Citations

International normalized ratio (INR) measurements manage risks of bleeding and clotting sequelae in the population with left ventricular assist device (LVAD). Studies suggest that point-of-care (POC) INR does not significantly differ from plasma INR (P-INR) values in other patient populations, although this has not been validated in a multicenter LVAD study. We sought to determine whether POC-INR and P-INR values differ significantly in the LVAD population and reviewed patients with permanent LVAD implantation at seven institutions internationally. Our cohort comprised of 279 paired POC-INR and P-INR checks in patients supported on average 630 ± 598 days postimplant with predominately HeartWare, HeartMate II, and HeartMate III devices. The population averaged 57.9 years of age, and there were 86.7% male. We found no statistically significant difference between POC-INR and P-INR values. International normalized ratio accuracy correlated weakly with the time between INR measurements (p < 0.001). When the time difference was less than 4 hours, the difference between INR pairs was significantly lower than measurements greater than 8 hours (p = 0.006). There was no statistically significant difference when comparing paired INR values and time after implant to INR check (p = 0.43), age (p = 0.12), known coagulopathy (p = 0.12), bleeding history (p = 0.22), or thrombosis history (p = 0.34). This is the first large multicenter international study comparing POC-INR and P-INR measurements in patients with LVAD and found no statistically significant difference between either methods, particularly when measured within less than 4 hours of each other.

9517 Background: Although PD-1/L1 axis directed therapies induce durable responses in some mm patients (pts), biomarkers of response remain elusive. We hypothesized that quantifying key immune suppression mechanisms within the tumor microenvironment would provide superior predictors of response to anti-PD-1 compared with single marker assessment. Methods: Pre-treatment tumor biopsies from 124 mm pts treated with anti-PD-1 at 7 academic centers were fluorescently stained with multiple immune markers in discovery (n = 24) and validation (n = 100) cohorts. Selected biomarker signatures, PD-1/PD-L1 interaction score (proportion of PD-1+ cells co-localized with PD-L1) and IDO1/HLA-DR co-expression were evaluated for anti-PD-1 treatment response and survival. Slides were imaged using Vectra; biomarker positive cells and their co-localization were objectively quantified in pathologist-selected regions using novel Automated Quantitative Analysis (AQUA) algorithms. Results: In the discovery cohort, high levels of PD-1/PD-L1 interaction score and/or IDO1/HLA-DR coexpression was strongly positively associated with response to anti-PD-1 (p = 0.0005). In contrast, other individual biomarkers (PD-1, PD-L1, CD8) were not associated with response or survival (p > 0.10). This finding was replicated in the validation cohort: pts with high PD-1/PD-L1 and/or IDO1/HLA-DR were more likely to respond to treatment (p = 0.009). These pts also experienced a three-fold increase in progression free survival (hazards ratio (HR) = 0.33; p = 0.003) and overall survival (HR = 0.34; p = 0.004). Multivariate analyses revealed that these findings were independent of BRAF mutation, stage, LDH and prior therapy. In the combined cohort (n = 124), 80% of responding pts had higher levels of PD-1/PD-L1 interaction scores and/or IDO1/HLA-DR. In contrast, PD-L1 expression alone (≥1% or ≥50%) was not predictive of PFS or OS (p > 0.1). Conclusions: This novel multiplexed method profiling key tumor-immune suppression pathways identified mm pts likely to respond to anti-PD-1 therapy. This method could help stratify patients for PD-1 monotherapy and be useful in guiding future clinical trials.

Abstract Castleman disease (CD) describes a group of heterogeneous hematologic disorders with characteristic histopathological features. CD can present with unicentric or multicentric (MCD) regions of lymph node enlargement. Some cases of MCD are caused by human herpesvirus-8 (HHV-8), whereas others are HHV-8–negative/idiopathic (iMCD). Treatment of iMCD is challenging, and outcomes can be poor because no uniform treatment guidelines exist, few systematic studies have been conducted, and no agreed upon response criteria have been described. The purpose of this paper is to establish consensus, evidence-based treatment guidelines based on the severity of iMCD to improve outcomes. An international Working Group of 42 experts from 10 countries was convened by the Castleman Disease Collaborative Network to establish consensus guidelines for the management of iMCD based on published literature, review of treatment effectiveness for 344 cases, and expert opinion. The anti–interleukin-6 monoclonal antibody siltuximab (or tocilizumab, if siltuximab is not available) with or without corticosteroids is the preferred first-line therapy for iMCD. In the most severe cases, adjuvant combination chemotherapy is recommended. Additional agents are recommended, tailored by disease severity, as second- and third-line therapies for treatment failures. Response criteria were formulated to facilitate the evaluation of treatment failure or success. These guidelines should help treating physicians to stratify patients based on disease severity in order to select the best available therapeutic option. An international registry for patients with CD (ACCELERATE, #NCT02817997) was established in October 2016 to collect patient outcomes to increase the evidence base for selection of therapies in the future.

AbstractBackgroundRenal dysfunction occurs commonly after heart transplantation (HTx) with wide inter‐individual variability but whether a genetic predisposition exists in these patients is unknown. Genomewide association studies (GWAS) have not been performed to assess the association of genetic variation with change in renal function after HTx.MethodsClinical and demographic data of patients who underwent HTx and provided blood samples and consent for genetic analysis were included. Genotyping was performed using Illumina Infinium Human CoreExome v1.0 analysis kit. A GWAS utilizing linear regression models was performed with estimated glomerular filtration rate (eGFR) at 1 year as the phenotype after adjusting for baseline eGFR prior to HTx and conversion from calcineurin inhibitor to sirolimus as primary immunosuppression therapy.ResultsA total of 251 HTx recipients were genotyped for 314,903 single nucleotide polymorphisms (SNPs). The mean (SD) age was 50 (12.5) years; most patients were of European origin (n = 243, 96.8%) and males (n = 179, 71.3%). After adjustment for potential confounders, two variants, rs17033285 (P = 4.3 × 10−7) and rs4917601 (P = 6.46 × 10−7), in a long non‐coding RNA (lncRNA) gene LINC01121 and a pseudogene BTBD7P2, were identified to have a significant association with change in GFR at 1 year after HTx.ConclusionsOur first of its kind GWAS demonstrates that genetic variation affects renal function after HTx independent of other risk factors. Agnostic genetic approaches such as these may lead to identification of novel biological pathways such as the role of lncRNAs in the development of renal dysfunction post‐HTx.