Browse Articles

TCM-based syndrome stratification and biological profiling of cancer-related fatigue: A cross-sectional study and scale validation.

e24137 Background: Cancer-related fatigue (CRF) is a prevalent symptom with limited interventions. Traditional Chinese Medicine (TCM) offers syndrome-based, holistic approaches that may provide insights for precision supportive care. Methods: A cross-sectional study of 383 CRF patients was conducted at Xiyuan Hospital. Using Two-Step cluster analysis and Delphi expert consensus, a TCM-based syndrome stratification model and diagnostic scale were developed and externally validated. Multilevel analyses examined demographic, emotional, and biological differences across subtypes. Results: Four TCM subtypes of CRF were identified: Subtype 01 (Liver Depression & Spleen Deficiency): Associated with mood disturbance, predominantly well-educated patients (head/neck or breast cancer), showing heavy emotional burden, elevated ALT/NEUT%, and decreased CD4+%/glucose. Subtype 02 (Yin Deficiency): Primarily female radiotherapy patients exhibiting the mildest fatigue, characterized by chronic inflammation and immune-coagulative imbalance. Subtype 03 (Yang Deficiency): Mainly older colorectal cancer patients, showing endocrine and immune dysregulation (elevated ProGRP, reduced γδT cells). Subtype 04 (Qi and Blood Deficiency): Common among low-income, lung cancer patients, presenting the most severe fatigue and abnormalities in coagulation, thyroid function, and hepatic metabolism. The diagnostic scale demonstrated good discrimination (AUC = 0.70–0.86), with high sensitivity and specificity, and was successfully validated externally. Significant differences across subtypes were confirmed in terms of demographic, fatigue, emotional, and biological characteristics. Conclusions: This study links symptom networks with TCM syndrome subtypes, highlighting emotional, endocrine, and immune factors in CRF heterogeneity. It provides a robust framework for precise TCM differentiation and biological profiling, supporting personalized strategies for global cancer care.

Venous thromboembolism as a trigger for acute cardiac decompensation during cancer hospitalizations: A National Inpatient Sample analysis, 2018–2022.

e23099 Background: Venous thromboembolism (VTE) is a common complication of malignancy, but its role as a trigger for acute cardiac and hemodynamic decompensation during hospitalization is poorly defined. Most studies emphasize VTE incidence rather than downstream inpatient severity. This study evaluated whether pulmonary embolism (PE) and deep vein thrombosis (DVT) are associated with disproportionate inpatient deterioration in hospitalized patients with cancer. Methods: We conducted a serial cross-sectional analysis of adult hospitalizations with a principal diagnosis of malignancy in the 2018–2022 Healthcare Cost and Utilization Project National Inpatient Sample. VTE was identified using any-diagnosis ICD-10-CM codes for PE (I26*) and DVT (I82*) and categorized as no VTE, DVT only, PE only, or PE with concurrent DVT. Outcomes included All Patient Refined Diagnosis Related Group (APR-DRG) severity, extreme severity (APR-DRG level 4), in-hospital mortality, shock, mechanical ventilation, length of stay (LOS), and hospitalization cost. Survey-weighted multivariable regression adjusted for demographics, payer, income quartile, admission type, cancer subtype, hospital characteristics, and year. Results: Among 961,848 unweighted cancer hospitalizations representing 4,809,239 admissions nationally, VTE occurred in 5.51 percent, including PE only in 2.00 percent, DVT only in 3.85 percent, and PE with DVT in 0.52 percent. Inpatient severity increased stepwise across VTE phenotypes. Mean APR-DRG severity increased from 2.51 with no VTE to 3.35 with DVT only, 3.63 with PE only, and 3.80 with PE plus DVT. Extreme severity occurred in 3.09 percent without VTE versus 8.49 percent, 11.68 percent, and 15.20 percent, respectively. Mortality increased from 4.01 percent to 9.67 percent, 13.76 percent, and 12.69 percent, with higher rates of shock and mechanical ventilation. LOS and costs were highest among PE plus DVT admissions. After adjustment, PE only was independently associated with extreme severity (OR 8.39, 95% CI 7.64 to 9.22), shock (OR 2.81, 95% CI 2.55 to 3.09), mechanical ventilation (OR 2.98, 95% CI 2.77 to 3.21), and mortality (OR 2.95, 95% CI 2.80 to 3.12). PE plus DVT conferred the highest risk of shock (OR 4.14, 95% CI 3.69 to 4.64) and extreme severity (OR 18.85, 95% CI 16.07 to 22.10). Conclusions: During cancer-related hospitalizations, venous thromboembolism, particularly pulmonary embolism, functions as a major trigger for acute cardiac and hemodynamic decompensation rather than an isolated thrombotic event. These findings highlight VTE as a key driver of inpatient severity, critical care utilization, and mortality in oncology populations.

Efficacy and safety of pralsetinib in <i>RET</i> fusion–positive solid tumors: Data from the TAPISTRY trial.

3144 Background: Pralsetinib is an oral tyrosine kinase inhibitor that selectively and potently targets oncogenic RET fusion and mutation proteins, present in multiple tumor types. We report results from the phase 2 TAPISTRY study (NCT04589845), a global, open-label, multicohort study evaluating the efficacy and safety of pralsetinib in a cohort of patients with RET fusion-positive solid tumors. Methods: Eligible patients ≥12 years old with unresectable, locally advanced or metastatic RET fusion-positive solid tumors received 400 mg pralsetinib QD until disease progression, loss of clinical benefit, or unacceptable toxicity. Independent review committee (IRC)-assessed objective response rate (ORR) was the primary end point. Key secondary end points included IRC-assessed duration of response (DOR) and progression-free survival (PFS), and overall survival (OS). Results: Forty-six patients were enrolled and received ≥1 pralsetinib dose; 78% had ≤1 prior line of therapy in the metastatic setting. Median age was 56 y (range: 12-79); 61% were male. Median treatment duration was 14.3 mo (range: 0.7-31.5). Cancers included thyroid (n=18, 39%); colorectal (n=9, 20%); head and neck (n=4, 9%); pancreatic (n=4, 9%); hepatobiliary (n=3, 7%); CNS, sarcoma, and neuroendocrine and adrenal (n=2, 4% each); gastroesophageal (n=1, 2%); and unknown primary origin (n=1, 2%). ORR for the efficacy evaluable population (n=39) was 67% (95% CI: 50, 81; Table), with 5 (13%) CRs and 21 (54%) PRs. Intracranial response was observed in 1/2 (50%) patients with baseline CNS metastases. All patients experienced treatment-related adverse events (TRAEs); 33/46 (72%) reported TRAEs grade ≥3. The most common TRAEs included anemia (n=18; 39%), increased AST (n=16; 35%), and decreased neutrophil count (n=13; 28%). Hypertension was reported in 11 (24%) patients, with 3 (7%) reporting grade ≥3. Safety results were consistent with the known pralsetinib profile, with no new signals. Conclusions: Pralsetinib demonstrated robust and durable activity against RET fusion-positive solid tumors, with an ORR of 67%. These data validate RET fusions as a tissue-agnostic target with sensitivity to RET inhibition, suggesting therapeutic utility of pralsetinib. Clinical trial information: NCT04589845 . Efficacy summary by tumor type. Overall(N=39) Thyroid (n=16) Pancreatic (n=3) Colorectal (n=8) Hepatobiliary (n=3) Head and Neck (n=3) ORR, % (95% CI) 67(50, 81) 81(54, 96) 67(9, 99) 38(9, 76) 33(1, 91) 100(29, 100) DOR, median, mo (95% CI) 26.7(14.7, NE) 26.7(26.7, NE) 3.9(3.7, NE) 12.2(5.7, NE) 14.9(NE) NE PFS, median, mo (95% CI) 16.5(7.2, NE) 30.3(16.3, NE) 5.6(1.9, NE) 6.5(1.6, 12.9) 8.3(1.4, NE) NE OS, median, mo (95% CI) 30.8(16.3, NE) NE(NE) 21.7(12.7, NE) 10.2(5.7, NE) 13.8(8.3, NE) NE Follow-up, median, mo (range) 14.5(2, 32) 19.4(10, 32) 12.6(2, 31) 9.2(2, 19) 8.3(2, 19) 14.3(14, 27) NE, not evaluable.

Thermally Induced Macromolecular Sequence Inversion in Triblock Copolymers and Terpolymers

ABSTRACT Dynamic control over polymer sequences remains a major challenge in synthetic macromolecules, limiting their adaptability relative to biomacromolecules. Herein, we introduce an intra‐macromolecular sequence inversion in triblock copolymers and terpolymers using a furan–maleimide–anthracene Diels–Alder system, enabling thermal reconfiguration at 120°C without altering composition or molecular weight. Bifunctional initiators bearing reversible Diels–Alder linkages allow the synthesis of symmetric (ABA) and asymmetric (ABC) triblock co/terpolymers. Upon heating, retro‐Diels–Alder dissociation followed by anthracene–maleimide (Anth–Mal) cycloaddition induces sequence inversion, yielding BAB or BAC architectures. Comprehensive experimental characterization confirms preservation of chain integrity, while revealing altered diffusion coefficients and distinct microphase‐separated morphologies, highlighting the pronounced influence of sequence on polymer properties. This strategy establishes a paradigm for programmable polymer metamorphosis, opening new avenues toward stimuli–responsive materials with tunable self‐assembly, crystallinity, and mechanical properties.

Gabapentin loaded nano-emulsion for the effective treatment of peripheral neurological pain: Formulation, characterization, and ex vivo studies

Microbial‐Semiconductor Hybrids Enable Near Infrared‐Driven Photosynthetic Hydrogen Production for Tumor‐Targeted Immunotherapy

ABSTRACT Photosynthetic hydrogen (H 2 )‐generating microbes represent a highly promising H 2 delivery platform for antitumor therapy due to their spontaneous tumor colonization and high catalytic selectivity. However, existing microbes suffer from inadequate near‐infrared (NIR) responsiveness and photoelectron injection. Here, we engineer a microbial‐semiconductor hybrid by electrostatically assembling copper sulfide‐loaded layered double hydroxide (LDH/CuS) nanosheets onto the surface of Rhodopseudomonas palustris ( R.P .) for NIR‐driven photosynthetic H 2 immunotherapy. The LDH/CuS enhances NIR capture and forms a p‒n heterojunction that weakens the electron exclusion barrier, enabling directed pumping of photogenerated electrons into R.P . Under 808 nm irradiation, the LDH/CuS heterojunction boosts photoelectron injection into the hydrogenase system of R.P . by 6.8‐fold, achieving highly efficient photosynthetic H 2 production. Notably, the R.P .@LDH/CuS actively colonizes hypoxic tumors with a high targeting efficiency of 73.2% and selectively converts tumor‐enriched lactic acid (LA) and glycogen into H 2 under NIR stimulation. Through the LA depletion and immunogenic cell death induction, the microbial‐semiconductor hybrid triggers potent antitumor immune responses, increasing infiltrated CD8 + T cells by over 9‐fold and achieving a remarkable tumor inhibition rate of 97.8%. This work presents an NIR‐driven biohybrid system with spatially directional electron pumping for efficient photosynthetic H 2 generation, advancing a promising paradigm for precision‐targeted tumor immunotherapy.

Kinetically Gated and Self‐Limiting Crystallization Enables Allosteric Phototheranostic Nanocrystals

ABSTRACT Crystalline organic nanomaterials with programmable photophysical functions hold great promise for precision medicine, however, achieving controlled crystallization and responsive activation remains challenging. Here we report a kinetically gated and self‐limiting crystallization (KGSLC) strategy for constructing allosteric phototheranostic nanocrystals. Through rational molecular design, the TCF acceptor unit governs intrinsic size confinement via surface hydration, while the hydroxyl group directs hydrogen‐bond‐assisted π – π stacking to promote highly crystalline assemblies. The resulting HICyT nanocrystals (HICyT NCs) exhibit strong near‐infrared absorption, dual‐type reactive oxygen species generation, and catalase‐like activity. A disulfide‐bridged prodrug, (HICyT) 2 S, further encodes tumor microenvironment‐triggered activation, converting into active HICyT NCs upon glutathione cleavage. The resulting nanocrystals enable deep‐tissue penetration, bright albumin‐activated NIR‐I/II fluorescence, and potent in vivo tumor ablation under irradiation. This kinetically programmed crystallization integrates structural precision, spatiotemporal activation, and real‐time imaging into a single organic platform, offering a promising route toward self‐reporting phototheranostic materials.

Traditional Chinese medicine (TCM) for prevention and management of anti-EGFR monoclonal antibody (mAb)–induced cutaneous adverse reactions in patients with metastatic colorectal cancer (mCRC): A retrospective analysis.

e15584 Background: Anti-EGFR mAb have significantly improved clinical outcomes in mCRC by inhibiting the EGFR signaling pathway. However, these agents can also disrupt EGFR function in normal tissues, causing acneiform eruptions. Shengma Biejia Decoction primarily clears heat and toxins, cools the blood, and disperses blood stasis, mainly for patterns of heat toxin invading the blood and combined stasis and heat. This offers a novel approach for preventing and treating these adverse reactions. Methods: This retrospective analysis included mCRC patients who received cetuximab at Longhua Hospital, Shanghai University of Traditional Chinese Medicine, from 2022 to 2025. A total of 41 patients were screened; after excluding those with incomplete records or who received only one cycle due to poor tolerance and switching therapies, 35 patients were enrolled. Based on clinical regimens, patients were divided into a TCM arm (n = 25) and a non-TCM arm (n = 10). Patients in the TCM arm received oral Shengma Biejia Decoction combined with cetuximab throughout treatment. One dose was decocted daily to 300 mL and taken warm in two divided doses, morning and evening. Patients in the non-TCM arm received conventional symptomatic treatment. The primary endpoint was the incidence of any grade skin reactions (per CTCAE 5.0) in both groups, compared using Fisher’s exact test. Results: At baseline, 28 patients (80.0%) were male and 34 (97.1%) had stage IV disease. Liver, lung, and peritoneal metastases were present in 20 (57.1%), 6 (17.1%), and 9 (25.7%) patients, respectively. Cetuximab was used as conversion therapy in 3 (8.6%), first-line in 23 (65.7%), and second-line or later in 11 (31.4%) patients. In the entire cohort, the incidence of any grade cutaneous adverse reactions was 31.4%, and severe reactions 8.6%. there was a significant difference in any grade skin reactions between the TCM arm and non-TCM arm (20.0% vs. 60.0%, p = 0.041) . Among 20 elderly patients (≥65 years), 14 and 6 patients were allocated to the TCM arm and non-TCM arm, the incidence of any grade skin reactions was 21.4% vs. 66.7%, respectively. These findings suggest the TCM formula may help reduce skin reactions in elderly patients undergoing antitumor therapy. Previous studies report anti-EGFR mAb–related any grade skin reactions rates up to 81.4%, while the overall incidence in our study was much lower. Conclusions: In patients with mCRC receiving cetuximab, concomitant use of Shengma Biejia Decoction–based TCM formula can significantly lessen skin reactions. At the same time, this regimen shows a favorable safety profile, and contributes to better overall quality of life. These findings provide TCM-based evidence to guide the clinical prevention and management of cetuximab-related skin reactions.

Adverse effects associated with immune checkpoint inhibitors in locally advanced nasopharyngeal carcinoma: A meta-analysis of randomized controlled trials.

e18105 Background: Immune checkpoint inhibitors (ICIs) are increasingly incorporated into curative-intent treatment strategies for locally advanced nasopharyngeal carcinoma (LA NPC), either with concurrent chemoradiation or following induction chemotherapy. While early efficacy results are promising, the toxicity profile of these combinations remains clinically relevant. We conducted a meta-analysis to characterize adverse events associated with the addition of ICIs to standard therapy in LA NPC. Methods: MEDLINE and EMBASE were systematically searched through January 10, 2026 to identify phase II and III randomized controlled trials evaluating ICIs added to standard therapy for LA NPC. Adverse events of interest included immune-related adverse events (irAEs), locoregional toxicities, general and hematologic adverse events, late adverse events, and serious treatment-related adverse events. Pooled risk ratios (RRs) with 95% confidence intervals (CIs) were calculated using a fixed-effects inverse variance model. Heterogeneity was assessed using Cochran’s Q and I² statistics. Results: Two randomized trials including 572 patients met inclusion criteria. Compared with standard therapy alone, ICI-containing regimens were associated with significantly higher rates of immune-related adverse events. The pooled RR for any-grade irAEs was 10.71 (95% CI: 6.43–17.85; p&lt;0.00001), with a corresponding increase in high-grade irAEs (RR 25.82; 95% CI: 8.35–173.38; p=0.0008). Hypothyroidism (any grade, predominantly grade 1–2) was more frequent with ICIs (RR 7.89; 95% CI: 4.11–15.16; p&lt;0.00001). Cutaneous toxicities were also increased, including rash (any grade RR 16.13; 95% CI: 6.20–41.95; p&lt;0.00001; high grade RR 13.28; 95% CI: 1.86–94.98; p=0.01) and pruritus (any grade RR 22.18; 95% CI: 7.04–69.85; p&lt;0.00001). In contrast, rates of locoregional toxicities, hematologic adverse events, late adverse events, serious treatment-related adverse events, and treatment-related mortality were similar between groups. Conclusions: In locally advanced nasopharyngeal carcinoma, the addition of immune checkpoint inhibitors to standard therapy increases immune-related adverse events, largely low grade, without a corresponding increase in locoregional, hematologic, or late toxicities. These findings support the overall tolerability of ICI-containing regimens in LA NPC with appropriate monitoring.

SARM1 inhibition to prevent chemotherapy-induced peripheral neuropathy: Translational and early clinical evaluation of SIR2501.

12148 Background: Chemotherapy-induced peripheral neuropathy (CIPN) is a common, cumulative, and often irreversible toxicity that limits dose intensity, disrupts cancer treatment, and substantially impairs quality of life. Despite its prevalence, no approved disease-modifying therapies exist. Axonal degeneration is a central pathological driver of CIPN. Sterile alpha and TIR motif–containing protein 1 (SARM1) is a key executioner of programmed axon degeneration across neurotoxic insults. Inhibiting SARM1 offers a mechanism-based strategy to prevent axonal injury without compromising anticancer activity. SIR2501 is a potent, selective, orally bioavailable small-molecule SARM1 inhibitor in clinical development for CIPN prevention. Methods: SIR2501 was evaluated in rodent models of paclitaxel (PTX)-induced peripheral neuropathy using prophylactic and therapeutic dosing paradigms. Endpoints included sensory neuropathy (mechanical allodynia), axonal injury biomarkers (serum neurofilament light chain [sNfL]), and peripheral nerve integrity (intraepidermal nerve fiber density). The impact of SIR2501 on PTX antitumor efficacy was assessed in rodent tumor models.A randomized, double-blind, placebo-controlled Phase 1 study in healthy volunteers evaluated safety, pharmacokinetics (PK), CNS penetration, and pharmacodynamic evidence of SARM1 target engagement following single and multiple ascending doses. Results: SIR2501 robustly attenuated PTX-induced neuropathy in preclinical models, with concordant functional, biomarker, and structural protection, and did not impair PTX-mediated tumor growth inhibition. In Phase 1, 82 volunteers received SIR2501 (up to 600 mg single dose; up to 150 mg once-daily multiple dose). SIR2501 was well tolerated, with no dose-limiting toxicities or clinically meaningful neurologic adverse events. PK supported once-daily dosing with minimal food effect and no CYP3A-mediated drug–drug interaction risk. Dose- and exposure-dependent suppression of circulating cyclic ADP-ribose (cADPR) confirmed SARM1 target engagement at plasma exposures aligned with preclinical efficacy. Conclusions: These translational data support SARM1 inhibition as a disease-modifying approach for CIPN. These data have enabled initiation of a global Phase 1b/2 trial of SIR2501 in patients receiving taxane-based chemotherapy in the United States, Australia, and China.

Mortality from myocardial infarction in GI malignancy from 1999 to 2020.

e16332 Background: Cancer patients are at higher risk of myocardial infarction. Malignancy creates conditions that increase the risk of coronary thrombosis, even in patients without classic atherosclerosis. In addition, myocardial infarction can be an adverse effect of certain chemotherapies. Recent research suggests that gastrointestinal cancers are one of the malignancies that place patients at highest risk for myocardial infarction. Examining mortality trends is critical for understanding how effective our approach to this has been over time. Methods: This retrospective study uses the CDC WONDER database, which contains national mortality data, to analyze trends in acute myocardial infarction mortality in patients with known history of gastrointestinal cancer. This was done using ICD-10 codes of C15-26 for GI cancers and I21 for acute myocardial infarction. Mortality data was analyzed across different demographic subgroups in the United States from 1999 to 2020 to assess for trends. Age-adjusted mortality rates (AAMRs) per 100,000 individuals were calculated and further stratified based on sex and race. Results: A total of 42,776 deaths from myocardial infarction were recorded in patients with GI cancers from 1999 to 2020. Overall AAMR decreased consistently from 1999 (0.961) to 2015 (0.389), then plateaued til 2019 (0.396), and then increased in 2020 (0.446). Men consistently had higher AAMRs than women, although there were decreases in both sexes during this time period. Men’s AAMR fell from 1.450 in 1999 to 0.649 in 2020, while women ’s AAMR fell from 0.633 in 1999 to 0.274 in 2020. The AAMR decrease over time was also seen across all races. In non-Hispanic Whites, it fell from 0.939 in 1999 to 0.434 in 2020. For African Americans, it was 1.32 in 1999 and 0.463 in 2020; for Hispanics, 0.729 in 1999 and 0.503 in 2020. Lastly, for AAPI, 0.432 in 1999 and 0.385 in 2020. Conclusions: Our analysis shows that the mortality rate from acute MI in patients with GI cancers has decreased over time. However, there are still significant racial and gender disparities in mortality that can be improved upon. Men continue to have notably higher mortality rates than women, with this disparity continuing over these two decades even as both of their mortality rates have fallen. Hispanic Americans and African Americans have higher mortality rates than non-Hispanic White Americans and Asian Americans/Pacific Islanders, although the difference has decreased over these two decades. While there is great progress that has been made, things can still be improved in this area. Age adjusted mortality rate (AAMR) per 100,000 from 1999 to 2020 for myocardial infarction in patients with gastrointestinal cancers. Group AAMR per 100,000 in 1999 AAMR per 100,00 in 2020 All 0.961 0.446 Men 1.450 0.649 Women 0.633 0.274 White Americans 0.939 0.434 African American 1.32 0.463 Hispanic Americans 0.729 0.503 Asian Americans/Pacific Islanders 0.432 0.385

A clinically deployable deep learning model for decision support and specimen triage in colorectal histopathology with international pathologist validation.

e15514 Background: Colorectal cancer is a leading cause of cancer-related mortality globally, with histopathology as the diagnostic gold standard. Pathologists must differentiate malignant, benign, and non-neoplastic tissue with high accuracy—a cognitively demanding task subject to interobserver variability. Rising specimen volumes and workforce constraints further challenge routine practice. Although deep learning has shown promise in digital pathology, computational demands hinder clinical adoption. We aimed to develop and validate a computationally efficient deep learning framework for colon histopathology classification, assess diagnostic performance preservation using a lightweight model trained via structured knowledge distillation; and to evaluate global clinical feasibility using expert-reviewed, multi-institutional data. Methods: We assembled 10,000 anonymized hematoxylin-eosin stained histopathological images representing malignant lesions, benign findings, and non-neoplastic controls from multi-institutional sources across six continents. Two independent expert pathologists reviewed all images to establish consensus ground truth. Following comprehensive preprocessing and stain-adaptive augmentation, images were stratified into training (60%), validation (20%), and testing (20%) cohorts. ResNet152 (60.3M parameters, 224×224 resolution), selected for its deep residual architecture, was trained as the reference model. ResNet18 (11.7M parameters, 81% parameter reduction) underwent structured knowledge distillation using soft probabilistic targets from ResNet152 via temperature-scaled cross-entropy loss. Model performance was evaluated on held-out test data and externally validated on independent datasets. Metrics included accuracy, sensitivity, specificity, F1-score, and AUROC. The optimized ResNet18 model was deployed in a cross-platform digital pathology application and independently assessed by pathologists across six continents for clinical utility and workflow integration. Results: ResNet152 achieved high diagnostic accuracy across tissue classes. The knowledge-distilled ResNet18 demonstrated comparable performance, with accuracy exceeding 97% on test data, balanced sensitivity and specificity, and AUROC &gt; 0.97 on external validation. Performance remained stable across geographically distinct datasets with variation in staining protocols. Pathologist evaluators reported the system valuable for diagnostic decision support and specimen triage. Conclusions: ResNet-based AI enables accurate and efficient histopathology classification. Knowledge distillation from ResNet152 to ResNet18 preserved performance while reducing parameters by 81% supporting deployment in diverse clinical settings.

Shifting demographics and cancer incidence projections in the United States.

e22618 Background: Over the last four decades, racial and ethnic diversity in the United States has increased substantially. Understanding how these demographic shifts will shape future cancer burden is critical for anticipating demands on the oncology care delivery systems. This study estimated overall and site-specific cancer incidence through 2030 by race and ethnicity. Methods: Using delay-adjusted incidence data from 2019-2022 (excluding 2020) in the population-based SEER national registry, we projected the number of invasive cancers overall and for the ten most common cancer sites through 2030. Projections were generated for the total population and for non-Hispanic American Indian and Alaskan Native (AIAN), non-Hispanic Asian American and Pacific Islander (AAPI), non-Hispanic Black, Hispanic, and non-Hispanic White (NHW) populations. Analyses used data-driven Joinpoint algorithm with Poisson variance and weighted Bayesian Information Criterion model selection method. Results: Based on current trends, an estimated 1,002,653 cancer cases will occur in 2030, representing a 19.4% increase from 2022, with substantial variation by race and ethnicity. The largest increases are projected among Hispanic (126,246 to 182,002 cases, 44.2%), followed by AAPI (57,339 to 81,701, 42.5%), AIAN (2,927 to 4,141 cases, 41.5%) and Black (95,467 to 119,189 cases, 24.9%) populations, whereas NHW populations are projected to experience the smallest increase (550,073 to 617,277 cases, 12.2%). Projected changes varied by cancer site across racial and ethnic groups. Among AIAN populations, relative increases ranged from 9.3% (43 to 47 cases) for cervical cancer to 88.1% (159 to 299 cases) for kidney cancer and decreases of 10.7% for liver cancer (112 to 100 cases) and 53.6% for bladder cancer (69 to 32 cases); among AAPI populations, from 7.7% (1,954 to 2,104 cases) for liver cancer to 61.3% (1,838 to 2,964 cases) for pancreatic cancer; among Hispanic populations, from 24.1% (7,624 to 9,461 cases) for lung cancer to 58.5% (4,016 to 6,366 cases) for pancreatic cancer; and among Black populations, from 6.4% (3,941 to 4,193 cases) for kidney cancer to 32.8% (3,255 to 4,321 cases) for pancreatic cancer and decreases of 6.2% for liver cancer (1976 to 1,854 cases) and 5.5% for lung cancer (10,063 to 9,510 cases). In contrast, projected changes across cancer sites among NHW populations were generally modest ( &lt; 15%), with declines observed for lung (11%, 63,866 to 56,853 cases), bladder (1.3%, 25,754 to 25,408 cases), and cervical (1.2%, 2,837 to 2,802 cases) cancers. Conclusions: Projected cancer incidence through 2030 varies by race, ethnicity, and cancer site, with Hispanic, AAPI, and AIAN populations expected to experience the largest increases. These projections can inform healthcare systems, public health agencies, and policymakers to plan effective cancer control strategies that address emerging disparities in future cancer burden.

Clinical yield and utility of germline multigene panel testing across hereditary cancer syndromes: A systematic review of real-world evidence.

e22664 Background: Germline multigene panel testing (MGPT) is widely used for hereditary cancer risk assessment , but real-world diagnostic yield and clinical utility vary across clinical contexts and populations . Published data from routine practice are fragmented and heterogeneous. We conducted a systematic review to synthesize evidence on MGPT performance across hereditary cancer syndromes. Methods: PubMed and related databases were searched through 2025 for observational studies of germline MGPT in hereditary cancer evaluation. We excluded somatic tests, population screening studies, single-gene analyses, and variant-only case reports. Data extracted included testing indications, panel gene content, pathogenic/likely pathogenic (P/LP) and variant-of-uncertain-significance (VUS) rates, and reported downstream clinical actions. Study quality was assessed using the ROBINS-I tool for non-randomized studies. Results: 209 studies met inclusion criteria (median cohort 215 patients; IQR 96–879). Panels ranged from 1 to 1,021 genes (median 25 genes; IQR 14–72); most panels targeted only BRCA1/2. Median P/LP detection was 13.4% (IQR 8.7%–20.1%). Individual median detection rates were illustrated in the table . Notably, 10–30% of patients harbored clinically actionable variants outside BRCA1/2. For example, panel testing in breast and colorectal cancer cohorts identified P/LP variants in CHEK2, PALB2, APC, and DNA mismatch repair genes . VUS rates were substantial (median 25%; IQR 14%–44%) and were highest in studies using larger panels and in underrepresented populations . 22 reported on management outcomes; among these, the median proportion of patients with documented management changes was 14.5%. For instance, one report found that 69% of patients with panel-identified mutations had revised clinical recommendations . Overall risk of bias was moderate-to-serious in most studies due to retrospective design, referral patterns, and incomplete follow-up. Conclusions: MGPT frequently uncovers actionable pathogenic variants beyond BRCA1/2, but diagnostic yields vary and are offset by a high burden of VUS . The impact of these findings on patient management remains poorly defined because outcome reporting is limited. These results underscore the need for prospective, standardized real-world data collection to clarify how MGPT results influence hereditary cancer care. Summary of included studies and median germline pathogenic/likely pathogenic (P/LP) variant detection rates stratified by hereditary cancer syndrome. Hereditary Cancer Syndrome Number of Studies Median P/LP Detection rate Breast &amp; Ovarian (HBOC) 87 14.8% Colorectal &amp; Polyposis 39 17.2% Pancreatic Cancer 22 15.2% Endometrial/Uterine 16 11.4% Others 45 13.3%

Early mortality and hospitalization following cholangiocarcinoma diagnosis by statin exposure: A TriNetX real-world analysis.

11195 Background: Statins are widely prescribed among patients with cardiometabolic comorbidities and are frequently continued at the time of cancer diagnosis. While statins have been hypothesized to exert antitumor and immunomodulatory effects, real-world data evaluating early clinical outcomes associated with statin exposure in patients with cholangiocarcinoma are limited. We assessed short-term mortality and hospitalization outcomes following cholangiocarcinoma diagnosis using a large federated electronic health record network. Methods: We conducted a retrospective cohort study using the TriNetX US Collaborative Network, comprising 68 healthcare organizations. Adult patients (≥18 years) diagnosed with intrahepatic bile duct carcinoma (ICD-10 C22.1), extrahepatic bile duct carcinoma (C24.0), or ampullary carcinoma (C24.1) between January 1, 2010, and December 11, 2024 were included. Patients were classified based on exposure to statins (rosuvastatin, simvastatin, fluvastatin, pravastatin, lovastatin, atorvastatin, or pitavastatin) within a prespecified temporal window relative to cancer diagnosis, with the index event defined accordingly. Propensity score matching (1:1) was performed to balance demographics, comorbidities, and laboratory characteristics, mitigating confounding by indication and immortal time bias. Outcomes included all-cause mortality, hospitalization, and sepsis at 30 and 90 days following the index event. Risk estimates and Kaplan–Meier survival analyses were performed. Results: After propensity score matching, baseline characteristics were well balanced between statin-exposed and non–statin-exposed cohorts. At 30 days following diagnosis, statin exposure was not associated with a significant difference in all-cause mortality. In contrast, at 90 days, statin exposure was associated with higher all-cause mortality (risk ratio 1.23; hazard ratio 1.30; log-rank P = .012) and increased hospitalization (risk ratio 1.29; hazard ratio 1.37). No significant differences in sepsis risk or hazard were observed between cohorts at either time point. Conclusions: In this real-world, propensity score–matched analysis of patients with cholangiocarcinoma, statin exposure was not associated with improved 30-day survival and was associated with higher 90-day mortality and hospitalization. Although causality cannot be inferred, these findings highlight clinically meaningful early outcome differences during the peri-diagnostic period and suggest that commonly prescribed cardiovascular medications may identify patients with increased baseline vulnerability at the time of cancer diagnosis. Future work integrating medication exposure with comorbidity burden, treatment patterns, and early care trajectories may help refine risk stratification during initial cholangiocarcinoma management.

Low-dose radiation therapy for peripheral joint osteoarthritis: Early U.S. community experience with pain, function, and medication outcomes.

e24051 Background: Osteoarthritis (OA) causes progressive pain and disability, yet non-surgical options are limited for patients who cannot tolerate long-term NSAIDs or opioids. European data suggest that low-dose radiotherapy (LDRT) may alleviate inflammatory pain, but U.S. outcomes remain largely unreported. This retrospective study evaluated pain, function, and medication trends following LDRT delivered in community oncology settings. Methods: Thirty patients (55 joints) with mild-to-moderate OA received LDRT (3 Gy in 6 fractions, 0.5 Gy/fraction) between 2023–2025. Pain was measured by the Numeric Rating Scale (NRS 0–10) and functional improvement by the von Pannewitz Score (VPS 0–4, lower = greater improvement). Analgesic use changes were recorded at 1–3 months post-therapy. The primary endpoint was change in NRS; secondary endpoints were ≥2-point or ≥30% NRS improvement, VPS ≤ 1, and reduction in analgesic use. Paired t-tests and descriptive statistics were applied (α = 0.05). Results: Mean baseline NRS 8.1 ± 1.4 improved to 3.5 ± 1.7 (Δ – 4.6; p &lt; 0.001). Twenty-five of 30 patients (83%) achieved a clinically meaningful NRS reduction (≥2 points or ≥30% improvement). Ninety-two percent of treated joints showed functional improvement (VPS ≤ 1). Twenty-three percent decreased analgesic use, and none required escalation. No acute or late toxicity occurred. Clinical response correlated with baseline pain intensity but not age or joint site. Conclusions: Community-based LDRT for peripheral joint OA was feasible, safe, and associated with significant, clinically meaningful reductions in pain and analgesic use. These findings parallel emerging randomized European data and support LDRT as a promising non-invasive adjunct for chronic OA pain. Prospective multicenter studies are warranted to confirm durability and optimize dose selection. Pain and analgesic outcomes following LDRT (n = 30 patients, 55 joints). Measure Baseline Follow-Up Change / Result NRS (0–10) 8.1 ± 1.4 3.5 ± 1.7 Δ – 4.6, p &lt; 0.001 ≥ 2-point NRS improvement (%) – 83 – VPS improved (%) – 92 – Analgesic use decreased (%) – 23 7 / 30 patients Analgesic escalation (%) – 0 None Values represent 1–3-month follow-up; significance by paired t-test.

Real-world experience with tarlatamab in extensive-stage small cell lung cancer at an academic center in Mississippi.

e20156 Background: Small cell lung cancer (SCLC) has poor outcomes, and patients from underserved rural and minority populations are underrepresented in clinical trials. Tarlatamab, a DLL3-directed bispecific T-cell engager approved in 2025 for previously treated extensive-stage SCLC, carries risks of CRS and ICANS; We report real-world safety and early outcomes in an underserved population. Methods: We conducted a retrospective chart review of patients with SCLC treated with Tarlatamab at a single academic center between May 2024 and January 2026. Data collected included demographics, geographic residence, prior therapies, treatment duration, radiographic response, survival outcomes, and treatment-related adverse events. Treatment was administered in a hospital-based outpatient setting. During cycle 1, patients were observed for 24 hours after day 1 and day 8 doses and 6–8 hours after day 15. CRS and ICANS were graded using standard criteria, including the Immune Effector Cell–Associated Encephalopathy (ICE) score. Results: Thirteen patients were identified; 12 were evaluable. Median age was 69.5 years (range, 56–80). Four patients (33%) were African American, five (41%) lived in rural counties, and nine (75%) were women. All had received ≥1 prior systemic therapy. ICANS occurred in 5 patients (50%; Grade 1, n = 2; Grade 2, n = 1; Grade 3, n = 2). CRS occurred in 5 patients (50%; Grade 1–2). All patients received dexamethasone premedication; those with ICANS required steroid escalation. Tocilizumab was given to 4 of 5 patients with CRS. No patients required ICU care; 2 required inpatient admission for Grade 2 ICANS. One patient died two weeks after cycle 1 day 15 from intracerebral seizures in the setting of progressive metastatic disease. Conclusions: In this real-world cohort from an underserved Southern state, Tarlatamab showed a manageable safety profile with meaningful representation of African American, rural, and female patients. Outpatient administration with structured monitoring was feasible, though vigilance for CRS and ICANS remains essential. These findings support broader evaluation in underrepresented populations. Remote monitoring strategies, including telemedicine and wearable devices, and expanded outreach and education for rural emergency departments, may improve early recognition and management of Tarlatamab-associated toxicities. Patient characteristics and outcomes. Parameter Value Total Patients 12 Median Age 69.5years Race Distribution African American: 4/12 (33%)White: 8/12 (67%) Median Distance from Treatment 40.85 miles (Range 12-91) ICANS Occurrence 5/12Grade 1: 2Grade 2: 1Grade 3: 2 CRS Occurrence 5/12 (Grade 1–2) ICANS Requiring Escalated Steroids 5/5 Tocilizumab for CRS 4/5 patients received one dose ICU Care Required 0/10 Required Inpatient Stay 2/12

Longer-term safety of pimicotinib in tenosynovial giant cell tumor (TGCT): Integrated analysis of phase 1 and phase 3 MANEUVER trial data.

11568 Background: TGCT is a rare, locally-aggressive neoplasm associated with significant morbidity and functional impairment. Colony-stimulating factor-1 receptor (CSF-1R) inhibitors are effective for unresectable TGCT, but current options may be limited by their long-term safety and tolerability. In the Phase 3 MANEUVER trial, pimicotinib (pimi), a highly-selective CSF-1R inhibitor, demonstrated robust tumor responses, clinically meaningful symptomatic and functional improvements, and a tolerable safety profile. This integrated analysis evaluated the longer-term safety of pimi from Phase 1 and 3 trials. Methods: Data for adult patients (pts) with TGCT treated with pimi 50 mg once daily from Phase 1 (NCT04192344, cut-off Dec 31, 2024) and Phase 3 (NCT05804045; MANEUVER, cut-off Mar 12, 2025) trials were pooled for an integrated safety analysis. The open-label Phase 1 study assessed safety, tolerability, and pharmacokinetics of pimi in advanced solid tumors. MANEUVER evaluated efficacy and safety of pimi in unresectable TGCT across a 24-week, double-blind, placebo-controlled phase; a 24-week open-label pimi treatment phase; and an ongoing long-term extension. All treatment-emergent adverse events (TEAEs) and adverse events of clinical interest (AECI) were analyzed and reported as frequencies. Results: In total, 158 pts were included; 65.8% were female and median age was 40.0 (range 18–76) years. Median pimi exposure was 385.5 days; 12.7% of pts had prior exposure to systemic therapy. TEAEs of any grade were reported by 99.4% of pts (Table); most pts reported a maximum grade of 1 (8.9%; n=14/158) or 2 (53.2%; n=84/158). The most reported AECI of any grade by pts were blood creatine phosphokinase (CPK) elevation (72.2%), aminotransferase elevation (59.5%), edema (excluding periorbital edema [POE]) (54.4%), rash (46.2%) and pruritus (43.0%); 20.9% reported fatigue. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The most common AECI leading to dose reduction were rash (5.1%) and edema (excluding POE) (3.2%); for dose interruption, blood CPK elevation (13.9%) and rash (13.3%) were most common. Most AECI resolved/improved following dose reduction or interruption. Treatment discontinuation due to AECI was rare (face edema, 0.6%; rash, 0.6%). Concomitant medication was most commonly used for rash (n=38/73), pruritus (n=31/68), and edema (n=22/86). Conclusions: Pimi showed sustained tolerability with no new safety signals, confirming a favorable safety profile in Phase 1 and 3 trials during extended treatment of &gt;1 year in a larger TGCT population. Clinical trial information: NCT04192344 ; NCT05804045 . Summary of TEAEs. TEAE Pts(N=158)n (%) Any 157 (99.4) Grade ≥3 59 (37.3) Serious 17 (10.8) DR serious 1 (0.6) Leading to dose reduction 33 (20.9) Leading to dose interruption 95 (60.1) Leading to discontinuation 8 (5.1) Resulting in death 1 (0.6) DR resulting in death 0 DR, drug related.

Chemotherapy (CT) use by Oncotype DX (O-Dx) recurrence score (RS) in hormone receptor–positive, HER2-negative (HR+/HER2-) invasive lobular carcinoma (ILC): A contemporary National Cancer Database (NCDB) analysis.

531 Background: ILC has a distinct biology and is considered less chemosensitive than invasive ductal carcinoma (IDC). O-Dx RS can guide adjuvant CT decisions for patients with HR+/HER2- breast cancer (BC); however, pivotal trials largely included patients with IDC. Patients with high RS have been shown to benefit from CT. Whether this genomic risk threshold is applied to patients with ILC in real-world practice is not well understood. We evaluated contemporary CT use by O-Dx RS and its association with overall survival (OS) in patients with ILC. Methods: Patients ≥18 years with HR+/HER2- ILC diagnosed from 2018-2022 who underwent surgery, had pT1-T3, pN0-N1 disease, and known O-Dx RS were identified in the NCDB. Baseline characteristics were compared by RS groups: 0-10 (low), 11-25 (intermediate), and &gt;25 (high). Multivariable logistic regression models identified factors associated with CT use in the overall cohort and stratified by RS. We evaluated the association between CT use and OS within each RS group, adjusting for covariates using propensity score matching (by year of diagnosis, age, pT, pN). Results: A total of 30,393 patients with early-stage HR+/HER2- ILC and O-Dx score were identified. Among them, 21% had low, 72% intermediate, and 7% high RS. Overall, 9.2% received CT, including 2.4% of those with low RS, 5.5% of intermediate RS, and 66% of high RS. CT use did not change over time (p=0.47). On multivariable analysis in all patients, higher RS was the key determinant of CT use (RS 11-25 vs 0-10: aOR=2.98, 95%CI 2.49-3.58; RS &gt;25 vs 0-10: aOR=333.4, 95%CI 266.8-416.7), while older age was associated with lower CT use (aOR=0.91, 95%CI 0.91-0.92). In multivariable models stratified by RS, clinicopathologic features, including younger age, larger tumor size, higher nodal stage, and higher grade, were associated with CT use in low and intermediate RS groups (i.e., pN1 aOR=18.64 for RS 0–10; aOR=7.37 for RS 11–25; both p&lt;0.001), whereas in high RS group, age had similar effect; however, tumor size and nodal status had significant but attenuated effects. In propensity-matched cohorts within RS groups, CT use was not associated with different OS in low RS (5-year OS 98% vs 100%, p=0.29) or intermediate RS (5-year OS 97% vs 97%, p=0.68) groups; however, in high RS group, CT use was associated with improved OS (5-year OS 96% vs 90%; p=0.01). Conclusions: In clinical practice, CT use in patients with ILC is guided by O-Dx RS but influenced by age and clinicopathologic risk. CT use conferred no OS benefit in patients with low or intermediate RS but was associated with OS benefit in high RS. Despite this, one-third of patients with ILC with high RS did not receive CT. These findings support RS-guided adjuvant CT decision-making in ILC and suggest that increasing CT use in patients with high RS may improve outcomes.

Transposable elements and homotypic niches as drivers of immune dynamics and resistance in melanoma epigenetic-based immunotherapy.

9531 Background: Melanoma plasticity facilitates immune evasion and therapy resistance through dynamic cell-state transitions. While epigenetic remodeling critically influences these processes, its role in reshaping the tumor ecosystem under therapeutic pressure remains unresolved. We investigated the molecular and spatial mechanisms underlying clinical response to epigenetic-based immunotherapy in the phase Ib NIBIT-M4 trial (NCT02608437), which evaluated the DNA methyltransferase inhibitor guadecitabine combined with the anti-CTLA4 antibody ipilimumab. Methods: We performed longitudinal single-cell multiome profiling (paired snRNA-seq and snATAC-seq) on tumor biopsies collected at baseline and during treatment (weeks 4 and 12) from five melanoma patients (two responders, three non-responders). To resolve the spatial architecture of cell states, we integrated these data with high-resolution spatial transcriptomics (Visium HD) across nine samples. Analyses focused on defining malignant meta-programs (MPs), tumor microenvironment (TME) remodeling, and the regulatory role of transposable elements (TEs). Results: Integrated analysis resolved seven malignant MPs. Responders exhibited progressive enrichment of an Antigen Presentation/Interferon program, coupled by coordinated TME remodeling with T- and B-cell expansion. Conversely, non-responders were enriched for a de-differentiated Neural crest-like state. Spatial modeling revealed that this resistant Neural crest-like program relies on homotypic clustering to form compact, centrally localized niches that stabilize its transcriptional identity. In contrast, Wnt/β-catenin subpopulations displayed a bimodal architecture, existing as either cohesive clusters or dispersed plastic cells. Epigenetic therapy reactivated TEs, which provided regulatory signals priming innate immunity and generated tumor-associated antigens that drove immunoediting in responders. Mechanistically, NFATC2 emerged as a master regulator of the Neural crest-like phenotype, and its inhibition promoted re-differentiation toward immunogenic states. Conclusions: Epigenetic-based immunotherapy dynamically reshapes the melanoma ecosystem by modulating TE activity and cell-state plasticity. Clinical response links to TE-driven immune priming, whereas resistance is maintained by spatially consolidated Neural crest-like niches stabilized by NFATC2. These findings identify spatial clustering as a principle of resistance and highlight NFATC2 as a potential therapeutic target.