Citations

AbstractIntroductionData regarding ventricular tachycardia (VT) or premature ventricular complex (PVC) ablation in patients with aortic valve (AV) intervention (AVI) is limited. Catheter ablation (CA) can be challenging given perivalvular substrate in the setting of prosthetic valves. We sought to investigate the characteristics, safety, and outcomes of CA in patients with prior AVI and ventricular arrhythmias (VA).MethodsWe identified consecutive patients with prior AVI (replacement or repair) who underwent CA for VT or PVC between 2013 and 2018. We investigated the mechanism of arrhythmia, ablation approach, perioperative complications, and outcomes.ResultsWe included 34 patients (88% men, mean age 64 ± 10.4 years, left ventricular (LV) ejection fraction 35.2 ± 15.0%) with prior AVI who underwent CA (22 VT; 12 PVC). LV access was obtained through trans‐septal approach in all patients except one patient who had percutaneous transapical access. One patient had combined retrograde aortic and trans‐septal approach. Scar‐related reentry was the dominant mechanism of induced VTs. Two patients had bundle branch reentry VTs. In the VT group, substrate mapping demonstrated heterogeneous scar that involved the peri‐AV area in 95%. Despite that, the site of successful ablation included the periaortic region only in 6 (27%) patients. In the PVC group, signal abnormalities consistent with scar in the periaortic area were noted in 4 (33%) patients. In 8 (67%) patients, the successful site of ablation was unrelated to the periaortic area. No procedure‐related complications occurred. The survival and recurrence‐free survival rate at 1 year tended to be lower in VT group than in PVC group (p = .06 and p = .05, respectively) with a 1‐year recurrence‐free survival rate of 52.8% and 91.7%, respectively. No arrhythmia‐related death was documented on long‐term follow‐up.ConclusionCA of VAs can be performed safely and effectively in patients with prior AVI.

Abstract OBJECTIVES The prevalence and aetiology of acute aortic dissection type A (AADA) in patients ≤30 years is unknown. The aims of this clinical study were to determine the prevalence and potential aetiology of AADA in surgically treated patients ≤30 years and to evaluate the respective postoperative outcomes in this selective group of patients in a large multicentre study. METHODS Retrospective data collection was performed at 16 participating international aortic institutions. All patients ≤30 years at the time of dissection onset were included. The postoperative results were analysed with regard to connective tissue disease (CTD). RESULTS The overall prevalence of AADA ≤30 years was 1.8% (139 out of 7914 patients), including 51 (36.7%) patients who were retrospectively diagnosed with CTD. Cumulative postoperative mortality was 8.6%, 2.2% and 1.4%. Actuarial survival was 80% at 10 years postoperatively. Non-CTD patients (n = 88) had a significantly higher incidence of arterial hypertension (46.6% vs 9.8%; P < 0.001) while AADA affected the aortic root (P < 0.001) and arch (P = 0.029) significantly more often in the CTD group. A positive family history of aortic disease was present in 9.4% of the study cohort (n = 13). CONCLUSIONS The prevalence of AADA in surgically treated patients ≤30 years is <2% with CTD and arterial hypertension as the 2 most prevalent triggers of AADA. Open surgery may be performed with good early results and excellent mid- to long-term outcomes.

Abstract Background In the United States, rare disease (RD) is defined as a condition that affects fewer than 200,000 individuals. Collectively, RD affects an estimated 30 million Americans. A significant portion of RD has an underlying genetic cause; however, this may go undiagnosed. To better serve these patients, the Mayo Clinic Program for Rare and Undiagnosed Diseases (PRaUD) was created under the auspices of the Center for Individualized Medicine (CIM) aiming to integrate genomics into subspecialty practice including targeted genetic testing, research, and education. Methods Patients were identified by subspecialty healthcare providers from 11 clinical divisions/departments. Targeted multi-gene panels or custom exome/genome-based panels were utilized. To support the goals of PRaUD, a new clinical service model, the Genetic Testing and Counseling (GTAC) unit, was established to improve access and increase efficiency for genetic test facilitation. The GTAC unit includes genetic counselors, genetic counseling assistants, genetic nurses, and a medical geneticist. Patients receive abbreviated point-of-care genetic counseling and testing through a partnership with subspecialty providers. Results Implementation of PRaUD began in 2018 and GTAC unit launched in 2020 to support program expansion. Currently, 29 RD clinical indications are included in 11 specialty divisions/departments with over 142 referring providers. To date, 1,152 patients have been evaluated with an overall solve rate of 14.1% and as high as 66.7% depending on the phenotype. Noteworthy, 42.7% of the solved or likely solved patients underwent changes in medical management and outcome based on genetic test results. Conclusion Implementation of PRaUD and GTAC have enabled subspecialty practices advance expertise in RD where genetic counselors have not historically been embedded in practice. Democratizing access to genetic testing and counseling can broaden the reach of patients with RD and increase the diagnostic yield of such indications leading to better medical management as well as expanding research opportunities.

Abstract Aims Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation. Whether the PDK/PDH axis plays a role in vascular inflammation and atherosclerotic cardiovascular disease remains unclear. Methods and results Gene profiling of human atherosclerotic plaques revealed a strong correlation between PDK1 and PDK4 transcript levels and the expression of pro-inflammatory and destabilizing genes. Remarkably, the PDK1 and PDK4 expression correlated with a more vulnerable plaque phenotype, and PDK1 expression was found to predict future major adverse cardiovascular events. Using the small-molecule PDK inhibitor dichloroacetate (DCA) that restores arterial PDH activity, we demonstrated that the PDK/PDH axis is a major immunometabolic pathway, regulating immune cell polarization, plaque development, and fibrous cap formation in Apoe−/− mice. Surprisingly, we discovered that DCA regulates succinate release and mitigates its GPR91-dependent signals promoting NLRP3 inflammasome activation and IL-1β secretion by macrophages in the plaque. Conclusions We have demonstrated for the first time that the PDK/PDH axis is associated with vascular inflammation in humans and particularly that the PDK1 isozyme is associated with more severe disease and could predict secondary cardiovascular events. Moreover, we demonstrate that targeting the PDK/PDH axis with DCA skews the immune system, inhibits vascular inflammation and atherogenesis, and promotes plaque stability features in Apoe−/− mice. These results point toward a promising treatment to combat atherosclerosis.

Abstract Background: The current first-line (1L) standard of care (SOC) for human epidermal growth factor receptor 2-positive (HER2+) metastatic breast cancer (MBC) is trastuzumab (T) plus pertuzumab (P) and a taxane. Despite advances in 1L SOC, most patients (pts) progress during maintenance therapy with T+P. Tucatinib is a tyrosine kinase inhibitor (TKI) approved in combination with T and capecitabine for adults with HER2+ MBC, with and without brain metastases (BM). In HER2CLIMB, the addition of tucatinib significantly prolonged progression-free survival (PFS) and overall survival (OS) in pts with HER2+ MBC and was well tolerated. Adding tucatinib also reduced the risk of disease progression or death in pts with untreated and/or active BM (Murthy et al. 2020, Curigliano et al. 2021). HER2CLIMB-05 investigates whether adding tucatinib to 1L SOC as maintenance therapy will extend PFS while maintaining quality of life (QOL). Methods: HER2CLIMB-05 (NCT05132582) is a phase 3, randomized, double-blind study evaluating tucatinib plus T+P as maintenance therapy for HER2+ MBC. Approximately 650 pts will be enrolled. Eligible pts will have advanced HER2+ disease, no progression on 4–8 cycles of prior 1L SOC, ECOG Performance Status of 0 or 1, and no or asymptomatic BM. Exclusion criteria include prior treatment with anti-HER2 and/or anti-epidermal growth factor receptor TKI (prior SOC for early BC is permitted) or inability to undergo contrast magnetic resonance imaging of the brain. Pts will be randomized 1:1 to receive either tucatinib or placebo twice daily, with T+P once every 21 days. Pts with HR+ disease may receive endocrine therapy. The primary endpoint is investigator-assessed PFS. Secondary endpoints include OS (key endpoint), time to deterioration of health-related QOL, central nervous system PFS, safety, and pharmacokinetic (PK) parameters. PFS and OS will be compared using a 2-sided stratified log-rank test between treatment groups. Time-to-event endpoints will be summarized using the Kaplan–Meier method. PK and safety data will be summarized using descriptive statistics. Enrollment is ongoing in the US, with additional sites planned. Citation Format: Erika Hamilton, Junji Tsurutani, Giuseppe Curigliano, Miguel Martín, Ciara C. O’Sullivan, Joo Hyuk Sohn, Konstantinos Tryfonidis, Libero Santarpia, Shan Yang, Véronique Diéras. Phase 3 study of tucatinib or placebo in combination with trastuzumab and pertuzumab as maintenance therapy for HER2+ metastatic breast cancer (HER2CLIMB-05, trial in progress) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr OT2-16-03.

Spinal cord tumors constitute a diverse group of rare neoplasms associated with significant mortality and morbidity that pose unique clinical and surgical challenges. Diagnostic accuracy and outcome prediction are critical for informed decision making and can promote personalized medicine and facilitate optimal patient management. Machine learning has the ability to analyze and combine vast amounts of data, allowing the identification of patterns and the establishment of clinical associations, which can ultimately enhance patient care. Although artificial intelligence techniques have been explored in other areas of spine surgery, such as spinal deformity surgery, precise machine learning models for spinal tumors are lagging behind. Current applications of machine learning in spinal cord tumors include algorithms that improve diagnostic precision by predicting genetic, molecular, and histopathological profiles. Furthermore, artificial intelligence-based systems can assist surgeons with preoperative planning and surgical resection, potentially reducing the risk of recurrence and consequently improving clinical outcomes. Machine learning algorithms promote personalized medicine by enabling prognostication and risk stratification based on accurate predictions of treatment response, survival, and postoperative complications. Despite their promising potential, machine learning models require extensive validation processes and quality assessments to ensure safe and effective translation to clinical practice.

Abstract Background Crohn’s disease (CD) and ulcerative colitis (UC), together known as inflammatory bowel diseases (IBD), affect approximately seven million people globally. The continuous rise in IBD prevalence and the aging of populations will inevitably lead to an increasing use of health care resources. In parallel with these trends, continuing innovations in IBD therapeutics, diagnostics, and preventatives are creating more options for IBD patients seeking to reduce their disease burden. These trends pose an imminent burden on health care systems and require that we identify modifiable cost drivers in IBD care and develop strategies for delivering equitable and affordable care for all patients. Methods This Lancet Gastroenterology & Hepatology Commission, consisting of a diverse faculty of health care professionals with expertise in the field of IBD and health economists, was formed to deliver an extensive summary of the literature and discuss key topics on the costs and cost-effectiveness of treating IBD in the present, and how this is likely to look in the future. Furthermore, it offers suggestions for how to deliver affordable IBD care in the coming years. The report’s focus was on high-income countries in Europe, North America, Australia and New Zealand, and Asia. Results The Commission drew together a wide range of expertise to discuss the current costs of IBD care, the drivers of increasing costs, as well as how to deliver affordable care for IBD in the future. The key conclusions are that (i) increases in health care costs must be evaluated against improved disease control and reductions in indirect costs, and (ii) that overarching systems for data interoperability, registries, and big data approaches must be established for continuous assessment of effectiveness, costs, and cost-effectiveness of care. International collaborations should be sought in order to evaluate novel models of care (such as value-based health care, including integrated health care and participatory health care models), as well as to improve the education and training of clinicians, patients, and policymakers. Measures to reduce the costs of IBD care are summarised in Table 1. Conclusion Increases in health care costs must be evaluated against improved disease control and reductions in indirect costs. Evaluations should be systematically aligned between countries and regions. Detailed analysis of the current epidemiology and the likely effects of changing IBD management on disease course and socioeconomic outcomes is essential; and will become even more imperative in the era of precision medicine, where complex biotechnologies will require expensive analyses, highly skilled personnel, and drug development for what may sometimes be relatively small patient groups.

TPS657 Background: Poorly differentiated neuroendocrine carcinoma (NEC) is an aggressive malignancy comprising both pulmonary and extrapulmonary primary sites. NEC includes both small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma (LCNEC), as well as other neuroendocrine carcinomas arising from any primary organ. A substantial portion (~40%) of NEC arises from gastrointestinal primary sites. The optimal systemic therapy beyond first line platinum and etoposide is not established. There is a critical need to improve upon the median survival in the second line, as most patients do not survive more than 6 months. The efficacy of single agent immune checkpoint inhibitors (ICIs) in NEC has been disappointing. One possible explanation for this is that the tumor microenvironment in NEC is non-inflamed. VSV-IFNβ-NIS is a vesicular stomatitis virus (VSV)-based oncolytic virus being tested in multiple early phase clinical trials. Preliminary studies of immune responses in patients receiving VSV-IFNβ-NIS therapy suggest some patients develop T cell responses to viral antigens and known tumor antigens. We hypothesize that VSV-IFNβ-NIS therapy may convert a non-inflamed or immune-excluded phenotype in NEC to a highly inflamed phenotype that sensitizes the tumor to ICIs. Methods: This is a phase 1-2 safety run-in study designed to determine the safety of VSV-IFNβ-NIS in combination with a single agent ICI, pembrolizumab, followed by dose expansion in patients with refractory non-small cell lung cancer (NSCLC) or NEC. The safety run-in portion of this study has been completed, and we are presently testing the recommended phase 2 dose (RP2D) of VSV-IFNβ-NIS in an expansion cohort of patients with SCLC or NEC of any primary site. Patients must have previously progressed on at least one line of systemic therapy. Prior treatment with checkpoint inhibitors is permitted. Patients are treated one time with the RP2D of 1.0x10^11 TCID50 VSV-IFNβ-NIS on day 1, followed by pembrolizumab on day 8 and then pembrolizumab every 21 days until progression, up to 2 years. The primary objective is to estimate the response rate by RECIST 1.1. Secondary objectives include estimation of disease-control rate, duration or response, progression-free survival, overall survival, and safety signals. The NEC expansion cohort will seek to enroll 10 patients. If at least one objective response is observed, and safety is confirmed, the regimen will be considered for future study. Clinical trial information: NCT03647163 .

AbstractIntroductionThromboembolic events after catheter ablation of ventricular tachycardia (VT) can result in significant morbidity. Thromboembolic prophylaxis after catheter ablation can be achieved by the use of antiplatelet agents, vitamin K antagonists, or direct oral anticoagulants (DOACs). The relative safety and efficacy of these modes of prophylaxis are uncertain. We sought to compare the outcomes of patients who received warfarin or DOACs for thromboembolic prophylaxis after catheter ablation of VT.Methods and ResultsAnticoagulation with DOACS was started after left ventricular VT ablation in a series of 42 consecutive patients with structural heart disease (67 ± 11 years, 3 women, ejection fraction 32 ± 14%). Duration of hospital stay, bleeding episodes, and thromboembolic events were compared to a historic consecutive group of patients (n = 38, 65 ± 13 years, 14 women, ejection fraction 36 ± 13%) in whom anticoagulation with a formerly described protocol of heparin and vitamin K antagonist was used after VT ablation procedures. Hospital stay was significantly shorter in the group where DOACs were used as compared to vitamin K antagonists (3.3 ± 1.8 vs. 5.0 ± 2.5 days postablation; p = 0.001) without an increase of bleeding or thromboembolic events.ConclusionAnticoagulation with DOACs is safe and shortens hospital stay in patients with structural heart disease undergoing left ventricular VT ablation procedures.