Search

Despite recent advances in immunotherapy with immune checkpoint inhibitors (ICI), many patients with non-small cell lung cancer (NSCLC) fail to respond or develop resistance after an initial response. In situ vaccination (ISV) with engineered viruses has emerged as a promising antigen-agnostic strategy that can both condition the tumor microenvironment (TME) and augment anti-tumor T cell responses to overcome immune resistance. We engineered a live attenuated viral vaccine, Hyper-Interferon Sensitive virus (HIS), by conducting a genome-wide functional screening and introducing eight interferon (IFN)-sensitive mutations in the influenza genome. Compared to wild-type (WT) influenza, HIS replication was attenuated in immunocompetent hosts, enhancing its potential as a safe option for cancer therapy. HIS ISV elicited robust yet transient type I IFN responses in murine NSCLCs, leading to an enrichment of polyfunctional effector Th1 CD4 and cytotoxic CD8 T cells into the tumor. HIS ISV demonstrated enhanced anti-tumor efficacy compared to WT in multiple syngeneic murine models of NSCLC with distinct driver mutations and varying mutational burden. This efficacy was dependent on host type 1 IFN responses and T lymphocytes. HIS ISV overcame resistance to anti-PD-1 in LKB-1 deficient murine NSCLC, resulting in improved overall survival and enduring systemic tumor-specific immunity. These studies provide compelling evidence to support further clinical evaluation of HIS as a novel 'off-the-shelf' ISV strategy for patients with NSCLC refractory to ICI.

Objectives: We hypothesized that emergency complications related to asymptomatic paraconduit hernias may occur less often than generally believed. Therefore, we assessed the occurrence and timing of paraconduit hernia diagnosis after esophagectomy, as well as outcomes of these asymptomatic patients managed with a watch-and-wait approach., Methods: From 2006 to 2021, 1214 patients underwent esophagectomy with reconstruction at the Cleveland Clinic. Among these patients, computed tomography scans were reviewed to identify paraconduit hernias. Medical records were reviewed for timing of hernia diagnosis, hernia characteristics, and patient symptoms, complications, and management. During this period, patients with asymptomatic paraconduit hernias were typically managed nonoperatively., Results: Paraconduit hernias were identified in 37 patients. Of these, 31 (84%) had a pre-esophagectomy hiatal hernia. Twenty-one hernias (57%) contained colon, 7 hernias (19%) contained pancreas, and 9 hernias (24%) contained multiple organs. Estimated prevalence of paraconduit hernia was 3.3% at 3 years and 7.7% at 10 years. Seven patients (19%) had symptoms, 4 of whom were repaired electively, with 2 currently awaiting repairs. No patient with a paraconduit hernia experienced an acute complication that required emergency intervention., Conclusions: The risk of paraconduit hernia increases with time, suggesting that long-term symptom surveillance is reasonable. Emergency complications as a result of asymptomatic paraconduit hernias are rare. A small number of patients will experience hernia-related symptoms, sometimes years after hernia diagnosis. Our findings suggest that observation of asymptomatic paraconduit hernias (watch and wait) may be considered, with repair considered electively in patients with persistent symptoms., (Copyright © 2023 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Objectives: To determine mechanisms of early and late failure after mitral valve repair for degenerative disease, identify factors associated with re-repair, and evaluate durability of re-repair., Methods: From January 2008 to July 2020, 330 reoperations were performed for recurrent mitral valve dysfunction after initial valve repair for degenerative disease. Mechanisms of repair failure were determined by review of preoperative imaging and operative reports. Multivariable analysis was performed to identify factors associated with likelihood of re-repair or replacement. Durability of re-repair was assessed using longitudinal analysis of postoperative echo data., Results: Eighty-five of 330 (26%) reoperations were performed for early repair failure within 1 year and 245/330 (74%) for late failure thereafter. Suture/annuloplasty dehiscence, systolic anterior motion, hemolysis, and ventricular remodeling were more common mechanisms of early failure and disease progression and fibrosis late failure. Forty percent (34/85) of early failures were re-repaired versus 24% (59/245) of late failures. Re-repair was more common than replacement in recent years and was associated with earlier reoperation (median 1.5 vs 3.9 years; P = .0001). No in-hospital deaths occurred after re-repair; 2 patients (0.8%) died after valve replacement. Freedom from severe mitral regurgitation after re-repair was 93% at 7 years., Conclusions: Mitral valve re-repair can be performed with low rates of mortality and morbidity for early and late valve dysfunction. Mechanisms of early repair failure differ from those of late failure and are generally more amenable to re-repair. In selected patients who present after failed repair, we prefer mitral re-repair to valve replacement whenever technically feasible., (Copyright © 2022 The American Association for Thoracic Surgery. Published by Elsevier Inc. All rights reserved.)

Rationale: Objective adherence to inhaled therapy by patients with chronic obstructive pulmonary disease (COPD) has not been reported., Objectives: To objectively quantify adherence to preventer Diskus inhaler therapy by patients with COPD with an electronic audio recording device (INCA)., Methods: This was a prospective observational study. On discharge from hospital patients were given a salmeterol/fluticasone inhaler with an INCA device attached. Analysis of this audio quantified the frequency and proficiency of inhaler use., Measurements and Main Results: Patients with COPD (n = 244) were recruited. The mean age was 71 years, mean FEV 1 was 1.3 L, and 59% had evidence of mild/moderate cognitive impairment. By combining time of use, interval between doses, and critical technique errors, thus incorporating both intentional and unintentional nonadherence, a measure "actual adherence" was calculated. Mean actual adherence was 22.6% of that expected if the doses were taken correctly and on time. Six percent had an actual adherence greater than 80%. Hierarchical clustering found three equally sized well-separated clusters corresponding to distinct patterns. Cluster 1 (34%) had low inhaler use and high error rates. Cluster 2 (25%) had high inhaler use and high error rates. Cluster 3 (36%) had overall good adherence. Poor lung function and comorbidities were predictive of poor technique, whereas age and cognition with poor lung function distinguished those with poor adherence and frequent errors in technique., Conclusions: These data may inform clinicians in understanding why a prescribed inhaler is not effective and to devise strategies to promote adherence in COPD.