Citations

Objective To demonstrate DNA sequencing analysis (DNAsa) of sinus cultures in patients with CRS is a reliable method of detecting pathogens in polymicrobial CRS infections. Methods After obtaining Institutional Review Board approval for this prospective cohort study, we selected a random sample of 50 patients with CRS at Medstar Georgetown University Hospital between September 2016 and March 2017. We defined CRS as a history of rhinosinusitis refractory to maximal medical therapy and prior endoscopic sinus surgery. Patients demonstrating active purulence in a sinus cavity were prospectively selected to undergo standard hospital cultures (SHC) and DNAsa cultures. Organisms identified in both methods were compared for each patient. Results Specimens were obtained from 29 female and 16 male patients with a mean age of 50 years. A total of 45 cultures were included in our final analysis; five cultures were excluded after inappropriate laboratory processing. Results from these patients were compared and analyzed. Cohen's weighted kappa analysis showed agreement between the two testing methods in identifying predominant microorganisms. DNAsa detected 31.9% more microorganisms compared to SHC ( P < 0.05). When multiple microorganisms were detected, DNAsa yielded more positive results compared to SHC ( P < 0.05). Conclusions DNAsa detects all microorganisms identified by SHC as well as predominant microorganisms not detected by SHC. Thus molecular pathogen identification may be more reliable for identifying multiple microorganisms as compared to standard culture techniques that identify only one or two microorganisms. In recalcitrant cases of CRS, DNAsa may provide better guidance in selection of appropriate antimicrobial treatment.

As a follow‐up to genome‐wide association analysis of common variants associated with ovarian carcinoma (cancer), our study considers seven well‐known ovarian cancer risk factors and their interactions with 28 genome‐wide significant common genetic variants. The interaction analyses were based on data from 9971 ovarian cancer cases and 15,566 controls from 17 case–control studies. Likelihood ratio and Wald tests for multiplicative interaction and for relative excess risk due to additive interaction were used. The top multiplicative interaction was noted between oral contraceptive pill (OCP) use (ever vs. never) and rs13255292 (p value = 3.48 × 10−4). Among women with the TT genotype for this variant, the odds ratio for OCP use was 0.53 (95% CI = 0.46–0.60) compared to 0.71 (95%CI = 0.66–0.77) for women with the CC genotype. When stratified by duration of OCP use, women with 1–5 years of OCP use exhibited differential protective benefit across genotypes. However, no interaction on either the multiplicative or additive scale was found to be statistically significant after multiple testing correction. The results suggest that OCP use may offer increased benefit for women who are carriers of the T allele in rs13255292. On the other hand, for women carrying the C allele in this variant, longer (5+ years) use of OCP may reduce the impact of carrying the risk allele of this SNP. Replication of this finding is needed. The study presents a comprehensive analytic framework for conducting gene–environment analysis in ovarian cancer.

BACKGROUND: There are few comparative data on the analgesic options used to manage patients undergoing minimally invasive repair of pectus excavatum (MIRPE). The Society for Pediatric Anesthesia Improvement Network was established to investigate outcomes for procedures where there is significant management variability. For our first study, we established a multicenter observational database to characterize the analgesic strategies used to manage pediatric patients undergoing MIRPE. Outcome data from the participating centers were used to assess the association between analgesic strategy and pain outcomes. METHODS: Fourteen institutions enrolled patients from June 2014 through August 2015. Network members agreed to an observational methodology where each institution managed patients based on their institutional standards and protocols. There was no requirement to standardize care. Patients were categorized based on analgesic strategy: epidural catheter (EC), paravertebral catheter (PVC), wound catheter (WC), no regional (NR) analgesia, and intrathecal morphine techniques. Primary outcomes, pain score and opioid consumption by postoperative day (POD), for each technique were compared while adjusting for confounders using multivariable modeling that included 5 covariates: age, sex, number of bars, Haller index, and use of preoperative pain medication. Pain scores were analyzed using repeated-measures analysis of variance with Bonferroni correction. Opioid consumption was analyzed using a multivariable quantile regression. RESULTS: Data were collected on 348 patients and categorized based on primary analgesic strategy: EC (122), PVC (57), WC (41), NR (120), and intrathecal morphine (8). Compared to EC, daily median pain scores were higher in patients managed with PVC (POD 0), WC (POD 0, 1, 2, 3), and NR (POD 0, 1, 2), respectively ( P < .001–.024 depending on group). Daily opioid requirements were higher in patients managed with PVC (POD 0, 1), WC (POD 0, 1, 2), and NR (POD 0, 1, 2) when compared to patients managed with EC ( P < .001). CONCLUSIONS: Our data indicate variation in pain management strategies for patients undergoing MIRPE within our network. The results indicate that most patients have mild-to-moderate pain postoperatively regardless of analgesic management. Patients managed with EC had lower pain scores and opioid consumption in the early recovery period compared to other treatment strategies.

Abstract Purpose: Although high glucocorticoid receptor (GR) expression in early-stage estrogen receptor (ER)-negative breast cancer is associated with shortened relapse-free survival (RFS), how associated GR transcriptional activity contributes to aggressive breast cancer behavior is not well understood. Using potent GR antagonists and primary tumor gene expression data, we sought to identify a tumor-relevant gene signature based on GR activity that would be more predictive than GR expression alone. Experimental Design: Global gene expression and GR ChIP-sequencing were performed to identify GR-regulated genes inhibited by two chemically distinct GR antagonists, mifepristone and CORT108297. Differentially expressed genes from MDA-MB-231 cells were cross-evaluated with significantly expressed genes in GR-high versus GR-low ER-negative primary breast cancers. The resulting subset of GR-targeted genes was analyzed in two independent ER-negative breast cancer cohorts to derive and then validate the GR activity signature (GRsig). Results: Gene expression pathway analysis of glucocorticoid-regulated genes (inhibited by GR antagonism) revealed cell survival and invasion functions. GR ChIP-seq analysis demonstrated that GR antagonists decreased GR chromatin association for a subset of genes. A GRsig that comprised n = 74 GR activation-associated genes (also reversed by GR antagonists) was derived from an adjuvant chemotherapy-treated Discovery cohort and found to predict probability of relapse in a separate Validation cohort (HR = 1.9; P = 0.012). Conclusions: The GRsig discovered herein identifies high-risk ER-negative/GR-positive breast cancers most likely to relapse despite administration of adjuvant chemotherapy. Because GR antagonism can reverse expression of these genes, we propose that addition of a GR antagonist to chemotherapy may improve outcome for these high-risk patients. Clin Cancer Res; 24(14); 3433–46. ©2018 AACR.

BackgroundAppropriate use criteria (AUC) provide physicians guidance in test selection, and can affect health care delivery, reimbursement policy and physician decision‐making.ObjectivesThe American Society of Dermatopathology, with input from the American Academy of Dermatology and the College of American Pathologists, sought to develop AUC in dermatopathology.MethodsThe RAND/UCLA appropriateness methodology, which combines evidence‐based medicine, clinical experience and expert judgment, was used to develop AUC in dermatopathology.ResultsWith the number of ratings predetermined at 3, AUC were developed for 211 clinical scenarios involving 12 ancillary studies. Consensus was reached for 188 (89%) clinical scenarios, with 93 (44%) considered “usually appropriate,” 52 (25%) “rarely appropriate” and 43 (20%) “uncertain appropriateness.”LimitationsThe methodology requires a focus on appropriateness without comparison between tests and irrespective of cost.ConclusionsThe ultimate decision of when to order specific test rests with the physician and is one where the expected benefit exceeds the negative consequences. This publication outlines the recommendations of appropriateness—AUC for 12 tests used in dermatopathology. Importantly, these recommendations may change considering new evidence. Results deemed “uncertain appropriateness” and where consensus was not reached may benefit from further research.

AimErdheim–Chester disease represents a clonal systemic proliferation of histiocytes. Bone is the most common site of involvement, although almost any organ, including the lungs, can be affected.Methods and resultsThe diagnosis of Erdheim–Chester disease can be difficult, owing to its rarity and protean presentation. Correlation between clinical, radiological and histological findings is mandatory for identification of the disease. Foamy histiocytes, lacking Langerhans cell markers, represent the typical histological findings, although their absence does not rule out Erdheim–Chester disease. Identification of BRAF mutation can be helpful in making the diagnosis, and allows for the development and application of targeted therapies in this setting.ConclusionsHerein, we describe two cases presenting with lung involvement and vertebral lesions, lacking the more typical long‐bone involvement. One case histologically mimicked Rosai–Dorfman disease. However, both cases harboured the pathognomonic BRAFV600E mutation.