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Real-world deployment of a multimodal artificial intelligence (AI) model for predicting response to neoadjuvant chemotherapy in early breast cancer.

534 Background: Multimodal AI models integrate morphological information from H&E-stained images with clinical information, identifying subtle disease signatures beyond the perceptual limits of human experts. However, the clinical utility of AI tools in real-world settings remains underexplored. Here, we evaluated Ataraxis Breast (ATX), a multimodal AI test predicting response to neoadjuvant chemotherapy, in a prospective silent trial. Methods: We previously assembled an international dataset of whole slide images of H&E-stained biopsy specimens and clinical information to develop ATX as a biomarker of neoadjuvant response. To evaluate real-world clinical translation, we conducted a prospective silent trial of ATX in patients with early breast cancer treated with neoadjuvant therapy at our center. None of these patients were included in the original training, validation, or test datasets. The primary outcome was pathologic complete response (pCR). Area under the receiver operating curve (AUROC) analyses were conducted. Results: The study cohort included 50 female patients treated during 2025, with a median age of 53.8 years. Tumor subtypes comprised 30% (n = 15) triple-negative breast cancer (TNBC), 24% (n = 12) HER2-positive disease, and 46% (n = 23) hormone receptor–positive (HR+), HER2-negative tumors. Overall, 66% (n = 33) of patients had node-positive disease, and 60% (n = 30) had grade 3 tumors. Notably, all patients with TNBC received pembrolizumab, whereas patients with HER2-positive tumors were treated with chemotherapy combined with HER2-directed therapies. The overall pathological complete response (pCR) rate in this external validation cohort was 34%. ATX scores were significantly higher among patients who achieved pCR (p = 0.005). Moreover, when evaluated as a predictive biomarker across the entire cohort, ATX achieved an AUROC of 0.745 (95% CI, 0.58–0.89) for pCR. These findings were consistent across predefined subgroup analyses, including patients with HR+/HER2− disease (AUROC = 0.73) and TNBC (AUROC = 0.77). Conclusions: In this prospective deployment study, among patients with early breast cancer treated with neoadjuvant chemotherapy, higher AI-derived predictions were independently associated with improved neoadjuvant therapy response. Given the accessibility of H&E-slides, ATX may serve as a scalable predictive biomarker in real-world settings.

Induction chemotherapy with nab-paclitaxel and cisplatin versus docetaxel, cisplatin, and fluorouracil followed by chemoradiotherapy in patients with stage III–IVA nasopharyngeal carcinoma: An open-label, noninferiority, randomized, controlled, phase 3 trial.

6013 Background: The docetaxel, cisplatin, and 5-fluorouracil (TPF) regimen is the standard induction therapy regimen for locoregionally advanced nasopharyngeal carcinoma (LANPC). However, it is associated with poor patient compliance and notable side effects. This phase 3 trial aimed to compare the efficacy and safety of induction chemotherapy with nab-paclitaxel plus cisplatin (nab-TP) with those of the TPF regimen in patients with LANPC. Methods: In this multicenter, noninferiority, open-label, randomized controlled trial, treatment-naive patients with LANPC were recruited from 5 hospitals in China and were randomly assigned to receive two cycles of nab-TP (nab-paclitaxel 260 mg/m², cisplatin 80 mg/m²) or TPF (docetaxel 60 mg/m², cisplatin 60 mg/m², 5-FU 3 g/m²), followed by concurrent chemoradiotherapy. The primary endpoint was the 3-year failure-free survival (FFS) rate (non-inferiority margin 10%) in the intention-to-treat population. Secondary endpoints included overall survival, treatment response, safety, and patient-reported outcomes. This trial is registered with chictr.org.cn (ChiCTR1800019922) and is now completed. Based on previous studies, we hypothesized that the 3-year FFS (approximately 80%) is the same between the TPF regimen and the nab-TP regimen for patients with LANPC. We specify a clinically acceptable noninferiority margin of 10%. The dropout rate in both arms was set at 4% per year. Accordingly, a minimum of 506 participants was needed to achieve 80% statistical power with a one-sided type I error of 2·5%. Results: Between January 22, 2019 and March 24, 2023, 515 patients (71·8% male; median age: 45 years (IQR 37–51)) were randomized: 259 to the nab-TP group and 256 to the TPF group. Compared with the TPF group, the nab-TP group had significantly better treatment compliance. With a median follow-up of 55·2 months, the 3-year FFS rate in the intention-to-treat population was 86·7% (95% confidence interval (CI): 82·6–90·9) in the nab-TP group and 88·2% (95% CI: 84·2–92·1) in the TPF group. The difference in the 3-year FFS between groups was -1·4% (95% CI: -7·2 to 4·3)(P non-inferiority = 0·0018). Compared with the TPF group, the nab-TP group had significantly lower incidences of grade 1+ leucopenia (34·0% vs. 62·6%, P < 0·0001), neutropenia (20·3% vs. 48·8%, P < 0·0001), electrolyte disturbances (86·3% vs. 96·5%, P < 0·0001), and diarrhea (28·5% vs. 39·0%, P = 0·012), whereas the nab-TP group had a higher incidence of nausea (91·0% vs. 85·4%, P =0·047). No treatment-related death was documented. Conclusions: In LANPC, nab-TP was non-inferior to TPF in terms of 3-year FFS rate and was associated with a significantly better safety and tolerability profile, supporting its use as a viable therapeutic alternative. Clinical trial information: ChiCTR1800019922.

Surgical complications and perioperative outcomes following total mesorectal excision in patients with locally advanced rectal cancer treated with short-course radiotherapy and chemo-immunotherapy: Updated data from the phase II Averectal trial.

e15667 Background: Total mesorectal excision (TME) in locally advanced rectal cancer (LARC) is challenging, particularly after neoadjuvant therapy. We analyzed surgical complications and perioperative outcomes from the Averectal trial (NCT03503630). Methods: The Averectal trial is a phase II, open-label, single-arm, multicenter study evaluating short-course radiotherapy (SCRT: 25 Gy in 5 fractions), followed by 6 cycles of mFOLFOX-6 plus avelumab (10 mg/kg every 2 weeks), with TME performed 4-6 weeks post-treatment in microsatellite stable (MSS) LARC. Surgeries were performed by experienced rectal surgeons under strict quality control using 2013 College of American Pathologists criteria. Operative parameters (approach, duration, blood loss, technique) and pathological features (CRM, EMVI, TRG) were recorded. Postoperative complications were graded by Clavien–Dindo classification, and serious adverse events (SAEs) documented. Results: Of 44 patients enrolled, 40 underwent TME (38 low anterior resections, 2 abdominoperineal resections). Surgical approach was open in 20 (50.0%), laparoscopic in 17 (42.5%), and robotic in 3 (7.5%). Diverting ileostomy was performed in 35 (87.5%). R0 resection was achieved in 32/34 (94.1%), with negative CRM in 31/34 (91.2%), TRG 0 in 17/39 (43.6%) and EMVI in 2/35 (5.7%). Median lymph node yield was 17 (range 0-42); 29/34 (85.3%) were node-negative. Median operative time was 268 minutes; median blood loss 182 mL with 2 patients receiving blood transfusion. Postoperative complications occurred in 16/40 patients (40%), averaging 1.5 per patient (range 1-4), totaling 48 events: Grade I (11 complications, 22.9%), Grade II (23 complications, 47.9%), Grade III (11 complications, 22.9%), and Grade IV (3 complications, 6.2%). Thirty-six complications (75.0%) were classified as SAEs. Frequent complications included ileus or bowel obstruction (8), abdominal abscess or infection (8), anastomotic leak (5), electrolyte disturbances (4), acute kidney injury (3), constipation (3), wound dehiscence (2), hernia (2), tumor perforation (1), and urinary retention (1). Most resolved within 1 week; 2 patients required > 1 month hospitalization, and 1 developed permanent sexual dysfunction. No significant difference was noted between open and minimally invasive surgery. Pathologic complete response was achieved in 37.5%. Local recurrence at 3 years occurred in 2.5%. Three patients (7.5%) died during follow-up, all due to disease progression unrelated to surgical complications. Conclusions: SCRT followed by mFOLFOX-6 plus avelumab and TME resulted in acceptable surgical morbidity and favorable oncologic outcomes. These findings support the safety and feasibility of this chemo-immunotherapy approach in MSS LARC. Clinical trial information: NCT03503630 .

Outcomes with enfortumab vedotin (EV) rechallenge after disease progression in metastatic urothelial carcinoma.

4578 Background: EV, alone (mono) or with pembrolizumab (EVP), is an established therapy for metastatic urothelial carcinoma (mUC). However, the activity with EV rechallenge after prior exposure and subsequent disease progression is not well defined. Methods: A retrospective institutional database of patients (pts) treated with EV mono (n=395) or EVP (n=256) for mUC was reviewed to identify pts who received EV rechallenge after disease progression. EV-free interval (EVFI) was defined as the time from last EV1 (initial) dose to first EV2 (rechallenge) dose. Investigator-assessed objective response rate (ORR; CR/PR), progression free survival (PFS), overall survival (OS), and duration of response (DoR, from first documented response) were summarized descriptively. Results: Of 42 pts identified, EV1 regimen was mono for 62% (n=26; EV1-mono) and EVP for 38% (n=16; EVP1). Median age was 77, 76% were male, and 45% had upper tract primary. Most pts (n=35; 83%) discontinued EV1 for toxicity, predominantly peripheral neuropathy. Median follow up from EV2 initiation was 26 mo (95% CI 17-NR). At rechallenge, 10 pts (24%) switched EV regimens (EV1-mono to EVP2, n=5; EVP1 to EV2-mono, n=5). EV2 was initiated at 1.25 mg/kg in four pts (9.5%), 1.0 mg/kg in 13 pts (31%), and ≤0.75 mg/kg in 25 pts (60%). Among response-evaluable pts (n=39), ORR to EV2 was 21% (8/39; 95% CI 9%-36%), including 2 CRs (5%), both with prior CR to EV1. No responses were observed in pts with SD/PD to EV1 (0/8; 0%), or those with EV1 PFS <6 mo (0/11; 0%). Among pts with long (>12 mo) or intermediate (6-12 mo) EVFI, ORR to EV2 was 33% (4/12) and 31% (4/13), respectively. No responses were reported with short (<6 mo) EVFI (0/14; 0%). EV2 was initiated at 0.75 mg/kg in 5/8 pts with CR/PR. Median PFS and OS estimated from EV2 start were 2.8 and 18.5 mo. Among pts with CR/PR, median DoR was 7.0 mo (95% CI 3.5-NR). At last follow up, three pts remained on EV2; 39 pts discontinued EV2 due to progression (74%, n=29), toxicity (23%, n=9) or pt preference (2.6%, n=1). Conclusions: In a real-world cohort, EV rechallenge demonstrated modest activity, primarily in pts with prior benefit from EV and EVFI >6 mo. These observations underscore the need for further studies to clarify the effects of repeated EV exposure and optimize patient selection. This is particularly relevant given efforts to mitigate toxicity and the emerging issue of recurrent disease after perioperative EVP. AllN = 42 EV1-monoN = 26 EVP1N = 16 EV1  ORR (95% CI) 79% (63%–90%) 85% (65%–96%) 69% (41%–89%)  Median PFS, mo (95% CI) 8.3 (7.5–9.9) 8.6 (7.7–19.1) 7.6 (5.5–11.9)  Median Time on EV, mo [IQR] 4.9 [3.7–7.2] 5.1 [4.1–8.7] 4.1 [2.4–5.7] EV2  ORR (95% CI)NE 8/39; 21% (9%-36%)3 5/25; 20% (7%–41%)1 3/14; 21% (5%–51%)2  Median PFS, mo (95% CI) 2.8 (2.6–5.1) 2.7 (2.6–5.3) 4.1 (2.6–NR)  Median OS, mo (95% CI) 18.5 (11.6–29.7) 18.5 (11.0–29.7) 15.2 (12.6–NR)  Median Time on EV, mo [IQR] 2.8 [1.9–5.6] 2.5 [1.9–5.1] 3.4 [1.9–6.1]

A phase I/IIa, image-guided, alpha-particle therapy study of [ ²⁰³ Pb]Pb-PSV359 and [ ²¹² Pb]Pb-PSV359 in patients with solid tumors that are known to be fibroblast activation protein (FAP)–positive.

e15146 Background: PSV359 is a novel theranostic radiopharmaceutical targeting fibroblast activation protein alpha (FAP-α), which is overexpressed in multiple solid tumors. PSV359 is designed for the delivery of targeted alpha-particle therapy, utilizing 203 Pb for SPECT imaging and ²¹²Pb for targeted radiotherapy. Here, we present preliminary data on the treatment of adult patients diagnosed with solid tumors whose disease has progressed despite standard therapy or for whom no standard therapy exists. Methods: This is an ongoing phase I/IIa, first-in-human, prospective, multicenter, open-label, dose-escalation and dose-expansion trial. The objectives are to investigate the safety, dosimetry, pharmacokinetics, and efficacy of [²¹²Pb]Pb-PSV359. The trial follows a modified Toxicity Probability Interval-2 study design. The phase I portion includes escalating dose cohorts starting at 2.5 mCi (92.5 MBq) [²¹²Pb]Pb-PSV359 and increasing sequentially to determine the recommended phase II dose. Each dose level is given in up to 4 cycles, 8 weeks apart, by intravenous infusion. Safety is evaluated for any DLTs during cycle 1 according to the Common Terminology Criteria for Adverse Events, v5.0, and efficacy by RECIST v1.1 criteria by the investigator. Results: As of 24 December 2025, 6 participants (50% male; median age: 68.5 years [range: 62-74]) with locally advanced or metastatic solid tumors (kidney [n = 3], pancreatic ductal adenocarcinoma [n = 1], ovarian [n = 1], esophageal [n = 1]) were enrolled. All patients had at least 2 prior lines of systemic therapy. No DLTs were reported, no dose reductions were required, and TEAEs were all grade 1 and 2 (40% each). Patient enrollment is ongoing, and updated results may be presented at the meeting. One participant withdrew before receiving therapy due to disease progression. The remaining participants received at least 1 dose of either 2.5 or 5 mCi [²¹²Pb]Pb-PSV359. Two participants reported SD as best response, and one was not evaluable for response due to pending scans. Conclusions: The dose levels of 2.5 and 5 mCi [²¹²Pb]Pb-PSV359 were found to be safe without DLTs. Dose-escalation is ongoing. Clinical trial information: NCT06710756 .

A global, randomized, double-blinded, phase 3 trial of vorasidenib vs placebo in patients with grade 2 glioma with an <i>IDH1/2</i> mutation (INDIGO): Updated efficacy and safety.

2010 Background: Grade 2 gliomas with isocitrate dehydrogenase 1/2 mutations (mIDH1/2) are diffuse, slowly progressive, malignant brain tumors with a poor long-term prognosis. In the Phase 3 INDIGO trial (NCT04164901) of patients (pts) with grade 2 mIDH1/2 glioma, vorasidenib (VOR), an oral, brain-penetrant, dual inhibitor of mIDH1/2, demonstrated a statistically significant and clinically meaningful improvement in the primary endpoint, progression-free survival (PFS) per blinded independent review committee (BIRC), and key secondary endpoint, time to next intervention (TTNI), vs placebo (PBO) at the preplanned interim analysis (data cut-off [DCO]: September 6, 2022). An additional 6 months of data up to study unblinding, March 7, 2023, showed that median PFS was not reached (95% confidence interval [CI]: 22.1 mos, not estimable [NE]) with VOR vs 11.4 mos (95% CI: 11.1, 13.9) with PBO, and median TTNI was NE (95% CI: NE, NE) with VOR vs 20.1 mos (95% CI: 17.5, 27.1) with PBO. Here, we present updated efficacy and safety results as of January 17, 2025, from pts randomized to VOR. Methods: Key eligibility criteria included residual/recurrent grade 2 mIDH1/2 oligodendroglioma or astrocytoma after surgery only; aged ≥12 years; Karnofsky performance score ≥80; measurable non-enhancing disease; surgery as only prior treatment; no immediate need of chemoradiotherapy (CT/RT). Pts were randomized 1:1 to VOR 40 mg daily in 28-day cycles or PBO. After study unblinding, pts receiving PBO were permitted to cross over to VOR. Primary endpoint: radiographic PFS per BIRC. Key secondary endpoint: TTNI. Results: 331 pts were randomized: 168 to VOR and 163 to PBO (median age: 40.0 years [range: 16–71]; oligodendroglioma: 172; astrocytoma: 159). As of January 17, 2025, 98/168 (58.3%) pts remained on VOR, and median follow-up was 41.6 mos (95% CI: 40.5, 42.7). Median PFS per investigator (INV) in pts randomized to VOR was 51.6 mos (95% CI: 45.2, NE), and median TTNI was NE (95% CI: 52.0 mos, NE). At 42 mos, 61.3% (95% CI: 52.5, 69.0) of pts were progression-free and 76.0% (95% CI: 68.4, 82.0) were not in need of CT/RT or surgery. Objective response rate per INV was 32.7% (95% CI: 25.7, 40.4). Median overall survival was not reached. PFS and overall response per BIRC will be presented. The safety profile of VOR was consistent with previous reports. No new safety signals were observed. Conclusions: In the randomized, Phase 3 trial of a targeted therapy in grade 2 mIDH1/2 glioma, over 3 years of follow-up in pts randomized to VOR support the robustness of PFS and TTNI results and confirm a durable and sustained treatment benefit with VOR. VOR is now approved in over 40 countries as a monotherapy for pts with grade 2 mIDH1/2 glioma following surgery. Clinical trial information: NCT04164901 .

Trends in lung cancer mortality among U.S. adults aged ≥55 before and after the introduction of immunotherapy: A CDC WONDER Joinpoint-style analysis.

8595 Background: Lung cancer remains the leading cause of cancer-related mortality in the United States. Although sustained reductions in tobacco use have contributed to gradual declines in incidence and mortality, recent therapeutic advances have transformed the management of non–small cell lung cancer. The introduction of immune checkpoint inhibitors (ICIs) in the early 2010s led to substantial survival gains in clinical trials and shifted treatment paradigms toward frontline and perioperative settings. Whether these advances have translated into accelerated reductions in lung cancer mortality at the population level remains incompletely characterized. Methods: We conducted a nationwide population-based analysis using the CDC WONDER Underlying Cause of Death database from 1999 to 2020. Lung cancer deaths were identified using ICD-10 codes C34.0–C34.9. Annual age-adjusted mortality rates per 100,000 population standardized to the 2000 U.S. population were analyzed. Among adults aged ≥55 years, joinpoint-style segmented log-linear regression was used to identify inflection points and estimate annual percent changes (APC) before and after the identified breakpoint. Results: From 1999 to 2020, age-adjusted lung cancer mortality declined substantially. Among adults aged ≥55 years, segmented regression identified a significant inflection point in 2011. Prior to 2011, mortality declined at −1.52% per year, whereas after 2011 the decline accelerated to −3.88% per year (p &lt; 0.001 for change in slope). In the overall population, mortality declined from 55.4 to 48.8 per 100,000 between 1999 and 2014 (APC −0.7%/year) and decreased more rapidly from 47.8 to 41.3 per 100,000 between 2015 and 2020 (APC −2.9%/year), representing more than a fourfold acceleration. Conclusions: In this nationwide age-adjusted analysis, lung cancer mortality demonstrated a sustained decline over two decades, with a marked acceleration beginning in the early 2010s. Although reductions in tobacco use remain an important contributor, the timing and magnitude of this acceleration, particularly among adults aged ≥55 years, are consistent with population-level benefits associated with advances in systemic therapy, including immune checkpoint inhibitors. These findings suggest that rapid clinical adoption of immunotherapy may have contributed to meaningful real-world improvements in lung cancer mortality. Age-adjusted U.S. lung cancer mortality before and after immunotherapy integration, 1999–2020. Era Years Start rate End rate Percent decline APC (% per year) Pre-immunotherapy 1999-2014 55.4 48.8 -10.5% -0.7 Immunotherapy era 2015-2020 47.8 47.8 -13.6% -2.9 APC = annual percent change. Rates are age-adjusted to the 2000 U.S. standard population.

Multicenter phase II trial of atezolizumab plus carboplatin and etoposide for extensive-stage small cell lung cancer older patients who underwent geriatric assessment (OLCSG2002 EPAS Trial).

8099 Background: Combination therapy with anti-PD-L1 monoclonal antibodies and chemotherapy (ICI-chemotherapy) is the current standard treatment for patients(pts) with extensive-stage small cell lung cancer (ES-SCLC). However, its safety and efficacy in older pts (≥ 71 years) remain limited. Given the pivotal role of geriatric assessment (GA) in the older care, prospective data remain scarce. This study aimed to clarify the efficacy and safety of ICI-chemotherapy in older pts and to evaluate the association between GA and survival. Methods: This multicenter prospective study enrolled pts ≥ 71 years with ES-SCLC who received atezolizumab plus carboplatin and etoposide as first-line therapy. The primary endpoint was 1-year survival rate (SR). Based on existing results, the expected value was 60%, the threshold was 40% (α-error = 0.1 [two-sided], power = 0.75). The calculated sample size was 32 pts. A pre-treatment G8 assessment was mandatory for all pts. Secondary endpoints included safety, objective response rate (ORR), progression-free survival (PFS), and overall survival (OS). Results: Between August 2022 and March 2024, a total of 32 pts were enrolled: median age 77 years (range 71–83); male/female = 27/5; PS 0/1 = 8/24, G8 scores ≥12 /＜12 /not collected were 19/12/1. The 1-year SR was 62.5% (95% confidence interval [CI]: 43.5–76.7). Median OS was 14.6 months (95% CI: 8.2–23.3), median PFS was 5.0 months (95% CI; 4.2–5.9), and ORR was 84.4% (95% CI; 66.3–93.7). Median OS by G8 (score ≥12 vs &lt; 12) was 15.4 vs 12.3 months. Cox regression analysis including clinically important factors for survival (age, PS, G8, bone and brain metastasis at diagnosis) identified brain (HR; 3.1, 95% CI: 1.06 to 8.87; p = 0.039) and bone metastases (HR 3.5, 95% CI: 1.20 to 10.1; p = 0.022) as an independent factor. grade ≥ 3 adverse events (AEs) occurred in 87.5% of pts, and dose reduction was required in 45.1%. The most frequent AE was neutropenia (93.8%); one treatment-related death (stroke) was reported. Conclusions: ICI-combined chemotherapy demonstrated efficacy comparable to that in existing studies, but greater caution was required regarding safety in older pts. While G8 status did not affect survival in SCLC pts, the presence of bone or brain metastasis at diagnosis was identified as an independent prognostic factor. Clinical trial information: jRCT1061200024.

Deciphering ctDNA release influencing factors in luminal breast cancer via single-cell spatial mapping.

e12596 Background: Circulating tumor DNA (ctDNA) is a promising non-invasive biomarker for detecting and monitoring HR+/HER2- breast cancer. However, its clinical utility is limited by tumor heterogeneity and dynamic release mechanisms. Understanding factors influencing ctDNA release is critical for improving its diagnostic and prognostic applications. Methods: We prospectively collected tumor tissues and matched blood samples from ten treatment-naive, II-III stage HR+/HER2- breast cancer patients, integrating single-cell full-length transcriptomic, mutational, and spatial transcriptomic data with plasma ctDNA mutations. Using a deep learning-based multi-omics framework, we computationally mapped ctDNA release at single-cell resolution by tracking clonal mutations co-existing in tumor subpopulations and plasma ctDNA. We systematically analyzed contributions of gene expression programs, functional driver mutations, spatial architectures, and tumor microenvironment (TME) cell-cell interactions to ctDNA release dynamics. Results: We identified eight epithelial states with distinct functional and spatial characteristics. ctDNA release was influenced by gene expression, functional mutations, spatial subclones, and TME composition (all p &lt; 0.05). Mesenchymal luminal progenitors with stemness features demonstrated high ctDNA release potential and exhibited significantly enriched B-cell interactions. PIK3CA mutations enhanced ctDNA release through TME remodeling and increased tumor-associated macrophage phagocytosis. Perivascular distance analysis revealed tumor regions distal from vasculature showed elevated ctDNA release, linked to hypoxia and cellular stress pathway activation (all p &lt; 0.01). Unsupervised clustering based on TME interactions stratified patients into five prognostic subgroups, with immunomodulatory TME profiles associated with poor overall survival and higher ctDNA release in METABRIC dataset (n = 1257, HR = 1.8, 95% CI: 1.2-2.5, p &lt; 0.001). Conclusions: Our study pioneers high-resolution spatial mapping of ctDNA release at single-cell level for the first time, provides insights into ctDNA release heterogeneity from cellular subpopulations, genomic alterations, and immune interactions. We identified luminal progenitors as high ctDNA release potential and elucidated how mutations and TME interactions influence ctDNA release. We stratified patients according to TME characteristics and analyzed the impact on tumor function, prognosis, and ctDNA release. These findings highlight the importance of tumor heterogeneity in ctDNA studies and its potential for precision medicine.

The association of <i>IDH</i> co-mutations with treatment outcomes and overall survival in <i>TP53</i> -mutated acute myeloid leukemia.

6520 Background: In acute myeloid leukemia (AML), TP53 mutations confer a dismal prognosis, with a median survival of ~6 months. While characteristics of TP53 aberrancy (multi-hit status) define an even more aggressive subset, little is known about the effect of IDH co-mutations on outcomes. An analysis of the Consortium on Myeloid Malignancies and Neoplastic Diseases (COMMAND) cohort suggests that TP53 +/ IDH + subjects (n = 24) have prolonged survival compared to TP53+/IDHwt , a finding that could inform our treatment approach in these patients. We therefore aimed to validate this finding in a larger cohort within the Flatiron Health Research Database. Methods: Patients over 18 years with TP53 + AML and IDH1 or 2 testing at diagnosis were selected within Flatiron Health. Demographics, cytogenetic/molecular testing, and treatments were compared using standardized mean difference (SMD), with SMD &gt; 0.2 indicating meaningful difference. Cox proportional hazards models controlling for age, sex, socioeconomic status, ECOG, multi-hit TP53 , secondary AML, and induction strategy were built to test the association of IDH co-mutations with Event Free Survival (EFS) and overall survival (OS). Sensitivity analyses considering receipt of an IDH inhibitor ( IDH i) and stem cell transplant (SCT) as time-varying covariates were also constructed. Finally, two subgroup analyses in the IDH + subcohort were performed to test associations between 1) IDH i in first line, and 2) hypomethylating agent/venetoclax (HMA/ven) in first line, and EFS and OS. Results: 753 TP53+ AML subjects with IDH testing at diagnosis were included. There were meaningful differences in the cytogenetic/mutational landscape of the IDH wt (n = 659) and IDH + (n = 94) cohorts, the latter with a lower incidence of multi-hit TP53 and myelodysplasia-related changes, and a higher incidence of ASXL1, DNMT3A, and TET2 co-mutations. In multivariable modeling, IDH co-mutations were not independently associated with EFS, though were strongly associated with improved overall survival (mOS 9.8 vs 6.1 months, HR 0.69, CI 0.52 – 0.92, p = 0.01). These associations persisted in sensitivity analyses treating IDH i and SCT as time-varying covariates. In analyses of the IDH + subcohort, receipt of IDH i or HMA/ven during first line did not associate with improved OS or EFS. Conclusions: In these data, IDH co-mutations are associated with improved OS in TP53 + AML, though there was no signal suggesting this was driven by choice of therapy. Our analysis is limited by its retrospective nature and a definition of “multi-hit” status that relied on concomitant presence of del17 and a TP53 point mutation. Though these results require further validation, they may currently inform the clinical approach to TP53 +/ IDH + AML by framing goals-of-care conversations. However, more work is needed to characterize the effect of treatment selection on outcomes in this population.

Is more always better?: Outcomes of TIP versus platinum doublet neoadjuvant chemotherapy in high-risk penile cancer.

e17032 Background: The optimal neoadjuvant chemotherapy (NACT) regimen for high-risk penile carcinoma (bulky, bilateral or pelvic nodes) is unclear. Although paclitaxel, ifosfamide and cisplatin (TIP) is used based on limited prospective data, platinum doublets are commonly used in real-world practice due to feasibility and toxicity concerns. Methods: We retrospectively analyzed patients with high-risk penile squamous carcinoma (clinical N2-N3) treated with NACT at Tata Memorial Centre between January 2016 and June 2025, comparing TIP with platinum doublet. Results: Among 58 patients (median age - 55 years), 31% were tobacco chewers, 15.5% were smokers, 22.4% were hypertensive and 13.8% were diabetic (Table 1). NACT regimens included paclitaxel carboplatin (60.3%), TIP (36.2%) and cisplatin 5-FU (3.4%). On histology, 8.6% were p16 positive and 37.9% were poorly differentiated. At a median follow-up of 10.5 months, TIP showed numerically longer DFS (8.9 vs 5.8 months, p = 0.55) and OS (12.6 vs 10.3 months, p = 0.564). Lung metastases occurred in 29.3%. Metronomic chemotherapy was offered to 22.4%; 41.4% were offered best supportive care. TIP had more grade 3/4 hematological toxicities (19% vs 8.1%) and hospitalizations (9.5% vs 8.1%), whereas platinum doublet had more gastro-intestinal toxicities (10.8% vs 0) and electrolyte disturbances (13.5% vs 4.8%), with rare serious events (encephalopathy, pneumonia and stroke) in both groups. Conclusions: In this real-world cohort, TIP showed numerically longer DFS and OS but higher hematologic toxicity, while platinum doublets were more feasible and better tolerated, underscoring the need for prospective studies in this rare disease. Characteristics TIP(n = 21) Platinum Doublet(n=37) p-value Age &gt; 60 years 7 (33.3%) 14 (37.8%) 0.732 ECOG PS 0.863 0 9 (42.9%) 15 (40.5%) 1 12 (57.1%) 22 (59.5%) Clinical N stage 0.234 N2 4 (19%) 3 (8.3%) N3 17 (81%) 33 (91.7%) Completed &gt; 3 cycles NACT 16 (76.2%) 29 (78.4%) 0.848 Response to NACT 0.273 Complete response 0 1 (2.7%) Partial response 12 (57.1%) 12 (32.4%) Stable disease 5 (23.8%) 11 (29.7%) Progressive disease 4 (19%) 13 (35.1%) Primary Surgery 0.487 Wide local excision 2 (9.5%) 4 (10.8%) Partial penectomy 13 (61.9%) 18 (48.6%) Total penectomy 5 (23.8%) 8 (21.6%) Not done 1 (4.8%) 7 (18.9%) Inguinal node dissection 0.049 Unilateral 0 1 (2.7%) Bilateral 18 (85.7%) 20 (54.1%) Pelvic node dissection 0.010 Unilateral 2 (9.5%) 3 (8.1%) Bilateral 15 (71.4%) 12 (32.4%) Pathological T stage 0.127 T1 5 (23.8%) 3 (8.1%) T2 7 (33.3%) 8 (21.6%) T3 5 (23.8%) 9 (24.3%) Pathological N stage 0.044 N0 2 (9.5%) 6 (16.2%) N1 1 (4.8%) 0 N3 15 (71.4%) 15 (40.5%) Extra-nodal extension 14 (66.7%) 14 (37.8%) 0.070 Adjuvant therapy 0.341 Radiation 2 (9.5%) 2 (5.4%) Chemoradiation 7 (33.3%) 7 (18.9%) Site of progression 0.947 Loco-regional 8 (38.1%) 15 (40.5%) Metastatic 10 (47.6%) 16 (43.2%)

Germline testing in Asian American and Pacific Islander women with breast cancer.

10605 Background: Per the American Cancer Society, the overall breast cancer incidence rate rose 1% per year from 2012 to 2021, while it increased 2.7% per year for Asian American and Pacific Islander (AAPI) women. Cases increased by 50% for AAPI women under age 50, on par with White women. This study was conducted to examine rates and results of germline genetic testing in AAPI women with breast cancer. Methods: In this retrospective analysis, AAPI women with breast cancer were identified from a non-consecutive dataset of patients undergoing multi-gene panel testing (MGPT) at a national clinical diagnostic laboratory. Descriptive statistics were performed and differences in variant frequencies between groups were assessed using two-proportion z-tests. Results: From January 2016 through April 2025, 3.8% of women who underwent germline genetic testing reported AAPI ancestry (50,043/1,320,261). AAPI women made up 4.1% of all women with breast cancer who underwent MGPT. Comparatively, the most recent U.S. Census data from 2024 showed 7.0% of the population self-identified as AAPI women. The median age of AAPI women who underwent germline testing was 54 years and the most frequent pathogenic/likely pathogenic (P/LP) variants in order were BRCA2, BRCA1, ATM, PALB2, TP53, and CHEK2 (56.0% of P/LP variants). Most AAPI women (79%) resided in large metropolitan areas, and more than half (53%) had private insurance. AAPI women with breast cancer had lower rates of P/LP variants compared with White women (6.8% vs. 9.2%; p&lt;0.0001) and all non-AAPI women tested (6.8% vs 8.9%; p&lt;0.0001). Among women ≤50 years, P/LP rates remained lower in AAPI compared with White women (7.9% vs 10.7%; p&lt;0.0001) and all non-AAPI women (7.9% vs 10.5%; p&lt;0.0001). Younger AAPI women exhibited higher P/LP rates than older AAPI women (11.2% &lt;40 vs 6.24% &gt;40), consistent with age-associated trends across ethnicities (14.0% all non-AAPI &lt;40 vs 8.45% all non-AAPI &gt;40). Conclusions: In this study cohort, AAPI women with breast cancer make up a smaller than expected proportion of all tested women with breast cancer, despite similar breast cancer incidence rates as White women. AAPI women with breast cancer who had genetic testing tended to reside in large metropolitan areas and have private insurance. These factors and others should be considered when thinking about how to broaden access to genetic testing and counseling in the future, especially in younger AAPI women who have comparably higher rates of P/LP variants.

Single-cell circulating tumor cell genomics of KRAS-independent oncogenic sub-populations and longitudinal clonal evolution in metastatic pancreatic adenocarcinoma.

4216 Background: KRAS mutations are a dominant oncogenic driver in metastatic pancreatic ductal adenocarcinoma (mPDAC) and are routinely detected using ctDNA. However, ctDNA reflects pooled signals from dominant high-shedding clones and may incompletely capture intra-patient heterogeneity or tumor evolution. Circulating tumor cells (CTCs) enable single-cell genomic interrogation and longitudinal tracking of evolving sub-populations. We compared genomic alterations, tumor heterogeneity, and pathway dynamics using ctDNA and single-cell CTC DNA in mPDAC. Methods: Under an MCW IRB approved protocol (PREDICT-MCW; NCT05802069), 16 patients with mPDAC receiving standard of care were enrolled. Peripheral blood was collected at baseline and longitudinally at 90-day intervals. Live single CTCs were isolated using the OncoIncytes platform with anti-EpCAM–based glass bead capture and gentle release. Genomic DNA from individual CTCs underwent linear amplification and targeted sequencing using a 1080-gene panel on the Illumina NextSeq 2000. Matched ctDNA was analyzed using the same panel. Variant calling used the iCore pipeline. Alterations were compared at gene and patient levels. Tumor heterogeneity was assessed using mutant-allele tumor heterogeneity (MATH). Results: CTC counts were highest at baseline (mean 6.5 CTCs per patient; range 2–11) and varied longitudinally with marked inter-patient heterogeneity. At first on-treatment assessment, 50% of evaluable patients showed reduced CTC counts, while others exhibited stable or increased levels. Across all timepoints, 49 altered genes were identified. Single-cell CTC profiling revealed broader genomic representation, with 32 genes (65%) detected exclusively in CTC-DNA, 14 (29%) shared with ctDNA, and 3 (6%) detected exclusively by ctDNA. At the patient level, CTC-DNA identified genomic alterations in all patients (16/16), whereas ctDNA detected alterations in 75% (12/16). At baseline, 61% of CTCs achieved ≥11× coverage across KRAS exon 2 and codon 12. KRAS alterations were detected in only 6% (1/16) of patients by CTC-DNA compared with 44% (7/16) by ctDNA, persisting longitudinally (13–19% vs 59–76%, CTC-DNA vs ctDNA). KRAS-negative CTCs harbored recurrent alterations in MAPK, DNA damage response, receptor tyrosine kinase, and tumor suppressor pathways. CTCs demonstrated higher intra-patient heterogeneity than ctDNA (MATH 50.5 vs 25, p &lt; 0.05). Conclusions: Single-cell CTC profiling reveals KRAS-independent tumor sub-populations present from baseline and dynamic clonal evolution not captured by ctDNA alone, revealing tumor heterogeneity and KRAS-independent disease biology. Paired CTC and ctDNA analysis provides complementary resolution of persistent atypical oncogenic and tumor suppressor sub-clones not evident from bulk liquid biopsy.

Updated results of the chemotherapy-free regimen of blinatumomab and ponatinib in patients with newly diagnosed Philadelphia-positive B-cell acute lymphoblastic leukemia.

6514 Background: Chemotherapy-free regimens incorporating blinatumomab (blina) and ponatinib have demonstrated promising activity in frontline Philadelphia-positive (Ph+) B-cell acute lymphoblastic leukemia (B-ALL). We report the long-term outcomes from an ongoing, phase II study of blina with ponatinib in adults with newly diagnosed (ND) Ph+ B-ALL. Methods: Patients (pts) ≥18 yrs with Ph+ B-ALL received up to 5 simultaneous cycles of blina with ponatinib 30 mg daily, reduced to 15 mg daily upon complete molecular response (CMR). Pts continued ponatinib for at least 5 yrs. IT chemo was increased from 12 to 15 with pt #64 to reduce the risk of central nervous system (CNS) relapse. Protocol was amended to add 2 cycles of high-dose methotrexate (MTX) and cytarabine for pts with WBC &gt;70x10 9 /L. Results: As of January 2025, 88 pts were enrolled (median age of 50 yrs [range, 18-83]; 19%&gt;70 yrs). Median baseline WBC was 15.2 x10 9 /L (0.6-322). 78% of pts had BCR::ABL1 p190 transcripts, 20% had p210. 25 out of 48 pts (52%) with SNP array testing had IKZF1+ genotype. The objective response rate was 96%, with a complete remission (CR) rate of 95%. Measurable residual disease (MRD)-negativity by next-generation sequencing (NGS) was achieved in 95% of evaluable pts; 43% after 1 cycle. CMR rates by RT-PCR was 83%, 67% after 1 cycle. Median follow-up was 3 yrs. 70 pts (79%) remain in molecular remission without allogeneic stem cell transplant (SCT). Of these, 1 received inotuzumab for MRD-positivity and 1 received CAR T-cell therapy. 2 pts (2%) went to SCT in CR1 due to persistent positive p190 transcripts; neither pt had NGS-MRD available. 11 pts (12%) relapsed (10 with p190 transcripts) after a median of 20 months (8-33) from CR: 5 were bone marrow only, 5 CNS only, and 1 extramedullary only; 7/11 relapsed pts (64%) had baseline WBC&gt;70x10 9 /L. Three of the 11 relapsed pts died. There were 2 early deaths, and 3 pts died in CR. Since increasing IT chemo to 15, there has been 1 CNS relapse. 3 pts received 2 cycles of high-dose MTX and cytarabine for WBC&gt;70x10 9 /L; none have relapsed. Median event-free survival (EFS) and overall (OS) have not yet been reached; 3-yr EFS and OS rates are 79% and 89%, respectively. Outcomes did not differ significantly by transcript type nor by NGS MRD clearance after C1. For pts with WBC≥70x10 9 /L vs. WBC&lt;70x10 9 /L, the 3-yr cumulative incidence of relapse (CIR) was 31% vs. 6.7% (p=0.005). The CIR for IKZF1+ vs non- IKZF1+ was 16% vs. 21% (p=0.6). Conclusions: Frontline blina with ponatinib induced deep, durable remission in Ph+ B-ALL, allowing most patients to avoid SCT. Relapses are seen with high presenting WBC, supporting the use of baseline-risk intensified strategies, including increased IT chemo, incorporation of high-dose chemo into consolidation, as well as CAR T-cell therapy. Clinical trial information: NCT03263572 .

RAINFOL-03 (ENGOT-EN-31/GOG-3128): A global, phase 3, open-label, randomized study of rinatabart sesutecan (Rina-S) vs investigator’s choice of chemotherapy in patients with endometrial cancer after platinum-based chemotherapy and programmed death-ligand 1 inhibition.

TPS5646 Background: Patients with recurrent endometrial cancer (EC) whose disease progresses after platinum-based chemotherapy (PBC) and programmed death (ligand) 1 [PD-(L)1] inhibition have a poor prognosis and limited, ineffective treatment options. Single-agent chemotherapy in this setting has been associated with low objective response rates (ORRs; ~15%) and median progression-free survival (PFS) of ~3-4 months. Rina-S is an investigational antibody-drug conjugate targeting folate receptor alpha (FRα) with a novel hydrophilic protease-cleavable linker and topoisomerase I inhibitor, exatecan, payload. In the phase 1/2 RAINFOL-01 trial (NCT05579366), Rina-S 100 mg/m 2 showed encouraging antitumor activity, with a 50% confirmed ORR, including 2 complete responses, and a manageable safety profile in patients with heavily pretreated EC after progression on PBC and a PD-(L)1 inhibitor (Winer IS, et al. J Clin Oncol . 2025:43[16 suppl]:3039). We report the design of RAINFOL-03, a global, open-label, randomized phase 3 study of Rina-S vs investigator’s choice (IC) therapy in patients with EC who have progressed on PBC and a PD(L)-1 inhibitor (NCT07166094). Methods: This phase 3 open-label study will enroll ~544 patients with recurrent or progressive EC (any subtype excluding neuroendocrine tumors, carcinosarcoma, or endometrial sarcoma), measurable per RECIST v1.1, who have received 1-3 prior lines of therapy, including PBC and a PD(L)-1 inhibitor. Patients will be randomized 1:1 to receive Rina-S 100 mg/m 2 intravenously every 3 weeks or IC therapy (paclitaxel or doxorubicin) until disease progression or unacceptable toxicity. Patients will be enrolled regardless of FRα expression level; however, FRα expression levels will be required for stratification at randomization. Dual primary endpoints are PFS per RECIST v1.1 by investigator assessment and overall survival. The key secondary endpoint is ORR per RECIST v1.1 by investigator assessment. Additional secondary endpoints include PFS and ORR per RECIST v1.1 by blinded independent central review (BICR), duration of objective response per RECIST v1.1 by investigator assessment and BICR, safety, and quality of life outcomes. The trial is currently recruiting. Clinical trial information: NCT07166094 .

Early deviations from guideline-concordant care in triple-negative breast cancer: A patient-reported analysis.

e13528 Background: Timely, guideline-concordant care (GCC) is critical to optimize outcomes in triple-negative breast cancer (TNBC). However, deviations from established guidelines often occur early in the care continuum, including symptom misinterpretation by patients or providers, delayed or incomplete diagnostic evaluation, and fragmented transitions to treatment. While quantitative studies have documented variability in treatment timeliness, patient-reported factors driving deviations from GCC during the early care pathway are poorly understood. Methods: As part of a larger mixed-methods study, we conducted a qualitative analysis using semi-structured interviews with a purposive sample of women with TNBC receiving treatment between 2017 and 2022 (n = 42). We oversampled Black and Hispanic/Latina women for representation. Interviews explored diagnostic experiences, care coordination, communication, treatment preparation, and navigation to treatment initiation. Interviews were recorded, transcribed, and analyzed using thematic analysis, iterative coding, and consensus procedures (IRR &gt; 90%), followed by reflexive thematic analysis to refine patterns related to early deviations from guideline-concordant care. The study received independent IRB approval. Results: Participants described multiple, interrelated disruptions in the early care pathway. Diagnostic uncertainty and symptom dismissal, particularly among younger and postpartum women, contributed to delayed diagnostic escalation. Communication gaps and information overload limited understanding of TNBC and readiness for decision-making. Navigation and coordination barriers, including insurance authorization, scheduling delays, and fragmented referrals, impeded timely treatment initiation. Psychosocial shock further compromised patients’ ability to self-advocate during early treatment planning. These factors frequently co-occurred and were compounded during the earliest phases of care. Conclusions: Patient-reported experiences reveal early, potentially modifiable factors contributing to deviations from GCC in TNBC. Although timely diagnosis and treatment initiation are essential in this rapidly progressive disease, the quality of early care also hinges on effective communication, coordinated care transitions, anticipatory symptom guidance, and robust navigation support. When these early-care functions are variable or inadequate (e.g., fragmented transitions, poor referral tracking, or limited decision support), patients are less prepared to make decisions and progress promptly from diagnosis to treatment initiation. These findings highlight a critical opportunity for early, structured interventions at diagnosis to strengthen care coordination, support decision readiness, and reduce preventable disruption in the early TNBC care pathway.

Real-world treatment patterns and clinical outcomes for patients with deficient mismatch repair (dMMR) metastatic colorectal cancer (mCRC).

e15550 Background: The 5-year follow up results of KEYNOTE-177 established pembrolizumab as a standard first-line treatment for dMMR mCRC, demonstrating improved response rates, progression-free survival (PFS) and tolerability over chemotherapy. Pembrolizumab became widely available as a first-line option in Australia following government reimbursement in August 2021. Real world treatment patterns and outcomes have not been reported. Methods: Consecutive patients with mCRC diagnosed between 1/8/2021 and 30/5/2025, and had dMMR as determined by immunohistochemistry test, were analysed, using data from TRACC, an Australian multi-site prospective registry. Clinicopathologic characteristics, treatment patterns and outcomes were examined. Results: From 32 sites, we identified 120 dMMR mCRC patients, of whom 109 (91%) received any systemic treatment. First-line treatment included pembrolizumab (n = 103, 94%), a clinical trial (n = 4, 4%), and chemotherapy (n = 2, 2%). Pembrolizumab treated patients had a median age of 75 years; 50% were also BRAF mutant. Further baseline characteristics are shown in the table. Median follow up was 25.8 months. The clinician-assessed response rate (partial or complete response) was 57%, with 17% of patients having progressive disease noted as best response. Median duration of therapy was 15.2 months. Discontinuation of pembrolizumab in 73 patients was due to progressive disease (37%), completion of 2 years of treatment (29%) and toxicity (15%). Median PFS was 37.9 months. Median overall survival (OS) was not reached, with a 12-month OS of 89% and 24-month OS of 73%. Conclusions: In this real-world population of dMMR mCRC patients, we noted older age, a greater proportion of BRAFV600E mutant, and poorer ECOG functional status compared with KEYNOTE-177. There has been rapid uptake of pembrolizumab as a new standard of care, with promising response rates, PFS and landmark OS achieved. Ongoing data collection are planned to explore predictors of immunotherapy response, and treatment and outcomes in the second line setting. Baseline characteristics. TRACC (n=103) KEYNOTE-177 pembrolizumab cohort (n=153) Age ≥ 65 years 76 (74%) 73 (48%) Male 44 (43%) 71 (46%) ECOG 0 40 (39%) 75 (49%) Charlson Comorbidity Index ≥4 56 (54%) - Primary tumor locationRight sideLeft sideOther / Unknown site 65 (63%)23 (22%)15 (15%) 102 (67%)46 (30%)5 (3%) Stage IV at diagnosis 53 (51%) 80 (52%) BRAF V600E mutant 51 (50%) 34 (22%) KRAS or NRAS mutant 15 (15%) 33 (22%) Site of metastasesLiverLungLymph nodesPeritoneum 40 (39%)15 (15%)44 (43%)27 (26%) -

Real-world outcomes comparing the use of GLP-1 agonists in patients with multiple myeloma and comorbid obesity: A propensity score–matched analysis from a global federated health research network.

7548 Background: Glucagon-like peptide-1 (GLP-1) receptor agonists are widely used for the treatment of type 2 diabetes and obesity, and emerging evidence suggests their benefits beyond glycemic control, including cardiovascular effects and potential anti-inflammatory and anti-proliferative properties. Therapeutic advances in multiple myeloma (MM) have improved the overall life-expectancy in our patients. However, metabolic comorbidities remain common, likely driven by disease burden, functional decline, ongoing inflammation, and treatment related effects. Our study evaluates the impact of GLP-1 receptor agonists on outcomes in patients with MM, exploring potential interactions between metabolic modulation and disease outcomes. Methods: We conducted a real-world retrospective cohort study using the TriNetX Global Collaborative Network, covering January 2000 to December 2025, encompassing data from 168 global healthcare organizations. Patients aged 18 and above with multiple myeloma were identified and then stratified into two groups based on treatment with GLP-1 agonists or not. The two groups were then propensity-matched based on age, sex, race, and various comorbidities. We assessed outcomes including overall mortality, myocardial infarction (MI), ischemic stroke, sepsis, anemia, pancreatitis, venous thromboembolism (VTE), and ED visits. Time-to-event analyses were performed using Kaplan-Meier methods and Cox proportional hazards models. Results: We identified 1716 patients with MM and obesity who received GLP-1 receptor agonists, and 13,491 patients with MM and obesity who did not receive GLP-1 therapy. After propensity matching, each cohort consisted of 1712 patients with well-balanced baseline characteristics. We followed these patients for 5 years from treatment initiation. Patients with MM who received GLP-1 had a significantly lower risk of overall mortality (Hazard Ratio [HR]: 0.423, 95% CI: 0.351-0.509, p-value &lt;0.001), MI (Risk Difference [RD]: -3.6 %, 95% CI: -5.4 % to -1.7 %, p-value &lt;0.001), ischemic stroke (RD: -1.7 %, 95% CI: -3.3 % to -0.1 %, p-value = 0.04), sepsis with and without shock (RD: -3.0 %, 95% CI: -4.9 % to -1.1 %, p-value = 0.002), and anemia (RD: -9.6 %, 95% CI: -12.9 % to -6.4 %, p-value &lt;0.001). There was no statistically significant difference in the rates of VTE, ED visits, and pancreatitis between the two cohorts. Conclusions: Our study revealed that patients with MM with obesity who received GLP-1 therapy had significantly lower rates of overall mortality, MI, ischemic stroke, sepsis with and without shock, and anemia. Additional longitudinal cohort studies are required to explore the associations between these agents and inform clinical practice guidelines in these patients.

Schottky‐Orbital Coupling Drives Ion‐Electron Transfer: Triggering Stable Fast‐Charging in MnV‐Based Phosphate Cathode

ABSTRACT Na 4 MnV(PO 4 ) 3 , characterized by cost‐effectiveness, high voltage, and tunable chemical structure, has drawn considerable attention. However, the practical deployment is hindered by drastic local structural distortions induced by over two electron transfers, coupled with intrinsically low electronic conductivity. Herein, a Schottky and 3 d ‐orbital coupling design paradigm is performed to synergistically tailor the TM‐O coordination environment and interfacial structures, thus breaking the dual bottlenecks of poor electrode kinetics and structural fragility. Therefore, the prepared Schottky‐orbital coupling mediated Na 4 MnV(PO 4 ) 3 (SOMV) cathode exhibits continuous multistep redox with a reversible discharge capacity of 143.9 mAh g −1 at 0.1 C. Theoretical calculations and experiment demonstrate that the in‐situ generated metallic Ni 2 P particles establish intimate contact with semiconducting phosphate particles, inducing the built‐in electric field and thus facilitating the coupled ion‐electron transfer and elevating the reaction‐limited current. Eventually, the SOMV cathode achieves a remarkable rate (82.5 mAh g −1 at 30 C) and fast‐charging performance (26 s to reach 88.5 mAh g −1 ). Moreover, the multiple TM 3 d ‐orbital coupling and reinforced TM─O bonds of SOMV grant the excellent long‐term cycling stability (75.0% capacity retention after 10 000 cycles at 30 C). A universal paradigm for boosting the coupled ion‐electron transfer is established via synergistic engineering of electronic and structural properties.

Exploring the impact of calcined Zn/Al layered double oxide in Congo Red removal: Mechanism and adsorption behavior