Browse Articles

Overall survival of patients with mucosal melanoma in the US before and after the advent of PD-1 based immune checkpoint inhibitor treatment.

9546 Background: Mucosal melanoma (MM) is a rare, aggressive melanoma subtype with poor survival. Prior to 2010, systemic therapy for MM was limited to chemotherapy, adjuvant interferon, and bolus interleukin-2; after 2015, immune checkpoint inhibitors (ICIs), specifically programmed cell death protein-1 (PD-1) based therapies, were widely adopted. The magnitude of overall survival (OS) benefit from ICIs in MM remains poorly defined. Methods: We conducted a retrospective cohort study of 8,125 patients with histologically confirmed MM from the National Cancer Database. Patients were stratified by diagnosis era (pre-ICI: diagnosed before 2010; post-ICI: diagnosed after 2015) and receipt of first-line systemic therapy (immunotherapy and/or chemotherapy versus none). Survival analysis was conducted using Kaplan-Meier methods and Cox proportional hazards models. Difference-in-differences (DID) models using Cox regression estimated survival improvements attributable to systemic therapy in the post-ICI era. Multivariable logistic regression was fitted to assess changes in the characteristics of patients receiving systemic therapy between eras. Subgroup analysis included metastatic patients and stratification by primary tumor site (genitourinary [GU], gastrointestinal [GI], head and neck [HN]). Covariates for multivariable models were selected a priori based on clinical relevance. Results: Median OS (mOS) significantly improved in the post-ICI era with covariate adjustment (36.2 vs. 25.0 months; HR: 0.63, 95% CI: 0.59-0.66). Adjusted DID analysis demonstrated survival benefits attributable to systemic therapy (HR: 0.86, 95% CI: 0.77-0.97). mOS of metastatic patients also improved in the post-ICI era (12.0 vs. 7.33 months; HR: 0.63, 95% CI: 0.54-0.73). All tumor sites demonstrated significantly longer mOS in the post-ICI era, with GU patients living the longest (49.5 months), followed by HN (34.5 months), and GI (24.4 months). Post-ICI systemic therapy recipients were more likely to be older and publicly insured, to have a high comorbidity burden (Charlson Deyo score), to be ineligible for surgery, and to receive immunotherapy alone compared to pre-ICI patients. Conclusions: Survival of MM patients has improved by 37% since the introduction of ICIs. While OS varies by tumor site, all sites showed relative improvement in the post-ICI era. DID analysis suggested that modern survival benefits are driven by ICIs despite an older and more clinically complex treatment population.

Multi-omics discovery and clinical validation of COL1A2 alternative splicing isoforms as liquid biopsy markers for metastasis surveillance in osteosarcoma.

3055 Background: Osteosarcoma (OS) is characterized by early metastatic dissemination, yet the lack of sensitive and tumor-specific tools for real-time surveillance remains a major barrier to improving patient outcomes. Methods: We performed an integrative multi-omics analysis of 424 OS patients, incorporating whole-exome sequencing, bulk RNA sequencing, short-read single-cell RNA sequencing, and single-cell long-read transcriptomics to resolve isoform-level AS alterations at single-cell resolution. Candidate isoforms were evaluated across plasma and peripheral blood datasets from 346 healthy controls to assess tumor specificity. Translational utility was tested in a prospective clinical trial (ChiCTR2400079438), comparing COL1A2 isoform–based circulating tumor cells (CTCs) detection with conventional VIM/TWIST1-based CTC assays and tumor-informed circulating tumor DNA (ctDNA) profiling. Results: OS exhibited widespread alternative splicing dysregulation across both tumor and stromal compartments, with extensive isoform remodeling revealed by single-cell long-read transcriptomics. Two metastasis-associated COL1A2 isoforms were detected in 98% of OS tumor cells but were entirely absent in healthy controls, demonstrating high tumor specificity. COL1A2 isoform–based CTCs detection significantly outperformed VIM- or TWIST1-based assays for predicting metastasis (AUC 0.833 vs. 0.531, P < 0.01) and achieved accuracy comparable to circulating tumor DNA (ctDNA) assays (AUC 0.833 vs. 0.861, P = 0.78). Notably, COL1A2 isoform–based CTCs detected metastatic progression 5.11 months earlier than conventional imaging, approximately two months earlier than ctDNA. Longitudinal analyses further revealed frequent loss of primary tumor–derived mutations during metastatic evolution, limiting the sensitivity of tumor-informed ctDNA assays, whereas COL1A2 isoform–based CTC detection remained robust. Conclusions: Collectively, this study provides the first systematic comparison of CTCs- and ctDNA-based surveillance strategies in OS and establishes COL1A2 isoform-based CTCs detection as a sensitive, specific, and mutation-agnostic liquid biopsy strategy. Clinical trial information: ChiCTR2400079438.

<i>SH2B3</i> in myeloid neoplasms: Potential pathogenic role of variants of uncertain significance.

e18584 Background: SH2B3 is an adaptor protein that downregulates JAK-STAT signaling by binding JAK2. Loss-of-function mutations in SH2B3 have been implicated in myeloproliferative neoplasms (MPN), myelodysplastic syndromes (MDS), and MDS/MPN. However, SH2B3 variants in myeloid neoplasms are classified as variants of uncertain significance (VUS), and their clinical relevance is poorly understood. This analysis aims to characterize the clinico-genomic features of patients with SH2B3 variants. Methods: We performed a single-center, retrospective study of patients with SH2B3 variants identified on myeloid targeted DNA-sequencing. Available clinical and genomic data were collected from electronic medical records. Results: Our cohort included 57 patients (62% female) with median age of 64 years. SH2B3 variants (all VUS) were largely SNVs (88%), with median VAF of 48.4% (4.2-79.1%). The most common variants were p.Glu395Lys (n=6), p.Asp485_Trp492del (n=5), and p.Ser213Arg (n=5), concentrated in PH and SH2 domains. Common pathogenic co-mutations (present in 41% of cases) included JAK2 (n=8), TET2 (n=7), and DNMT3A (n=5). Hematologic abnormalities were common: thrombocytosis (32%), anemia (30%), leukocytosis (28%), thrombocytopenia (25%), and basophilia (23%). Overall, 34 patients (60%) had a cytopenic (anemia, neutropenia, and/or thrombocytopenia) phenotype, and 20 (35%) had a cytoses (leukocytosis, polycythemia, and/or neutrophilia) phenotype. Bone marrow evaluation (n=44) showed hypocellularity (25%), megakaryocytic atypia (32%), and hyperplasia (30%); 16% harbored abnormal karyotypes. Notably, in patients without pathogenic co-mutations (n=33), characteristic hematologic abnormalities (thrombocytosis 30%, anemia 21%, and thrombocytopenia 21%) and bone marrow morphologic changes (megakaryocytic atypia 30%) were common. Only 6% of this subset had a myeloid malignancy diagnosis, suggesting underestimation of these neoplasms. Conclusions: SH2B3 variants are associated with frequent hematologic abnormalities and characteristic bone marrow morphologic changes, even in the absence of pathogenic co-mutations. Hence, detection of the SH2B3 variant, even if a VUS, should raise suspicion of MDS or MPN in appropriate context. External validation of our findings is being performed using NIH’s All of Us database, and updated results will be presented at the meeting. Clinico-genomic characteristics of patients with SH2B3 variants. All (N=57) SH2B3 Variants With Pathogenic Co-mutation (N=24) SH2B3 Variants Without Pathogenic Co-mutation (N=33) Age, median (range) 64 (20-87) 67 (33-87) 62 (20-82) Hematology Thrombocytosis, n (%) 18 (32%) 8 (33%) 10 (30%) Anemia, n (%) 17 (30%) 10 (42%) 7 (21%) Leukocytosis, n (%) 16 (28%) 9 (38%) 7 (21%) Thrombocytopenia, n (%) 14 (25%) 7 (29%) 7 (21%) Bone Marrow (n=44) Megakaryocytic atypia, n (%) 15 (34%) 8 (38%) 7 (30%) Dysplasia, n (%) 6 (14%) 4 (19%) 2 (9%)

Sensitivity of portal vein ctDNA versus peripheral blood in predicting postoperative liver metastasis adjuvant therapy in colorectal cancer.

3139 Background: The detection of minimal residual disease (MRD) in colorectal cancer (CRC) is crucial for predicting postoperative recurrence, particularly liver metastasis. While peripheral blood (PB) liquid biopsy is widely used, portal vein blood (PVB) may offer higher sensitivity due to direct drainage of the hepatic circulation. Methods: We prospectively enrolled 297 CRC patients undergoing curative surgery. Intraoperative portal vein blood (PVB) and matched preoperative peripheral blood (PB) samples were collected simultaneously. Cell-free DNA was sequenced using a targeted 689-gene panel (1.5 Mb). Variants were filtered to retain only those with increased allele frequency (AF) in PVB relative to PB or exclusive detection in PVB (AF ≥1%), followed by stringent germline and noise removal. Binary mutation matrices were constructed for both blood sources. Machine learning (random forest, SVM, logistic regression, gradient boosting) was used to identify predictive gene signatures separately for PVB and PB. Model performance was compared using five-fold cross-validation. Results: PVB-derived ctDNA detected a significantly higher number of tumor-specific mutations compared to PB (mean 3.2 vs. 1.4 mutations per patient, p&lt;0.001). PVB contained significantly higher ctDNA concentration (median 8.4 ng/mL vs 2.1 ng/mL in PB, p&lt;0.001). A 20-gene panel selected from PVB data demonstrated superior predictive accuracy for liver metastasis compared to PB-derived markers. When validated in the same cohort, the PVB panel achieved an AUC of 0.849 (95% CI: 0.802–0.891) versus 0.714 (95% CI: 0.653–0.771) for PB-based prediction (p=0.003). Sensitivity for predicting liver metastasis was 70.0% for PVB versus 48.5% for PB. The PVB panel identified 26.6% of mutation carriers as high-risk, with 100% specificity (no recurrence in mutation-negative patients). In contrast, the PB model failed to achieve comparable risk stratification, with lower positive predictive value and higher false-negative rates. Conclusions: Portal vein blood ctDNA analysis is significantly more sensitive and accurate than peripheral blood in predicting postoperative liver metastasis in CRC. PVB-based liquid biopsy provides superior risk stratification, which could better inform adjuvant therapy decisions—identifying high-risk patients for intensified surveillance or treatment, while reducing overtreatment in low-risk patients. These findings support the clinical integration of PVB sampling for MRD detection in CRC surgical practice.

Machine learning approach for prediction of immune-related pneumonitis.

12153 Background: Immune-related adverse events (irAE) associated with immune checkpoint inhibitors (ICI) substantially contribute to treatment-related morbidity, yet reliable pretreatment predictors remain unavailable. Immune-related pneumonitis (irP) is among the most serious irAE and is associated with a significant risk for mortality. Machine learning (ML) offers an opportunity to analyze complex clinical data to improve risk stratification. We aimed to develop a personalized ML-based model to identify and predict irP from electronic health records (EHR) using patient characteristics prior to ICI initiation. Methods: We extracted data from the EHR of patients with solid malignancies, in various disease stages, who were treated with ICI at Cedars-Sinai Medical Center between 2015 and 2024. For each patient, we collected comprehensive treatment data, including demographics and clinical variables from structured fields and clinical notes. Variables not reliably captured in structured fields, such as smoking or family history, were extracted using our pipeline. Using a large language model (LLM)-based pipeline, we identified irAE cases, enabling precise extraction and classification of irAE subtypes, and validated results against physician annotations for irP (excluding pneumonitis due to other causes). Chi-square analyses assessed associations between features and irAE. We used TPOT, an automated machine learning tool, to develop predictive models and explore sampling strategies for class imbalance. The model was trained on a balanced dataset, evaluated on an unbalanced test set (80/20 split), and hyperparameter-optimized using five-fold cross-validation. Results: Our study included 4,302 cancer patients treated with ICI, of whom 910 were identified by our pipeline as having an irAE and 276 cases of irP. The model achieved a sensitivity of 0.964 on a physician-annotated irP dataset. The best-performing predictive model was a tree-based classifier with an AUC of 0.68. Chi-square analysis identified significant associations (p &lt; 0.05) between irP and multiple clinical features, including prior lung disease, radiotherapy, age at immunotherapy, comorbidity burden, and inflammatory markers. Odds ratio analysis based on model-derived risk score quartiles, showing that patients in the highest-risk quartile exhibited an average 10.3-fold increase in the odds of developing pneumonitis compared to those in the lowest-risk quartile. Conclusions: This study establishes a strong baseline for ML algorithms to identify and predict irP specifically in patients treated with ICI, using EHR-derived data. Our results demonstrate that pre-treatment clinical and laboratory variables can be effectively used to stratify irP risk. Future research should aim to refine these predictive models and incorporate a broader range of EHR-based features to further improve predictive performance and clinical applicability.

ARTEMIDE-Biliary02: A phase 3, randomized, global study of rilvegostomig or durvalumab with chemotherapy as first-line (1L) treatment for advanced biliary tract cancer (BTC).

TPS4253 Background: Biliary tract cancer (BTC) is the second most common hepatic malignancy, comprising 15% of liver tumors. BTC incidence is rising worldwide, and the majority of patients are diagnosed late where the median survival is approximately one year. Chemoimmunotherapy with gemcitabine and cisplatin combined with either durvalumab or pembrolizumab is the current first-line (1L) standard for advanced BTC. To enhance the clinical benefit from immune checkpoint inhibitors, dual blockade of the programmed cell death-1 (PD-1) and T cell immunoreceptor with Ig and ITIM domains (TIGIT) pathways may be an effective strategy. Rilvegostomig, a monovalent, Fc-reduced, bispecific anti-PD-1/anti-TIGIT antibody, has shown promising preliminary efficacy in combination with gemcitabine and cisplatin for 1L treatment of advanced BTC (Zhou J, et al. ASCO 2025 [Abstract 4080]). The phase 3 ARTEMIDE-Biliary02 study (NCT07221253) assesses the efficacy and safety of rilvegostomig or durvalumab in combination with gemcitabine and cisplatin for 1L treatment of advanced BTC. Methods: Eligible participants (aged ≥ 18 years) have unresectable, locally advanced/metastatic BTC (intrahepatic cholangiocarcinoma [iCCA], extrahepatic CCA [eCCA], or gallbladder cancer [GBC]), previously untreated in the advanced setting, no prior immunotherapy, centrally confirmed programmed cell death ligand-1 (PD-L1) status, and ECOG PS of 0/1. Approximately 1100 participants will be randomized (1:1) to receive rilvegostomig or durvalumab, both in combination with gemcitabine and cisplatin, until radiological progression per RECIST v1.1. Participants will be stratified by PD-L1 expression (tumor area positivity &lt; 1% vs ≥ 1%), disease status (initially unresectable vs recurrent), primary tumor site (iCCA vs eCCA vs GBC), and geographic region (Asia vs rest of world). The primary endpoint is overall survival (OS) in the PD-L1 ≥ 1% population, defined as time from randomization until date of death due to any cause. Key secondary endpoints include OS in the intent-to-treat (ITT) population and progression free survival (PFS), defined as time from randomization until radiological progression per RECIST v1.1, in both the PD-L1 ≥ 1% and ITT populations. Other secondary endpoints include objective response rate, duration of response, PFS rates (defined as time from randomization until earliest progression event) in both the PD-L1 ≥ 1% and ITT populations, safety/tolerability, and patient-reported outcomes. OS will be assessed using a stratified log-rank test adjusting for stratification factors. A stratified Cox proportional hazards model will estimate the hazard ratio and associated 95% confidence interval. Enrollment started in December 2025 and is ongoing across Asia, Australia, Europe, and the Americas. Clinical trial information: NCT07221253 .

Machine learning risk stratification in a US-based database to identify subgroups of patients with head and neck cancer who benefit from adding chemotherapy to pembrolizumab.

e18007 Background: First-line treatment for recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) includes pembrolizumab or pembrolizumab plus chemotherapy, guided by PD-L1 when available. Although both were established as standards in KEYNOTE-048, they were not directly compared, leaving optimal patient selection unclear. We hypothesized that machine learning (ML)–predicted baseline prognosis modifies chemotherapy benefit, with higher-risk patients more likely to benefit from chemotherapy’s rapid clinical effects. Methods: Using the Flatiron Health Research Database, we identified patients with R/M HNSCC treated with first-line pembrolizumab or pembrolizumab plus chemotherapy and positive or unknown PD-L1. A gradient-boosted survival model predicted 6-month survival from baseline clinical variables using cross-validation, then calibrated via isotonic regression. Heterogeneity of absolute treatment benefit was evaluated using overlap-weighted regression with 2-year restricted mean survival time (RMST) pseudo-observations. We summarized the continuous treatment-effect function using a crossover point, defined as the baseline 6-month survival probability at which the estimated RMST benefit of adding chemotherapy reached a clinically meaningful magnitude (≥30 days). Patients were stratified by this survival probability, and survival was compared between treatments using inverse probability treatment weighting (IPTW). Results: Among 1,736 patients, 1,095 received pembrolizumab and 641 received pembrolizumab plus chemotherapy. Median age was 68 years, 78% were male, median follow-up was 24 months, and PD-L1 was positive in 17.9%, with 82.1% unknown. The model achieved 6-month AUC 0.75 with good calibration (Brier 0.17). Chemotherapy benefit increased as predicted survival worsened: for every 10 percentage-point decrease in predicted 6-month survival, patients gained 24 days in 2-year RMST with combination therapy (p&lt;0.001). The crossover point corresponded to a baseline 6-month survival probability of 64%. Patients below the crossover survival probability (31.2%)—characterized by worse ECOG, weight loss, lower HPV positivity, bone metastases, and hypoalbuminemia—derived significant benefit from adding chemotherapy in the IPTW-adjusted survival analysis, while those above (68.8%) showed no benefit (Table 1). Conclusions: An ML model trained on nationally-representative data identified subgroups of patients with R/M HNSCC who benefit from adding chemotherapy to pembrolizumab. RMST differences stratified by crossover survival probability. 6-month Survival &lt;64% 6-month Survival ≥64% 1-year RMST Δ 52.5 (22.2-80.1) 1.0 (-13.1-15.3) 2-year RMST Δ 84.4 (27.0-142.3) -17.3 (-51.6-18.2) RMST differences (Pembro+Chemo - Pembro) in days; 95% CI in parentheses.

Safety and efficacy of dostarlimab monotherapy as first-line treatment in programmed cell death-ligand 1–positive recurrent/metastatic head and neck squamous cell carcinoma: Results from a phase 2 trial.

6037 Background: The use of immune checkpoint inhibitors (ICIs) in recurrent/metastatic (R/M) head and neck squamous cell carcinoma (HNSCC) has improved patient outcomes and showed benefit in the perioperative setting. The GALAXIES H&amp;N-202 study (NCT06062420) evaluated novel immunotherapy combinations versus dostarlimab monotherapy in patients with R/M programmed cell death-ligand 1 (PD-L1)-positive HNSCC. Here, we present updated safety and efficacy results for patients who received dostarlimab monotherapy. Methods: GALAXIES H&amp;N-202 is a multicenter, open-label, randomized, Phase 2 study assessing immunotherapy as monotherapy or in combination as first-line treatment (1L) in adults with R/M PD-L1-positive (combined positive score [CPS] ≥1) HNSCC. The dostarlimab monotherapy arm comprised patients randomized to receive dostarlimab 500 mg every 3 weeks until progression, unacceptable toxicity, death, or withdrawal. Investigator-confirmed objective response rate (ORR) per Response Evaluation Criteria in Solid Tumours (RECIST) version 1.1 was the primary endpoint, and safety was a secondary endpoint. Outcomes were analyzed descriptively. Results: At data cutoff (July 14, 2025), 66 patients were enrolled in the dostarlimab monotherapy arm. All patients had ≥4.5 months of follow-up from first dose. The mean patient age was 64.7 years, 80% were male, and 53% had lung metastases. After a median treatment duration of 19.0 weeks (range: 3.0–69.0), ORR was 27.3% (95% confidence interval [CI]: 17.0, 39.6) overall and 42.4% (25.5, 60.8) for those with a CPS ≥20 (Table), and median PFS (95% CI) was 4.2 (2.7, 5.8) and 7.8 (3.0, NE) months, respectively. Treatment-emergent adverse events (TEAEs) occurred in 59 (91%) patients and treatment-related adverse events (TRAEs) in 33 (51%) patients. Three (5%) patients discontinued treatment due to TEAEs. Grade ≥3 TEAEs were reported in 21 (32%) patients and Grade ≥3 TRAEs in 3 (5%) patients. Seventeen (26%) patients experienced serious adverse events (SAEs) and 3 (5%) experienced treatment-related SAEs. Fatal SAEs were reported in 7 (11%) patients; none were treatment related. Conclusions: Dostarlimab monotherapy showed encouraging antitumor activity, particularly in patients with a CPS ≥20, and a consistent safety profile in 1L R/M HNSCC that is comparable to other ICIs in HNSCC. Clinical trial information: NCT06062420 . Efficacy outcomes. Confirmed ORR per RECIST v1.1, n (%) [95% CI] n=66 CPS ≥20 (n=33) 14 (42.4) [25.5, 60.8] CPS 1–19 (n=33) 4 (12.1) [3.4, 28.2] Overall 18 (27.3) [17.0, 39.6] Best response, n (%) n=66 Complete response 1 (1.5) Partial response 17 (25.8) Stable disease 23 (34.8) Progressive disease 17 (25.8) Not evaluable 8 (12.1) CI, confidence interval; CPS, combined positive score; ORR, objective response rate; RECIST, Response Evaluation Criteria in Solid Tumors.

Erratum: First-In-Human, Phase I Dose-Escalation and Dose-Expansion Study of Trophoblast Cell-Surface Antigen 2–Directed Antibody-Drug Conjugate Datopotamab Deruxtecan in Non–Small-Cell Lung Cancer: TROPION-PanTumor01

Mortality caused by coexisting malignant neoplasms and type 2 diabetes mellitus in U.S. adults: A CDC WONDER analysis (1999–2020).

11123 Background: Type 2 diabetes mellitus (T2DM) and malignant neoplasms are among the most prevalent chronic diseases worldwide. When coexisting, they substantially increase morbidity and mortality. However, national trends in cancer-related mortality among patients with T2DM in the United States remain underexplored. Methods: We analyzed CDC WONDER mortality data (1999–2020) to identify deaths among U.S. middle-aged (55–74 years) and older adults (≥75 years) in which both malignant neoplasms (ICD-10 C00–C97) and T2DM (ICD-10 E11.0–E11.9) were listed as causes of death on death certificates. Age-adjusted mortality rate (AAMR) per 100,000 were calculated and stratified by sex, age group, race/ethnicity, and urbanization status. Trends in overall AAMRs were analyzed using the Joinpoint Regression Program to calculate the average annual percentage change (APC), with statistical significance set at ≤ 0.05. Results: From 1999 to 2020, a total of 255,154 U.S. adult deaths involved both T2DM and malignant neoplasms. The AAMR increased significantly over the study period (APC 2.91%; 95% CI 2.32–3.50; p&lt;0.01). Joinpoint regression identified an inflection point around 2011, after which mortality accelerated markedly (APC 6.67%; 95% CI 4.94–8.42). Mortality rates were consistently higher in men compared with women (overall AAMR 13.4 vs. 7.28; p&lt;0.01). Older adults experienced the highest mortality burden (overall AAMR 23.4; APC 2.83%; 95% CI 2.25–3.41), while middle-aged adults demonstrated a steeper relative increase (2.14; 3.40%; 2.72–4.07). Marked racial and ethnic disparities were observed. Asian or Pacific Islanders (API) showed the steepest rise (APC 5.96%; 95% CI 5.35–6.58), followed by Hispanics (5.12%; 4.61–5.63), non-Hispanic (NH) Whites (2.66%; 2.03–3.28), NH Blacks (2.47%; 1.87–3.07), and American Indian/Alaska Natives (AI/AN) (3.15%; 1.03–5.32). Overall AAMRs were highest among AI/AN (15.2) and NH Black adults (11.5), followed by Hispanics (10.5), NH Whites (9.39), and API (7.34). Rural populations consistently had higher mortality rate (overall AAMR 12.9; APC 1.20%; p&lt;0.01), whereas urban populations demonstrated a greater relative increase (8.98; 3.24%; p&lt;0.01). Regionally, the West experienced the most rapid increase in mortality, while the highest overall rates were observed in Nebraska, West Virginia, and Minnesota. Conclusions: Mortality among U.S. adults with concomitant T2DM and malignant neoplasms increased markedly from 1999 to 2020, significant disparities by sex, age, race/ethnicity, region, and urbanization. Integrated public health strategies linking diabetes management with cancer prevention, targeted screening, and equity-focused interventions are urgently needed.

A kidney-sparing approach using disitamab vedotin plus toripalimab for high-risk upper urinary tract urothelial carcinoma in patients with impaired renal function: Preliminary results from a phase II trial.

e16607 Background: Radical nephroureterectomy (RNU) is the gold standard for high-risk upper urinary tract urothelial carcinoma (UTUC). However, for patients with a solitary kidney, renal insufficiency, or bilateral disease, RNU necessitates permanent renal replacement therapy. This phase II trial (NCT06354231) evaluates the clinical activity and safety of Disitamab Vedotin (DV), a HER2-targeted ADC, combined with Toripalimab as a kidney-sparing strategy for this vulnerable population. Methods: This ongoing study enrolls high-risk UTUC patients for whom RNU is clinically unsuitable. The regimen comprises 6 induction cycles of DV (2.0 mg/kg) plus Toripalimab (3.0 mg/kg) Q2W. Patients achieving a response (CR, PR, or SD) proceed to kidney-sparing surgery (endoscopic ablation), followed by consolidation with 12 cycles of DV and 1-year Toripalimab maintenance. The primary endpoint is 1-year kidney-intact disease-free survival (KIDFS). Results: As of the data cutoff, 9 patients were enrolled with a median follow-up of 12.4 months. Baseline HER2 status (IHC) was 2+ (n = 4), 1+ (n = 4), and 0 (n = 1), Among the 9 patients, 7 were evaluable for response. Of the 2 non-evaluable (NE) patients, one withdrew consent for personal reasons after 2 cycles, and one remains awaiting the first assessment. In the evaluable cohort (n = 7), tumor responses during induction included 4 partial responses (PR) and 3 stable diseases (SD). Following endoscopic ablation, the 6-month clinical complete response (cCR) rate was 100% (7/7). The 1-year KIDFS rate reached 100% (4/4) in patients with at least 12 months of follow-up. The safety profile was manageable, with no grade ≥3 treatment‐related adverse event (TRAE) observed to date. The most frequent TRAEs included grade 1 hand-foot syndrome (4/7) and grade 2 hepatic dysfunction (2/7). Conclusions: The combination of DV and Toripalimab demonstrates encouraging preliminary activity and a favorable safety profile in high-risk UTUC. Achieving 100% kidney retention in evaluable cases suggests this paradigm could provide a viable nephron-sparing alternative for patients ineligible for RNU. Continued enrollment will further characterize long-term oncologic and functional outcomes. Clinical trial information: NCT06354231 .

Path analysis of factors associated with nurses’ pain management practices in older adults with cognitive impairment: A cross-sectional study

Background Pain management is essential, yet inadequate management is linked to anxiety, depression, and poor quality of life. Evidence in Thailand is limited for older adults with cognitive impairment. This study examined factors associated with pain management practices among nurses. Design Secondary descriptive correlational study. Methods A secondary cross-sectional analysis used an existing dataset (1 September-27 October 2023); no new data were collected. Institutional Review Board approval was obtained on 4 February 2024; the dataset was accessed on 5 February 2024. Guided by Social Cognitive Theory, 174 full-time registered nurses completed self-administered paper questionnaires, including a modified version of the Tool for Evaluating the Ways Nurses Assess Pain, the Collaboration and Satisfaction Care Decisions Instrument, and the Pain Management Self-Efficacy Questionnaire. Data were analyzed using descriptive statistics, Spearman’s correlation, and structural equation modeling. Results All nurses were female; most held a bachelor’s degree (95.40%); mean age 31.47 ± 6.98 years. The model showed good fit and explained 37% of the variance in nurses’ pain management practices. Direct effects on nurses’ pain management practices were observed for nurses’ perceptions of collaboration with physicians (β = 0.28, p &lt; 0.001, 95% CI [0.16, 0.41]) and nurses’ pain management self-efficacy (β = 0.34, p  &lt; 0.001, 95% CI [0.20,0.47]). Nurses’ knowledge and attitudes toward pain management, nurses’ perceptions of collaboration with physicians, and years of nursing experience also had indirect effects on nurses’ pain management practices through nurses’ pain management self-efficacy (β = 0.08, p &lt; 0.05, 95% CI [0.02, 0.14]), β = 0.08, p &lt; 0.01, 95% CI [0.03, 0.13], and β = 0.13, p &lt; 0.01, 95% CI [0.05, 0.20], respectively. Conclusions Pain management self-efficacy plays a key role in nursing practice. Building it through targeted interventions, training, and institutional support may improve pain management competencies for older adults with cognitive impairment.

Pentagonal lid-driven cavity flow with heated triangular blockage in convective boundary layer

Digital Microneedles for Multiplexed Transdermal Sensing via Fluorescent QR Codes (Adv. Mater. 36/2026)

Kinetic‐Programmed Hydrolysis Enables Intelligent Time‐Evolving Phosphorescence in Water

ABSTRACT The development of aqueous room‐temperature phosphorescent (RTP) materials with dynamically programmable afterglow remains a significant challenge. Herein, we report a universal and programmable synthesis paradigm that overcomes this limitation by orchestrating the hydrolysis kinetics of aminosilanes. This approach constructs silylated carbon dots (Si‐CDs) with dual‐emission centers covalently locked within a rigid silica matrix. The aminosilane precursor serves as a multifunctional building block, simultaneously acting as the carbon source, electron donor, and molecular bridge, which synergistically enhances intersystem crossing while effectively suppressing non‐radiative decay. The resulting ultra‐small nanoparticles (7–9 nm) exhibit exceptional aqueous RTP performance, including a long lifetime of 859 ms and a high quantum yield of 29.3%. More importantly, we pioneer the concept of programmable time‐dependent phosphorescence (TDP), enabling on‐demand, dynamic color evolution (e.g., from red to blue) through precise kinetic control. This intelligent temporal color coding, attributed to the synergy between charge‐transfer modulation and matrix confinement, opens a new dimension for optical information security. We further demonstrate its transformative potential in autofluorescence‐free in vivo bioimaging, advanced anti‐counterfeiting, and dynamic 3D data encryption. This work provides a versatile platform for the rational design of next‐generation intelligent photonic nanomaterials.

Homologous cell type markers highlight subdivisions of the domestic chick hippocampal formation

An inhibitor of GCN2 and the integrated stress response directly targets ZAK protein kinase to limit cytotoxicity

Prognostic impact of tumor recurrence dynamics in patients with HR+/HER2- advanced breast cancer treated with ET+CDK4/6i: Results from the multicenter, Italian study PALMARES-2.

1092 Background: Endocrine sensitivity/resistance (ES/ER) is a key prognostic and predictive factor in patients (pts) with Hormone Receptor-positive, Human Epidermal growth factor Receptor 2-negative advanced Breast Cancer (HR+/HER2- aBC). Cyclin Dependent Kinase 4/6 inhibitors (CDK4/6i)+Endocrine Therapy (ET) are standard 1 st line therapy for HR+/HER2- aBC pts regardless of tumor ES/ER status at diagnosis. However, the prognostic value of tumor recurrence dynamics within ES/ER groups has never been investigated. Methods: We conducted a pre-planned analysis of the multicenter, real-world, Italian study PALMARES-2 (NCT06805812) to evaluate the prognostic role of tumor recurrence dynamics, de novo aBC presentation and distant recurrence-free interval (DFRI) in pts with HR+/HER2- aBC treated with 1 st line ET+CDK4/6i between January 2016 and September 2024. DRFI was defined as the time from surgery to the detection of aBC. The primary endpoint was real-world progression-free survival (rwPFS), defined as the time between ET+CDK4/6i initiation and disease progression (PD) or patient death. Results were adjusted through Multivariable Cox regression for 16 relevant covariates. Results: Of 4,234 pts enrolled, 2,858 (67.5%) had ES and 1,376 (32.5%) had ER disease at aBC diagnosis. Median follow-up was 38.6 and 42.7 months, respectively. After adjustment, ER was associated with poorer rwPFS compared to ES (adjusted hazard ratio [aHR] 1.78, 95% CI 1.60-1.96). In the ER cohort, secondary tumor resistance with recurrence during years (y) 3-5 of adjuvant (adj) ET or &lt;1 y from its end, and recurrence during extended adj ET or &lt;1 y from its end, were associated with increasingly better rwPFS when compared to primary resistance (Table). In the ES cohort, pts with tumor recurrence &gt;10 y from adj ET end had significantly longer rwPFS when compared to pts recurring &lt;10 y from adj ET end, or pts with no prior adj ET or de novo aBC (Table). Among pts with recurrent disease (N=2,792), any additional y of DRFI resulted in 3% reduction in the risk of disease progression (aHR:0.97, 95% CI: 0.96-0.99). Conclusions: The current ES/ER classification fails to capture the whole spectrum of prognostic heterogeneity in HR+/HER2- aBC pts treated with 1 st line ET+CDK4/6i. Recurrence dynamics, including DRFI, improve prognostic classification and may inform treatment selection and personalised patient management in this clinical context. Clinical trial information: NCT06805812 . Recurrence dynamic N rwPFS (mo) aHR (95% CI) Primary resistant 334 13.4 Ref Secondary resistant-during 5 y adj ET 668 15.7 0.85 (0.72-0.99) Secondary resistant-during extended adj ET 375 19.4 0.73 (0.61-0.89) No adjuvant ET 288 30.0 0.46 (0.36-0.59) 1-5 y from adj ET end 453 29.3 0.54 (0.45-0.65) 5-10 y from adj ET end 377 32.6 0.50 (0.40-0.61) &gt;10 y from adj ET end 275 45.2 0.30 (0.23-0.40) De novo aBC 1422 31.3 0.50 (0.42-0.59)

Clinical candidate JNC-1043, importin ß inhibitor (first in class), to target incurable cancers, TNBC, and colon cancer.

e15096 Background: JNC-1043 is an importin ß inhibitor, first in class drug candidate for TNBC (triple negative breast cancer) and incurable cancer therapy. JNC-1043 exhibits strong binding affinity to importin ß, and an excellent anti-cancer effect against various cancer cell lines and in vivo xenograft models. In addition, JNC-1043 exhibits radio-sensitizer effects by blocking of IR-induced invasion. Methods: JNC-1043 is evaluated in vitro against several cancer cell lines, TNBC, Lung, Ovarian, Gastric, Blood and other cancer cell lines and in vivo evaluation with two Xenograft models, TNBC and Colon cancer. PK and Toxicity study of JNC-1043 was carried out in Rats, Beagle dogs and/or Cynomolgus Monkeys. Results: Importin ß inhibitory effect and Cell viability (CC 50 ) of JNC-1043 show &lt; 1.0 μM in the enzyme and 0.07~1.17 μM against various cancer cell lines, respectively. And 2 in vivo Xenograft models in PO administration for 10~14 days exhibit 75 % reduction of cancer size compared to MOCK control. PK profile of JNC-1043 PO dosing is excellent in SD Rats and Monkeys, T1/2 = 6.3 hr and 7.9 hr, respectively. Regarding Toxicity profile, once daily oral gavage administration to SD rats is well tolerated for 14 days at dose levels of 125, 250, 500 mg/kg/day. NOAEL after daily oral gavage dosing in rats for 14 days was determined to be more than 500 mg/kg/day. Conclusions: JNC-1043 is an importin ß inhibitor and promising clinical candidate for cancer therapy especially TNBC. This poster presents results of JNC-1043 studies that are MOA, in vitro and in vivo efficacy , PK and Tox. studies, and CMC.

Features of euthyroid disorder syndrome in cancer patients with different tumor localizations.

e24093 Background: Euthyroid sick syndrome (ESS) is a complex of thyroid status changes associated with non-thyroidal pathology. However, the specific features of thyroid disorders depending on tumor location remain poorly understood. The aim of this study was to investigate the characteristics of thyroid status in primary cancer patients with different localizations of malignant tumors in the early stages of the disease (T1-2N0M0). Methods: The study included treatment-naive patients of both sexes, aged 45–59 years, with clinically and morphologically confirmed diagnoses: breast cancer (BC, n = 25), uterine cancer (UC, n = 25), lung cancer (LC, n = 28), renal cell cancer (RCС, n = 29), and cutaneous melanoma (СM, n = 25). Serum levels of thyroid-stimulating hormone (TSH), total and free thyroxine (T4), and total triiodothyronine (T3) were measured by radioimmunoassay (RIA). The control group comprised 42 healthy donors (mean age 53.5 ± 8.6 years). Statistical analysis was performed using parametric and nonparametric tests with appropriate adjustments for multiple comparisons. Results: A significant decrease in TSH levels (by 33%, p &lt; 0.05) was observed only in patients with cutaneous melanoma (CM). Patients with other tumor types showed no significant differences in TSH compared to reference values. Total thyroxine (T4) levels increased by an average of 1.8-fold in all lung cancer (LC) patients and in 16% of breast cancer (BC) patients. In contrast, T4 levels were reduced by 1.4–1.7-fold in patients with renal cell cancer (RCC) and uterine cancer (UC). Total triiodothyronine (T3) concentration was decreased by 1.3–1.5-fold in RCC and CM patients but increased by 1.6-fold in patients with UC. Free T3 (FT3) levels were elevated by 1.3–1.8-fold in BC, LC, and CM patients but decreased by 1.5-fold in RCC patients. Free T4 (FT4) levels were reduced by 1.5-fold in RCC patients and increased by 1.4-fold in UC patients, with no significant changes observed in other groups. Conclusions: The development of malignant tumors at different sites leads to distinct patterns of euthyroid sick syndrome (ESS). A universal finding across all patient groups was a dissociation between total and free thyroid hormone fractions, suggesting a potential disruption in their peripheral metabolism. Notably, significant alterations in serum TSH levels were observed only in patients with cutaneous melanoma (CM); TSH remained within the reference range for all other tumor types. The identified ESS variants included a hyperthyroxinemic pattern in lung cancer (LC) and a subset of breast cancer (BC) cases, a hypothyroid-like pattern with a reduction in all hormone fractions in renal cell cancer (RCC), and a profile indicative of peripherally activated thyroid hormone metabolism in uterine cancer (UC).