e15030 Background: Interstitial lung disease (ILD) is a clinically relevant adverse event associated with trastuzumab-deruxtecan (T-DXd). Reported ILD incidence often does not account for competing clinical events, potentially leading to risk overestimation. In parallel, real-world data on patient- and treatment-related risk factors remain limited. We aimed to estimate the cumulative incidence of T-DXd–related ILD using a competing-risk approach and to identify clinical and inflammatory factors associated with increased risk. Methods: We retrospectively collected data from 406 patients with metastatic breast cancer (223 HER2-positive, 162 HER2-low; 21 missing data) treated with T-DXd between October 2024 and January 2026 in 16 Italian Institutions. Competing events included death without ILD and treatment discontinuation due to disease progression or other non-ILD causes. Cumulative incidence functions (CIF) were estimated for each event. For risk factor analysis, 74 candidate variables were evaluated, including 10 clinical characteristics, 20 prior treatment variables, 24 concomitant diseases and drugs, and 20 baseline inflammatory biomarkers. Gray’s test was used for univariable screening, followed by multivariable Fine–Gray regression. Results: Seventy-four patients (18.3%) developed T-DXd–related ILD, with a median time to onset of 5.5 months and a mean of 8.4 months. The CIF of first ILD was 14.5% at 10 months and 16.8% at 20 months, plateauing at 18.8% at 50 months. No significant differences in ILD incidence were observed between HER2-positive and HER2-low disease (Gray test p = 0.83). Disease progression was the most frequent competing event, affecting 47.3% of patients at 10 months and 73.3% at 50 months. In univariate analysis, higher continuous neutrophil-to-lymphocyte ratio (NLR), impaired renal clearance (CLcr), prior lung radiotherapy (RT), smoking, and visceral disease were associated with increased ILD risk, while prior Trastuzumab exposure was protective. No correlation was seen for concomitant disease and drugs. In multivariable analysis, reduced creatinine clearance (sHR 3.53, 95% CI 1.64–7.58; p = 0.001), prior lung radiotherapy (sHR 2.40, 95% CI 1.08–5.33; p = 0.032), and higher baseline neutrophil-to-lymphocyte ratio (sHR 1.14, 95% CI 1.05–1.24; p = 0.002) remained independently associated with increased ILD risk. Conclusions: In this multicenter real-world cohort, the cumulative incidence of T-DXd–related ILD was approximately 19%, accounting for competing risks. The high frequency of competing events underscores the importance of competing-risk methodology for accurate toxicity estimation. Baseline renal impairment, prior lung radiotherapy, and systemic inflammatory status identified patients at increased risk and may support risk-adapted monitoring and earlier clinical intervention during T-DXd treatment.

Endometrial cancer (EC) is a hormone-dependent malignancy whose global incidence is steadily rising. Increasing evidence suggests that exposure to endocrine-disrupting chemicals (EDCs) may contribute to EC development through interference with hormonal signaling mediated by estrogen receptors (ER). This systematic review aimed to synthesize the available epidemiological evidence on the association between exposure to EDCs and the risk of EC. A comprehensive search of MEDLINE, EMBASE, Scopus, the Cochrane Library, and ClinicalTrials.gov was conducted up to April 2025, following PRISMA 2020 recommendations. Eligible studies included observational or interventional designs assessing quantified exposure to EDCs and EC incidence or risk. Eight studies met the inclusion criteria (five case-control, two cohort, and one randomized controlled trial), comprising 2, 609 EC cases and 1, 577 controls. Cadmium emerged as the EDC most frequently associated with EC, reported in five studies, four of which demonstrated a significant positive association, particularly among lean postmenopausal women. In contrast, evidence regarding bisphenol A (BPA) and its metabolites was inconsistent: only mono-n-butyl phthalate (MnBP) showed a positive correlation with EC in one study, while BPA and dibutyl phthalate (DBP) did not. Nonylphenol and octylphenol were also found to be positively associated with EC risk in a single study. Conversely, neither lead exposure nor dietary intake of isoflavones was associated with EC incidence. Overall, available epidemiological evidence supports a potential association between cadmium exposure and increased EC risk, while data for other EDCs remain limited and inconclusive. Substantial heterogeneity in exposure assessment, study design, and confounder adjustment limits comparability across studies and precludes definitive conclusions. Further well-designed longitudinal studies with standardized and repeated exposure measurements are needed to clarify causal relationships between EDC exposure and endometrial carcinogenesis.Systematic Review Registrationhttps://inplasy.com/inplasy-2025-6-0030/, identifier INPLASY202560030.

ABSTRACT:Immune checkpoint inhibitors (ICIs) have successfully revolutionized cancer therapy, but their immune-mediated adverse events include rare, often severe myocarditis. Although dual ICI blockade is associated with increased cardiotoxic risk, little is known about the potential effects of triplet combinations currently under clinical investigation. We developed a coculture model of human cardiomyocytes and human peripheral blood mononuclear cells (hPBMCs) to evaluate immune-mediated cytotoxicity induced by ICIs. HFCs were exposed for 48h to nivolumab plus relatlimab, ipilimumab, or atezolizumab, either alone or in triplet combinations. Cell lysis was quantified by LDH release. Cytokine secretion (IL-2, granzyme B, and additional inflammatory mediators including NLRP3 activation pathway) was measured by ELISA. Digital microscopy was used for morphological assessment. Triplet combinations of nivolumab-relatlimab with ipilimumab or atezolizumab induced significantly higher cardiomyocyte lysis than single agents or doublets ( P < 0.001). This effect correlated with a robust increase in IL-2 and granzyme B secretion, and activation of proinflammatory cytokines and NLRP3 inflammasome-related mediators. Microscopic analyses confirmed immune cell activation and reduced density of HFCs exposed to triplets. Our findings demonstrate that ICI triplets elicit potent immune activation against cardiomyocytes, providing the first preclinical evidence of direct cardiotoxic potential in this setting. These results highlight the need for enhanced clinical surveillance and cardio-oncology monitoring in patients receiving triple ICI combinations, because these regimens expand in clinical practice.

1091 Background: Activating PIK3CA mutations occur in approximately 40% of hormone receptor–positive (HR+)/HER2-negative breast cancers and drive resistance to endocrine therapy. The PI3Kα-selective inhibitor alpelisib combined with fulvestrant significantly improves progression-free survival, as demonstrated in the SOLAR-1 trial, but its clinical benefit is limited by frequent treatment-induced hyperglycemia. Beyond metabolic toxicity, hyperglycemia promotes oxidative stress, inflammation, and mitochondrial dysfunction, thereby increasing cardiovascular vulnerability and potentially reactivating oncogenic PI3K/AKT signaling through compensatory hyperinsulinemia. Retrospective clinical evidence suggests that sodium–glucose cotransporter-2 (SGLT2) inhibitors may mitigate these effects. We investigated the direct redox-dependent cardiotoxic effects of alpelisib and fulvestrant under hyperglycemic conditions and evaluated whether dapagliflozin confers cardioprotection in human cardiomyocytes. Methods: Human iPSC-derived cardiomyocytes were exposed to alpelisib and fulvestrant under hyperglycemic conditions (25 mM glucose) in the absence or presence of dapagliflozin. Cell viability (MTS), mitochondrial membrane potential, reactive oxygen species generation, lipid peroxidation (MDA and 4-HNE), intracellular antioxidant defenses (GSH/GSSG, SOD, catalase/GPx), inflammatory and inflammasome-related mediators (IL-1β, IL-18, IL-6, TNF-α, NLRP3, MyD88), and apoptotic signaling (caspase-3/7 activity) were quantified. Cardiac injury was assessed by high-sensitivity cardiac troponin I and T release. Transcriptomic profiling was performed to interrogate cardiometabolic and redox signaling pathways. Results: Alpelisib and fulvestrant synergistically induced a pro-oxidative and pro-inflammatory injury phenotype characterized by mitochondrial depolarization, increased ROS and lipid peroxidation, depletion of antioxidant defenses, activation of the NLRP3/IL-1 axis, and caspase-dependent apoptosis. Dapagliflozin markedly restored redox homeostasis, preserved mitochondrial integrity, suppressed inflammasome and cytokine signaling, and reduced troponin release, indicating robust cardioprotection. Transcriptomic analysis confirmed coordinated downregulation of oxidative stress, inflammatory, and insulin-stress pathways. Conclusions: Dapagliflozin directly protects human cardiomyocytes from hyperglycemia-driven, PI3Kα inhibitor–associated oxidative injury by restoring redox and mitochondrial homeostasis. These findings provide a strong mechanistic rationale for repurposing SGLT2 inhibitors as dual cardio-metabolic protectants in precision oncology.

Urothelial carcinoma predominantly affects older patients, who often exhibit frailty, comorbidities, renal impairment, and reduced physiological reserve. We evaluated overall survival (OS) and progression-free survival (PFS) with first-line immune-based strategies in patients aged ≥65 years with advanced or metastatic urothelial carcinoma. The aim was to characterize treatment effects within this age-defined subgroup, not to determine whether age modifies treatment efficacy compared with younger patients. Methods: We conducted a systematic review and meta-analysis of phase 3 randomized trials published from January 2015 to May 2026 reporting age-specific survival outcomes. Combination regimens were compared with platinum-based chemotherapy using random-effects models. Results: Combination strategies improved OS versus chemotherapy (HR 0.79, 95% CI 0.64–0.96), although heterogeneity was substantial (I2 = 69.7%) and the prediction interval crossed the null (0.48–1.27). Class-specific HRs were 0.56 (95% CI 0.26–1.20) for ADC plus ICI, 0.85 (0.77–0.95) for ICI plus chemotherapy, and 0.91 (0.34–2.42) for dual-checkpoint inhibition. PFS favoured experimental treatment but remained imprecise (HR 0.54, 95% CI 0.27–1.08; I2 = 89.5%). Excluding ADC plus ICI trials attenuated the OS effect (HR 0.88, 95% CI 0.80–0.96), indicating that the pooled estimate was influenced by these trials. ICI monotherapy did not improve OS. Conclusions: First-line immune-based combinations improved survival in selected patients aged ≥65 years, but benefit varied across treatment classes and should not be considered uniform across regimens. These findings do not establish whether age modifies treatment efficacy. Age-specific safety data were insufficient to define the benefit–risk profile of individual strategies.

Immune checkpoint inhibitors (ICIs) have transformed the therapeutic landscape of oncology but are increasingly associated with cardiovascular immune-related adverse events (irAEs), including myocarditis, heart failure, arrhythmias, and vascular complications. Among these, ICI-associated myocarditis represents the most severe manifestation, often characterized by high mortality and challenging early diagnosis. Detecting subclinical myocardial injury before irreversible cardiomyocyte necrosis occurs remains a major unmet need in contemporary cardio-oncology. This narrative expert review critically examines the biological rationale, preclinical evidence, and emerging clinical data supporting the potential role of heart-type fatty acid-binding protein (H-FABP) as an adjunctive biomarker of early immune-mediated myocardial injury during ICI therapy. H-FABP is a small cytosolic lipid chaperone abundantly expressed in cardiomyocytes and rapidly released into the circulation following subtle membrane destabilization and metabolic stress, frequently preceding detectable troponin elevation in other forms of myocardial injury. Experimental studies support a mechanistic association between H-FABP release, inflammasome activation, cytokine amplification, mitochondrial dysfunction, and immune-metabolic cardiomyocyte stress. Preliminary clinical observations further suggest that H-FABP elevations may occur during ICI treatment even in the absence of overt myocarditis or concomitant increases in high-sensitivity cardiac troponins (hs-cTns). Although H-FABP cannot replace hs-cTn, which remains the cornerstone biomarker for the diagnosis of clinically significant ICI-associated myocarditis, its rapid kinetics and sensitivity to early metabolic membrane injury support its potential role as an investigational adjunctive biomarker for early surveillance and risk stratification. This approach may be particularly relevant in patients receiving high-risk combination ICI regimens or in individuals with pre-existing cardiovascular disease. However, current evidence remains limited, and large prospective multicenter studies integrating H-FABP with hs-cTns, natriuretic peptides, cardiac magnetic resonance imaging, and clinical outcomes are required before routine clinical implementation can be considered.

Background: Polyploid and chromosomal copy number gains (CNGs) cells may serve as key mediators of tumor plasticity, therapeutic resistance, and clonal evolution. Despite growing interest, their biological and clinical relevance in colorectal cancer, particularly in the metastatic setting, remains poorly defined. Methods: We performed an integrated morphological, cytogenetic, and genomic analysis of metastatic colon cancer. A tissue microarray comprising 100 tumors was evaluated, of which 47 cases were fully assessable for morphology and fluorescence in situ hybridization (FISH). Polyploid nuclei and chromosomal CNGs were assessed morphologically and cytogenetically. High-resolution targeted sequencing (TruSight Oncology 500) was conducted to characterize genomic alterations. Bioinformatic analyses included Gene Ontology enrichment and Phenolyzer network modeling. Associations with clinicopathological variables and survival outcomes were explored. Results: Polyploid nuclei and/or chromosomal CNGs were identified in approximately 25% of evaluable cases. These alterations were enriched in right-sided CRCs and in older patients, suggesting a link with age-related genomic instability. Polyploid/CNG tumors did not show significant enrichment for canonical CRC driver mutations (RAS, TP53, SMAD4), although trends toward co-occurrence with BRAF mutation and mutual exclusivity with HER2 amplification were observed. Integrative bioinformatic analyses highlighted dysregulation of pathways involved in mitotic control, centrosome organization, and DNA replication stress. Conclusions: In metastatic colon cancer, the presence of genome-wide copy number gain may delineate a tumor subset with distinctive clinicopathological and molecular characteristics. Further studies are warranted to elucidate the biological significance of these features and to explore their potential implications for tumor evolution, treatment response, and clinical stratification.

Hormone receptor–positive breast cancer (HR+ BC) represents the most common breast cancer subtype and is increasingly characterized by long-term survivorship complicated by substantial cardiometabolic and cardiovascular morbidity. Endocrine therapies, including aromatase inhibitors, selective estrogen receptor modulators and degraders, and ovarian suppression, remain central to disease control but promote metabolic dysfunction, vascular injury, and systemic inflammation, thereby increasing cardiovascular disease (CVD) risk and potentially contributing to endocrine resistance. These alterations are also associated with adverse changes in adipose tissue distribution, increased visceral fat accumulation, and dysregulated lipid metabolism, further amplifying cardiometabolic risk. Consequently, CVD has emerged as a leading cause of non-cancer mortality among breast cancer survivor. We performed a comprehensive narrative review of mechanistic, preclinical, and clinical evidence evaluating the cardiometabolic and oncologic effects of sodium–glucose cotransporter 2 inhibitors (SGLT2i) in the context of breast cancer and cardio-oncology. Literature from experimental models, observational and real-world studies was synthesized to delineate the biological pathways through which SGLT2i may influence cardiovascular risk, metabolic health, and endocrine therapy resistance in HR + BC. SGLT2 inhibitors, originally developed as glucose-lowering agents, confer robust cardiovascular and renal protection that extends beyond glycemic control. Emerging evidence indicates that SGLT2i modulate key biological pathways relevant to HR+ BC survivorship, including insulin–IGF-1 signaling, PI3K–Akt–mTOR and AMPK pathways, adipose tissue inflammation, hepatic steatosis, endothelial dysfunction, myocardial energetics, and systemic inflammatory tone. In addition, SGLT2i promote favorable adipose tissue remodeling, with preferential reduction in visceral adiposity and improvement in adipokine profiles, and induce lipid metabolism reprogramming characterized by enhanced fatty acid oxidation and reduced hepatic lipogenesis, contributing to improved cardiometabolic homeostasis. Observational and propensity-matched studies in oncology populations associate SGLT2i use with reduced incidence of heart failure, attenuation of cancer therapy–related cardiac dysfunction, and improved cardiovascular outcomes, including in breast cancer survivors exposed to cardiotoxic therapies. Beyond cardiovascular protection, converging data suggest that SGLT2i may indirectly mitigate or delay resistance to endocrine therapy by suppressing hyperinsulinemia-driven growth signaling, remodeling adipokine and inflammatory networks, and altering tumor–host metabolic interactions. SGLT2 inhibition represents a promising systems-level strategy at the intersection of cardio-oncology, metabolism, and endocrine resistance in HR+ breast cancer. By simultaneously targeting glucose homeostasis, adipose tissue dysfunction, and lipid metabolism, SGLT2i may improve both cardiovascular outcomes and long-term cancer control. Dedicated prospective trials are urgently needed to define their clinical role in breast cancer survivorship and precision cardio-oncology.

e20602 Background: Immune checkpoint inhibitors (ICIs) have transformed the management of solid tumors, particularly non–small cell lung cancer (NSCLC), yet durable benefit is achieved only in a subset of patients. The gut microbiota is a key modulator of antitumor immunity, and systemic antibiotic therapy (ABT), frequently prescribed in oncology, can disrupt microbial homeostasis. Observational studies suggest that ABT may impair ICI efficacy, but results remain heterogeneous, warranting an updated synthesis with tumor-specific analyses. Methods: We conducted a systematic review and meta-analysis according to PRISMA 2020 guidelines. PubMed, Scopus, and EMBASE were searched for studies published between 2018 and 2025 evaluating the association between ABT exposure and time-to-event outcomes in patients with solid tumors treated with ICIs. Eligible studies reported a clearly defined ABT exposure window. Random-effects models were considered primary. A pre-specified sensitivity analysis focused on NSCLC, the largest and most methodologically homogeneous subgroup. Results: Fifteen studies encompassing 52,489 patients were included. Overall, ABT exposure was associated with worse overall survival (OS; random-effects HR 1.16, 95% CI 1.03–1.29) and numerically inferior progression-free survival (PFS; random-effects HR 1.11, 95% CI 0.95–1.27).In the NSCLC sensitivity analysis, 45,896 patients were analyzed. For OS, moderate heterogeneity was observed (I² = 51%), with a pooled fixed-effect HR of 1.05 (95% CI 0.996–1.11), indicating a consistent trend toward worse survival with ABT exposure. For PFS, no heterogeneity was detected (I² = 0%), and ABT exposure was associated with a significantly increased risk of disease progression (HR 1.16, 95% CI 1.02–1.30), with concordant fixed- and random-effects estimates. Conclusions: ABT administered in temporal proximity to ICIs is associated with inferior survival outcomes, with particularly robust and consistent evidence for worsened PFS in NSCLC. These findings support a microbiome-mediated impairment of immunotherapy efficacy and underscore the importance of cautious ABT stewardship in patients with NSCLC receiving ICIs. Prospective studies integrating microbiome profiling and standardized ABT exposure definitions are warranted.

Patients with solid tumors receiving systemic anticancer therapy face an increased risk of herpes zoster (HZ), a complication that can delay or disrupt ongoing oncologic treatments. Although the recombinant zoster vaccine (RZV) is recommended for immunocompromised adults, real-world data on its implementation and tolerability during active cancer treatment settings remain limited. We conducted a retrospective, single-center observational study at the Oncology Department of the "G. Martino" University Hospital, Messina, Italy. Between July 2022 and January 2025, the standard two-dose RZV schedule was systematically offered to adult patients with solid tumors who were receiving or scheduled to start systemic therapies. Endpoints included the operational feasibility of vaccination during oncologic care, safety, and HZ occurrence during follow-up. Overall, 42 patients received at least one RZV dose, and 37 (88.1%) completed the two-dose schedule. Patients were receiving different systemic anticancer treatments, mainly chemotherapy (59.5%), followed by chemo-immunotherapy and immunotherapy. RZV showed a favorable safety profile. Injection-site pain was the most frequently reported local adverse event, while systemic reactions, including fever and headache, were mild and transient. No severe vaccine-related adverse events or delays in oncologic treatment were observed. After a median follow-up of 11.5 months, no clinically documented HZ episodes occurred, although this finding should be interpreted descriptively given the limited sample size. Our experience suggests that integrating RZV into routine outpatient oncology workflows is feasible and well tolerated in patients undergoing active systemic treatments.

BACKGROUND Hepatocellular carcinoma (HCC) is the most common primary liver malignancy. It typically develops in patients with advanced chronic liver disease and only rarely occurs during pregnancy. CASE SUMMARY We report the case of a 46-year-old woman with HBeAg-negative chronic hepatitis B virus (HBV) infection, persistently low HBV DNA levels, and normal aminotransferase values, who developed HCC in a non-cirrhotic liver during a pregnancy achieved through assisted reproduction techniques. Antiviral therapy with Entecavir was initiated shortly before conception because of an increase in HBV DNA levels and was subsequently switched to Tenofovir during pregnancy. Despite a spontaneous miscarriage, alpha-fetoprotein levels continued to rise, prompting magnetic resonance imaging, which revealed a solitary hepatic nodule measuring 18 mm. The patient underwent hepatic resection, and histological examination confirmed a moderately differentiated HCC. Despite complete surgical resection, two early recurrences occurred within 15 months. Tumour and non-tumour liver tissues were collected intra-operatively, snap-frozen, and processed for molecular analyses to assess total HBV DNA, covalently closed circular DNA and HBV RNA levels. CONCLUSION HBV infection and pregnancy-related immunological imbalance may contribute to HCC development, underscoring the need for careful surveillance in HBsAg-positive women.

Aim: The aim of this study is to investigate the molecular and functional features underlying the clinical heterogeneity between oligometastatic (OM) and polymetastatic (PM) colon cancer. Methods: We performed a genotype-phenotype analysis in a homogeneous cohort of 127 patients with metastatic colon cancer (mCC) profiled using the same next-generation sequencing platform (TruSight Oncology® 500). OM disease was defined as the presence of one to three metastatic lesions per involved organ, involving no more than two organs overall, with all lesions measuring < 70 mm in maximum diameter and no single lesion > 25 mm. Molecular alterations, microsatellite instability (MSI), tumor mutational burden (TMB), and overall survival (OS) were analyzed. Gene Ontology (GO) enrichment and Phenolyzer network analyses were applied to explore functional differences between prognostically distinct molecular subgroups. Results: OM patients showed a striking survival advantage compared with PM patients [median OS not reached versus 29 months; hazard ratio (HR): 0.20, P < 0.0001], validating the clinical distinction between the two phenotypes. PM disease was significantly enriched for RAS mutations, whereas OM disease was associated with MSI-high status and elevated TMB. Canonical driver alterations were largely shared between groups, and Phenolyzer analysis revealed similar core oncogenic networks centered on adenomatous polyposis coli (APC), tumor protein p53 (TP53), and epidermal growth factor receptor (EGFR). In contrast, GO analysis demonstrated selective enrichment in PM tumors for molecular functions related to ATP binding, nucleotide binding, and protein kinase activity, consistent with enhanced bioenergetic demand and signaling intensity. Conclusions: These findings support refined biological stratification of mCC and the exploration of personalized, metastasis-directed strategies, potentially incorporating immunological modulation in OM disease.