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 Electronic health record (EHR) algorithms for defining patient cohorts are commonly shared as free-text descriptions that require human intervention both to interpret and implement. We developed the Phenotype Execution and Modeling Architecture (PhEMA, http://projectphema.org) to author and execute standardized computable phenotype algorithms. With PhEMA, we converted an algorithm for benign prostatic hyperplasia, developed for the electronic Medical Records and Genomics network (eMERGE), into a standards-based computable format. Eight sites (7 within eMERGE) received the computable algorithm, and 6 successfully executed it against local data warehouses and/or i2b2 instances. Blinded random chart review of cases selected by the computable algorithm shows PPV ≥90%, and 3 out of 5 sites had >90% overlap of selected cases when comparing the computable algorithm to their original eMERGE implementation. This case study demonstrates potential use of PhEMA computable representations to automate phenotyping across different EHR systems, but also highlights some ongoing challenges.

Background: TDP-43 has been shown to be strongly associated with memory loss, smaller hippocampal volumes, and faster rates of hippocampal atrophy in Alzheimer’s disease (AD) patients with an amnestic presentation. Whether TDP-43 has any clinical or anatomical associations in AD patients with non-amnestic phenotype is unknown. Objective: To determine whether TDP-43 plays a significant role in the clinic-anatomic features of non-amnestic AD. Methods: All cases with pathologically confirmed intermediate-high probability AD from 1996–2012 were identified and retrospectively sub-classified into amnestic versus non-amnestic dementia at the time of presentation. Neurofibrillary tangle counts were performed in those with a non-amnestic presentation using thioflavin-S microscopy in the hippocampus and three neocortical regions, and all cases were subtyped into hippocampal-sparing, limbic-predominant, and typical AD pathology. TDP-43 immunoreactivity was used to assess for the presence of TDP-43. Statistical analyses helped determine whether pathologic subtype or TDP-43 was more strongly associated with clinico-imaging features. Results: Out of 172 pathologically confirmed AD cases, 36 (19%) were classified as non-amnestic. Twenty-five of these 36 (69%) had typical pathology, 0 limbic-predominant pathology, and 11 (31%) hippocampal-sparing pathology. Eleven (44%) of the 25 cases with typical pathology were TDP-43+. Of the 11 cases with hippocampal-sparing pathology, 4 (36%) were TDP-43+. There were no differences in demographic, clinical, or neuroimaging features in those with TDP-43 versus those without except for older age at onset ( p = 0.02) and age at death ( p = 0.02) in those with TDP-43. AD pathological subtype accounted for slightly more of the variances in the neocortex than TDP-43. Conclusion: In non-amnestic AD, we find little evidence that clinical or anatomical features of the disease are related to TDP-43.

Background and Purpose— White matter hyperintensities (WMH) on brain magnetic resonance imaging are typical signs of cerebral small vessel disease and may indicate various preclinical, age-related neurological disorders, such as stroke. Though WMH are highly heritable, known common variants explain a small proportion of the WMH variance. The contribution of low-frequency/rare coding variants to WMH burden has not been explored. Methods— In the discovery sample we recruited 20 719 stroke/dementia-free adults from 13 population-based cohort studies within the Cohorts for Heart and Aging Research in Genomic Epidemiology consortium, among which 17 790 were of European ancestry and 2929 of African ancestry. We genotyped these participants at ≈250 000 mostly exonic variants with Illumina HumanExome BeadChip arrays. We performed ethnicity-specific linear regression on rank-normalized WMH in each study separately, which were then combined in meta-analyses to test for association with single variants and genes aggregating the effects of putatively functional low-frequency/rare variants. We then sought replication of the top findings in 1192 adults (European ancestry) with whole exome/genome sequencing data from 2 independent studies. Results— At 17q25, we confirmed the association of multiple common variants in TRIM65 , FBF1 , and ACOX1 ( P <6×10 −7 ). We also identified a novel association with 2 low-frequency nonsynonymous variants in MRPL38 (lead, rs34136221; P EA =4.5×10 −8 ) partially independent of known common signal ( P EA(conditional) =1.4×10 −3 ). We further identified a locus at 2q33 containing common variants in NBEAL1 , CARF , and WDR12 (lead, rs2351524; P all =1.9×10 −10 ). Although our novel findings were not replicated because of limited power and possible differences in study design, meta-analysis of the discovery and replication samples yielded stronger association for the 2 low-frequency MRPL38 variants ( P rs34136221 =2.8×10 −8 ). Conclusions— Both common and low-frequency/rare functional variants influence WMH. Larger replication and experimental follow-up are essential to confirm our findings and uncover the biological causal mechanisms of age-related WMH.

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: Underrepresentation of African American women as research participants contributes to health disparities. Contemporary studies have focused on clinical trial (CT) participation; epidemiologic and genetic studies utilizing medical records and/or biological samples have received less attention. In partnership with The Links, Incorporated (The Links), a national service organization of professional African American women, this study sought to examine attitudes regarding chart review (CR) studies, genetic studies/biobanking (GEN), and CTs; develop; and evaluate an online education-to-action program. Methods: In phase 1, focus groups were convened with members of The Links to inform the content and format of the program. Phases 2 and 3 involved designing and evaluating the program, respectively. Results: Thirty-four women across three focus groups shared attitudes and perceptions regarding research and provided guidance for program development. Subsequently, 244 women completed the program (77% response rate), including pre- and post-assessments. Participants indicating that they “definitely” or “probably” (responses combined) intend to participate in research increased from 36.5% to 69.3% (pre/post-program). Agreement with the statement “research in the U.S. is ethical” increased (52.9% to 74.4%) as did factual knowledge regarding each of the study types. There was a decrease in reporting “little or no understanding” of study types (Pre/Post: GEN: 66%/24.9%, CR: 62.9%/18.4%, CTs: 40.7%/15.5%). Pre-program, few were “very positive” about the study types (14.3% GEN, 15.0% CR, 28.6% CTs); post-program ratings increased and equalized (42.8% GEN, 43.0% CR, 42.5% CTs). Conclusions: An online education-to-action program targeting professional African American women improved knowledge, perceptions of ethics, and intent to participate in biomedical research.

BACKGROUND As the number of cutaneous surgeries continues to increase, it is important to evaluate the safety of dermatologic surgery in the outpatient setting. OBJECTIVE The authors sought to determine postoperative bleeding, infection, dehiscence, and necrosis rates in office-based dermatologic surgery using large flap, large graft, and interpolation flap repairs. The authors evaluated the relationship between these complications and surgical site, closure type, repair size, antibiotic use, and antithrombotic use. METHODS Eligible patients were identified through searching the electronic medical records from one Mohs micrographic surgeon at University Hospitals Medical Center. Patient information, surgery characteristics, and complication information were collected. Univariate and multivariate analyses were conducted to reveal associations between each complication and closure type, repair size, repair site, antithrombotic use, and antibiotic use. RESULTS Three hundred and thirty-one reconstruction procedures after Mohs micrographic surgery and excision qualified for the study. The rates of postoperative infection, hemorrhage, hematoma, necrosis, and dehiscence were 5%, 0.3%, 2.4%, 3%, and 0.9%, respectively. CONCLUSION Complications were infrequent and non–life-threatening. The authors' results indicate that dermatologic surgery using large flaps, interpolation flaps, and large grafts is safe in the office setting.