Prospective Multicenter International Registry of Ultrasound-Facilitated Catheter-Directed Thrombolysis in Intermediate-High and High-Risk Pulmonary Embolism (KNOCOUT PE).

BACKGROUND: Prior clinical trials have demonstrated the efficacy of ultrasound-facilitated catheter-directed thrombolysis (USCDT) for the treatment of acute intermediate-risk pulmonary embolism (PE) using reduced thrombolytic doses and shorter infusion durations. However, utilization and safety of such strategies in broader PE populations remain unclear. The KNOCOUT PE (The EKoSoNic Registry of the Treatment and Clinical Outcomes of Patients With Pulmonary Embolism) registry is a multicenter international registry designed to study the treatment of acute PE with USCDT, with focus on safety outcomes. METHODS: The KNOCOUT PE prospective cohort included 489 patients (64 sites internationally) with acute intermediate-high or high-risk PE treated with USCDT between March 2018 and June 2020. Principal safety outcomes were independently adjudicated International Society on Thrombosis and Haemostasis major bleeding at 72 hours post-treatment and mortality within 12 months of treatment. Additional outcomes included change in right ventricular/left ventricular ratio and quality of life measures over 12 months. RESULTS: Mean alteplase (r-tPA [recombinant tissue-type plasminogen activator]) infusion duration was 10.5 hours. Mean total r-tPA dose was 18.1 mg, with 31.0% of patients receiving ≤12 mg. Major bleeding events within 72 hours occurred in 1.6% (8/489) of patients. One patient experienced worsening of a preexisting subdural hematoma after USCDT and therapeutic anticoagulation, which ultimately required surgery. All-cause mortality at 30 days was 1.0% (5/489). Improvement in PE quality of life score was observed with a 41.1% (243/489, 49.7%) and 44.2% (153/489, 31.3%) mean relative reduction by 3 and 12 months, respectively. CONCLUSIONS: In a prospective observational cohort study of patients with intermediate-high and high-risk PE undergoing USCDT, mean r-tPA dose was 18 mg, and the rates of major bleeding and mortality were low. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT03426124.

Outcomes in High-Risk Pulmonary Embolism Patients Undergoing FlowTriever Mechanical Thrombectomy or Other Contemporary Therapies: Results From the FLAME Study.

BACKGROUND: Hemodynamically unstable high-risk, or massive, pulmonary embolism (PE) has a reported in-hospital mortality of over 25%. Systemic thrombolysis is the guideline-recommended treatment despite limited evidence. The FLAME study (FlowTriever for Acute Massive PE) was designed to generate evidence for interventional treatments in high-risk PE. METHODS: The FLAME study was a prospective, multicenter, nonrandomized, parallel group, observational study of high-risk PE. Eligible patients were treated with FlowTriever mechanical thrombectomy (FlowTriever Arm) or with other contemporary therapies (Context Arm). The primary end point was an in-hospital composite of all-cause mortality, bailout to an alternate thrombus removal strategy, clinical deterioration, and major bleeding. This was compared in the FlowTriever Arm to a prespecified performance goal derived from a contemporary systematic review and meta-analysis. RESULTS: A total of 53 patients were enrolled in the FlowTriever Arm and 61 in the Context Arm. Context Arm patients were primarily treated with systemic thrombolysis (68.9%) or anticoagulation alone (23.0%). The primary end point was reached in 9/53 (17.0%) FlowTriever Arm patients, significantly lower than the 32.0% performance goal (P<0.01). The primary end point was reached in 39/61 (63.9%) Context Arm patients. In-hospital mortality occurred in 1/53 (1.9%) patients in the FlowTriever Arm and in 18/61 (29.5%) patients in the Context Arm. CONCLUSIONS: Among patients selected for mechanical thrombectomy with the FlowTriever System, a significantly lower associated rate of in-hospital adverse clinical outcomes was observed compared with a prespecified performance goal, primarily driven by low all-cause mortality of 1.9%. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT04795167.

Calcium/Calmodulin-Dependent Protein Kinase II Delta Inhibition and Ventricular Remodeling After Myocardial Infarction: A Randomized Clinical Trial.

Importance: After anterior ST-segment elevation myocardial infarction (STEMI), left ventricular (LV) remodeling results in heart failure and death. Calcium/calmodulin-dependent protein kinase II delta (CaMKIId) is a key molecular mediator of adverse LV remodeling. Objective: To determine whether NP202, an orally active inhibitor of CaMKIId, prevents LV remodeling in patients after anterior STEMI with early residual LV dysfunction. Design, Setting, and Participants: A randomized, double-blind, placebo-controlled multicenter clinical trial of NP202 vs placebo in patients after primary percutaneous coronary intervention (PCI) for anterior STEMI was performed from November 19, 2015, to August 1, 2018. The study was performed at 32 sites across the US, Australia, and New Zealand. Patients presenting with anterior STEMI who underwent PCI within 12 hours of symptom onset and left ventricular ejection fraction (LVEF) less than 45% on screening echocardiogram 48 hours after primary PCI were included in the study. Baseline cardiovascular magnetic resonance (CMR) imaging was performed within 5 days of the STEMI and before administration of the study drug. Follow-up CMR was performed after 3 months. Data were analyzed from November 19, 2015, to August 1, 2018. Interventions: Patients were randomly assigned to NP202, 1000 mg, daily for 3 months vs corresponding placebo. Main Outcomes and Measures: The primary end point was change in LV end-systolic volume index (LVESVi) on CMR. Secondary end points were change in LV end-diastolic volume index, change in LVEF, change in infarct size, and change in diastolic function. Safety and tolerability were also assessed. Results: A total of 147 patients (mean [SD] age, 58 [11] years; 129 men [88%]; 130 White patients [88%]) who experienced anterior STEMI treated with primary PCI were randomized to receive NP202 (73 [49.7%]) or placebo (74 [50.3%]). Baseline LVEF was similar between groups. At baseline, patients randomized to NP202 had greater LVESVi (48.2 mL/m2) than that in the placebo group (41.3 mL/m2; P = .03). However, the groups were otherwise well matched. For the primary end point of change in LVESVi from baseline to 3 months, there was no significant difference between the placebo (median [interquartile range] change, -0.60 [-9.28 to 5.99] mL/m2) and NP202 groups (-3.53 [-9.24 to 4.81] mL/m2) (P = .78). There was also no difference in the secondary efficacy end points assessed by CMR. NP202 was well tolerated and demonstrated an acceptable safety profile. Major adverse cardiac and cerebrovascular event rates were similar between groups. Two deaths occurred in each group during the follow-up period. Conclusions and Relevance: Three months of treatment with NP202 after primary PCI for anterior STEMI with residual LV dysfunction did not improve LV remodeling. The drug was safe and well tolerated. Trial Registration: ClinicalTrials.gov Identifier: NCT02557217.

Seborrheic Keratosis With Prominent Clear Cell Changes-A Rare But Important Diagnostic Variant.

Seborrheic keratoses, although exceedingly common, occasionally have morphologic similarities to other lesions that complicate a typically straightforward diagnosis. The authors present a case of a 69-year-old man with a left shoulder lesion that displayed characteristic clinical and microscopic features of seborrheic keratosis on biopsy. However, diffuse and prominent clear cells were also noted. These stained strongly with Periodic acid-Schiff and were diastase sensitive, suggestive of glycogen accumulation and possible trichilemmal differentiation. This case is presented to demonstrate a unique and striking example of clear cell change within a seborrheic keratosis and to briefly review the published literature on this finding, which is rarely reported and demands close examination to exclude more aggressive neoplasms.

Adjuvant Radiotherapy for Stages II and III Resected Thymoma: A Single-institutional Experience.

INTRODUCTION: The role of adjuvant radiation for Masaoka stages II and III thymoma remains controversial. The aim of this study was to evaluate the clinical benefit of radiation therapy for resected stages II and III thymoma patients. METHODS: We retrospectively reviewed the medical records of 175 thymoma patients treated from July 1996 to January 2013 at University of Washington Medical Center; 88 patients with adequate follow-up and who met histologic criteria were included. We evaluated progression-free survival (PFS) and overall survival (OS), and compared these outcomes in patients treated by surgery (S) alone versus surgery plus radiotherapy (S+RT). Cox regression models and log-rank tests were used to compare PFS and OS for S versus S+RT, and they were further assessed by margin-positive versus margin-negative subgroups using Kaplan-Meier curves. RESULTS: Among the 88 thymoma patients, 22 were stage II and 18 were stage III. For all stages II and III patients, adjuvant radiation was not identified as a significant predictor for PFS (P=0.95) or OS (P=0.63). A positive surgical margin predicted for a worse OS (hazard ratio=7.1; P=0.004). Further investigation revealed for resection margin-positive patients; S+RT had higher OS than S alone (P=0.006). CONCLUSIONS: For stages II and III thymoma, postoperative adjuvant radiation was not associated with statistically significant differences in PFS or OS in this study. Our results indicated a potential OS benefit of adjuvant RT in patients with positive resection margins, and therefore may be considered in this patient population.

Effect of preoperative pulmonary hypertension on outcomes in patients with severe aortic stenosis following surgical aortic valve replacement.

Pulmonary hypertension (PH) is prevalent in patients with aortic stenosis (AS); however, previous studies have demonstrated inconsistent results regarding the association of PH with adverse outcomes after aortic valve replacement (AVR). The goal of this study was to evaluate the effects of preoperative PH on outcomes after AVR. We performed a regional prospective cohort study using the Northern New England Cardiovascular Disease Study Group database to identify 1,116 consecutive patients from 2005 to 2010 who underwent AVR ± coronary artery bypass grafting for severe AS with a preoperative assessment of pulmonary pressures by right-sided cardiac catheterization. PH was defined as a mean pulmonary artery pressure of ≥25 mm Hg, with severity based on the pulmonary artery systolic pressure-mild, 35 to 44 mm Hg; moderate, 45 to 59 mm Hg; and severe, ≥60 mm Hg. We found that PH was present in 536 patients (48%). Postoperative acute kidney injury, low-output heart failure, and in-hospital mortality increased with worsening severity of PH. In multivariate logistic regression, severe PH was independently associated with postoperative acute kidney injury (adjusted odds ratio 4.1, 95% confidence interval [CI] 1.7 to 10, p = 0.002) and in-hospital mortality (adjusted odds ratio 6.9, 95% CI 2.5 to 19.1, p <0.001). There was a significant association between PH and decreased 5-year survival (adjusted log-rank p value = 0.006), with severe PH being associated with the poorest survival (adjusted hazard ratio 2.4, 95% CI 1.3 to 4.2, p = 0.003). In conclusion, severe PH in patients with severe AS is associated with increased rates of in-hospital adverse events and decreased 5-year survival after AVR.

Classification and treatment of coronary artery bifurcation lesions: putting the Medina classification to the test.

BACKGROUND: Coronary bifurcation lesions are common, difficult to treat, and associated with poorer outcomes compared to non-bifurcation lesions. The Medina classification has been widely adopted as the preferred system to classify bifurcation lesions, however there have been little efforts to characterize this metric. The objective of this study was to characterize the inter-observer variability of the Medina classification and examine its contribution to treatment selection strategy. METHODS AND MATERIALS: We invited 150 interventional cardiologists from the United States and Europe to complete an online survey evaluating 12 freeze frame coronary angiograms of bifurcation lesions. Each respondent was asked to characterize the bifurcation lesions using the Medina classification and other metrics including side branch vessel size and angle. Respondents were asked to designate either a provisional (1 stent) or dedicated (2 stent) treatment strategy. 'Complex' lesions were defined as Medina scores 1.1.1, 0.1.1, or 1.0.1. RESULTS: A total of 49 interventional cardiologists responded. In 7 of the 12 angiograms evaluated, there was >75% agreement regarding lesion classification using the Medina system. There was moderate inter-observer agreement when using Medina to classify lesions as 'Complex' vs. 'non-Complex'. 'Complex' bifurcation designation and side branch size were predictive of selection of a dedicated treatment strategy, whereas side branch angle was not. CONCLUSIONS: The Medina classification is a useful tool in characterizing coronary bifurcation lesions. For the majority of the angiograms evaluated there was good inter-observer agreement in lesion classification using the Medina system. 'Complex' bifurcation designation and side branch size were predictive of selection of a dedicated treatment strategy.

A call to action: variability in guidelines for cardiac evaluation before renal transplantation.

BACKGROUND AND OBJECTIVES: Candidates for renal transplantation are at increased risk for complications related to cardiovascular disease; however, the optimal strategy to reduce this risk is not clear. The aim of this study was to evaluate the variability among existing guidelines for preoperative cardiac evaluation of renal transplant candidates. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: A consecutive series of renal transplant candidates (n=204) were identified, and four prominent preoperative cardiac evaluation guidelines, pertaining to this population, were retrospectively applied to determine the rate at which each guideline recommended cardiac stress testing. RESULTS: The rate of pretransplant cardiac stress testing would have ranged from 20 to 100% depending on which guideline was applied. The American Heart Association/American College of Cardiology (ACC/AHA) guideline resulted in the lowest rate of testing (20%). In our population, 178 study subjects underwent stress testing: 17 were found to have ischemia and 10 underwent revascularization. The ACC/AHA approach would have decreased the number of noninvasive tests from 178 to 39; it would have identified only 4 of the 10 patients who underwent revascularization. The three other guidelines (renal transplant-specific guidelines) recommended widespread pretransplant cardiac testing and thus identified nearly all patients who had ischemia on stress testing. CONCLUSIONS: The ACC/AHA perioperative guideline may be inadequate for identifying renal transplant candidates with coronary disease; however, renal transplant-specific guidelines may provoke significant overtesting. An intermediate approach based on risk factors specific to the ESRD population may optimize detection of coronary disease and limit testing.

Non-invasive detection of pulmonary hypertension prior to renal transplantation is a predictor of increased risk for early graft dysfunction.

BACKGROUND: Early graft dysfunction is a significant complication after renal transplantation and is a marker of adverse outcomes. Although multiple predictors of graft dysfunction have been previously described, the reported prevalence of pulmonary hypertension (pulmonary HTN) in the dialysis population (40-50%), along with biologic and physiologic principles, led us to hypothesize that pulmonary HTN might be an additional risk factor for early graft dysfunction. METHODS: We performed a retrospective study that screened all adult renal transplants performed at our institution over a 3-year period and limited the evaluation to those subjects who had an estimated pulmonary artery systolic pressure on a preoperative echocardiogram report (n = 55). The primary outcome of this study was to investigate the impact of pulmonary HTN on early graft dysfunction using a combined endpoint of delayed graft function or slow graft function. RESULTS: Among patients receiving a living donor kidney, early graft dysfunction was not observed regardless of pulmonary HTN status. However, among patients receiving a deceased donor kidney, pulmonary HTN was found to be associated with a significant increased risk of early graft dysfunction (56 vs 11.7%, P = 0.01). Univariate and multivariable logistic regression supported this observation as an independent risk factor beyond potential confounding recipient, donor and graft-based risk factors for early graft dysfunction (P < 0.05). CONCLUSION: Pulmonary HTN detected on non-invasive imaging prior to renal transplantation appears to be an independent predictor of early graft dysfunction among those patients who receive a deceased donor kidney.

Heterogeneity of CD80 gene transcription by human keratinocytes to allergens and irritants: relevance to allergic contact dermatitis in vivo.

Using an in vitro assay for CD80 promoter activity, the transcriptional response of primary cultured human keratinocytes from different donors in response to allergens and irritants was studied. The CD80 promoter activity was increased reproducibly after exposure to certain chemicals. The epithelial cell lines HeLa and HaCaT also increased CD80 transcriptional activity in response to exposure to a panel of different allergens and irritants. Normal or immortalized keratinocytes responded reproducibly with a unique pattern to a panel of chemicals in which the culture increases CD80 transcription after exposure to certain chemicals and has no increase in CD80 transcription after exposure to other chemicals. Some keratinocyte cultures responded positively to certain chemicals whereas others did not respond to the same chemicals. Cultured keratinocytes from 16 of 20 adult donors (80%) responded to nitrochlorobenzene in vitro by increasing CD80 transcriptional activity, thus predicting subsequent sensitization to this same hapten (chi2= 7.2, P <0.0073). Thus, a keratinocyte CD80 gene expression assay exhibits good sensitivity in predicting allergic contact dermatitis for sensitizers such as dinitrochlorobenzene. These data suggest that there is a rationale for developing the use of gene-transcription-based predictive assays to identify individual susceptibility to cutaneous reactivity after exposure to allergens and irritants.