Citations

Platinum-based chemotherapy is the standard of care with concern to first-line systemic therapy for metastatic disease in urothelial cancer (UC). Resistance to chemotherapy despite an initial response is linked with the ability to remove platinum-based DNA adducts and to repair chemotherapy-induced DNA lesions by various DNA repair proteins. The Rad9-Rad1-HUS1 complex that is loaded onto DNA at sites of damage is involved in checkpoint activation as well as DNA repair. Here, we addressed for the first time the potential influence of HUS1 expression in urothelial carcinogenesis (using two human basal urothelial cancer cell lines UM-UC-3 and HT1197) and its role as a potential therapeutic target for predicting responses to platinum-based chemotherapy. Specific inhibition of HUS1 expression in both cell lines was achieved by specific siRNA and validated by Western blot. In order to define the possible importance of HUS1 in the regulation of cellular proliferation, parental and resistant cells were treated with increasing concentrations of either control or HUS1 siRNA. HUS1 protein expression was observed in both human basal urothelial cancer cell lines UM-UC-3 and HT1197. In cisplatin-sensitive cells, knock-down of HUS1 inhibited cellular proliferation in the presence of cisplatin. On the contrary, knock-down of HUS1 in resistant cells did not result in a re-sensitization to cisplatin. Finally, RNAseq data from the Cancer Genome Atlas provided evidence that HUS1 expression is a significant prognostic factor for poor survival in UC patients. In summary, HUS1 may acts as an oncogene in UC and might be a key determinant of the cellular response to cisplatin-based chemotherapy.

Background: Measuring quality of care indicators is important for clinicians and decision making in health care to improve patient outcomes. Objective: The primary objective was to identify quality of care indicators for patients with upper tract urothelial carcinoma (UTUC) and to validate these in an international cohort treated with radical nephroureterectomy (RNU). The secondary objective was to assess the factors associated with failure to validate the pentafecta. Design: We performed a retrospective multicenter study of patients treated with RNU for EAU high-risk (HR) UTUC. Outcome measurements and statistical analysis: Five quality indicators were consensually approved, including a negative surgical margin, a complete bladder-cuff resection, the absence of hematological complications, the absence of major complications, and the absence of a 12-month postoperative recurrence. After multiple imputations and propensity-score matching, log-rank tests and a Cox regression were used to assess the survival outcomes. Logistic regression analyses assessed predictors for pentafecta failure. Results: Among the 1718 included patients, 844 (49%) achieved the pentafecta. The median follow-up was 31 months. Patients who achieved the pentafecta had superior 5-year overall- (OS) and cancer-specific survival (CSS) compared to those who did not (68.7 vs. 50.1% and 79.8 vs. 62.7%, respectively, all p < 0.001). On multivariable analyses, achieving the pentafecta was associated with improved recurrence-free survival (RFS), CSS, and OS. No preoperative clinical factors predicted a failure to validate the pentafecta. Conclusions: Establishing quality indicators for UTUC may help define prognosis and improve patient care. We propose a pentafecta quality criteria in RNU patients. Approximately half of the patients evaluated herein reached this endpoint, which in turn was independently associated with survival outcomes. Extended validation is needed.

AbstractBackgroundThough infrequent, incomplete left atrial appendage closure (LAAC) may result from residual leaks. Percutaneous closure has been described though data is limited.MethodsWe compiled a registry from four centers of patients undergoing percutaneous closure of residual leaks following LAAC via surgical means or with the Watchman device. Leak severity was classified as none (no leak), mild (1–2 mm), moderate (3–4 mm), or severe (≥5 mm). Procedural and clinical success was defined as the elimination of leak or mild residual leak at the conclusion of the procedure or follow‐up, respectively.ResultsOf 72 (age 72.2 ± 9.2 years; 67% male) patients, 53 had undergone prior LAAC using the Watchman device and 19 patients surgical LAAC. Mean CHADS2‐VA2Sc score was 4.0 ± 1.8. The median leak size was 5 mm, range: 2–13). A total of 13 received Amplatzer Vascular Plug‐II, 18 received Amplatzer Duct Occluder‐II and 40 patients received coils. One underwent closure using a 21 mm‐Watchman. Procedural success was 94%. Zero surgical and nine Watchman patients (13%) had a residual leak at procedural‐end (five mild, three moderate, and one severe)—only one patient had no reduction in leak size. Overall leak size reduction was 94%. Two (3%) had intraoperative pericardial effusion. There were no device embolizations, device‐related thrombi, or procedural deaths. Clinical success was maintained at 94%. Two had cerebrovascular accidents—at 2 days (transient ischemic attack) and 10 months postprocedure. Two had major bleeding outside the 30‐day periprocedural window.ConclusionPercutaneous closure of residual leaks following left atrial appendage closure is feasible and associated with good outcomes. The procedural risk appears to be satisfactory.

Abstract Aims Mitral valve prolapse (MVP) is a common valvular heart disease with a prevalence of &gt;2% in the general adult population. Despite this high incidence, there is a limited understanding of the molecular mechanism of this disease, and no medical therapy is available for this disease. We aimed to elucidate the genetic basis of MVP in order to better understand this complex disorder. Methods and results We performed a meta-analysis of six genome-wide association studies that included 4884 cases and 434 649 controls. We identified 14 loci associated with MVP in our primary analysis and 2 additional loci associated with a subset of the samples that additionally underwent mitral valve surgery. Integration of epigenetic, transcriptional, and proteomic data identified candidate MVP genes including LMCD1, SPTBN1, LTBP2, TGFB2, NMB, and ALPK3. We created a polygenic risk score (PRS) for MVP and showed an improved MVP risk prediction beyond age, sex, and clinical risk factors. Conclusion We identified 14 genetic loci that are associated with MVP. Multiple analyses identified candidate genes including two transforming growth factor-β signalling molecules and spectrin β. We present the first PRS for MVP that could eventually aid risk stratification of patients for MVP screening in a clinical setting. These findings advance our understanding of this common valvular heart disease and may reveal novel therapeutic targets for intervention.

Background: Pulsed field ablation (PFA) is a novel form of ablation using electrical fields to ablate cardiac tissue. There are only limited data assessing the feasibility and safety of this type of ablation in humans. Methods: PULSED AF (Pulsed Field Ablation to Irreversibly Electroporate Tissue and Treat AF; https://www.clinicaltrials.gov ; unique identifier: NCT04198701) is a nonrandomized, prospective, multicenter, global, premarket clinical study. The first-in-human pilot phase evaluated the feasibility and efficacy of pulmonary vein isolation using a novel PFA system delivering bipolar, biphasic electrical fields through a circular multielectrode array catheter (PulseSelect; Medtronic, Inc). Thirty-eight patients with paroxysmal or persistent atrial fibrillation were treated in 6 centers in Australia, Canada, the United States, and the Netherlands. The primary outcomes were ability to achieve acute pulmonary vein isolation intraprocedurally and safety at 30 days. Results: Acute electrical isolation was achieved in 100% of pulmonary veins (n=152) in the 38 patients. Skin-to-skin procedure time was 160±91 minutes, left atrial dwell time was 82±35 minutes, and fluoroscopy time was 28±9 minutes. No serious adverse events related to the PFA system occurred in the 30-day follow-up including phrenic nerve injury, esophageal injury, stroke, or death. Conclusions: In this first-in-human clinical study, 100% pulmonary vein isolation was achieved using only PFA with no PFA system–related serious adverse events. Graphic Abstract: A graphic abstract is available for this article.

AbstractBackgroundIntracardiac electrogram data remain one of the primary diagnostic inputs guiding complex ablation procedures. However, the technology to collect, process, and display intracardiac signals has known shortcomings and has not advanced in several decades.ObjectiveThe purpose of this study was to evaluate a new signal processing platform, the PURE EP™ system (PURE), in a multi‐center, prospective study.MethodsIntracardiac signal data of clinical interest were collected from 51 patients undergoing ablation procedures with PURE, the signal recording system, and the 3D mapping system at the same time stamps. The samples were randomized and subjected to blinded, controlled evaluation by three independent electrophysiologists to determine the overall quality and clinical utility of PURE signals when compared to conventional sources. Each reviewer assessed the same (92) signal sample sets and responded to (235) questions using a 10‐point rating scale. If two or more reviewers rated the PURE signal higher than the control, it was deemed superior.ResultsA total of 93% of question responses showed consensus amongst the blinded reviewers. Based on the ratings for each pair of signals, a cumulative total of 164 PURE signals out of 218 (75.2%) were statistically rated as Superior for this data set (p < .001). Only 14 PURE signals out of 218 were rated as Inferior (6.4%).ConclusionThe PURE intracardiac signals were statistically rated as superior when compared to conventional systems.

Coronavirus disease 2019 (COVID-19) has presented substantial challenges to patient care and impacted healthcare delivery, including cardiac electrophysiology practice throughout the globe. Based upon the undetermined course and regional variability of the pandemic, there is uncertainty as to how and when to resume and deliver electrophysiology services for patients with arrhythmia. This joint document from representatives of the Heart Rhythm Society, American Heart Association, and American College of Cardiology seeks to provide guidance for clinicians and institutions reestablishing safe electrophysiological care. To achieve this aim, we address regional and local COVID-19 disease status, the role of viral screening and serological testing, return-to-work considerations for exposed or infected health care workers, risk stratification and management strategies based on COVID-19 disease burden, institutional preparedness for resumption of elective procedures, patient preparation and communication, prioritization of procedures, and development of outpatient and periprocedural care pathways.

The diagnosis and treatment of rare genitourinary tumors is inherently challenging. The Rare Diseases Act of 2002 initially defined a rare disorder as one that affects fewer than 200,000 Americans. The lack of widely available clinical guidelines, limited research funding, and inaccessible clinical trials often lead to difficulty with treatment decisions to guide practitioners in rendering effective care for patients with rare genitourinary cancers. This article will discuss basic tenets of diagnosis and treatment as well as recent developments and clinical trials in rare non-urothelial bladder cancers and penile squamous cell cancers.