Citations

Abstract Purpose: PD-1/L1 axis–directed therapies produce clinical responses in a subset of patients; therefore, biomarkers of response are needed. We hypothesized that quantifying key immunosuppression mechanisms within the tumor microenvironment by multiparameter algorithms would identify strong predictors of anti–PD-1 response. Experimental Design: Pretreatment tumor biopsies from 166 patients treated with anti–PD-1 across 10 academic cancer centers were fluorescently stained with multiple markers in discovery (n = 24) and validation (n = 142) cohorts. Biomarker-positive cells and their colocalization were spatially profiled in pathologist-selected tumor regions using novel Automated Quantitative Analysis algorithms. Selected biomarker signatures, PD-1/PD-L1 interaction score, and IDO-1/HLA-DR coexpression were evaluated for anti–PD-1 treatment outcomes. Results: In the discovery cohort, PD-1/PD-L1 interaction score and/or IDO-1/HLA-DR coexpression was strongly associated with anti–PD-1 response (P = 0.0005). In contrast, individual biomarkers (PD-1, PD-L1, IDO-1, HLA-DR) were not associated with response or survival. This finding was replicated in an independent validation cohort: patients with high PD-1/PD-L1 and/or IDO-1/HLA-DR were more likely to respond (P = 0.0096). These patients also experienced significantly improved progression-free survival (HR = 0.36; P = 0.0004) and overall survival (HR = 0.39; P = 0.0011). In the combined cohort, 80% of patients exhibiting higher levels of PD-1/PD-L1 interaction scores and IDO-1/HLA-DR responded to PD-1 blockers (P = 0.000004). In contrast, PD-L1 expression was not predictive of survival. Conclusions: Quantitative spatial profiling of key tumor-immune suppression pathways by novel digital pathology algorithms could help more reliably select melanoma patients for PD-1 monotherapy. Clin Cancer Res; 24(21); 5250–60. ©2018 AACR.

Abstract Aims Early studies from the 1990s have shown that statins improve survival and attenuate cardiac allograft vasculopathy (CAV). However, little contemporary data are available on the incremental benefit of statins with the current use of new-generation immunosuppressive agents and the use of coronary intravascular ultrasound for assessment of CAV. We sought to investigate the effect of early statin (ES) as compared with late statin (LS) initiation after heart transplantation (HT) on long-term CAV progression and clinical outcomes in a large contemporary HT cohort. Methods and results We analysed a cohort of 409 adult HT recipients. CAV progression was assessed by serial coronary intravascular ultrasound volumetric measurements of the differences between baseline and last follow-up plaque volume (PV) and plaque index (PV/vessel volume ratio). CAV progression and clinical outcomes were compared between the ES (<2 years after HT) and the LS (>2 years after HT) groups. During a median follow-up of 8.2 years, ES resulted in significantly lower change (Δ) of plaque index (+3.8% ± 1.7% vs. +8.2% ± 3.6%; P = 0.0008) and PV (+0.8 ± 0.3 vs. +1.9 ± 1.2; P = 0.045) compared with LS group. In a Cox proportional hazards regression model and after adjustment for baseline characteristics, ES was associated with a 52% decreased risk of CAV-associated events (hazard ratio 0.48, 95% confidence interval: 0.27–0.91; P = 0.025) and a 42% decreased risk of the composite endpoint of all-cause mortality and CAV-associated events (hazard ratio 0.58, 95% confidence interval: 0.38–0.91; P = 0.019). Conclusions Early initiation of statin therapy after HT results in attenuated CAV progression as well as in decreased CAV-related events and mortality.

AbstractSoluble ST2 (sST2) is a novel biomarker of inflammation and fibrosis. Elevated sST2 levels (≥35 ng/mL) are associated with worse outcomes in patients with heart failure (HF). There are sparse data regarding the significance of sST2 levels after heart transplantation (HTx). The study aims were to evaluate trends in soluble ST2 levels after the resolution of HF status with HTx and association between post‐HTx sST2 levels and outcomes. Plasma sST2 levels were measured at baseline (median [IQR] of 118 days pre‐HTx) and 12 months post‐HTx in 62 subjects who were stratified into two groups by post‐HTx sST2 levels < or ≥35 ng/mL: “Group 1” or “Group 2,” respectively. Plasma sST2 levels were elevated in 58% of patients pre‐HTx and in 50% of patients post‐HTx. There was no association between elevated sST2 levels before and after HTx, and no significant differences in baseline characteristics between Group 1 and Group 2 patients. Group 2 as compared to Group 1 HTx recipients had significantly higher incidence of antibody‐mediated rejection (AMR) for the entire post‐transplant follow‐up period (32% vs 4%, P = 0.006). There was no association between post‐HTx sST2 level status and other post‐HTx outcomes including survival. In conclusion, elevated plasma sST2 levels after HTx are associated with increased risk for AMR.

Background: Lateral meniscus posterior root tears (LMPRTs), if left untreated, can cause devastating effects to the knee, with rapid articular cartilage degeneration and loss of the meniscus as a secondary stabilizer. Detection and surgical repair of these defects have been linked to favorable outcomes, but preoperative identification of LMPRTs continues to be challenging. Purpose: To determine the rate of LMPRTs diagnosed preoperatively on magnetic resonance imaging (MRI) in a consecutive series of arthroscopically confirmed LMPRTs. Study Design: Case series; Level of evidence, 4. Methods: A retrospective cohort of 45 consecutive patients with arthroscopically confirmed LMPRTs between 2010 and 2017 were included in this study. The preoperative MRI report for each patient was evaluated and compared with intraoperative findings. Each preoperative MRI study was then reviewed by 2 fellowship-trained musculoskeletal radiologists who worked in consensus. Results: A total of 45 patients (32 males, 13 females) with arthroscopically confirmed LMPRTs and a mean age of 27 years (range, 14-54 years) were included in the study. Only 15 of 45 LMPRTs (33%) were initially diagnosed on preoperative MRI. Past or concurrent anterior cruciate ligament (ACL) reconstruction was present in 37 of 45 cases (82%). Upon retrospective review, 15 of the 30 missed LMPRTs were “clearly evident,” 12 “subtly evident,” and 3 “occult” (unavoidably missed). There were no significant differences in the rate of LMPRT diagnosis based on history of prior knee surgery, meniscus extrusion, or tearing of the meniscofemoral ligament. Conclusion: Despite improved identification of other meniscus tear patterns on MRI, a high percentage of LMPRTs were still missed. In the setting of previous ACL reconstruction, if the root cannot be confidently identified, the MRI interpretation should indicate that “the root is poorly visualized” to alert the surgeon to thoroughly evaluate this structure. The surgeon should maintain a high index of suspicion and carefully probe the posterior root of the lateral meniscus at the time of arthroscopy, especially in cases of ACL injury.

The purpose of this series is to review the appearance of plantar fibromatosis with high‐resolution ultrasonography (US) and highlight a new imaging sign termed the “comb sign.” A retrospective study was performed for patients with a clinical diagnosis of plantar fibromatosis. Charts of 43 patients (age range, 26–77 years; mean age, 54 years) were reviewed to gather patient demographics and symptoms. Several US characteristics were evaluated with emphasis on any new imaging features. A total of 57 plantar fibromas in 43 patients were examined. Plantar fibromatosis was seen as a lobular marginated oval nodule along the superficial plantar fascia involving the central or medial cord, often at the middle third (84%) of the plantar fascia, showing posterior acoustic enhancement (65%), mixed echogenicity (82%), and intralesional vascularity (53%). Slightly more than half (51%) of the lesions showed a previously unrecognized appearance, designated the comb sign. This sign was more commonly seen in the setting of larger fibromas (P < .05). Plantar fibromatosis is usually a clinical diagnosis that can be aided by a typical US appearance. Although the imaging characteristics are largely similar to prior literature, this series suggests that most show mixed echogenicity and posterior acoustic enhancement, and approximately half show internal vascularity. A new US sign, termed the comb sign, shows alternating bands of hypoechogenicity and isoechogenicity, particularly in larger plantar fibromas, and can help in further characterization.

Variability in response to antiplatelet therapy can be explained in part by pharmacogenomics, particularly of the CYP450 enzyme encoded by CYP2C19. Loss-of-function and gain-of-function variants help explain these interindividual differences. Individuals may carry multiple variants, with linkage disequilibrium noted among some alleles. In the current pharmacogenomics era, genomic variation in CYP2C19 has led to the definition of pharmacokinetic phenotypes for response to antiplatelet therapy, in particular, clopidogrel. Individuals may be classified as poor, intermediate, extensive, or ultrarapid metabolizers, based on whether they carry wild type or polymorphic CYP2C19 alleles. Variant alleles differentially impact platelet reactivity, concentration of plasma clopidogrel metabolites, and clinical outcomes. Interestingly, response to clopidogrel appears to be modulated by additional factors, such as sociodemographic characteristics, risk factors for ischemic heart disease, and drug-drug interactions. Furthermore, systems medicine studies suggest that a broader approach may be required to adequately assess, predict, preempt, and manage variation in antiplatelet response. Transcriptomics, epigenomics, exposomics, miRNAomics, proteomics, metabolomics, microbiomics, and mathematical, computational, and molecular modeling should be integrated with pharmacogenomics for enhanced prediction and individualized care. In this review of pharmacogenomic variation of CYP450, a systems medicine approach is described for tailoring antiplatelet therapy in clinical practice of precision cardiovascular medicine.

AbstractBackgroundFrailty, including low muscle mass, is an emerging risk factor for poor outcomes after lung transplant. The sarcopenia index (SI)—(serum creatinine value/cystatin C value) × 100—is a novel blood test to approximate muscle mass. We sought to validate SI among lung transplant patients.MethodsWe retrospectively identified adult lung transplant recipients from 2000 through 2012 at our institution who underwent computed tomography within 1 year before transplant and had preserved blood samples. Creatinine and cystatin C values were measured using the samples and used to calculate SI. Muscle mass was estimated by computed tomographic measurement of skeletal muscle cross‐sectional surface area (SA) at the L1 to L3 vertebral levels. Correlation between SI and SA was evaluated.ResultsOf 28 patients meeting eligibility criteria, most were white (96%) and men (54%). Median (interquartile range) body mass index, SI, and SA were 25.9 (22‐30) kg/m2, 106 (91‐119), and 157 (113‐195) cm2, respectively. The Pearson correlation coefficient between SI and SA was significant at L2 (0.43; P = .02) and L3 (0.41; P = .03).ConclusionSarcopenia index is a potentially objective measure for estimating muscle mass that is noninvasive and less expensive. Sarcopenia index could be considered in lung transplant candidate selection following prospective validation in larger cohorts.

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