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Immune checkpoint inhibitor (ICI)‐associated myocarditis is a rare, potentially life‐threatening complication of immunotherapy. We report a case of a 60‐year‐old female with a history of colorectal cancer treated with nivolumab immunotherapy who presented with new cardiomyopathy complicated by cardiogenic shock and ventricular arrhythmias. Treatment of ICI‐associated myocarditis requires aggressive immunosuppression and supportive therapy. In this case, the patient required advanced mechanical circulatory support as a bridge to recovery. This case highlights the complexity of diagnosis, haemodynamic management, and treatment of fulminant ICI myocarditis.

The only potentially curative treatment for lung adenocarcinoma patients remains complete resection of early-stage tumors. However, many patients develop recurrence and die of their disease despite curative surgery. Underlying mechanisms leading to establishment of systemic disease after complete resection are mostly unknown. We therefore aimed at identifying molecular signatures of resected lung adenocarcinomas associated with the risk of an early relapse. The study comprised 89 patients with totally resected stage IA–IIIA lung adenocarcinomas. Patients suffering from an early relapse within two years after surgery were compared to patients without a relapse in two years. Patients were clinically and molecular pathologically characterized. Tumor tissues were immunohistochemically analyzed for the expression of Ki67, CD45, CD4, CD8, PD1, PD-L1, PD-L2 and CD34, by Nanostring nCounter PanCancer Immune Profiling Panel as well as a comprehensive methylome profiling using the Infinium MethylationEPIC BeadChip. We detected differential DNA methylation patterns as well as significantly differentially expressed genes associated with an early relapse after complete resection. Especially, CD1A was identified as a potential biomarker, whose reduced expression is associated with an early relapse. These findings might help to develop biomarkers improving risk assessment and patient selection for adjuvant therapy as well as establish novel targeted therapeutic strategies.

Biological determinants of survival in advanced heart failure (AdHF) are linked to systems biological properties of disease severity including age, comorbidities, and frailty. We hypothesize that a...

Cytomegalovirus (CMV) causes mostly asymptomatic but lifelong infection. Primary infection or reactivation in immunocompromised individuals can be life-threatening. CMV viremia often occurs in solid organ transplant (SOT) recipients and associates with decreased graft survival and higher mortality. Furthering understanding of impaired immunity allowing CMV reactivation is critical to guiding anti-viral therapy and examining CMV's impact on outcomes of SOT. This study characterized longitudinal immune responses to CMV in 31 kidney transplant recipients with CMV viremia and matched, non-viremic recipients. Subjects were sampled three- and twelve-months post-transplant, with additional samples one-week and one-month post-viremia. Peripheral blood mononuclear cells (PBMC) were stained for NK and T cell markers. PBMC transcriptomes were characterized by RNA-Seq. Plasma proteins were quantified by Luminex. CD8 T cell transcriptomes were characterized by single-cell RNA-Seq. Pre-viremia, patients had high levels of IL-15 with concurrent expansion of immature CD56bright NK cells. Post-viremia, mature CD56dim NK cells and CD28- CD8 T cells upregulating inhibitory and NK-associated receptors were expanded. Phenotype of NK cells and CD28- CD8 T cells were associated with control of viremia. These findings suggest signatures of innate activation may be prognostic for CMV reactivation post-transplant, while CD8 T cell functionality is critical for effective control of CMV.

Noninvasive immunologic analysis of peripheral blood holds promise for explaining the mechanism of development of adverse clinical outcomes, and may also become a method for patient risk stratification before or after mechanical circulatory support device (MCSD) implantation. Dysregulation of the innate immune system is associated with increased patient age but has yet to be evaluated in the older patient with advanced heart failure undergoing MCSD surgery. Patients pre- and post-MCSD implantation had peripheral blood mononuclear cells (PBMC) and serum isolated. Multiparameter flow cytometry was used to analyze markers of innate cell function, including monocyte subtypes. Multiplex cytokine analysis was performed. MELD-XI and SOFA scores were utilized as surrogate markers of outcomes. Increased levels of pro-inflammatory cytokines including IL-15, TNF-α, and IL-10 were associated with increased MELD-XI and SOFA scores. IL-8, TNF- α, and IL-10 were associated with risk of death after MCSD implantation, even with correction for patient age. Increased frequency of ‘classical’ monocytes (CD14 + CD16−) were associated with increased MELD-XI and SOFA scores. This suggests that inflammation and innate immune system activation contribute to progression to multiorgan system failure and death after MCSD surgery. Development of noninvasive monitoring of peripheral blood holds promise for biomarker development for candidate selection and patient risk stratification.

Purpose of the Review This is a comprehensive update on failing Fontan physiology and the role of heart and combined heart and liver transplantation in the current era. Recent Findings Single ventricle physiology encompasses a series of rare congenital cardiac abnormalities that are characterized by absence of or hypoplasia of one ventricle. This effectively results in a single ventricular pumping chamber. These abnormalities are rarely compatible with long-term survival if left without surgical palliation in the first few years of life. Surgical treatment of single ventricle physiology has evolved over the past 60 years and is characterized by numerous creative innovations. These include the development of arteriopulmonary shunts, the evolution of partial cavopulmonary connections, and the eventual development of the “Fontan” operation. Regardless of the type of Fontan modification, the long-term consequences of the Fontan operation are predominantly related to chronic central venous hypertension and the multi-organ consequences thereof. Atrial arrhythmias can further compromise this circulation.Patients with single ventricle physiology represent a special sub-segment of congenital cardiac transplants and are arguably the most challenging patients considered for transplantation. Summary This review describes in detail the challenges and opportunities of heart and liver transplantation in Fontan patients, as viewed and managed by the experienced team at the Ahmanson/UCLA Adult Congenital Heart Center.

For most patients with end-stage heart failure, heart transplantation is the treatment of choice. Allograft rejection is one of the major post-transplantation complications affecting graft outcome and survival. Recent advancements in science and technology offer an opportunity to integrate genomic and other omics-based biomarkers into clinical practice, facilitating noninvasive evaluation of allograft for diagnostic and prognostic purposes. Omics, including gene expression profiling (GEP) of blood immune cell components and donor-derived cell-free DNA (dd-cfDNA) are of special interest to researchers. Several studies have investigated levels of dd-cfDNA and miroRNAs in blood as potential markers for early detection of allograft rejection. One of the achievements in the field of transcriptomics is AlloMap, GEP of peripheral blood mononuclear cells (PBMC), which can identify 11 differentially expressed genes and help with detection of moderate and severe acute cellular rejection in stable heart transplant recipients. In recent years, the utilization of GEP of PBMC for identifying differentially expressed genes to diagnose acute antibody-mediated rejection and cardiac allograft vasculopathy has yielded promising results. Advancements in the field of metabolomics and proteomics as well as their potential implications have been further discussed in this paper.

Immunologic impairment may contribute to poor outcomes after implantation of mechanical circulatory support device (MCSD), with infection often as a terminal event. The study of immune dysfunction is of special relevance given the growing numbers of older patients with heart disease. The aim of the study was to define which immunologic characteristics are associated with development of adverse clinical outcomes after MCSD implantation. We isolated peripheral blood mononuclear cells (PBMC) from patients pre- and up to 20 days post-MCSD implantation and analyzed them by multiparameter flow cytometry for T cell dysfunction, including terminal differentiation, exhaustion, and senescence. We used MELD-XI and SOFA scores measured at each time point as surrogate markers of clinical outcome. Older patients demonstrated increased frequencies of terminally differentiated T cells as well as NKT cells. Increased frequency of terminally differentiated and immune senescent T cells were associated with worse clinical outcome as measured by MELD-XI and SOFA scores, and with progression to infection and death. In conclusion, our data suggest that T cell dysfunction, independently from age, is associated with poor outcomes after MCSD implantation, providing a potential immunologic mechanism behind patient vulnerability to multiorgan dysfunction and death. This noninvasive approach to PBMC evaluation holds promise for candidate evaluation and patient monitoring.

Heart failure (HF) is a complex clinical syndrome that results from structural or functional cardiovascular disorders causing a mismatch between demand and supply of oxygenated blood and consecutive failure of the body’s organs. For those patients with stage D HF, advanced therapies, such as mechanical circulatory support (MCS) or heart transplantation (HTx), are potentially life-saving options. The role of risk stratification of patients with stage D HF in a value-based healthcare framework is to predict which subset might benefit from advanced HF (AdHF) therapies, to improve outcomes related to the individual patient including mortality, morbidity and patient experience as well as to optimize health care delivery system outcomes such as cost-effectiveness. Risk stratification and subsequent outcome prediction as well as therapeutic recommendation-making need to be based on the comparative survival benefit rationale. A robust model needs to (I) have the power to discriminate (i.e., to correctly risk stratify patients); (II) calibrate (i.e., to show agreement between the predicted and observed risk); (III) to be applicable to the general population; and (IV) provide good external validation. The Seattle Heart Failure Model (SHFM) and the Heart Failure Survival Score (HFSS) are two of the most widely utilized scores. However, outcomes for patients with HF are highly variable which make clinical predictions challenging. Despite our clinical expertise and current prediction tools, the best short- and long-term survival for the individual patient, particularly the sickest patient, is not easy to identify because among the most severely ill, elderly and frail patients, most preoperative prediction tools have the tendency to be imprecise in estimating risk. They should be used as a guide in a clinical encounter grounded in a culture of shared decision-making, with the expert healthcare professional team as consultants and the patient as an empowered decision-maker in a trustful safe therapeutic relationship.

Background Cytomegalovirus (CMV) is one of the most common infections after transplantation and continues to cause significant morbidity and mortality. Current guidelines recommend 3-6 months of post-transplant prophylaxis with 900mg daily of valganciclovir in heart transplant recipients. At our institution, however, the protocol is to use 450mg daily of valganciclovir for 6-12 months for intermediate risk (R+) patients and 900 mg daily for high risk (D+/R-) patients. In this study we aimed to identify underlying patient characteristics associated with detectable viral load above the quantifiable threshold. Table 1. Comparison of patients with a CMV viral above and below 137. Methods We retrospectively reviewed medical records of adult (≥ 18 years) heart transplant recipients with detectable CMV viremia from 2016-2018 resulted during routine clinical screening. Results Ninety-seven heart transplant recipients with a detectable CMV viral load were identified. Of those, 38 (37.2%) had a quantifiable viral load above the 137 IU/mL threshold. When compared to the individuals with a detectable viral load below the threshold (< 137 IU/mL), they had similar age at time of transplant, increased likelihood of donor/recipient CMV IgG mismatch, and were more frequently on 900mg daily of prophylaxis at time of viremia. Of the individuals with CMV DNAemia above the threshold, the median time to viremia was 271.4 days and the median peak viral load was 701 IU/mL. When limiting analysis to only recipients who were CMV IgG positive, patients with viremia had similar age and more likely to be on 900mg daily of valganciclovir as prophylaxis when compared to individuals with CMV viremia < 137 IU/mL. When comparing CMV D+/R- patients, age and rates of 900mg valganciclovir as prophylaxis were similar (Table 1). Conclusion We found that despite receipt of CMV prophylaxis, an appreciable number of both R+ and D-/R+ heart transplant recipients developed breakthrough DNAemia despite being on prophylaxis of valganciclovir as recommended by guidelines. Despite receipt of the higher 900 mg daily dose, high risk patients had higher rates of breakthrough DNAemia at our institution compared with R+ intermediate risk patients. More research is needed to evaluate the optimal dose and duration for prophylaxis in heart transplant patients against CMV. Disclosures All Authors: No reported disclosures

Purpose We previously reported that preoperative differentially expressed genes can predict short-term recovery and long-term survival in patients after mechanical circulatory support (MCS)-surgery. Here, we aimed to train and independently validate an algorithm in a larger mixed-intervention cohort. This algorithm is based on preoperative clinical and transcriptomic data that can predict 1-year survival after various interventions. Methods A retrospective study was conducted on 96 AdHF-patients undergoing MCS-surgery to identify clinical predictors of 1-year survival. Subsequently, a study was conducted on 77 patients evaluated for various AdHF-interventions to train (n=29) and validate (n=48) the algorithm (Table, Figure). In this prospective cohort, blood samples were collected within 30-days pre-intervention. In all studies, clinical data was collected within 30-days before and 1-year post-S/IT. All patients were assigned survivor/non-survivor status based on 1-year post-intervention outcome. Results Age, white blood cell count, respiratory rate, and minimum diastolic blood pressure yielded the highest correlation with 1-year survival status. An algorithm was trained by combining clinical and transcriptomic predictors on 29 samples from AdHF-patients undergoing MCS-surgery. The algorithm was validated on an independent set of 48 samples from patients undergoing various AdHF-interventions. Prediction of 1-year survival using 4 clinical parameters alone achieved an AUC=0.69. Adding 12 differentially expressed genes to the clinical model improved the AUC=0.90 and demonstrated 71% sensitivity, 90% specificity, 56% positive predictive value, and 95% negative predictive value. Conclusion The algorithm can increase accurate survival prediction by AUC>0.1 compared to clinical data alone and warrants further study in larger longitudinal cohorts.

With ongoing advancements in cancer-related treatments, the number of cancer survivors continues to grow globally, with numbers in the United States predicted to reach 18 million by 2020. As a result, it is expected that a greater number of patients will present with chemotherapy-related side effects. One entity in particular, chemotherapy-related cardiomyopathy (CCMP), is a known cardiotoxic manifestation associated with agents such as anthracyclines, trastuzumab, and tyrosine kinase inhibitors. Although such effects have been described in the medical literature for decades, concrete strategies for screening, prevention, and management of CCMP continue to be elusive owing to limited studies. Late recognition of CCMP is associated with a poorer prognosis, including a lack of clinical response to pharmacologic therapy, and end-stage heart failure. A number of advanced cardiac therapies, including cardiac resynchronization therapy, ventricular assist devices, and orthotopic cardiac transplantation, are available to for end-stage heart failure; however, the role of these therapies in CCMP is unclear. In this review, management of end-stage CCMP with the use of advanced therapies and their respective effectiveness are discussed, as well as clinical characteristics of patients undergoing these treatments. The relative paucity of data in this field highlights the importance and need for larger-scale longitudinal studies and long-term registries tracking the outcomes of cancer survivors who have received cardiotoxic cancer therapy to determine the overall incidence of end-stage CCMP, as well as prognostic factors that will ultimately guide such patients toward receiving appropriate end-stage care.

The Mediator complex is a key regulator of gene transcription and several studies demonstrated altered expressions of particular subunits in diverse human diseases, especially cancer. However a systematic study deciphering the transcriptional expression of the Mediator across different cancer entities is still lacking. We therefore performed a comprehensive in silico cancer vs. benign analysis of the Mediator complex subunits (MEDs) for 20 tumor entities using Oncomine datasets. The transcriptional expression profiles across almost all cancer entities showed differentially expressed MEDs as compared to benign tissue. Differential expression of MED8 in renal cell carcinoma (RCC) and MED12 in lung cancer (LCa) were validated and further investigated by immunohistochemical staining on tissue microarrays containing large numbers of specimen. MED8 in clear cell RCC (ccRCC) associated with shorter survival and advanced TNM stage and showed higher expression in metastatic than primary tumors. In vitro, siRNA mediated MED8 knockdown significantly impaired proliferation and motility in ccRCC cell lines, hinting at a role for MED8 to serve as a novel therapeutic target in ccRCC. Taken together, our Mediator complex transcriptome proved to be a valid tool for identifying cancer-related shifts in Mediator complex composition, revealing that MEDs do exhibit cancer specific transcriptional expression profiles.

Purpose Kidney disease is a common comorbidity seen in heart disease, and so the number of patients undergoing combined heart-kidney transplantation (HKT) continues to increase, as well as the number of waitlisted patients for HKT. Recent evidence suggests a favorable immunomodulatory effect for combined HKT, making these patients ideal candidates for non-invasive monitoring for rejection and injury. The use of gene-expression profile testing (AlloMap®) in HKT recipients vs heat transplant (HT) alone has remained uncertain with earlier reports suggesting higher values in HKT, while more recent reports suggesting equivocal results between the two. Additionally, the profile of donor-derived cell-free DNA (dd-cfDNA) (AlloSure®) in HKT has not yet been evaluated. Methods The Utility of dd-cfDNA in Association with Gene Expression Profiling (D-OAR) registry is a prospective, observation study of HT recipients monitored with AlloMap and AlloSure. The D-OAR registry and prospectively collected data from UCLA Medical Center were assessed for patients who underwent HKT with associated AlloSure and AlloMap scores and compared to patients who underwent HT alone. The cumulative distribution functions of AlloMap and AlloSure scores were stratified by HT vs. HKT. Patients with CMV and acute cellular rejection (≥2R) were excluded from the analysis. Results There were 300 HT recipients and 14 HKT recipients. Baseline characteristics were similar between groups. The median AlloMap and AlloSure scores for HT recipients (N=300) were 29 and 0.09% respectively, while for HKT recipients (N=14) AlloMap and AlloSure scores were 33.5 and 0.41% respectively. See table 1 Conclusion There were slightly higher AlloMap scores in HKT vs HT patients, while AlloSure results in HKT were significantly higher. Further work to establish baseline parameters and understand changes to these parameters during rejection episodes would benefit HKT patients by allowing non-invasive monitoring for rejection and graft injury.

As immunotherapy use in various malignancies expands, immune checkpoint inhibitor (ICI) myocarditis is a rare but potentially fatal complication requiring a high degree of clinical suspicion for early diagnosis and treatment. A 60 year-old female with colon cancer status post 3 months of nivolumab

We describe a simple bioinformatics method for biomarker discovery that is based on the analysis of global transcript levels in a population of inbred mouse strains showing variation for disease-related traits. This method has advantages such as controlled environment and accessibility to heart and plasma tissue in the preclinical selection stage. We illustrate the approach by identifying candidate heart failure (HF) biomarkers by overlaying mouse transcriptome and clinical traits from 91 Hybrid Mouse Diversity Panel (HMDP) inbred strains and human HF transcriptome from the Myocardial Applied Genomics Network (MAGNet) consortium. We found that some of the top differentially expressed genes correlated with known human HF biomarkers, such as galectin-3 and tissue inhibitor of metalloproteinase 1. Using ELISA assays, we investigated one novel candidate, Glycoprotein NMB, in a mouse model of chronic β-adrenergic stimulation by isoproterenol (ISO) induced HF. We observed significantly lower GPNMB plasma levels in the ISO model compared to the control group (p-value = 0.007). In addition, we assessed GPNMB plasma levels among 389 HF cases and controls from the METabolic Syndrome In Men (METSIM) study. Lower levels of GPNMB were also observed in patients with HF from the METSIM study compared to non-HF controls (p-value < 0.0001). In summary, we have identified several candidate biomarkers for HF using the cardiac transcriptome data in a population of mice that may be directly relevant and applicable to human populations.

BackgroundDonor-specific HLA antibodies (DSA) are associated with increased rates of rejection and of graft failure in cardiac transplantation. The goal of this study was to determine the association of preformed and posttransplant development of newly detected DSA (ndDSA) with antibody-mediated rejection (AMR) and characterize the clinical relevance of complement-activating DSA in heart allograft recipients.MethodsThe study included 128 adult and 48 pediatric heart transplant patients transplanted between 2010 and 2013. Routine posttransplant HLA antibody testing was performed by IgG single-antigen bead test. The C3d single-antigen bead assay was used to identify complement-activating antibodies. Rejection was diagnosed using International Society for Heart and Lung Transplantation criteria.ResultsIn this study, 22 patients were transplanted with preexisting DSA, and 43 patients developed ndDSA posttransplant. Pretransplant (P < 0.05) and posttransplant (P < 0.001) ndDSA were associated with higher incidence of AMR. Patients with C3d + DSA had significantly higher incidence of AMR compared with patients with no DSA (P < 0.001) or patients with C3d-DSA (P = 0.02). Nine (36%) of 25 patients with AMR developed transplant coronary artery disease compared with 17 (15.9%) of 107 patients without AMR (P < 0.05). Among the 47 patients who received ventricular assistant device (VAD), 7 of 9 VAD+ patients with preformed DSA experienced AMR compared with 7 of 38 VAD+ patients without preformed DSA, indicating presensitization to donor HLA significantly increased the risk of AMR (P < 0.01).ConclusionsPreformed and posttransplant ndDSA were associated with AMR. C3d + DSA correlates with complement deposition on the graft and higher risk of AMR which may permit the application of personalized immunotherapy targeting the complement pathway.

Heart failure (HF) is a complex clinical syndrome that causes systemic hypoperfusion and failure to meet the body’s metabolic demands. In an attempt to compensate, chronic upregulation of the sympathetic nervous system and renin-angiotensin-aldosterone leads to further myocardial injury, HF progression and reduced O2delivery. This triggers progressive organ dysfunction, immune system activation and profound metabolic derangements, creating a milieu similar to other chronic systemic diseases and presenting as advanced HF with severely limited prognosis. We hypothesize that 1-year survival in advanced HF is linked to functional recovery potential (FRP), a novel clinical composite parameter that includes HF severity, secondary organ dysfunction, co-morbidities, frailty, disabilities as well as chronological age and that can be diagnosed by a molecular biomarker.

Background As the population of patients with a Fontan palliation grows so does, the number of patients with cardiac failure necessitating orthotopic heart transplant (OHT) and combined heart-liver transplant (CHLT). There is recent evidence that current era cardiac transplant in Fontan patients has improved outcomes, but most studies have a preponderance of pediatrics patients in their cohorts. We examine our institutional experience with adult OHT and CHLT transplantation for failed Fontan physiology. Methods and results Retrospective analysis of patients at the Ahmanson/UCLA Adult Congenital Heart Disease Center who underwent OHT or CHLT for failing Fontan physiology from January 1, 2002 to May 31, 2017. We identified 20 patients with single-ventricle physiology and Fontan palliation who underwent OHT or CHLT. The median age was 29.5 years (range 19-44). Five patients underwent CHLT because of biopsy proven hepatic cirrhosis. The median length of hospital stay was 23 days (range 8-76) post-OHT and 51 days (range 26-77) post-CHLT. During a median follow-up of 56 months (range 2-178), there was one mortality occurring at 34 months post-OHT due to coronary vasculopathy. Most frequent early postoperative complications included bleeding and infection (55% and 20%, respectively) and surgical reintervention for bleeding complications (n = 8, 40%). One CHLT patient experienced clinically significant hepatic rejection requiring admission and steroid treatment. Conclusions Despite inherent risks and complexities of OHT or CHLT in patients with a failed Fontan, transplant is a reasonable therapy. Peri- and postoperative complications are common and may require surgical reintervention. Continued observation of practices and unifying themes may help improve patient selection, pre- and postoperative treatment and ultimately outcomes.

Purpose Multiorgan Dysfunction Syndrome (MOD) contributes to adverse outcomes in advanced heart failure (AdHF) patients after mechanical circulatory support (MCS) implantation and is associated with aberrant Peripheral Blood Mononuclear Cells (PBMC) activity. We hypothesize that a subset of previously reported 12 preoperative differentially expressed genes (DEGs) correlating with both, Functional Recovery Potential (FRP) (28 genes) and One Year Survival (1YS) (105 genes) [Bondar 2017], could directly predict FRP-related 1YS after MCS surgery. Methods In 29 patients undergoing MCS-surgery in a tertiary academic medical center from 2012 to 2014, PBMC samples were collected on day-1. Clinical data were collected on day-1, day 8 and 1 year after surgery. FRP was classified as Improving if SOFA+MELD-XI scores improved from day -1 to day 8 (n=17) and Non-improving if either one or both scores did not improve from day -1 to day 8 (n=12). The 1YS showed 18 Surviving and 11 Non-surviving patients. Next-generation RNA sequencing transcriptome analysis was performed on purified mRNA and analyzed using Strand NGS. DEGs were identified by Mann-Whitney test with Benjamini-Hochberg correction. We used a support vector machine algorithm to predict FRP- and 1YS-status. Results 1YS was 88% in Improving and 27% in Non-improving groups (log rank p=0.00182). The 12 preoperative DEGs predicted 1YS (accuracy 86%). Hierarchical Clustering analysis (Figures 1A and 1B) demonstrated the consistent expression pattern between FRP and 1YS, suggesting a biological link, supported by gene ontology and pathway analyses. Conclusion In AdHF patients undergoing MCS, the previously reported 12 genes could directly predict the FRP-related 1-year survival. We currently explore the utility of this PBMC biomarker to improve outcome prediction for AdHF patients undergoing various high-risk interventions [Deng 2018].

Purpose Use of HCV NAT+ donor hearts may aid in expanding the donor pool. However, limited single center data exist. We aim to assess the short-term impact of use of HCV NAT+ hearts in a national dataset. Methods 8256 HT patients with reported donor HCV NAT status were identified from UNOS (2010-2018), of which 88 received an HCV NAT positive (HCV+) donor. Exclusions included age proportional hazard regression analysis (adjusted for age, sex, diabetes , race, ischemic time , dialysis, life support & HLA mismatch) was performed. Results 88 pts underwent successful HT with HCV NAT positive donors. Predominant etiologies did not differ (p=0.169). During study period, 826 pts died post HT (NAT + vs -: 9.1 vs 10.0, p=0.77). Crude 1, 6 & 12 m post-HT survival was NAT+ [96, 91, 82%] vs NAT- [97, 93, 91%] (log-rank, p Multivariate analysis yielded a hazard ratio of 1.45 (CI 0.65-3.28) comparing NAT+ to NAT- recipients. Conclusion Short-term survival is similar between HCV NAT+ versus NAT- HT recipients. This data is promising and represents a step forward in expanding the donor pool. Further study is warranted to assess the long-term impact of this donor population.

Cardiac amyloidosis in the United States is most often due to myocardial infiltration by immunoglobulin protein, such as in AL amyloidosis, or by the protein transthyretin, such as in hereditary and senile amyloidosis. Cardiac amyloidosis often portends a poor prognosis especially in patients with systemic AL amyloidosis. Despite better understanding of the pathophysiology of amyloid, many patients are still diagnosed late in the disease course. This review investigates the current understanding and new research on the diagnosis and treatment strategies in patients with cardiac amyloidosis. Myocardial amyloid infiltration distribution occurs in a variety of patterns. Structural and functional changes on echocardiography can suggest presence of amyloid, but CMR and nuclear imaging provide important complementary information on amyloid burden and the amyloid subtype, respectively. While for AL amyloid, treatment success largely depends on early diagnosis, for ATTR amyloid, new investigational agents that reduce production of transthyretin protein may have significant impact on clinical outcomes. Advancements in the non-invasive diagnostic detection and improvements in early disease recognition will undoubtedly facilitate a larger proportion of patients to receive early therapy when it is most effective.

Background Multiorgan dysfunction syndrome contributes to adverse outcomes in advanced heart failure (AdHF) patients after mechanical circulatory support (MCS) implantation and is associated with aberrant leukocyte activity. We tested the hypothesis that preoperative peripheral blood mononuclear cell (PBMC) gene expression profiles (GEP) can predict early postoperative improvement or non-improvement in patients undergoing MCS implantation. We believe this information may be useful in developing prognostic biomarkers. Methods & design We conducted a study with 29 patients undergoing MCS-surgery in a tertiary academic medical center from 2012 to 2014. PBMC samples were collected one day before surgery (day -1). Clinical data was collected on day -1 and day 8 postoperatively. Patients were classified by Sequential Organ Failure Assessment score and Model of End-stage Liver Disease Except INR score (measured eight days after surgery): Group I = improving (both scores improved from day -1 to day 8, n = 17) and Group II = not improving (either one or both scores did not improve from day -1 to day 8, n = 12). RNA-sequencing was performed on purified mRNA and analyzed using Next Generation Sequencing Strand. Differentially expressed genes (DEGs) were identified by Mann-Whitney test with Benjamini-Hochberg correction. Preoperative DEGs were used to construct a support vector machine algorithm to predict Group I vs. Group II membership. Results Out of 28 MCS-surgery patients alive 8 days postoperatively, one-year survival was 88% in Group I and 27% in Group II. We identified 28 preoperative DEGs between Group I and II, with an average 93% prediction accuracy. Out of 105 DEGs identified preoperatively between year 1 survivors and non-survivors, 12 genes overlapped with the 28 predictive genes. Conclusions In AdHF patients following MCS implantation, preoperative PBMC-GEP predicts early changes in organ function scores and correlates with long-term outcomes. Therefore, gene expression lends itself to outcome prediction and warrants further studies in larger longitudinal cohorts.

Purpose: The Mediator complex is a multiprotein assembly, which serves as a hub for diverse signaling pathways to regulate gene expression. Because gene expression is frequently altered in cancer, a systematic understanding of the Mediator complex in malignancies could foster the development of novel targeted therapeutic approaches. Experimental Design: We performed a systematic deconvolution of the Mediator subunit expression profiles across 23 cancer entities (n = 8,568) using data from The Cancer Genome Atlas (TCGA). Prostate cancer–specific findings were validated in two publicly available gene expression cohorts and a large cohort of primary and advanced prostate cancer (n = 622) stained by immunohistochemistry. The role of CDK19 and CDK8 was evaluated by siRNA-mediated gene knockdown and inhibitor treatment in prostate cancer cell lines with functional assays and gene expression analysis by RNAseq. Results: Cluster analysis of TCGA expression data segregated tumor entities, indicating tumor-type–specific Mediator complex compositions. Only prostate cancer was marked by high expression of CDK19. In primary prostate cancer, CDK19 was associated with increased aggressiveness and shorter disease-free survival. During cancer progression, highest levels of CDK19 and of its paralog CDK8 were present in metastases. In vitro, inhibition of CDK19 and CDK8 by knockdown or treatment with a selective CDK8/CDK19 inhibitor significantly decreased migration and invasion. Conclusions: Our analysis revealed distinct transcriptional expression profiles of the Mediator complex across cancer entities indicating differential modes of transcriptional regulation. Moreover, it identified CDK19 and CDK8 to be specifically overexpressed during prostate cancer progression, highlighting their potential as novel therapeutic targets in advanced prostate cancer. Clin Cancer Res; 23(7); 1829–40. ©2016 AACR.

Objective The study aimed to analyze the risk factors and long-term outcomes associated with coronary artery aneurysms (CAAs) after successful percutaneous coronary intervention (PCI) and drug-eluting stent (DES) implantation in patients with CTOs. Background There are sporadic data available on post-procedure CAAs after transcatheter revascularization for CTOs. Methods and results A total of 141 patients with 149 CTOs who underwent successful CTO-PCI and DES implantation with angiographic follow-up from 2004 to 2010 were included. Patients were divided into CAA group and non-CAA group according to the presence of CAAs in the follow-up angiography. The independent predictors and major adverse cardiac events (MACEs) including cardiac death, myocardial infarction (MI) and target-vessel revascularization (TVR) were compared between two groups. The incidence of CAAs was 11.4% (17/149) after index procedure. Multivariate analysis showed that age (OR: 0.925, CI 0.873–0.980, P = 0.008), ostial occlusion (OR: 6.715, CI 1.473–30.610, P = 0.014), the parallel wire technique (OR: 6.167, CI 1.709–22.259, P = 0.005) and DES length (OR: 1.030, CI 1.002–1.058, P = 0.036) were the independent predictors of CAAs after successful CTO-PCI and DES implantation. MACEs were similar between two groups (adjusted hazard ratio 0.670; 95% CI 0.160–2.808; P = 0.584) during the 5-year follow-up. Conclusions The independent predictors of CAAs after successful CTO-PCI and DES implantation are age, ostial occlusion, the parallel wire technique and DES length. CAAs after index procedure are not frequently associated with adverse clinical events under dual antiplatelet therapy. Further large clinical studies are warranted to explore the clinical implications of patients with this distinct new entity.

Protein temporal dynamics play a critical role in time-dimensional pathophysiological processes, including the gradual cardiac remodeling that occurs in early-stage heart failure. Methods for quantitative assessments of protein kinetics are lacking, and despite knowledge gained from single-protein studies, integrative views of the coordinated behavior of multiple proteins in cardiac remodeling are scarce. Here, we developed a workflow that integrates deuterium oxide (2H2O) labeling, high-resolution mass spectrometry (MS), and custom computational methods to systematically interrogate in vivo protein turnover. Using this workflow, we characterized the in vivo turnover kinetics of 2,964 proteins in a mouse model of β-adrenergic–induced cardiac remodeling. The data provided a quantitative and longitudinal view of cardiac remodeling at the molecular level, revealing widespread kinetic regulations in calcium signaling, metabolism, proteostasis, and mitochondrial dynamics. We translated the workflow to human studies, creating a reference dataset of 496 plasma protein turnover rates from 4 healthy adults. The approach is applicable to short, minimal label enrichment and can be performed on as little as a single biopsy, thereby overcoming critical obstacles to clinical investigations. The protein turnover quantitation experiments and computational workflow described here should be widely applicable to large-scale biomolecular investigations of human disease mechanisms with a temporal perspective.

ACC Stage C heart failure includes those patients with prior or current symptoms of heart failure in the context of an underlying structural heart problem who are primarily managed with medical therapy. Although there is guideline-based medical therapy for those with heart failure with reduced ejection fraction (HFrEF), therapies in heart failure with preserved ejection fraction (HFpEF) have thus far proven elusive. Emerging therapies such as serelaxin are currently under investigation and may prove beneficial. The role of advanced surgical therapies, such as mechanical circulatory support, in this population is not well defined. Further investigation is warranted for these therapies in patients with Stage C heart failure.

Purpose Malignancy remains a major cause of morbidity and mortality after HT with limited predictors of outcome. Given that development of malignancy (CA) is linked to degree of immunosuppression, we sought to evaluate the incidence of malignancy and its potential correlation with immune function assay (IFA) results pre and post-CA diagnosis in HT. Methods 2100 adult and pediatric OHTs performed at our institution March 1991 and April 2018 were analyzed. Pre-HT CA was correlated with post-HT recurrence or development of new CA. IFA results were assessed at the time of CA diagnosis and 3m/6m/12m prior. Multivariate Cox proportional hazard regression analysis was performed. Results A total of 55 OHT (2.6%) had either pre- (12) or post-OHT (48) malignancy (CA). The majority of patients were male (83.6%, p0.06), Caucasian (72.7%, p=0.0006), and had smoking hx (49.1%, p=0.004). 33% had a family hx of CA. Treated rejection was associated with increased risk of post-Tx CA (p Conclusion Low immune function assay results were not seen prior to diagnosis of CA, as expected, and results demonstrated minimal variability. Further study is warranted to better understand the potential correlation of immune function assay results with development of post-HT malignancy.

Purpose Cardiac transplant surgeries can be complicated, prolonged, resource-heavy procedures that may be affected by the timing of the surgery. We analyzed data from Ronald Reagan UCLA Medical Center (RRUCLA MC) to evaluate for a “weekend effect” on mortality comparing transplant surgeries that occurred on a weekday versus during the weekend. Methods We conducted a retrospective, cohort analysis of the RR UCLA MC data for all heart-only transplant patients between from 1987 to 2018 comparing mortality rates between weekday transplants (WDT) versus weekend transplants (WET). The exclusion criteria included age proportional hazard regression analysis (adjusted for age, sex, diabetes , race, ischemic time , need for dialysis, on life support, wait time, and HLA mismatch) was performed. Survival was censored at 12 years. Results 1,548 patients received heart transplants between 1987-2018 at RR UCLA MC, of which 1129 patients received a transplant on a weekday and 419 patients received a transplant during the weekend. Overall, the mortality for WDT and WET were 53.3% and 53.5% (p=0.89), respectively. The breakdown of cardiovascular and non-cardiovascular mortality were similar for both WDT (15.0%, 38.4%, respectively) and WET (15.3%, 38.2%) (p=0.54). Furthermore, there was no significant difference in cause of death between WDT vs WET, looking specifically at graft failure , rejection, infection, cardiovascular , malignancy, multi-organ failure , and other causes. Conclusion Based on this retrospective, cohort analysis of the RR UCLA MC data, there was no mortality “weekend effect” observed for cardiac transplantation surgeries.

Purpose Cardiac transplant surgeries can be complicated, prolonged, resource-heavy procedures that may be affected by the timing of the surgery. We analyzed the UNOS Organ Registry to evaluate for a “weekend effect” on mortality comparing transplant surgeries that occurred on a weekday versus during the weekend. Methods Conducted a retrospective, cohort analysis of the UNOS Organ Registry of all heart-only transplant patients from 1987 to 2018 comparing mortality rates between weekday transplants (WDT) versus weekend transplants (WET). The exclusion criteria included age Results 55,670 patients received heart transplants between 1987-2018 per the UNOS Organ Registry, of which 40,504 patients received a transplant on a weekday and 15,166 patients received a transplant during the weekend. Overall, the mortality for WDT and WET were 52% and 52% (p=0.98), respectively. The unadjusted hazard ratio for WET is 1.00 (p=0.89; 95% CI 0.97-1.03) and the adjusted hazard ratio for WET is 1.00 (p=0.93; 95% CI 0.97-1.03). The breakdown of cardiovascular and non-cardiovascular mortality were similar between both groups: WDT (15.8%, 36.2%, respectively) and WET (15.8%, 36.2%, respectively). Furthermore, there was no significant difference in cause of death between WDT vs WET, looking specifically at graft failure, rejection, infection, cardiovascular, malignancy, multi-organ failure, and other. Conclusion Based on this retrospective, cohort analysis of the UNOS Organ Registry there was no mortality “weekend effect” observed for cardiac transplantation surgeries.

Clear cell renal cell carcinoma (ccRCC) is a common human malignancy. Despite numerous efforts, there is still no reliable biomarker or combination of biomarkers available for daily practice. Our study was designed to explore the expression profile of messenger RNA (mRNA) and long non-coding RNA (lncRNA) transcripts in ccRCC in order to identify potential diagnostic biomarkers for patients with ccRCC. Total RNA from corresponding normal and malignant tissue of 15 patients with ccRCC was isolated. Expression profiling was performed using a custom Agilent gene expression microarray which allowed the analysis of 34,144 mRNA and 32,183 lncRNA transcripts. We observed that a subset of mRNA (n=1064; 3.1%) and lncRNA (n=1308; 4.1%) transcripts are dysregulated (fold change>2) in ccRCC tissue. The relative higher number of differentially expressed lncRNAs indicates that lncRNA profiling may be better suited for diagnostic purposes; a number of so far unknown RNAs with potential diagnostic interest in ccRCC are identified by our gene expression profiling study. The data are deposited in the Gene Expression Omnibus (GSE61763).

Antibody-mediated rejection (AMR) has become an increasingly recognized entity in heart transplantation linked to poor outcomes. Treatment algorithms for AMR vary from institution to institution, and therapeutic options remain limited. Responses to standard therapies, such as plasmapheresis, intravenous immunoglobulin, corticosteroids, and rituximab, are not always apparent. Bortezomib, a first-in-class 26S proteasome inhibitor that was approved by the U.S. Food and Drug Administration for multiple myeloma, is emerging as an alternative therapy option for AMR. Proteasome inhibition results in depletion of plasma cells, a primary source of antibody production. Additionally, a major function of the 26S proteasome is antigen processing for HLA Class I presentation. We postulated that compared with Class II responses, bortezomib would be more effective in preventing de novo Class I antibody production. To date, there have not been published reports of the variable immunologic responses of specific HLA antibody types to bortezomib in heart transplantation. Here we report the first case series, to our knowledge, of the differential effect on donor-specific and third-party antibodies in heart transplant recipients treated with bortezomib. Institutional review board approval was obtained. A retrospective review was conducted of all adult patients receiving bortezomib for biopsy-proven or clinically suspected AMR from August 2010 to January 2012. Diagnosis of AMR consisted of positive endomyocardial biopsy by histology and immunohistochemistry, hemodynamic changes, or significant changes in donor-specific antibody (DSA) mean fluorescence intensity (MFI). An antibody MFI cutoff of Z5,000 was used, and a Z50% change in MFI was considered significant. Treatment consisted of plasmapheresis followed by bortezomib (0.7–1 mg/m intravenous push) on Day 1, 4, 7, and 10 followed by a 3-day course of plasmapheresis beginning 72 hours after the last bortezomib dose. Treatment efficacy was determined by clinical or histologic improvement or a significant change in DSA. Antibody MFI was determined via single-antigen Luminex assay (Luminex (R), One Lambda Inc., Canoga, Park, CA). Antibody samples were obtained on Day 5, 11, 14, and 30 and at each clinical follow-up. To study the antibody response to treatment, we constructed a matrix of data of all tested antibodies and used hierarchical clustering based on the Pearson correlation to generate a clustered heat map. The Pearson correlation is a standardized measure of linear dependency between 2 variables and was used because of its independence of scale, allowing for the identification of variables undergoing similar relative changes without dependence on absolute magnitudes or units. Wilcoxon signed rank test was used to calculate statistical significance of MFI changes. Statistical analysis was done using R (R Foundation for Statistical Computing, Vienna, Austria).

Castration-resistant prostate cancer (CRPC) is the most aggressive form of prostate cancer (PCa) and remains a significant therapeutic challenge. The key to the development of novel therapeutic targets for CRPC is to decipher the molecular alterations underlying this lethal disease. The aim of our study was to identify therapeutic targets for CRPC by assessing somatic copy number alterations (SCNAs) by whole-exome sequencing on five CRPC/normal paired formalin-fixed paraffin-embedded (FFPE) samples, using the SOLiD4 next-generation sequencing (NGS) platform. Data were validated using fluorescence in situ hybridization (FISH) on a PCa progression cohort. PTK2 and YWHAZ amplification, mRNA and protein expression were determined in selected PCa cell lines. Effects of PTK2 inhibition using TAE226 inhibitor and YWHAZ knock-down on cell proliferation and migration were tested in PC3 cells in vitro. In a larger validation cohort, the amplification frequency of YWHAZ was 3% in localized PCa and 48% in CRPC, whereas PTK2 was amplified in 1% of localized PCa and 35% in CRPC. YWHAZ knock-down and PTK2 inhibition significantly affected cell proliferation and migration in the PC3 cells. Our findings suggest that inhibition of YWHAZ and PTK2 could delay the progression of the disease in CRPC patients harbouring amplification of the latter genes. Furthermore, our validated whole-exome sequencing data show that FFPE tissue could be a promising alternative for SCNA screening using next-generation sequencing technologies. Copyright © 2013 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Heart failure (HF) and obesity are commonly seen in the USA. Although obesity is associated with traditional cardiovascular disease, its relationship with HF is complex. Obesity is an accepted risk factor for incident HF. However, in patients with established HF, there exists a paradoxical correlation, with escalating BMI incrementally protective against adverse outcomes. Despite this relationship, patients with HF may desire to lose weight to reduce comorbidities or to improve quality of life. Thus far, studies have shown that intentional weight loss in obese patients with HF does not increase risk, with strategies including dietary modification, physical activity, pharmacotherapy, and/or surgical intervention.

Background— Alternate waiting list strategies expand listing criteria for patients awaiting heart transplantation (HTx). We retrospectively analyzed clinical events and outcome of patients listed as high-risk recipients for HTx. Methods and Results— We analyzed 822 adult patients who underwent HTx of whom 111 patients met high-risk criteria. Clinical data were collected from medical records and outcome factors calculated for 61 characteristics. Significant factors were summarized in a prognostic score. Age >65 years (67%) and amyloidosis (19%) were the most common reasons for alternate listing. High-risk recipients were older (63.2±10.2 versus 51.4±11.8 years; P P =0.0005). Prior cerebral vascular accident, albumin 2 prior sternotomies were associated with poor survival after HTx. A prognostic risk score (CARRS [CVA, albumin, re-HTx, renal dysfunction, and sternotomies]) derived from these factors stratified survival post-HTx in high-risk (3+ points) versus low-risk (0–2 points) patients (87.9% versus 52.9% at 1-year; 65.9% versus 28.4% at 5-year post-HTx; P P =0.46). Conclusions— High-risk patients had reduced survival compared with regular patients post-HTx. Among patients previously accepted for alternate donor listing, application of the CARRS score identifies patients with unacceptably high mortality after HTx and those with a survival similar to regularly listed patients.

Background The implantation of mechanical circulatory support devices in heart failure patients is associated with a systemic inflammatory response, potentially leading to death from multiple organ dysfunction syndrome. Previous studies point to the involvement of many mechanisms, but an integrative hypothesis does not yet exist. Using time-dependent whole-genome mRNA expression in circulating leukocytes, we constructed a systems-model to improve mechanistic understanding and prediction of adverse outcomes. Methods We sampled peripheral blood mononuclear cells from 22 consecutive patients undergoing mechanical circulatory support device (MCS) surgery, at 5 timepoints: day −1 preoperative, and postoperative days 1, 3, 5, and 8. Clinical phenotyping was performed using 12 clinical parameters, 2 organ dysfunction scoring systems, and survival outcomes. We constructed a strictly phenotype-driven time-dependent non-supervised systems-representation using weighted gene co-expression network analysis, and annotated eigengenes using gene ontology, pathway, and transcription factor binding site enrichment analyses. Genes and eigengenes were mapped to the clinical phenotype using a linear mixed-effect model, with Cox models also fit at each timepoint to survival outcomes. Results We inferred a 19-module network, in which most module eigengenes correlated with at least one aspect of the clinical phenotype. We observed a response of advanced heart failure patients to surgery orchestrated into stages: first, activation of the innate immune response, followed by anti-inflammation, and finally reparative processes such as mitosis, coagulation, and apoptosis. Eigengenes related to red blood cell production and extracellular matrix degradation became predictors of survival late in the timecourse corresponding to multiorgan dysfunction and disseminated intravascular coagulation. Conclusions Our model provides an integrative representation of leukocyte biology during the systemic inflammatory response following MCS device implantation. It demonstrates consistency with previous hypotheses, identifying a number of known mechanisms. At the same time, it suggests novel hypotheses about time-specific targets. Electronic supplementary material The online version of this article (doi:10.1186/s12920-017-0288-8) contains supplementary material, which is available to authorized users.

Small non-coding RNAs (sncRNA

Although head and neck squamous cell carcinoma (HNSCC) is the sixth most common tumour entity worldwide, it remains a clinical challenge. Large-scale explorative genomic projects have identified several genes as potential targets for therapy, including fibroblast growth factor receptor 3 (FGFR3). The aim of this study was to investigate the biological significance of wild-type and mutated FGFR3 to evaluate its potential as a novel therapeutic target in HNSCC. FGFR3 protein expression was analysed in a large HNSCC tissue cohort (n = 536) and FGFR3 mRNA expression from The Cancer Genome Atlas (TCGA; n = 520). Moreover, FGFR3 wild-type and mutant versions were overexpressed in vitro, and both proliferation and migration was assessed with and without BGJ398 (a specific FGFR1-3 inhibitor) treatment. Although FGFR3 expression for both cohorts decreased during tumour progression, high FGFR3 expression levels were observed in a small subset of patients. In vitro, FGFR3 overexpression led to increased proliferation, whereas migration was not altered. Moreover, FGFR3-overexpressing cells were more sensitive to BGJ398. Cells overexpressing FGFR3 mutant versions showed increased proliferation compared to wild-type FGFR3 under serum-reduced conditions and were largely as sensitive as the wild-type protein to BGJ398. Taken together, the results of this study demonstrate that although FGFR3 expression decreases during HNSSC progression, it plays an important role in tumour cell proliferation and thus may be a potential target for therapy in selected patients suffering from this dismal tumour entity.

Background Clear cell renal cell carcinoma (ccRCC) is among the most common human malignancies. Methods In order to provide better understanding of the molecular biology of ccRCC and to identify potential diagnostic/prognostic biomarker and therapeutic targets, we utilized a microarray to profile mRNA expression of corresponding normal and malignant renal tissues. Real-time PCR, Western Blot and immunohistochemistry were applied to study the expression of candidate biomarkers. ccRCC cell lines were treated with sertraline to inhibit the dopamine transporter SLC6A3. Results Differential expression of fourteen mRNAs, yet not studied in ccRCC in depth, was confirmed using qPCR (upregulation: SLC6A3, NPTX2, TNFAIP6, NDUFA4L2, ENPP3, FABP6, SPINK13; downregulation: FXYD4, SLC12A1, KNG1, NPHS2, SLC13A3, GCGR, PLG). Up-/downregulation was also confirmed for FXYD4, KNG1, NPTX2 and SLC12A1 by Western Blot on the protein level. In contrast to the mRNA expression, protein expression of the dopamine transporter SLC6A3 was lower in ccRCC compared to normal renal tissue. Immunohistochemistry indicated that this decrease was due to higher concentrations of SLC6A3 in the proximal tubules. Immunohistochemical analyses further demonstrated that high SLC6A3 expression in ccRCC tissue was correlated with a shorter period of recurrence-free survival following surgery. Treatment of ccRCC cells with the SLC6A3 inhibitor sertraline induced dose-dependent cell-death. Conclusion Our study identified several novel biomarkers with diagnostic potential and further investigations on sertraline as therapeutic agent in ccRCC patients are warranted. Electronic supplementary material The online version of this article (doi:10.1186/s12943-016-0495-5) contains supplementary material, which is available to authorized users.

Outcomes of arrhythmogenic right ventricular cardiomyopathy (ARVC) patients after heart transplantation have not been well studied. Diagnostic criteria were established in 1994 and subsequently revised in 2010. We sought to better characterize this population in a national cohort.A total of 35,138 heart transplant-only recipients were identified from the United Network for Organ Sharing (UNOS) Thoracic Registry (1994-2011); 73 had ARVC. The non-ARVC group included ischemic cardiomyopathy, restrictive cardiomyopathy, dilated cardiomyopathy, hypertrophic cardiomyopathy, and other. Survival was censored at 12 years. Multivariate Cox proportional hazard regression analysis was adjusted for age, sex, DM, race, ischemia time, dialysis, life support, wait time, and HLA mismatch.There were 73 ARVC and 35,065 non-ARVC patients. The ARVC cohort was associated with less ventricular assist device use (P = .001) and significantly decreased pulmonary arterial and capillary wedge pressures (P .001). Survivals at 1, 5, and 10 years were, respectively, ARVC 87%, 81%, and 77%, and non-ARVC 87%, 72%, and 53% (log rank P = .07). The ARVC unadjusted hazard ratio for all-cause mortality was 0.59 (95% confidence interval [CI] 0.34-1.04; P = .073). Multivariate analysis yielded a hazard ratio of 0.68 (95% CI 0.35-1.30; P = .25). ARVC survival was similar to restrictive, hypertrophic, and dilated cardiomyopathies and significantly better than ischemic cardiomyopathy.This is the largest reported series of ARVC after heart transplantation, of which 11% were pediatric. Survival was similar to the non-ARVC cohort, with improved survival over ischemic and restrictive etiologies.

// Anne von Massenhausen 1, 2, 3, * , Christine Sanders 1, 2, 3, * , Britta Thewes 1, 2, 3 , Mario Deng 4, 5 , Angela Queisser 1, 2, 3 , Wenzel Vogel 4, 5 , Glen Kristiansen 2, 3 , Stefan Duensing 6 , Andreas Schrock 3, 7 , Friedrich Bootz 3, 7 , Peter Brossart 3, 8 , Jutta Kirfel 2, 3 , Lynn Heasley 9 , Johannes Bragelmann 1, 3, 8, * , Sven Perner 4, 5 * 1 Section of Prostate Cancer Research, University Hospital of Bonn, Bonn, Germany 2 Institute of Pathology, University Hospital of Bonn, Bonn, Germany 3 Center for Integrated Oncology Cologne/Bonn, University Hospital of Bonn, Bonn, Germany 4 Pathology of the University Hospital of Luebeck, Luebeck, Germany 5 Leibniz Research Center Borstel, Borstel, Germany 6 Department of Urology, University of Heidelberg, Heidelberg, Germany 7 Department of Otorhinolaryngology/Head and Neck Surgery, University Hospital of Bonn, Bonn, Germany 8 Department of Hematology/Oncology, University Hospital of Bonn, Bonn, Germany 9 Department of Craniofacial Biology, University of Colorado Anschutz Medical Campus, Aurora, Colorado, USA * These authors have contributed equally to this work Correspondence to: Sven Perner, email: Sven.Perner@uksh.de Keywords: head and neck cancer, MERTK, targeted therapy Abbreviations: HNSCC, head and neck squamous cell carcinoma; MERTK, MER proto-oncogene tyrosine kinase; FAK, focal adhesion kinase; TCGA, The Cancer Genome Atlas Received: January 07, 2016 Accepted: March 28, 2016 Published: April 13, 2016 ABSTRACT Although head and neck cancer (HNSCC) is the sixth most common tumor entity worldwide therapy options remain limited leading to 5-year survival rates of only 50 %. MERTK is a promising therapeutic target in several tumor entities, however, its role in HNSCC has not been described yet. The aim of our study was to investigate the biological significance of MERTK and to evaluate its potential as a novel therapeutic target in this dismal tumor entity. In two large HNSCC cohorts (n=537 and n=520) we found that MERTK is overexpressed in one third of patients. In-vitro, MERTK overexpression led to increased proliferation, migration and invasion whereas MERTK inhibition with the small molecule inhibitor UNC1062 or MERTK knockdown reduced cell motility via the small GTPase RhoA. Taken together, we are the first to show that MERTK is frequently overexpressed in HNSCC and plays an important role in tumor cell motility. It might therefore be a potential target for selected patients suffering from this dismal tumor entity.

Background Prior studies have identified risk factors for survival in patients with end-stage heart failure (HF) requiring left ventricular assist device (LVAD) support. However, patients with biventricular HF may represent a unique cohort. Methods We retrospectively evaluated a consecutive cohort of 113 adult, end-stage HF patients at University of California Los Angeles Medical Center who required BIVAD support between 2000 and 2009. Results Survival to transplant was 66.4%, with 1-year actuarial survival of 62.8%. All patients were Interagency Registry for Mechanically Assisted Circulatory Support (INTERMACS) Level 1 or 2 and received Thoratec (Pleasanton, CA) paracorporeal BIVAD as a bridge to transplant. Univariate analyses showed dialysis use, ventilator use, extracorporal membrane oxygenation use, low cardiac output, preserved LV ejection fraction (restrictive physiology), normal-to-high sodium, low platelet count, low total cholesterol, low high-density and high-density lipoprotein, low albumin, and elevated aspartate aminotransferase were associated with increased risk of death. We generated a scoring system for survival to transplant. Our final model, with age, sex, dialysis, cholesterol, ventilator, and albumin, gave a C-statistic of 0.870. A simplified system preserved a C-statistic of 0.844. Patients were divided into high-risk or highest-risk groups (median respective survival, 367 and 17 days), with strong discrimination between groups for death. Conclusions We have generated a scoring system that offers high prognostic ability for patients requiring BIVAD support and hope that it may assist in clinical decision making. Further studies are needed to prospectively validate our scoring system.

Next generation sequencing (NGS) technologies have revolutionized cancer research allowing the comprehensive study of cancer using high throughput deep sequencing methodologies. These methods detect genomic alterations, nucleotide substitutions, insertions, deletions and copy number alterations. SOLiD (Sequencing by Oligonucleotide Ligation and Detection, Life Technologies) is a promising technology generating billions of 50 bp sequencing reads. This robust technique, successfully applied in gene identification, might be helpful in detecting novel genes associated with cancer initiation and progression using formalin fixed paraffin embedded (FFPE) tissue. This study’s aim was to compare the validity of whole exome sequencing of fresh-frozen vs. FFPE tumor tissue by normalization to normal prostatic FFPE tissue, obtained from the same patient. One primary fresh-frozen sample, corresponding FFPE prostate cancer sample and matched adjacent normal prostatic tissue was subjected to exome sequencing. The sequenced reads were mapped and compared. Our study was the first to show comparable exome sequencing results between FFPE and corresponding fresh-frozen cancer tissues using SOLiD sequencing. A prior study has been conducted comparing the validity of sequencing of FFPE vs. fresh frozen samples using other NGS platforms. Our validation further proves that FFPE material is a reliable source of material for whole exome sequencing.

We evaluated two composite risk scores, (Heart Failure Survival Score, HFSS; German Transplant Society Score, GTSS), and depression as predictors of mortality and competing waiting-list outcomes [high-urgency transplantation (HU-HTx), elective transplantation, delisting because of clinical improvement] in 318 heart transplant (HTx) candidates (18% women; aged 53 ± 11 years) from 17 hospitals and newly registered with Eurotransplant. Demographic variables and depression (Hospital Anxiety and Depression Scale, HADS) were assessed using questionnaires. Variables to compute HFSS and GTSS, age, medications, and outcomes were provided by Eurotransplant. At 12 months, 33 patients died, 83 received urgent HTx, 30 elective HTx, and 17 were delisted because of improvement. Applying cause-specific Cox regressions, only the HFSS was significantly associated with 1-year mortality [HR = 0.64 (95% CI = 0.43-0.95), P = 0.029]. The GTSS was the strongest predictor of HU-HTx [HR= 1.02 (95% CI = 1.01-1.02), P < 0.001]. Low depression scores contributed significantly to clinical improvement, even after adjusting for age and risk scores [HADS: HR = 0.12 (95% CI = 0.02-0.89), P = 0.039]. These findings confirm the usefulness of composite risk scores for the prediction of mortality and HU-HTx, validating both scores for their intended use. The finding that depression was an independent predictor of the waiting-list outcome clinical improvement suggests that considering patients' psychological attributes in addition to their medical characteristics is advisable.