Citations

Abstract Background: The limited efficacy of oncolytic virotherapy (OV) in gastrointestinal malignancies has been attributed to an immunologically inert tumor microenvironment. While cisplatin is widely used as a cytotoxic agent, its immunomodulatory effects remain incompletely defined. We hypothesized that cisplatin may reprogram the tumor immune landscape to enable more effective OV-mediated anti-tumor responses. Methods: We evaluated the effects of cisplatin in combination with two distinct oncolytic platforms, vesicular stomatitis virus (VSV) and adenovirus (AdV), across both in vitro and in vivo colorectal cancer models. In vivo efficacy was assessed using MC38 subcutaneous and peritoneal metastatic models, with analysis of tumor growth, survival, and toxicity. Immune profiling was performed using single-cell RNA sequencing (scRNA-seq), flow cytometry, and bulk RNA sequencing to interrogate changes in CD8+ T cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Cisplatin markedly enhanced OV-mediated anti-tumor efficacy across models, resulting in sustained tumor control and improved survival in both subcutaneous and peritoneal disease settings. This effect was conserved across viral platforms, indicating a virus-agnostic interaction. Mechanistically, cisplatin induced a robust interferon (IFN)–dominant transcriptional program, characterized by upregulation of interferon-stimulated genes, including IRF7, IRF9, and ISG15. Single-cell analysis revealed that combination therapy reshaped the CD8+ T cell compartment, promoting the expansion of a population with transcriptional and functional features of central memory T cells (Tcm), alongside reduced exhaustion signatures. These changes were accompanied by enhanced cytokine signaling pathways associated with T cell maintenance and function, including IL-2, IL-7, and IL-15. In vitro, the combination of cisplatin and OV increased tumor cell death and interferon-γ production, supporting a model in which cytotoxic and immunostimulatory effects are mechanistically linked. A phase I clinical trial has been initiated. In gastric cancer, patients with retroperitoneal metastases are being treated with OV in combination with PD-1 blockade (ongoing). In colorectal cancer, the strategy is being evaluated in the neoadjuvant setting with an rectal preservation approach. Conclusions: Our findings identify a previously unrecognized role for cisplatin in priming an interferon-driven immune program that promotes Tcm differentiation and function, thereby enabling durable responses to oncolytic virotherapy. This work provides a mechanistic rationale for leveraging chemotherapy-induced immune reprogramming to enhance viro-immunotherapy and supports the clinical translation of this strategy in gastrointestinal malignancies. Citation Format: Joseph Brandon. Parker, Zhongyi Dong, Tao Liu, Qisen Guo, Haoyu Zhang, Bo Ni, Long Bai, Yiwen Chen, Jiasheng Zong, Xiang Xia, Jiaojiao Zheng, Hoang Tran Pham, Aya Elalfy, Demarcus Ingram, Ahmed Abdel-Hakeem, Muhammad Ali, Shannon Hartzell, Zizhen Zhang, Vivienne Yang. Cisplatin primes an interferon-driven CD8+ central memory T cell program to enable oncolytic virotherapy in gastrointestinal cancer malignancies [abstract]. In: Proceedings of AACR Drug Discovery and Development (AACR D3) Conference; 2026 Jul 21-24; Boston, MA. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(14_Suppl):Abstract nr B024.

Abstract Aims Nutritional counselling is a core component of cardiac rehabilitation (CR), yet the evidence base for specific dietary interventions within CR remains fragmented. This scoping review aimed to map the range of nutritional interventions evaluated in adult CR programmes, characterize their reported outcomes, and identify key gaps in current evidence and practice. Methods and results Following the Arksey and O’Malley framework and reporting according to PRISMA-ScR, a systematic search of PubMed, Embase, Web of Science, and Cochrane Library was conducted from inception to June 2026. Eligible studies included randomized controlled trials, non-randomized trials, and observational studies evaluating an explicitly described nutritional intervention within a structured CR programme in adults with established cardiovascular disease. Of 2765 identified records, 35 studies met eligibility criteria. Interventions spanned Mediterranean and heart-healthy dietary patterns, calorie-restriction and weight-loss programmes, comprehensive lifestyle interventions, structured nutrition education and counselling, supplementation, functional foods, and individualized diet prescriptions. Across categories, improvements in body weight, central adiposity, and adherence to cardioprotective dietary recommendations were commonly reported, particularly when nutrition was delivered with repeated contact and individualized support. Effects on lipid profiles, inflammatory markers, blood pressure, functional capacity, and clinical outcomes were more variable. Conclusion Nutritional interventions within CR were most consistently associated with improvements in intermediate behavioural, anthropometric, and cardiometabolic outcomes, particularly when structured and reinforced over time. However, heterogeneity in study design, intervention delivery, comparator groups, outcome reporting, and follow-up duration precludes definitive conclusions about comparative efficacy, optimal intervention format, or the magnitude of benefit. Greater standardization, longer follow-up, and further evaluation of personalized nutritional strategies are needed to strengthen the nutritional component of CR.

ABSTRACT Background In patients with atrial fibrillation (AF) and heart failure with reduced ejection fraction (HFrEF), atrioventricular node ablation (AVNA) and permanent pacing are often pursued when rhythm control is not pursued. Biventricular pacing (BiVP) has demonstrated benefits over right ventricular pacing, while conduction system pacing (CSP) has emerged as an alternative. However, evidence directly comparing CSP with BiVP in this high‐risk population remains inconsistent. Objective To compare CSP versus BiVP in patients with AF and HFrEF undergoing AVNA, focusing on cardiac function, clinical outcomes, and procedural metrics. Methods Following PRISMA guidelines, we searched PubMed, Scopus, and Web of Science through February 2026 for studies comparing CSP and BiVP in adults with AF and HFrEF undergoing AVNA. Outcomes included all‐cause mortality, heart failure hospitalization (HFH), changes in left ventricular ejection fraction (LVEF), QRS duration, New York Heart Association (NYHA) class, pacing threshold, procedure duration, and fluoroscopy duration. A random‐effects model was used to pool mean differences (MDs) or risk ratios (RRs) with 95% confidence intervals (CIs). Results Six studies (one randomized crossover trial and five observational studies; N = 766 patients: CSP = 356, BiVP = 410) were included. All‐cause mortality was significantly reduced in favor of CSP (RR 0.64 [CI: 0.44 to 0.94], p = 0.02, I 2 = 0%). There was also a trend towards lower HFH, but it marginally missed statistical significance (RR 0.77 [CI: 0.58 to 1.03], p = 0.08; I 2 = 0%). Additionally, CSP decreased NYHA class (MD ‐0.64 [CI: −1.18 to −0.10], p = 0.02; I 2 = 85%) and significantly reduced QRS duration (MD −33.56 ms [CI: −52.36 to −14.76], p = 0.0005; I 2 = 97%). LVEF improvement did not significantly differ between groups (MD 4.51% [95% CI: −1.50 to 10.52], p = 0.14; I 2 = 98%). Procedure duration and fluoroscopy times did not show statistically significant difference between the two groups (MD −11.54 min [CI: −50.05 to 26.97], p = 0.56, I 2 = 96%), and (MD −5.75 min [CI: −13.13 to 1.63], p = 0.13, I 2 = 88%), respectively. Overall pacing thresholds did not significantly differ between CSP and BiVP; however, modality‐specific subgroup analysis showed comparable thresholds between HBP and BiVP, whereas LBBP was associated with significantly lower pacing thresholds than BiVP. Conclusions Among patients with AF and HFrEF undergoing AVNA, CSP may offer symptomatic and electrocardiographic advantages over BiVP, with a possible signal toward improved major clinical outcomes that requires confirmation in larger randomized studies.

e14545 Background: Durable antitumor immunity depends on the maintenance of stem-like CD8⁺ T cells capable of sustaining long-term effector responses. Oncolytic viruses (OVs) are potent immunomodulatory agents that reshape the tumor microenvironment and augment antitumor immunity. We hypothesized that platinum-based chemotherapy alters tumor-intrinsic type I interferon (IFN-I) signaling in a manner that can be functionally restored by OV therapy, thereby promoting the generation and persistence of stem-like CD8⁺ T cells. Methods: Tumor cells treated with platinum chemotherapy were evaluated in vitro for changes in IFN-I pathway activity, OV replication, and markers of immunogenic cell death (ICD). Syngeneic mouse tumor models were used to assess antitumor efficacy and immune remodeling following combination therapy. Tumor-infiltrating lymphocytes were analyzed by single-cell RNA sequencing and multiparameter flow cytometry to define CD8⁺ T-cell states and functional programs. Guided by these preclinical findings, a clinical trial combining XELOX, PD-1 blockade, and OV therapy was initiated (ChiCTR2500107607). Results: Platinum chemotherapy significantly suppressed tumor-intrinsic IFN-I signaling, while OV therapy restored antiviral responses, enhanced viral replication, and increased ICD in vitro. In vivo, the combination strategy resulted in superior tumor control and profound remodeling of the tumor immune microenvironment. The most pronounced immunologic effect was observed within the stem-like CD8⁺ T-cell compartment. Combination therapy induced a distinct population of TCF7⁺ ISG15^high NFATC1^low AP-1^low CD8⁺ T cells, characterized by restrained activation, enhanced persistence, and reduced propensity toward terminal exhaustion. In IRF7-deficient tumors, this stem-like CD8⁺ T-cell population failed to emerge and antitumor efficacy was significantly diminished, indicating that moderate tumor-intrinsic IFN-I signaling is required for this immune state. Conclusions: Tumor-intrinsic type I interferon signaling is a critical determinant of synergy between platinum chemotherapy and oncolytic virotherapy, enabling the maintenance of durable stem-like CD8⁺ T-cell immunity. These findings establish a mechanistic rationale for combining platinum chemotherapy, oncolytic viruses, and immune checkpoint blockade and support ongoing clinical translation. Clinical trial information: ChiCTR2500107607.

4235 Background: Malignant portal vein tumor thrombus (PVTT) arising from hepatic metastases is associated with poor prognosis, rapid hepatic decompensation, and limited effective local treatment options despite systemic therapy. In real-world practice, local treatment intensity is frequently adapted to disease burden and treatment response. We evaluated outcomes of a risk-adapted, step-up local treatment strategy using microwave ablation (MWA) alone or in combination with iodine-125 (I-125) seed implantation for patients with malignant PVTT. Methods: We retrospectively reviewed patients with hepatic metastases treated with MWA with or without I-125 seed implantation between 2023 and July 2025. In clinical practice, MWA alone was preferentially used for patients with relatively limited disease burden, while MWA plus I-125 was employed as an escalation strategy for patients with more advanced PVTT or disease progression following MWA alone. The primary endpoint was PVTT-directed local outcome, defined as portal vein patency and/or local control of tumor thrombus on follow-up imaging. Secondary endpoints included progression-free survival (PFS), overall survival (OS), hepatic function changes, and treatment-related toxicity. Survival analyses were considered exploratory. Results: A total of 73 patients were included, of whom 50 were treated with MWA alone and 23 with MWA plus I-125 seed implantation. Patients receiving MWA plus I-125 demonstrated more advanced disease characteristics, including universal presence of PVTT and higher disease stage, consistent with treatment escalation by disease severity. Among patients with PVTT, MWA plus I-125 achieved portal vein patency and/or local control in 65% at first follow-up imaging. Treatment-related toxicities were manageable, with no unexpected grade ≥3 adverse events attributable to I-125 implantation. Median PFS was 11.5 months in patients treated with MWA alone and 9.9 months in patients treated with MWA plus I-125, consistent with greater baseline disease burden in the latter group. Conclusions: MWA alone and MWA plus I-125 function as complementary components of a risk-adapted, step-up local treatment strategy for malignant PVTT from hepatic metastases. Escalation to MWA plus I-125 appears feasible in patients with advanced or refractory PVTT and demonstrates a potential signal for improved PVTT-directed local control and portal vein patency. Prospective studies focused on PVTT-specific endpoints are warranted.

ABSTRACT Background The optimal long‐term antithrombotic strategy after apparently successful catheter ablation of atrial fibrillation (AF) remains uncertain, particularly in patients who meet conventional guideline thresholds for oral anticoagulation (OAC). Objectives To compare continuation versus cessation strategies of long‐term OAC after successful AF ablation and to quantify net clinical benefit (NCB) integrating thromboembolic and bleeding outcomes. Methods We searched PubMed, Cochrane CENTRAL, and Embase from inception through February 2026 for randomized and comparative observational studies evaluating long‐term OAC continuation versus cessation (no OAC and/or switch to aspirin) after successful AF ablation. Risk of bias was assessed using RoB2 for randomized trials and a modified Newcastle–Ottawa Scale (NOS) for observational studies. Random‐effects meta‐analyses used a restricted maximum likelihood estimator with Hartung–Knapp adjustment. NCB was calculated as: thromboembolic event rate − (1.5 × major bleeding rate). Results Six studies met the inclusion criteria (four randomized trials and two observational cohorts). Stroke/transient ischemic attack (TIA) events were reported in six studies and were not significantly different between OAC continuation and cessation strategies (OR 0.69; 95% CI 0.24–1.99; p = 0.49). Systemic embolism (three studies) did not differ between groups ( p = 0.12). Major bleeding (five studies) was numerically higher with continued OAC but not statistically significant (OR 2.07; 95% CI 0.88–4.86; p = 0.09). In NCB analysis, continued OAC yielded more negative or near‐neutral NCB values, whereas, the cessation strategies were less negative or marginally positive; the fixed‐effect risk difference in NCB (continued OAC vs cessation) was +0.00067 (95% CI −0.00279 to +0.00413). Conclusion This meta‐analysis suggests that after successful AF ablation, continuing OAC does not significantly reduce stroke risk compared to cessation or switching to aspirin, but it may increase major bleeding. While NCB trends favor cessation, the low absolute event rates and the risk of silent AF recurrence necessitate caution.

Abstract Background Cancer therapies have prolonged survival in lymphoma. However, lymphoma patients may develop significant coronary artery disease (CAD), which may be treated by percutaneous coronary intervention (PCI). The characteristics and outcomes of lymphoma patients treated by PCI are not well studied. Methods We reviewed lymphoma patients undergoing PCI at our institution between 2010 and 2020 and compared them to a cohort without cancer. Patient characteristics and predictors of long-term mortality and major adverse cardiac events (MACE) (death, myocardial infarction, target lesion revascularization) were studied using descriptive statistics and survival analysis utilizing a Cox proportional hazards model. Results Of the 11,953 patients in the study cohort, 83 had a history of lymphoma meeting study criteria. Lymphoma patients, as compared to non-lymphoma patients were similar with respect to age, sex, hypertension, diabetes, hyperlipidemia, prior MI, and prior PCI (all p=ns). Over a median follow-up of 3.9 (1.0, 5.0) years, the mortality at 5 years was higher in lymphoma versus non-lymphoma patients (47.5% vs 29.8%) (P=0.005) (Figure). After adjusting for age, sex, hypertension, diabetes, shock, smoking status, heart failure, and chronic renal disease, lymphoma was an independent predictor of mortality (OR 1.59; 95% CI 1.07-2.36, p=0.02). Lymphoma was not independently associated with MACE. Discussion Lymphoma patients undergoing PCI have significantly lower survival rates than non-cancer controls. After accounting for important cardiac risk factors, lymphoma was independently associated with higher long term mortality.

Babesiosis and Lyme disease are tick-borne infections endemic to the northeastern and upper Midwestern United States. Although both diseases can involve multiple organ systems, acute liver failure (ALF) is exceedingly uncommon. Co-infection with Babesia microti and Borrelia burgdorferi may exacerbate disease severity, create diagnostic uncertainty, and delay appropriate therapy. We describe a 77-year-old man with type II diabetes mellitus, stage IV chronic kidney disease, and heart failure with preserved ejection fraction who presented with dyspnea, cough, and peripheral edema. Initial evaluation suggested decompensated heart failure and acute kidney injury consistent with cardiorenal syndrome. Within 24 h, however, he developed ALF (total bilirubin 6.8 mg/dL; aspartate aminotransferase 2656 U/L; alanine aminotransferase 1421 U/L; INR 3.5), thrombocytopenia (95 × 10 9 /L), acute anemia (hemoglobin 7.7 g/dL), and encephalopathy. Initial infectious, autoimmune, and ischemic evaluations were unrevealing. Despite empiric antimicrobial therapy with intravenous ceftriaxone, vancomycin, and doxycycline, his condition rapidly deteriorated, and he died. Postmortem testing identified B. microti parasitemia of 2.4% and B. burgdorferi co-infection. This case highlights the importance of considering tick-borne coinfections in patients presenting with ALF and shock, even in the absence of classic features such as fever, rash, or overt hemolysis. Increased clinician awareness of atypical presentations of endemic tick-borne diseases may help reduce diagnostic delays and improve outcomes in severe or unusual clinical scenarios.

Background: We conducted an updated meta-analysis of the routine use of cerebral embolic protection (CEP) devices in Transcathter Aortic Valve Replacement (TAVR). This analysis follows the recent BHF PROTECTED TAVI trial which is the largest randomized controlled trial to date. Methods: Electronic databases were searched through April 2025 for eligible randomized controlled trials (RCTs). The primary outcome was overall incidence of stroke, disabling stroke and non-disabling stroke all reported at 2-5 days and 30 days were primary outcomes for our analyses. Results: 8 RCTs with a total of 11,692 patients were included. No statistically significant difference was found between CEP group and the control group in overall stroke incidence at 2-5 days and 30 days as the following (RR=0.95, 95%CI: [0.75,1.19], p=0.64) and (RR=0.93, 95%CI: [0.57,1.53], p=0.79). Similarly, the pooled analysis revealed no statistically significant difference between the two groups in terms of disabling stroke at 2-5 days (RR=0.70, 95%CI: [0.41,1.18], p=0.18), and at 30 days (RR=1.18, 95%CI: [0.36,3.87], p=0.78). CEP group and control group didn’t show statistically significant difference in non- disabling stroke at 2-5 days and 30 days as the results showed: (RR=1.17, 95%CI: [0.84,1.63], p=0.36) and (RR=0.86, 95%CI: [0.49,1.51], P=0.61) respectively. Conclusion: Our meta-analysis found no statistically significant evidence that cerebral embolic protection (CEP) devices reduce the incidence of stroke—disabling or non-disabling in the 2-5 days following TAVR or after 30 days. Major bleeding, major vascular complication and AKI showed no statistically significant results indicating a neutral safety profile.