Concurrent inhibition of CDK2 adds to the anti-tumour activity of CDK4/6 inhibition in GIST.

BACKGROUND: Advanced gastrointestinal stromal tumour (GIST) is characterised by genomic perturbations of key cell cycle regulators. Oncogenic activation of CDK4/6 results in RB1 inactivation and cell cycle progression. Given that single-agent CDK4/6 inhibitor therapy failed to show clinical activity in advanced GIST, we evaluated strategies for maximising response to therapeutic CDK4/6 inhibition. METHODS: Targeted next-generation sequencing and multiplexed protein imaging were used to detect cell cycle regulator aberrations in GIST clinical samples. The impact of inhibitors of CDK2, CDK4 and CDK2/4/6 was determined through cell proliferation and protein detection assays. CDK-inhibitor resistance mechanisms were characterised in GIST cell lines after long-term exposure. RESULTS: We identify recurrent genomic aberrations in cell cycle regulators causing co-activation of the CDK2 and CDK4/6 pathways in clinical GIST samples. Therapeutic co-targeting of CDK2 and CDK4/6 is synergistic in GIST cell lines with intact RB1, through inhibition of RB1 hyperphosphorylation and cell proliferation. Moreover, RB1 inactivation and a novel oncogenic cyclin D1 resulting from an intragenic rearrangement (CCND1::chr11.g:70025223) are mechanisms of acquired CDK-inhibitor resistance in GIST. CONCLUSIONS: These studies establish the biological rationale for CDK2 and CDK4/6 co-inhibition as a therapeutic strategy in patients with advanced GIST, including metastatic GIST progressing on tyrosine kinase inhibitors.

Primary intra-abdominal melanoma arising in association with extracutaneous blue naevus: a report of two cases.

AIMS: Blue naevi are uncommon dermal melanocytic neoplasms characterised by GNAQ/GNA11 mutations, which very rarely progress to melanoma. Such melanomas also often have BAP1 mutations, and lack genetic events associated with conventional melanoma. Exceptionally, blue naevi arise in extracutaneous locations; one melanoma arising in this setting has been reported. We report the clinicopathological, immunohistochemical and molecular genetic features of two cases of melanoma arising in extracutaneous blue naevus. METHODS AND RESULTS: Both arose in males, aged 25 and 63 years, with no history of other melanocytic lesions, and presented as large, painful intra-abdominal masses. The tumours were dark-brown/black, multilobulated, involved small intestinal mesentery and consisted of a predominantly fascicular and spindled, but occasionally nested and epithelioid, proliferation of variably pigmented, relatively monotonous cells with pale cytoplasm and ovoid nuclei with mild to moderate atypia. Mitotic activity was variable but generally low. Both cases showed areas of conventional and cellular blue naevus. Recurrent tumour in one case showed predominantly epithelioid morphology and greater cytological atypia and mitotic activity. One case expressed Melan-A, SOX10 and CD117, with absent expression of S100 protein and DOG1; the other expressed Melan-A, HMB45 and S100 protein. Next-generation sequencing identified GNAQ and BAP1 mutations in one case and GNA11 mutation in the other. Both patients developed widespread metastatic disease. CONCLUSION: Exceptionally rare, aggressive melanomas arising in extracutaneous blue naevi should be distinguished from metastatic melanoma, gastrointestinal stromal tumour and malignant melanotic nerve sheath tumour, especially given the significant therapeutic and prognostic differences between these different entities.

Acute Kidney Injury With Ventricular Assist Device Placement: National Estimates of Trends and Outcomes.

RATIONALE & OBJECTIVE: Ventricular assist devices (VADs) are used for end-stage heart failure not amenable to medical therapy. Acute kidney injury (AKI) in this setting is common due to heart failure decompensation, surgical stress, and other factors. Little is known about national trends in AKI diagnosis and AKI requiring dialysis (AKI-D) and associated outcomes with VAD implantation. We investigated national estimates and trends for diagnosed AKI, AKI-D, and associated patient and resource utilization outcomes in hospitalizations in which implantable VADs were placed. STUDY DESIGN: Cohort study of 20% stratified sample of US hospitalizations. SETTING & PARTICIPANTS: Patients who underwent implantable VAD placement in 2006 to 2015. EXPOSURE: No AKI diagnosis, AKI without dialysis, AKI-D. OUTCOMES: In-hospital mortality, length of stay, estimated hospitalization costs. ANALYTICAL APPROACH: Multivariate logistic and linear regression using survey design methods to account for stratification, clustering, and weighting. RESULTS: An estimated 24,140 implantable VADs were placed, increasing from 853 in 2006 to 3,945 in 2015. AKI was diagnosed in 56.1% of hospitalizations and AKI-D occurred in 6.5%. AKI diagnosis increased from 44.0% in 2006 to 2007 to 61.7% in 2014 to 2015; AKI-D declined from 9.3% in 2006 to 2007 to 5.2% in 2014 to 2015. Mortality declined in all AKI categories but this varied by category: those with AKI-D had the smallest decline. Adjusted hospitalization costs were 19.1% higher in those with diagnosed AKI and 39.6% higher in those with AKI-D, compared to no AKI. LIMITATIONS: Administrative data; timing of AKI with respect to VAD implantation cannot be determined; limited pre-existing chronic kidney disease ascertainment; discharge weights not derived for subpopulation of interest. CONCLUSIONS: A decreasing proportion of patients undergoing VAD implantation experience AKI-D, but mortality among these patients remains high. AKI diagnosis with VAD implantation is increasing, possibly reflecting changes in AKI surveillance, awareness, and coding.

Effect of concomitant mitral valve procedures for severe mitral regurgitation during left ventricular assist device implantation.

The effect of performing a concomitant mitral valve procedure (MVP) during continuous-flow left ventricular assist device (CF-LVAD) implantation has been reported for patients with moderate-to-severe mitral regurgitation (MR), but moderate MR is less of a clinical concern for CF-LVAD patients. There is a paucity of reports focusing on patients with severe MR. Thus, the purpose of this study was to analyze the effect of performing a concomitant MVP during CF-LVAD implantation in patients with severe preoperative MR. Between November 2003 and March 2016, 526 patients underwent primary implantation of a CF-LVAD at our center. Patients with severe MR who underwent a concomitant MVP were compared to those who did not in regard to overall survival, perioperative complications, postoperative echocardiography data, bridge-to-transplantation success, and CF-LVAD explantation. Of the 108 patients with severe MR, 26 underwent a concomitant MVP and 82 did not. These groups showed no difference in survival (p = 0.61). Additionally, the two groups had similar rates of postoperative right heart failure (p = 0.69) and readmissions (p = 0.42). The 24-month follow-up echocardiography results were also similar. Furthermore, the groups showed no difference in bridge-to-cardiac transplantation success (30.0% vs 25.0%, p = 0.80) or CF-LVAD explantation rates (0.0% vs 0.0%. p = 1.0). Our findings suggest that patients with severe MR who undergo a MVP during CF-LVAD implantation do not have superior outcomes to those who do not. However, assessments of other outcomes may show some benefits to performing concomitant MVPs.

Severe LVAD-related infections requiring surgical treatment: Incidence, predictors, effect on survival, and impact of device selection.

BACKGROUND: Left ventricular assist devices (LVADs) are being used more frequently for treating refractory, advanced heart failure. However, infection remains a frequent complication. In this study, we analyzed the incidence of severe infections in LVAD recipients to determine its impact on survival. METHODS: From May 2009 through March 2016, 437 patients with advanced heart failure underwent implantation of a continuous-flow LVAD (n = 314, HeartMate II LVAD [Abbott Laboratories, Abbott Park, IL]; n = 123 HeartWare HVAD [Medtronic, Minneapolis, MN]). We analyzed the rate of severe device infection requiring surgical intervention or involving sepsis and the impact of severe infection on outcomes in patients on long-term LVAD support. RESULTS: Infection occurred in 244 patients (HeartMate II, n = 186; HVAD, n = 58); severe infections developed in 160 patients (HeartMate II, n = 119; HVAD, n = 41). HeartMate II recipients had 344 severe infection events (0.63 events per patient-year [EPPY]), whereas HeartWare recipients had 89 severe infection events (0.42 EPPY; P = 0.047). HeartMate II recipients had a higher incidence of pump infections (P < 0.001). Severe infections did not significantly affect survival (P = 0.42). CONCLUSIONS: Although HeartMate II patients had a significantly higher incidence of pump infections requiring surgical treatment, survival was not adversely affected. The difference in postoperative infection rates may be an important factor in device type selection.

Device exchange from Heartmate II to HeartWare HVAD.

BACKGROUND: Despite technological advancements, pump durability and pump-related complications continue to affect and adversely impact the lives of patients with end-stage heart failure on left ventricular assist device (LVAD) support. In an attempt to avoid recurrent LVAD-related complications, there may be circumstances where it is clinically advantageous to exchange a patient's device from HeartMate II to HeartWare HVAD. However, there is a paucity of data that describes the safety and feasibility of such an approach. OBJECTIVE: We present the largest single-center series of HeartMate II (HMII) to HeartWare (HVAD) device exchanges. METHODS: A retrospective review of 11 patients who underwent HMII to HVAD exchange from 2012 to 2017 was conducted to evaluate patient characteristics, incidence of postoperative complications, and survival. RESULTS: Eleven male patients (mean age 55 ± 14.4 years) underwent HMII to HVAD device exchange. One patient expired on postoperative day 7 secondary to sepsis. One patient was lost-to-follow-up after 23 months. An additional three patients died at 5, 7, and 24 months. Mean follow-up after device exchange was 1555 ± 311 days for the remaining six patients. None of the 11 study patients underwent LVAD explant, further device exchange, or heart transplant. CONCLUSION: Exchange of an HMII LVAD to an HVAD can be performed safely with acceptable perioperative morbidity and mortality.

Bridging to a Long-Term Ventricular Assist Device With Short-Term Mechanical Circulatory Support.

Implanting short-term mechanical circulatory support (MCS) devices as a bridge-to-decision is increasingly popular. However, outcomes have not been well studied in patients who receive short-term MCS before receiving long-term left ventricular assist device (LVAD) support. We analyzed outcomes in our single-center experience with long-term continuous-flow (CF)-LVAD recipients with pre-implantation short-term MCS. From November 2003 through March 2016, 526 patients (mean age, 54.7 ± 13.5 years) with chronic heart failure (mean ejection fraction, 21.7 ± 3.6%) underwent implantation of either the HeartMate II (n = 403) or the HeartWare device (n = 123). Before implantation, 269 patients received short-term MCS with the TandemHeart, the Impella 2.5/5.0, an intra-aortic balloon pump (IABP), venoarterial extracorporeal membrane oxygenation (VA-ECMO), or the CentriMag. The short-term MCS patients were compared with the CF-LVAD-only patients regarding preoperative demographics, incidence of postoperative complications, and long-term survival. The 269 patients received the following short-term MCS devices: 57 TandemHeart, 27 Impella, 172 IABP, 12 VA-ECMO, and 1 CentriMag. Survival at 30 days, 6 months, 1 year, and 2 years was 94.2, 87.2, 79.4, and 72.4%, respectively, for CF-LVAD-only patients versus 91.0, 78.1, 73.4, and 65.6%, respectively, for short-term MCS + CF-LVAD patients (P = 0.17). Within the short-term MCS group, survival at 24 months was poorest for patients supported with VA-ECMO or the TandemHeart (P = 0.03 for both), and survival across all four time points was poorest for patients supported with VA-ECMO (P = 0.02). Short-term MCS was not an independent predictor of mortality in multivariate Cox regression models (hazard ratio = 1.12, 95% confidence interval = 0.84-1.49, P = 0.43). In conclusion, we found that using short-term MCS therapy-except for VA-ECMO-as a bridge to long-term CF-LVAD support was not associated with poorer survival.

HeartMate II implantation technique that spares the sternum and ascending aorta.

Left ventricular assist devices (LVADs) have become the standard therapy for patients with end-stage heart failure, and the use of LVADs for long-term support has grown exponentially over the past decade. As the number of LVAD implantations has increased, surgeons have faced more challenging cases, such as those in which the patient has previously undergone a sternotomy. The HeartMate II is one of the most widely implanted LVADs. The standard procedure for HeartMate II implantation is median sternotomy and sewing the outflow graft to the ascending aorta. However, in patients with sternal comorbidities, it can be advantageous to use a less invasive approach that avoids this procedure. We describe the case of a 64-year-old man with a history of end-stage ischemic cardiomyopathy who had previously undergone a median sternotomy and a coronary artery bypass grafting operation and had patent grafts. He required a HeartMate II LVAD (destination therapy), which was implanted via a left subcostal incision; the pump was placed subdiaphragmatically, and the outflow graft was sewed to the descending aorta to avoid a complicated redo cardiac operation via median sternotomy and to minimize the risk of injuring the patent bypass grafts. The patient survived for more than 500 days postoperatively. This approach is feasible and could be a safer method for implanting a HeartMate II device in patients with serious comorbidities that preclude the use of the traditional implantation techniques.

Outcomes in patients with advanced heart failure and small body size undergoing continuous-flow left ventricular assist device implantation.

Left ventricular assist devices (LVADs) have become a preferred treatment option for patients with end-stage heart failure when used as a bridge to transplant or as a destination therapy. However, the association between small body size and postoperative outcomes for continuous-flow (CF) LVAD recipients is still being studied. We sought to determine whether body surface area (BSA) is associated with patient outcomes after CF-LVAD implantation. The study cohort of our single-center, retrospective review consisted of all patients (n = 526) who underwent CF-LVAD implantation (n = 403 HeartMate II, n = 123 HeartWare) between November 2003 and March 2016 regardless of indication. Patients were stratified into 2 cohorts according to their BSA measurements: small BSA (<1.5 m2, n = 13) and non-small BSA (≥1.5 m2, n = 513). We compared the survival of the small-BSA cohort with that of the non-small-BSA cohort. Patients with a small BSA had lower survival rates at 1, 6, 12, and 24 months (76.9, 61.5, 53.8, and 38.5%, respectively) than did patients with a non-small BSA (90.4, 80.9, 74.7, and 67.6% respectively; overall, p = 0.004). Cox proportional hazard analysis showed that a small BSA was an independent predictor of postoperative mortality (hazard ratio = 0.22, 95% confidence interval = 0.05-0.97, p < 0.04). These findings highlight the adverse impact of a small BSA on outcomes after CF-LVAD implantation.

Effect of obesity on outcomes in patients undergoing implantation of continuous-flow left ventricular assist devices.

The purpose of this study was to analyze the effect of obesity on outcomes after continuous-flow left ventricular assist device (CF-LVAD) implantation. A single-center retrospective analysis was performed on 526 chronic heart failure patients who were implanted with the HeartMate II CF-LVAD (n = 403) or HeartWare HVAD (n = 123) between November 2003 and March 2016. Patients were stratified into 4 groups based on BMI: underweight (< 18.5 kg/m2, n = 18, 3.4%), normal-weight (18.5-25 kg/m2, n = 173, 32.9%), overweight (25-30 kg/m2, n = 182, 30.2%), and obese (> 30 kg/m2, n = 153, 33.5%). The underweight group was excluded because of its small sample size. Records were reviewed to determine the incidence of postoperative complications and survival. Survival at 1, 6, 12, and 24 months were similar among normal-weight (91.3, 84.4, 76.3, and 67.6%), overweight (90.4, 80.8, 76.5, and 69.6%), and obese patients (90.7, 74.7, 65.3, and 61.3%, p = 0.24). Additionally, obesity was not a significant predictor of mortality in Cox proportional hazard models (hazard ratio 0.98, 95% confidence interval 0.766-1.277, p = 0.13). These findings suggest that appropriately selected obese patients receive similar survival benefit from CF-LVADs compared to non-obese patients, and obesity should not serve as a contraindication to CF-LVAD implantation.

Acute kidney injury after implantation of a left ventricular assist device: a comparison of axial-flow (HeartMate II) and centrifugal-flow (HeartWare HVAD) devices.

Continuous-flow left ventricular assist devices (CF-LVADs) are increasingly being used to treat advanced, refractory chronic heart failure. Herein, we sought to determine the incidence of postoperative acute kidney injury (AKI) in axial-flow (HeartMate II; HM-II) and centrifugal-flow (HVAD) CF-LVAD recipients, as well as the effect of AKI on mortality. The study cohort comprised 520 patients who received a HM-II (n = 398) or HVAD (n = 122) at our center between November 2003 and March 2016. Their records were reviewed to determine the incidence of RIFLE-defined AKI after LVAD implantation. We compared the perioperative characteristics, postoperative complications, and survival rates of the patients with and without AKI and differentiated the outcomes based on device type (HM-II or HVAD). Seventy-five patients (14.4%) developed AKI postoperatively. Patients with AKI after LVAD implantation had significantly reduced survival compared to patients without AKI (p = 0.01). Cox proportional hazards models showed that AKI was a significant independent predictor of mortality (HR = 1.54, p = 0.03). Preoperative mechanical circulatory support and prolonged cardiopulmonary bypass time were independent predictors of AKI. The incidence of AKI was similar for HM-II and HVAD recipients (p = 0.25). There was no significant difference in AKI rates for the HM-II and HVAD recipients. Developing AKI adversely affected survival.

Predictive value of preoperative serum albumin levels on outcomes in patients undergoing LVAD implantation.

BACKGROUND: We performed a single-center retrospective analysis to determine whether preoperative serum albumin levels were associated with postoperative adverse events and short- and long-term survival in patients who underwent continuous-flow left ventricular assist device (CF-LVAD) implantation. METHODS: From November 2003 through March 2016, 526 patients underwent CF-LVAD implantation. Patients whose preoperative serum albumin level was normal (≥3.5 g/dL) were compared to patients with preoperative hypoalbuminemia (<3.5 g/dL), which was further categorized as moderate (2.5-3.5 g/dL) or severe (<2.5 g/dL). These groups were compared regarding preoperative demographics, incidence of postoperative complications, and long-term survival. RESULTS: Patients with hypoalbuminemia had higher serum levels of liver enzymes (P < 0.05) and total bilirubin (P < 0.001) and significantly lower platelet counts (P = 0.02) and prealbumin levels (P < 0.001) than patients with normal preoperative albumin levels. Survival in patients with moderate and severe preoperative hypoalbuminemia was significantly decreased compared with patients with normal preoperative serum albumin levels (P < 0.001). Preoperative hypoalbuminemia was also associated with higher incidences of postoperative infection, gastrointestinal bleeding, neurological dysfunction, and acute kidney injury (P ≤ 0.01 for all) but did not affect the success of bridge to transplantation or survival after transplantation. CONCLUSIONS: Our data demonstrated that there is a significant association of preoperative low serum albumin levels with postoperative adverse outcomes and lower survival rates. This highlights the importance of a patient's preoperative nutritional status on postoperative outcomes after CF-LVAD implantation.

Immunotherapy with single agent nivolumab for advanced leiomyosarcoma of the uterus: Results of a phase 2 study.

BACKGROUND: Immunotherapy has changed the therapeutic landscape in oncology. Advanced uterine leiomyosarcoma (ULMS) remains an incurable disease in most cases, and despite new drug approvals, improvements in overall survival have been modest at best. The goal of this study was to evaluate programmed-death 1 (PD-1) inhibition with nivolumab in this patient population. METHODS: This single-center phase 2 trial completed enrollment between May and October 2015. Patients received 3 mg/kg of intravenous nivolumab on day 1 of each 2-week cycle until disease progression or unacceptable toxicity. The primary endpoint was objective response rate. We assessed PD-1, PD-ligand 1 (PD-L1), and PD-L2 expression in archival tumor samples and variations in immune-phenotyping of circulating immune cells during treatment. RESULTS: Twelve patients were enrolled in the first stage of the 2-stage design. A median of 5 (range, 2-6) 2-week cycles of nivolumab were administered. Of the 12 patients, none responded to treatment. The overall median progression-free survival was 1.8 months (95% confidence interval, 0.8-unknown). The study did not open the second stage due to lack of benefit as defined by the statistical plan. Archival samples were available for 83% of patients. PD-1 (>3% of cells), PD-L1, and PD-L2 (>5% and >10% of tumor cells, respectively) expression were observed in 20%, 20%, and 90% of samples, respectively. No significant differences were observed between pre- and posttreatment cell phenotypes. CONCLUSION: Single-agent nivolumab did not demonstrate a benefit in this cohort of previously treated advanced ULMS patients. Further biomarker-driven approaches and studies evaluating combined immune checkpoint-modulators should be considered. Cancer 2017;123:3285-90. © 2017 American Cancer Society.

Left ventricular outflow tract closure during LVAD implantation: 2 cases of patients supported for over 6 years.

We previously reported a series of 5 patients with advanced heart failure and aortic insufficiency (AI) who underwent concomitant left ventricular outflow tract (LVOT) closure at the time of continuous-flow left ventricular assist device (CF-LVAD) implantation. Although this technique of treating AI has been shown to be effective in the short term, its long-term durability has not been well studied. Here, we report the long-term outcomes of two patients with severe AI who underwent LVOT closure at the time of CF-LVAD implantation. Each of the two patients survived for more than 6 years without any complications related to LVOT closure.

Total artificial heart implantation for biventricular failure due to eosinophilic myocarditis.

Idiopathic hypereosinophilic syndrome is a condition of unknown etiology characterized by proliferation of eosinophils and their infiltration into tissues. Although cardiac involvement is rare, eosinophilic myocarditis can lead to life-threating fulminant congestive heart failure. Treatment of patients with eosinophilic myocarditis is challenging as heart failure can be caused by biventricular dysfunction. To our knowledge, this is the first case reported in the literature describing a patient with acute severe biventricular heart failure caused by eosinophilic myocarditis with mural left ventricular apical thrombus who was successfully treated with implantation of a total artificial heart as a bridge to heart transplant.

Clinical utility of carotid duplex ultrasound prior to cardiac surgery.

OBJECTIVE: Clinical utility and cost-effectiveness of carotid duplex examination prior to cardiac surgery have been questioned by the multidisciplinary committee creating the 2012 Appropriate Use Criteria for Peripheral Vascular Laboratory Testing. We report the clinical outcomes and postoperative neurologic symptoms in patients who underwent carotid duplex ultrasound prior to open heart surgery at a tertiary institution. METHODS: Using the combined databases from our clinical vascular laboratory and the Society of Thoracic Surgery, a retrospective analysis of all patients who underwent carotid duplex ultrasound within 13 months prior to open heart surgery from March 2005 to March 2013 was performed. The outcomes between those who underwent carotid duplex scanning (group A) and those who did not (group B) were compared. RESULTS: Among 3233 patients in the cohort who underwent cardiac surgery, 515 (15.9%) patients underwent a carotid duplex ultrasound preoperatively, and 2718 patients did not (84.1%). Among the patients who underwent carotid screening vs no screening, there was no statistically significant difference in the risk factors of cerebrovascular disease (10.9% vs 12.7%; P = .26), prior stroke (8.2% vs 7.2%; P = .41), and prior transient ischemic attack (2.9% vs 3.3%; P = .24). For those undergoing isolated coronary artery bypass grafting (CABG), 306 (17.8%) of 1723 patients underwent preoperative carotid duplex ultrasound. Among patients who had carotid screening prior to CABG, the incidence of carotid disease was low: 249 (81.4%) had minimal or mild stenosis (<50%); 25 (8.2%) had unilateral moderate stenosis (50%-69%); 10 (3.3%) had bilateral moderate stenosis; 9 (2.9%) had unilateral severe stenosis (70%-99%); 5 (1.6%) had contralateral moderate stenosis; 2 (0.7%) had bilateral severe stenosis; 4 (1.3%) had unilateral occluded with contralateral less than 50% stenosis, 1 (0.3%) had unilateral occluded with contralateral (70%-99%) stenosis; and 1 had bilateral occluded carotid arteries. Primary outcomes of patients who underwent isolated CABG showed no difference in the perioperative mortality (2.9% vs 4.3%; P = .27) and stroke (2.9% vs 2.6%; P = .70) between patients undergoing preoperative duplex scanning and those who did not. Primary outcomes of patients who underwent open heart surgery also showed no difference in the perioperative mortality (5.1% vs 6.9%; P = .14) and stroke (2.6% vs 2.4%; P = .85) between patients undergoing preoperative duplex scanning and those who did not. Operative intervention of severe carotid stenosis prior to isolated CABG occurred in 2 of the 17 patients (11.8%) identified who underwent carotid endarterectomy with CABG. CONCLUSIONS: In this study, the correlation between preoperative duplex-documented high-grade carotid stenosis and postoperative stroke was low. Prudent use of preoperative carotid duplex ultrasound should be based on the presence of cerebrovascular symptoms and the type of open heart surgery.

Serotonin Syndrome Following Methylene Blue Administration for Vasoplegic Syndrome.

Methylene blue (MB) has been used for additional blood pressure support in patients who develop severe, refractory vasoplegia; however, MB can induce serotonin syndrome, especially when used in conjunction with other serotonergic agents. We describe a case of serotonin syndrome in a patient who received MB for vasoplegic syndrome after left ventricular assist device implantation and discuss its presentation and management.

Effect of Body Mass Index on Outcomes in Left Ventricular Assist Device Recipients.

BACKGROUND AND AIM: Obesity is associated with higher mortality following heart transplantation, but there remains no consensus regarding outcomes in left ventricular assist device (LVAD) recipients. We sought to determine the impact of body mass index (BMI) on outcomes in patients undergoing LVAD implantation. METHODS: This was a single-institution retrospective review, including all patients who received a HeartMate II LVAD or HeartWare HVAD between March 2006 and June 2014. Patients were stratified into three groups based on normal (<25 kg/m(2) ), overweight (25-30 kg/m(2) ), and obese (>30 kg/m(2) ) BMI. RESULTS: Two hundred patients were included in the analysis. Mean BMI was 28.3 kg/m(2) , (27% normal, 36% overweight, and 36.5% obese). Obese patients were younger (51.9 years, p = 0.03) and had higher incidence of diabetes (58.9% vs. 24.1%; p < 0.001) and peripheral vascular disease (16.4% vs. 1.9%; p = 0.03). Normal BMI patients were more likely to undergo LVAD implantation as destination therapy compared to the overweight and obese groups (67% vs. 39% vs. 51%; p = 0.01) and had higher incidence of postoperative stroke/transient ischemic attack (22.2% vs. 6.9% vs. 12.3%; p = 0.04) and postoperative bleeding requiring reoperation (27.8% vs. 12.5% vs. 9.6%; p = 0.01). Survival at one, three, and five years was similar across all BMI groups. BMI was not an independent predictor of overall survival. CONCLUSIONS: Appropriately-selected patients at the extremes of BMI can safely undergo LVAD implantation with no difference in survival. BMI should not in itself be considered a contraindication to LVAD placement.

Phase 1 study of oral abexinostat, a histone deacetylase inhibitor, in combination with doxorubicin in patients with metastatic sarcoma.

BACKGROUND: It has been demonstrated that several inhibitors of histone deacetylase (HDAC) can enhance chemotherapy-induced apoptosis and reduce sarcoma tumor volume in preclinical models. The authors sought to determine the maximum tolerated dose, pharmacokinetics/pharmacodynamics, safety, and toxicity of the HDAC inhibitor abexinostat (PCI-24781) when administered with doxorubicin to patients with metastatic sarcomas. METHODS: Participants were enrolled in a standard, phase 1, 3 + 3, dose-escalation study design. Abexinostat was administered on days 1 through 5 with 75 mg/m(2) of doxorubicin administered on day 4 of every 21-day cycle until patients developed disease progression or drug intolerance or reached a cumulative lifetime doxorubicin dose of 450 mg/m(2). Granulocyte-colony-stimulating factor (G-CSF) support was provided at physician discretion on arm A and was provided to all participants in arm B. From 3 to 6 participants initially received abexinostat 30 mg/m(2) twice daily, and subsequent cohorts were administered doses of 15 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily. All patients without progressive disease after receiving a cumulative lifetime doxorubicin dose of 450 mg/m(2) were given the option to continue with abexinostat as a single agent until they developed disease progression. RESULTS: In total, 22 participants (10 who had previously experienced tumor growth after doxorubicin therapy) were enrolled (6 in arm A, 14 in arm B), 20 were evaluable for dose-limiting toxicity (DLT), and 17 were evaluable for radiologic response. In arm A, participants received abexinostat 15 mg/m(2) or 30 mg/m(2) twice daily. DLTs of grade 3 and 4 neutropenia were observed in 2 of 3 participants who received abexinostat 30 mg/m(2) twice daily. Neither of those patients received G-CSF prophylaxis. In arm B, participants received abexinostat at doses of 30 mg/m(2), 45 mg/m(2), or 60 mg/m(2) twice daily, all with mandated G-CSF support. Two DLTs were observed at the 60 mg/m(2) twice-daily dose (grade 3 infection, grade 4 thrombocytopenia). The pharmacokinetics of abexinostat were not affected by doxorubicin. HDAC activity, as measured by histone acetylation in peripheral blood mononuclear cells, was maximally inhibited at the abexinostat 30 mg/m(2) twice-daily dose. Of the 17 participants who were evaluable for radiologic response, 1 patient had a partial response, 9 patients had stable disease, and 7 patients had progressive disease as their best response; and 8 patients completed ≥ 5 cycles. Three of those participants had stable disease as their most recent disease status when the current report was written. Four participants who continued on monotherapy remained in stable disease for a median of 9.8 weeks after completing doxorubicin. The most common toxicities were fatigue, thrombocytopenia, and anemia. No study-related deaths were observed. CONCLUSIONS: The maximum tolerated dose for abexinostat was 45 mg/m(2) twice daily administered on days 1 through 5 when patients received doxorubicin 75 mg/m(2) on day 4 of a 3-week cycle and G-CSF support was mandated. Toxicities were manageable, and tumor responses were observed. Additional studies are needed to further define the specific contributions of HDAC inhibition in patients who receive doxorubicin for the treatment of metastatic sarcoma.

Phase 2 trial of aromatase inhibition with letrozole in patients with uterine leiomyosarcomas expressing estrogen and/or progesterone receptors.

BACKGROUND: Advanced uterine leiomyosarcoma (ULMS) is an incurable disease. A significant percentage of cases of ULMS express estrogen and/or progesterone receptors (ER and/or PR). To the authors' knowledge, the role of estrogen suppression in disease management is not known. METHODS: The authors performed a single-arm phase 2 study of the aromatase inhibitor letrozole at a dose of 2.5 mg daily in patients with unresectable ULMS with ER and/or PR expression confirmed by immunohistochemistry. Tumor assessments were performed at baseline, 6 weeks, 12 weeks, and every 8 weeks thereafter. Toxicity was monitored throughout treatment. The primary endpoint was the progression-free survival at 12 weeks. RESULTS: A total of 27 patients was accrued, with a median of 2 prior treatment regimens (range, 0-9 treatment regimens). The median duration of protocol treatment was 2.2 months (range, 0.4 months-9.9 months). The 12-week progression-free survival rate was 50% (90% confidence interval, 30%-67%). The best response was stable disease in 14 patients (54%; 90% CI, 36%-71%). Three patients, all of whom had tumors expressing ER and PR in > 90% of tumor cells, continued to receive letrozole for > 24 weeks. The most common reason for treatment discontinuation was disease progression (85%). Letrozole was found to be well tolerated. CONCLUSIONS: Letrozole met protocol-defined criteria as an agent with activity in patients with advanced ULMS. Patients with the longest progression-free survival rate were those whose tumors strongly and diffusely expressed ER and PR.