE in L+ when compared to L- was statistically significant at years 1, 3, and 5 at 2.014 (95% CI 1.455-2.787), 1.883 (95% CI 1.451-2.787) and 1.659 (95% CI 1.318-2.088) with log-rank p&lt;0.01. HR for VTE in L+ when compared to L- was statistically significant at years 1, 3, and 5 at 2.501 (95% CI 1.937-3 .229), 1.802 (95% CI 1.491-2.178), and 1.561 (95% CI 1.32-1.847) with log-rank p&lt;0.01. Risk of transformation to AML in L+ when compared to L- at years 1, 3, and 5 was significant with HRs being 9.806 (95% CI 6.575-14.627), 8.823 (95% CI 6.334-12.29), 9.371 (95% CI 6.813-12.891) with log-rank p&lt;0.01. Conclusions: In this large real-world, propensity-matched cohort, leukocytosis in myelofibrosis was associated with significantly higher risks of all-cause mortality, thromboembolic events, and transformation to acute myeloid leukemia across 1-, 3-, and 5-year time points. These findings underscore leukocytosis as a powerful adverse prognostic marker in MF and highlight the need for closer surveillance and risk-adapted therapeutic strategies in this high-risk population.

Guidance conformance of mainstream germline cancer testing by oncology providers in the Veterans Health Administration.

e13571 Background: Mainstream germline testing, where oncology providers obtain consent and order testing directly, facilitates timely access to genetic testing for treatment decisions. The Veterans Health Administration promoted mainstreaming of a 62-gene multi-cancer germline testing panel for certain cancer diagnoses: breast, high-grade or metastatic prostate, ovarian/fallopian tube/primary peritoneal/serous uterine, pancreatic/ampullary adenocarcinoma, medullary thyroid, pheochromocytoma/paraganglioma, colorectal cancer diagnosed before age 50, and mesothelioma. We retrospectively evaluated conformance to guidance for adoption of mainstream testing. Methods: We analyzed all germline genetic tests ordered across VA facilities from February 2023 through December 2025. Test orders were categorized as conforming oncology (mainstream-eligible cancer diagnosis), non-conforming oncology (other cancer diagnosis), or non-oncology tests. For orders placed by oncology providers, clinical appropriateness was determined by ICD-10 code alignment with specified mainstream-eligible cancer types. Conformance to guidance was defined as ordering the 62-gene panel for patients with one of the specified mainstream-eligible cancer diagnoses. Primary outcome was rate of conformance to guidance in our mainstream testing model. Results: Among 13,339 genetic tests ordered by 204 providers across 143 facilities, 3,306 (24.7%) used mainstream testing and 10,033 (75.3%) used traditional genetics. Of mainstream orders, 3,130 (94.7%) were guidance conforming and placed by 109 providers, 161 (4.9%) were non-conforming oncology tests placed by 34 providers, and 15 (0.5%) were non-oncology tests placed by 10 providers. The most common conforming tests were in prostate (55.9%), breast (14.1%) and pancreatic cancers (6.6%), while the most common non-conforming tests with a documented indication were ordered in patients with family history of malignancy (12.1%), lung cancer (9.7%) and melanoma (4.8%). Conclusions: Our findings demonstrate that high fidelity to germline cancer genetic testing guidance by oncology providers is achievable under the mainstream model with 94.7% of testing conforming to guidance. This is critical to our understanding of the effectiveness of mainstreaming and the ability to replicate and scale-up mainstreaming in different health care settings.

Adoption of Bayesian Optimal Interval (BOIN) design in phase I oncology trials, trends, and challenges.

e23006 Background: Traditionally, the 3+3 design (also known as classic design) has been the most widely used design in Phase I trials due to its simplicity and ease of implementation. However, it has several limitations, such as inefficiency in identifying the optimal dose and a high probability of under-dosing patients. The FDA has discouraged reliance on this design, as it does not formally model the probabilistic relationship between dose and toxicity. The Bayesian Optimal Interval (BOIN) design optimizes dose selection, reduces the number of patients exposed to subtherapeutic or overly toxic doses, and improves trial efficiency. The FDA's Oncology Center of Excellence (OCE) and its Project Optimus initiative encourage the adoption of adaptive and model-based dose-escalation methods, making BOIN a preferred alternative. Methods: A search of ClinicalTrials.gov was conducted, filtering for Phase I trials in solid tumors initiated in 2025. Trials were categorized based on dose-escalation design, investigational medicinal product (IMP) type, and other relevant parameters. All phase 1 trials started in 2025 were selected and analyzed. Results: Of the 641 Phase I trials initiated globally in 2025 for solid tumors, the majority employed the 3+3 design, often alongside accelerated titration or dose optimization strategies. Only 68 trials utilized the BOIN design or other adaptive design, which was slightly more prevalent in trials investigating targeted therapies and biologics. Conclusions: Despite growing interest in BOIN, Bayesian methods remain underutilized, with adoption progressing slowly. While the 3+3 design persists as the dominant approach, the FDA urges sponsors to justify its use and encourages the transition to more flexible, statistically rigorous and probabilistically based designs like BOIN to improve both the efficiency and safety of dose-finding in early-phase oncology trials.

Transcriptome-wide profiling of antibody–drug conjugate (ADC) targets across solid tumors with IHC validation in a sub-cohort.

e15177 Background: The expanding use of ADCs and other expression-driven therapies requires biomarker assessment beyond DNA alterations. Transcriptome-wide RNA expression profiling enables quantitative, multi-target assessment, with immunohistochemistry validation supporting clinical use. Methods: Transcriptome-wide RNA profiling was performed on 1903 FFPE tumor samples using a 20,802-gene panel (Exacta). Elevated RNA expression (log₂ fold-change &gt; 2) was assessed for established and emerging ADC targets, including cell-surface antigens ( CLDN18, TROP2 , Nectin-4), receptor tyrosine kinases ( ERBB2, ERBB3, EGFR, MET ), and lineage-associated markers ( DLL3 matched CLDN18 .2 IHC was available in a sub-cohort (N = 68) and served as the reference standard for RNA diagnostic performance. Results: Expression patterns demonstrated both pan-tumor distribution and expected organ-specific enrichment, with CLDN18 enriched in gastroesophageal, gastric, pancreatic, and esophageal cancers; ERBB2 in breast and upper gastrointestinal tumors; and MET in lung and gastric cancers. Several targets, including TROP2 and ERBB3 , showed broad cross-tumor expression, supporting tumor-agnostic ADC strategies. Co-expression of multiple actionable targets was frequently observed. Overall, at least one ADC-relevant target was identified in 60.5% (1151/1903) of tumors, while 23.4% (446/1903) harbored ≥2 potential ADC targets. In the CLDN18 .2 IHC sub-cohort (N = 68), 25% of cases were IHC positive. Using IHC as the reference, RNA expression demonstrated strong concordance, with sensitivity 88.2%, specificity 94.1%, PPV 83.3%, NPV 96.0%, and overall accuracy 92.6%. Conclusions: Transcriptome-wide RNA expression profiling complements DNA-based comprehensive genomic profiling by enabling expression-driven ADC biomarker assessment. Concordance with CLDN18 .2 IHC supports analytical validity, while limited tumor-specific cohorts and single-marker IHC highlight the need for broader multi-marker validation studies. Prevalence of ADC-relevant therapeutic targets identified by transcriptome-wide RNA expression profiling. ADC Target Overall Incidence (%, N=1903) Organ-Specific Incidence (%; n/N) CLDN18 9.3 Gastroesophageal 45.5% (56/123),Gastric 52.9% (36/68),Esophageal 22% (9/41),Pancreatic 38.4% (33/86) MET 10.8 Lung 30.6% (30/98),Gastric 25% (17/68) ERBB2 22.1 Breast 15.3% (55/360),Gastric 27.9% (19/68),Gastroesophageal 26.8% (33/123) DLL3 10.4 Neuroendocrine 42.3% (11/26) TROP2 17.9 Prostate 57% (20/35),Urothelial 50% (7/14),Ovary 34.1% (71/208),Lung 10.2% (10/98),Pancreatic 4.7% (4/86),Breast TNBC 2.7% (3/112) Nectin-4 8.1 Urothelial 14.3% (2/14),Breast 13.9% (50/360),Lung 9.2% (9/98) ERBB3 12.7 Lung 27.6% (27/98) EGFR 5.6 Lung 8.2% (8/98)