Citations

Background Diabetes mellitus (DM) is a risk factor for morbidity and mortality in patients with heart failure. The effect of DM on post–left ventricular assist device (LVAD) implantation outcomes is unclear. This study sought to investigate whether patients with DM had worse outcomes than patients without DM after LVAD implantation and whether LVAD support resulted in a better control of DM. Methods and Results We retrospectively reviewed 341 consecutive adults who underwent implantation of LVAD from 2007 to 2016. Patient characteristics and adverse events were studied and compared between patients with and without DM. One hundred thirty-one patients (38%) had DM. Compared with patients without DM, those with DM had higher rates of ischemic cardiomyopathy, LVAD implantation as destination therapy, and increased baseline body mass index. In a proportional hazards (Cox) model with adjustment for relevant covariates and median follow-up of 16.1 months, DM was associated with increased risk of all-cause mortality (hazard ratio, 1.73; 95% confidence interval: 1.18–2.53; P =0.005) and increased risk of nonfatal LVAD-related complications, including a composite of stroke, pump thrombosis, and device infection (hazard ratio, 2.1; 95% confidence interval: 1.35–3.18; P =0.001). Preoperative hemoglobin A1c was not significantly associated with mortality or adverse events among patients with DM. LVAD implantation resulted in a remarkable decrease in hemoglobin A1c levels (7.4±1.9 pre-LVAD versus 6.0±1.5 and 6.3±1.4 after 3 and 12 months post-LVAD, respectively; P <0.0001) and a significant reduction in requirements of DM medications. Conclusions DM is associated with increased rates of all-cause mortality and major adverse events despite favorable glycemic control after LVAD implantation.

Atrial fibrillation (AF) and tricuspid regurgitation (TR) are common in patients undergoing left ventricular assist device (LVAD) implantation. TR progression is associated with the presence of AF, and questions remain as to who benefits from tricuspid valve procedures (TVPs). We examined the impact of preoperative AF on TR progression after LVAD implantation. From February 2007 to May 2014, 250 patients underwent LVAD implantation at our institution. Patients with concomitant TVP were excluded from this analysis (113 patients). The indication for LVAD was destination therapy in 80 patients (58%) and the etiology of heart failure was ischemic in 73 (53%). Follow-up was available in all early survivors for a total of 393 patient-years of support. Of the 137 non-TVP patients, 52 (38%) had AF preoperatively. Observed overall survival at 1, 3, and 5 years was 82%, 67%, and 55%, respectively. Median grade of TR increased from 2 preoperatively to 3 (p = 0.04) in the AF group and 2.2 (p = 0.75) in the non-AF group at 5 years of follow-up. We also observed a significant difference in the degree of TR between groups at 3 months (p = 0.03) and 12 months (p = 0.01) postimplantation, and a trend toward significance at 18 (p = 0.06) and 24 (p = 0.07) months. The presence of AF is associated with early progression of TR after LVAD implantation. Addition of concomitant TVP in patients with preoperative AF may be considered in patients with less than severe TR. The impact of these findings on right ventricular failure/remodeling remains to be evaluated.

Wait times have increased for patients approved for heart transplants. We reviewed United Network for Organ Sharing (UNOS) data for 14,242 patients listed for isolated heart transplant (2009–2013) to develop a risk score model for timing left ventricular assist device (LVAD) implantation in bridge-to-transplant patients. We used a multivariable Cox proportional hazards regression model with subsequent bootstrap resampling for internal validation to develop a scoring system that combined risk factors, weighted by the corresponding regression coefficients, to define an individual’s risk score. Four risk factors were identified (body mass index, blood type, region, and urgency status) to be significantly and independently associated with wait time (p < 0.001), showing adequate model discrimination (C = 0.704) and calibration. Higher risk scores correlated with shorter wait times. Our model corresponded closely with observed transplant rates, predicting longer wait times for lower status, larger size, certain blood groups, and some UNOS regions. This tool has the potential to more accurately describe the wait-time duration for an individual patient, which may influence care decisions. The wait-time discrepancies (blood types/regions) reinforce the need to reevaluate the geographic-allocation policy. The proposed review of the UNOS heart allocation policy may make this model especially relevant.

Although improvement in cardiac output and hemodynamic parameters is routinely demonstrated in patients implanted with continuous-flow left ventricular assist devices (CF-LVADs), improvement in exercise capacity is inconsistently seen. Our purpose was to determine whether native cardiac factors, LVAD factors, or comorbid factors were associated with lack of improvement. Review of all patients undergoing preimplant cardiopulmonary exercise testing (CPET) and CPET on LVAD therapy at one institution was performed between 2007 and 2014 (n = 49). Comprehensive assessment of echocardiographic parameters, right heart catheterization data, medications, and comorbid illness was undertaken. There was no mean improvement in peak oxygen consumption (VO2; 11.8–12.4 ml/kg/min; p = 0.26), although exercise time (5.1 [46% predicted] to 5.8 min [56% predicted]; p = 0.02) and nadir of the ratio of minute ventilation to carbon dioxide production slope (VE/VCO2; 39–36; p = 0.001) improved. Factors most strongly associated with improvement in VO2 were Heartmate II pulsatility index (PI; R = 0.48; p = 0.001), power (R = −0.40; p = 0.009), pump flow (R = −0.40; p = 0.008), and pump speed (R = −0.32; p = 0.04). Peak heart rate (HR) was also associated with improvement in VO2 (R = 0.41; p = 0.004). Left ventricular ejection fraction (LVEF; R = 0.004; p = 0.77), right ventricular (RV) function (R = 0.22; p = 0.28), and aortic valve opening (R = 0.20; p = 0.57) were not associated with improvement in VO2. Our data suggest that less reliance on LVAD support was modestly associated with improvement in exercise capacity. Further studies should seek to determine the optimal level of device support prospectively in relation to exercise capacity.

Abstract Background: In vivo synergy with concurrent PI3-Kinase inhibition and PARP inhibition has been observed in BRCA-deficient and BRCA-proficient preclinical models of triple negative breast cancer (TNBC) and ovarian cancer (OC). A phase I trial of the oral pan-class I PI3-Kinase inhibitor BKM120 and the PARP inhibitor olaparib demonstrated anti-cancer activity in TNBC and OC, both in patients with and without germline BRCA1 and BRCA2 (BRCA) mutations. However, CNS toxicity (depression) and liver function test abnormalities limited dose escalation of BKM120 prompting evaluation of the alpha specific PI3-Kinase inhibitor BYL719 (which has no CNS toxicity) in combination with olaparib. Methods: Olaparib was administered twice daily (tablet formulation) and BYL719 daily on a 28-day cycle, both orally. A 3 + 3 dose-escalation design was employed with primary objectives of defining the maximum tolerated dose (MTD) and recommended phase 2 dose of the combination of BYL719 and olaparib, and secondary objectives of defining toxicity, activity, and pharmacokinetic profiles of both agents. Eligibility included recurrent TNBC or high grade serous (HGS) OC, or any histology OC or breast cancer (BC) with presence of a known germline BRCA mutation, performance status of 0-1 and measurable/evaluable cancer. Patients with platinum sensitive or resistant or refractory OC were eligible and prior PARP inhibitor use was allowed. Dose-expansion cohorts at the MTD were enrolled for both BC and OC. Results: 46 patients (16 BC and 30 OC) have been enrolled in the study; 28 patients participated in the dose escalation portion of the study (4 BC and 24 OC). Two patients with OC did not receive study drugs because of ineligibility. MTD was defined as BYL719 200mg once daily and olaparib 200mg twice daily. Dose limiting toxicities included hyperglycemia, rash and fever with decreased neutrophil count. Four patients (3 OC and 1 BC) discontinued protocol therapy because of toxicity (2 for hyperglycemia, 1 for nausea and 1 for allergic reaction). Most common toxicities included nausea, hyperglycemia, fatigue, diarrhea and vomiting. At the MTD, 6 patients with OC and 12 patients with BC were enrolled into a dose expansion cohort. The OC expansion cohort has completed enrollment, while the BC cohort is still enrolling. Among patients with OC who received study drugs (28 patients, 26 (93%) with platinum resistant disease), objective response rate (ORR) by RECIST 1.1 was 36% (10/28 patients, all partial responses (PRs)). Median duration of response was 167 days (range 16-398 days); 5 of 10 patients with PR remain on treatment. ORR was 33% for patients with germline BRCA mutations and 31% for patients without germline BRCA mutations. Among patients without germline BRCA mutations with platinum resistant OC, ORR was 29%. Conclusions: Combined BYL719 and olaparib is feasible, and similar clinical benefit was observed in patients with and without germline BRCA mutations. The activity of this combination in OC patients without germline BRCA mutations and with platinum resistant disease was higher than expected from olaparib monotherapy and warrants further investigation. This work was funded in part by the Stand Up To Cancer Ovarian Dream Team. Clinical trial: NCT01623349. Citation Format: Panagiotis A. Konstantinopoulos, William T. Barry, Michael Birrer, Shannon N. Westin, Sarah Farooq, Karen Cadoo, Christin Whalen, Weixiu Luo, Hui Liu, Carol Aghajanian, David B. Solit, Gordon B. Mills, Barry S. Taylor, Helen Won, Michael F. Berger, Sangeetha Palakurthi, Joyce F. Liu, Lew Cantley, Scott H. Kaufmann, Elizabeth M. Swisher, Alan D. D'Andrea, Eric Winer, Gerburg M. Wulf, Ursula A. Matulonis. Phase I study of the alpha specific PI3-Kinase inhibitor BYL719 and the poly (ADP-Ribose) polymerase (PARP) inhibitor olaparib in recurrent ovarian and breast cancer: Analysis of the dose escalation and ovarian cancer expansion cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr CT008. doi:10.1158/1538-7445.AM2017-CT008

Reversal of pulmonary hypertension has been observed in patients during a bridge to transplant with a left ventricular assist device. Total artificial heart (TAH) implant prevents subsequent right heart catheterization. Consequently, controversy exists over whether the prosthetic right ventricle improves or exacerbates pulmonary hypertension. A pulmonary artery (PA) pressure monitor was placed in two patients undergoing TAH implant, as a bridge to transplant. One patient had pulmonary hypertension at implant; the other had normal pulmonary pressures. Daily measurements were taken of systolic, diastolic, and mean PA pressures throughout support. Patient 1 received successful transplant after TAH support of 91 days. Systolic/diastolic (mean) PA pressures steadily decreased from 55/39 (28) mm Hg at implant to 29/18 (7) mm Hg currently. Patient 2 received support for 101 days before death due to abdominal ischemic complications. Pulmonary arterial pressures stayed consistent throughout this period, from 26/17 (20) mm Hg at implant to 23/13 (17) mm Hg at the time of death. These findings suggest that an implantable PA pressure monitor may be useful in optimizing hemodynamics and planning appropriate timing of transplant with TAH support.

ObjectivesTo describe acute and mid‐term results of hybrid perventricular device closure of muscular ventricular septal defects (mVSDs).BackgroundPerventricular device closure of mVSDs can mitigate technical limitations of percutaneous closure and need for cardiopulmonary bypass or ventriculotomy with a surgical approach.MethodsThis is a multicenter retrospective cohort study of patients undergoing hybrid perventricular mVSD device closure from 1/2004 to 1/2014. Procedural details, adverse events, outcomes, and follow‐up data were collected. Patients were divided into two groups: (1) simple (mVSD closure alone) and (2) complex (mVSD closure with concomitant cardiac surgery).ResultsForty‐seven patients (60% female) underwent perventricular mVSD device closure at a median age of 5.2 months (IQR 1.8–8.9) and weight of 5.1 kg (IQR 4.0–6.9). Procedural success was 91% [100% (n = 22) simple and 84% (n = 21/25) complex]. Adverse events occurred in 19% (9/47) [9% (2/22) simple and 28% (7/25) complex]. Hospital length of stay (LOS) was shorter in the simple vs. complex group (4 vs. 14 days, P < 0.01). At mid‐term follow‐up of 19.2 months (IQR 2.3–43) 90% of pts had complete mVSD closure; none developed late heart block, increased atrioventricular (AV) valve insufficiency or ventricular dysfunction.ConclusionsPerventricular device closure of simple mVSD was associated with a high rate of procedural success, few adverse events, and short hospital LOS. Procedural adverse events were associated with the presence of concomitant complex surgery. Residual mVSD, AV valve insufficiency, or ventricular dysfunction were uncommon at mid‐term follow‐up. © 2017 Wiley Periodicals, Inc.

Abstract Purpose: Little is known about the molecular signatures associated with specific metastatic sites in breast cancer. Using comprehensive multi-omic molecular profiling, we assessed whether alterations or activation of the PI3K–AKT–mTOR pathway is associated with specific sites of breast cancer metastasis. Experimental Design: Next-generation sequencing–based whole-exome sequencing was coupled with reverse-phase protein microarray (RPPA) functional signaling network analysis to explore the PI3K–AKT–mTOR axis in 32 pretreated breast cancer metastases. RPPA-based signaling data were further validated in an independent cohort of 154 metastatic lesions from breast cancer and 101 unmatched primary breast tumors. The proportion of cases with PI3K–AKT–mTOR genomic alterations or signaling network activation were compared between hepatic and nonhepatic lesions. Results: PIK3CA mutation and activation of AKT (S473) and p70S6K (T389) were detected more frequently among liver metastases than nonhepatic lesions (P &lt; 0.01, P = 0.056, and P = 0.053, respectively). However, PIK3CA mutations alone were insufficient in predicting protein activation (P = 0.32 and P = 0.19 for activated AKT and p70S6K, respectively). RPPA analysis of an independent cohort of 154 tumors confirmed the relationship between pathway activation and hepatic metastasis [AKT (S473), mTOR (S2448), and 4EBP1 (S65); P &lt; 0.01, P = 0.02, and P = 0.01, respectively]. Similar results were also seen between liver metastases and primary breast tumors [AKT (S473) P &lt; 0.01, mTOR (S2448) P &lt; 0.01, 4EBP1 (S65) P = 0.01]. This signature was lost when primary tumors were compared with all metastatic sites combined. Conclusions: Breast cancer patients with liver metastasis may represent a molecularly homogenized cohort with increased incidence of PIK3CA mutations and activation of the PI3K–AKT–mTOR signaling network. Clin Cancer Res; 23(16); 4919–28. ©2017 AACR.

Abstract Lysinibacillus massiliensis, formerly Bacillus massiliensis, is an environmental Gram-positive bacillus that is generally non-pathogenic. Rare case reports in immunosuppressed patients have described sepsis with this organism. In this study, we report a case of L massiliensis as a cause of infectious panniculitis mimicking erythema nodosum after infusion of autologous adipose-derived stem cells in an immunosuppressed patient with refractory Crohn’s disease. This case highlights the importance of care providers to consider exposures and host factors when interpreting culture results with otherwise benign organisms.