Citations

Abstract Uterine leiomyosarcoma (ULMS) is an orphan disease that frequently recurs and metastasizes, with patients undergoing multiple lines of chemotherapy due to lack of effective therapeutic targets. To address this gap, we used single-cell RNA sequencing and spatial transcriptomic analysis to comprehensively profile ULMS. We uncovered multiple states of tumor cells, including tumor cells with mesenchyme-like features, ischemic tumor cells defined by a MYC program, inflammatory tumor cells with active interferon signaling, and stem cell-like hormone receptor-positive cells. The inferred spatial correlates of these tumor cell states demonstrated unique localization patterns. By correlating these signatures to bulk RNA sequencing data, we demonstrate the relevance of these findings to clinical outcomes. Finally, using the single-cell integration and drug response prediction algorithm (scIDUC), we propose drug predictions that may target specific tumor states. Our findings suggest new avenues for further exploration of individualized and multifaceted therapeutic strategies to treat ULMS.

Introduction: Whether echocardiographic (echo) markers of left ventricular (LV) remodeling and diastolic dysfunction contribute incremental and independent prognostic information to clinical risk markers in patients (Pts) with coronary artery disease and severe LV systolic dysfunction is unclear. We sought to determine which echo variables provide the greatest prognostic value in the Surgical Treatment for Ischemic Heart Failure (STICH) population. Methods: Pts enrolled in STICH for whom transmitral Doppler (E/A ratio) was available on a baseline echo interpreted by an echo core laboratory blinded to treatment and outcomes formed the analysis cohort. Comprehensive datasets to account for missing echo data were created by multiple imputation and the impact on all-cause mortality was determined with the Cox’s regression model. Results: E/A ratio could be measured in 1511 of the 2136 Pts enrolled in STICH. Amongst markers of diastolic dysfunction, E/A ratio was the most significant predictor of mortality (χ 2 41.05, p <0.001) with a non-linear, u-shaped, relationship. Mortality was lowest with E/A ratio = 1.0, and increased for E/A ratio <0.6 and >1.0 up to 2.3, beyond which there was no further increase in risk. The combination of larger LV end-systolic volume index (LVESVI), low or high E/A ratio, and mitral regurgitation severity grade, had highly significant incremental negative effects on mortality (χ 2 69.65, p<0.001) when added to a multivariable model with clinical risk markers. Overall, creatinine (χ 2 30.00, p <0.001), followed by LVESVI (χ 2 27.26, p<0.001), age, and E/A ratio (χ 2 12.46, p<0.001) were among the most significant predictors of mortality and accounted for 74% of the total prognostic information. LVESVI and E/A ratio were stronger predictors of poor prognosis than New York Heart Association (NYHA) functional class, hemoglobin, diabetes, stroke, or atrial fibrillation. Conclusions: Echo markers of advanced LV remodeling and diastolic dysfunction add incremental prognostic value to clinical risk markers and are more predictive of poor prognosis than advanced NYHA functional class or anemia. LVESVI and E/A ratio outperformed other echo markers and should be considered standard in assessing risk in Pts with ischemic LV dysfunction.

Abstract Aims: We sought to determine which echocardiographic markers of left ventricular (LV) remodeling and diastolic dysfunction can contribute as incremental and independent prognostic information in addition to current clinical risk markers of ischemic LV systolic dysfunction in the Surgical Treatment for Ischemic Heart Failure (STICH) trial.Methods and Results: The cohort consisted of 1511 of 2136 patients in STICH for whom baseline transmitral Doppler (E/A ratio) could be measured by an echocardiographic core laboratory blinded to treatment and outcomes, and prognostic value of echocardiographic variables was determined by a Cox regression model. E/A ratio was the most significant predictor of mortality amongst diastolic variables with lowest mortality for E/A closest 0.8, although mortality was consistently low for E/A 0.6 to 1.0. Mortality increased for E/A <0.6 and > 1.0 up to approximately 2.3, beyond which there was no further increase in risk. Larger LV end-systolic volume index (LVESVI) and E/A <0.6 and >1.0 had incremental negative effects on mortality when added to a clinical multivariable model, where creatinine, LVESVI, age, and E/A ratio accounted for 74% of the prognostic information for predicting risk. LVESVI and E/A ratio were stronger predictors of prognosis than New York Heart Association functional class, anemia, diabetes, history of atrial fibrillation, and stroke.Conclusions: Echocardiographic markers of advanced LV remodeling and diastolic dysfunction added incremental prognostic value to current clinical risk markers. LVESVI and E/A ratio outperformed other markers and should be considered as standard in assessing risks in ischemic heart failure. E/A closest to 0.8 was the most optimal filling pattern.

Abstract Aims: We sought to determine which echocardiographic markers of left ventricular (LV) remodeling and diastolic dysfunction can contribute as incremental and independent prognostic information in addition to current clinical risk markers of ischemic LV systolic dysfunction in the Surgical Treatment for Ischemic Heart Failure (STICH) trial.Methods and Results: The cohort consisted of 1511 of 2136 patients in STICH for whom baseline transmitral Doppler (E/A ratio) could be measured by an echocardiographic core laboratory blinded to treatment and outcomes, and prognostic value of echocardiographic variables was determined by a Cox regression model. E/A ratio was the most significant predictor of mortality amongst diastolic variables with lowest mortality for E/A closest 0.8, although mortality was consistently low for E/A 0.6 to 1.0. Mortality increased for E/A <0.6 and > 1.0 up to approximately 2.3, beyond which there was no further increase in risk. Larger LV end-systolic volume index (LVESVI) and E/A <0.6 and >1.0 had incremental negative effects on mortality when added to a clinical multivariable model, where creatinine, LVESVI, age, and E/A ratio accounted for 74% of the prognostic information for predicting risk. LVESVI and E/A ratio were stronger predictors of prognosis than New York Heart Association functional class, anemia, diabetes, history of atrial fibrillation, and stroke.Conclusions: Echocardiographic markers of advanced LV remodeling and diastolic dysfunction added incremental prognostic value to current clinical risk markers. LVESVI and E/A ratio outperformed other markers and should be considered as standard in assessing risks in ischemic heart failure. E/A closest to 0.8 was the most optimal filling pattern.

Abstract Aims Hypothesis 1 of the Surgical Treatment for Ischemic Heart Failure (STICH) trial enrolled 1212 patients with an LVEF of ≤35% and CAD amenable to coronary artery bypass grafting (CABG). Patients were randomized to CABG and optimal medical therapy (MED) or MED alone. The objective was to assess whether or not patients with diabetes mellitus (DM) enrolled in the STICH trial would have greater benefit from CABG than patients without DM. Methods and results The characteristics and clinical outcomes of patients with and without DM randomized to CABG and MED or MED alone were compared. DM was present in 40%. At baseline, patients with DM had more triple vessel CAD, higher LVEF, and smaller left ventricular volumes. In patients with DM, the primary outcome of all-cause mortality occurred in 39% of patients in the MED group and 39% in the CABG group [hazard ratio (HR) with CABG 0.96, 95% confidence interval (CI) 0.73–1.26]. In patients without DM, the primary outcome occurred in 41% of patients in the MED group and 32% in the CABG group (HR with CABG 0.80, 95% CI 0.63–1.02). While numerically it would appear that the treatment effect of CABG is blunted in patients with DM, there was no significant interaction between DM and treatment group on formal statistical testing. Conclusions Patients with DM enrolled in the STICH trial had more triple vessel disease, smaller hearts, and higher LVEF than those without DM. CABG did not exert greater benefit in patients with DM.

Background— Whether mitral valve repair during coronary artery bypass grafting (CABG) improves survival in patients with ischemic mitral regurgitation (MR) remains unknown. Methods and Results— Patients with ejection fraction ≤35% and coronary artery disease amenable to CABG were randomized at 99 sites worldwide to medical therapy with or without CABG. The decision to treat the mitral valve during CABG was left to the surgeon. The primary end point was mortality. Of 1212 randomized patients, 435 (36%) had none/trace MR, 554 (46%) had mild MR, 181 (15%) had moderate MR, and 39 (3%) had severe MR. In the medical arm, 70 deaths (32%) occurred in patients with none/trace MR, 114 (44%) in those with mild MR, and 58 (50%) in those with moderate to severe MR. In patients with moderate to severe MR, there were 29 deaths (53%) among 55 patients randomized to CABG who did not receive mitral surgery (hazard ratio versus medical therapy, 1.20; 95% confidence interval, 0.77–1.87) and 21 deaths (43%) among 49 patients who received mitral surgery (hazard ratio versus medical therapy, 0.62; 95% confidence interval, 0.35–1.08). After adjustment for baseline prognostic variables, the hazard ratio for CABG with mitral surgery versus CABG alone was 0.41 (95% confidence interval, 0.22–0.77; P =0.006). Conclusion— Although these observational data suggest that adding mitral valve repair to CABG in patients with left ventricular dysfunction and moderate to severe MR may improve survival compared with CABG alone or medical therapy alone, a prospective randomized trial is necessary to confirm the validity of these observations. Clinical Trial Registration— URL: http://www.clinicaltrials.gov . Unique identifier: NCT00023595.