Citations

Abstract Purpose: Androgen receptor (AR) variant AR-V7 is a ligand-independent transcription factor that promotes prostate cancer resistance to AR-targeted therapies. Accordingly, efforts are under way to develop strategies for monitoring and inhibiting AR-V7 in castration-resistant prostate cancer (CRPC). The purpose of this study was to understand whether other AR variants may be coexpressed with AR-V7 and promote resistance to AR-targeted therapies. Experimental Design: We utilized complementary short- and long-read sequencing of intact AR mRNA isoforms to characterize AR expression in CRPC models. Coexpression of AR-V7 and AR-V9 mRNA in CRPC metastases and circulating tumor cells was assessed by RNA-seq and RT-PCR, respectively. Expression of AR-V9 protein in CRPC models was evaluated with polyclonal antisera. Multivariate analysis was performed to test whether AR variant mRNA expression in metastatic tissues was associated with a 12-week progression-free survival endpoint in a prospective clinical trial of 78 CRPC-stage patients initiating therapy with the androgen synthesis inhibitor, abiraterone acetate. Results: AR-V9 was frequently coexpressed with AR-V7. Both AR variant species were found to share a common 3′ terminal cryptic exon, which rendered AR-V9 susceptible to experimental manipulations that were previously thought to target AR-V7 uniquely. AR-V9 promoted ligand-independent growth of prostate cancer cells. High AR-V9 mRNA expression in CRPC metastases was predictive of primary resistance to abiraterone acetate (HR = 4.0; 95% confidence interval, 1.31–12.2; P = 0.02). Conclusions: AR-V9 may be an important component of therapeutic resistance in CRPC. Clin Cancer Res; 23(16); 4704–15. ©2017 AACR.

Purpose To use a national database to determine (1) the incidence of joint infection after elbow arthroscopy, (2) identify independent patient‐related risk factors for infection, and (3) determine the influence of concomitant intra‐articular corticosteroid injection on infection risk. Methods The 100% Medicare Standard Analytic Files were queried to identify patients who underwent elbow arthroscopy from 2005 to 2012. Postoperative elbow infections occurring within 6 months of surgery were identified using both International Classification of Diseases, 9th Revision codes for postoperative infection and Current Procedural Terminology codes for the surgical treatment of a postoperative infection. Patients were excluded if their initial arthroscopic procedure was performed for infection. A multivariate binomial logistic regression analysis was then used to evaluate patient‐related risk factors for postoperative infection. Results Of the 2,704 elbow arthroscopy cases identified, 42 (1.55%) developed a postoperative infection. The annual incidence of infections did not increase significantly over the course of the study ( P = .374). A number of patient demographics and medical comorbidities significantly increased the risk of infection. The most notable factors included age ≥ 65 years (odds ratio [OR] 2.38, P = .006), body mass index > 40 (OR 1.97, P = .024), tobacco usage (OR 1.80, P = .046), alcohol usage (OR 4.01, P < .001), diabetes mellitus (OR 2.10, P = .015), inflammatory arthritis (OR 2.81, P < .001), hypercoagulable disorder (OR 2.51, P = .015), and intra‐articular corticosteroid injection at the time of arthroscopy (OR 2.79, P = .006). Conclusions The annual number of elbow arthroscopies performed in the United States has increased steadily; however, the postoperative infection rate remained consistently low at 1.55%. There are a number of patient‐specific risk factors that increase this risk with OR ranging from 1.97 to 4.01. Similarly, patients who receive an intra‐articular corticosteroid injection at the time of surgery are nearly 3 times (OR 2.79) more likely to develop a postoperative infection. Level of Evidence Level III, case‐control study.

The medicolegal autopsy is part of a death investigation that determines the cause and manner of death and the extent of the testing performed is variable and is directed by the specifics of a particular case. Published studies disagree on the value of routine examination of microscopic sections of internal organs in forensic cases and no studies have specifically reviewed the utility of routine neuropathology microscopic sections. We reviewed the Miami-Dade County Medical Examiner Department and Mayo Clinic computer databases to determine whether routine brain histology is of value in medicolegal autopsies and the impact on the cause and manner of death. Consecutive cases from each institution were analyzed to determine whether the microscopic neuropathological findings revealed a previously unrecognized disease, changed the cause or manner of death, or significantly impacted the death investigation. In the cases in which the immediate cause of death was attributable to central nervous system (CNS) pathology, the cause of death was readily apparent from the gross brain examination. If CNS pathology was the proximate cause of death, contributed significantly to the death, or was a significant part of the death investigation, full appreciation of the neuropathology required microscopic examination and often additional special/immunostains. We conclude that microscopic brain examination is needed in selected medicolegal autopsies to exclude and/or diagnose underlying disease processes, particularly if the gross examination doesn't reveal an obvious explanation of the CNS pathology or the clinical history suggests underlying neuropathology.

AbstractIgM myeloma is a rare hematologic malignancy for which the clinicopathological features and patient outcomes have not been extensively studied. We carried out a multicenter retrospective study in patients with diagnosis of IgM myeloma defined by >10% marrow involvement by monoclonal plasma cells, presence of an IgM monoclonal paraproteinemia of any size, and anemia, renal dysfunction, hypercalcemia, lytic lesions and/or t(11;14) identified by FISH. A total of 134 patients from 20 centers were included in this analysis. The median age at diagnosis was 65.5 years with a male predominance (68%). Anemia, renal dysfunction, elevated calcium and skeletal lytic lesions were found in 37, 43, 19, and 70%, respectively. The median serum IgM level was 2,895 mg dL−1 with 19% of patients presenting with levels >6,000 mg dL−1. International Staging System (ISS) stages 1, 2, and 3 were seen in 40 (33%), 54 (44%), and 29 (24%) of patients, respectively. The malignant cells expressed CD20 (58%) and cyclin D1 (67%), and t(11;14) was the most common cytogenetic finding (39%). The median overall survival (OS) was 61 months. Higher ISS score was associated with worse survival (P = 0.02). Patients with IgM myeloma present with similar characteristics and outcomes as patients with more common myeloma subtypes.

Purpose The stiffness of a myocardial infarct affects the left ventricular pump function and remodeling. Magnetic resonance elastography (MRE) is a noninvasive imaging technique for measuring soft‐tissue stiffness in vivo. The purpose of this study was to investigate the feasibility of assessing in vivo regional myocardial stiffness with high‐frequency 3D cardiac MRE in a porcine model of myocardial infarction, and compare the results with ex vivo uniaxial tensile testing. Methods Myocardial infarct was induced in a porcine model by embolizing the left circumflex artery. Fourteen days postinfarction, MRE imaging was performed in diastole using an echocardiogram‐gated spin‐echo echo‐planar‐imaging sequence with 140‐Hz vibrations and 3D MRE processing. The MRE stiffness and tensile modulus from uniaxial testing were compared between the remote and infarcted myocardium. Results Myocardial infarcts showed increased in vivo MRE stiffness compared with remote myocardium (4.6 ± 0.7 kPa versus 3.0 ± 0.6 kPa, P = 0.02) within the same pig. Ex vivo uniaxial mechanical testing confirmed the in vivo MRE results, showing that myocardial infarcts were stiffer than remote myocardium (650 ± 80 kPa versus 110 ± 20 kPa, P = 0.01). Conclusions These results demonstrate the feasibility of assessing in vivo regional myocardial stiffness with high‐frequency 3D cardiac MRE. Magn Reson Med 79:361–369, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

AbstractAimsPlatelets retain cytoplasmic messenger RNA and are capable of protein biosynthesis. Several diseases are known to impact the platelet transcriptome but the effect of non‐valvular atrial fibrillation (NVAF) on platelet RNA transcript is essentially unknown. The aim of this study was to evaluate the impact of NVAF on platelet RNA transcript by measuring platelet genes expression in consecutive NVAF patients before and 3‐4 months after pulmonary vein isolation (PVI) and compared to normal sinus rhythm controls (NSR).Methods and ResultsRNA from isolated platelets were reverse transcribed, assayed against 15 genes using real‐time qPCR, and expressed as mean cycle threshold (ΔCt) using beta‐2‐microglobulin as endogenous control. Expression of all evaluated genes, except cathepsin A gene, was significantly lower (higher ΔCt) in 103 NVAF patients compared to 55 NSR controls. Insulin‐like growth factor binding protein acid labile subunit gene (IGFALS) had expression more than 16 fold‐lower (17.0±2.8 vs 12.5±3.8, P<.001), follow by genes encoding for prostacyclin receptor, and for von Willebrand factor which had fourfold lower expression compared to NSR controls. Gender, type of atrial fibrillation, heart failure, hypertension, prior stroke, diabetes mellitus, and atherosclerosis were associated with different gene expression. Following PVI, expression of four genes significantly increased, particularly IGFALS gene (increased 256‐fold) and ADAMT gene increased 16‐fold); expression of three genes significantly decreased, and expression of eight genes has not changed.ConclusionsPlatelets are capable to respond to the circulatory environment of NVAF by altering transcript and changing prothrombotic status. This shows platelet potential for molecular “reprogramming” possibly induced by flow disturbances of NVAF.

IntroductionDofetilide is a class III antiarrhythmic prescribed to cardiovert persistent atrial fibrillation (AF) to sinus rhythm (SR).HypothesisTo determine the clinical predictors of cardioversion and readmission in persistent AF patients on dofetilide.MethodsWe analyzed 160 patients with persistent AF who were started on dofetilide and followed for 1 year. We examined age, sex, race, hypertension, diabetes, smoking, dyslipidemia, CAD, left ventricular ejection fraction (LVEF), creatinine, BMI and concomitant use of calcium channel blockers (CCB), β‐blockers in a multivariable logistic regression model. We also examined the same predictors in Cox regression model for AF‐related readmission within 1 year of follow‐up.Results13.5% individuals did not convert to SR on dofetilide. 55.6% converted on the first dose and 83.1% converted by the fourth dose. In multivariable logistic models, dyslipidemia (OR: 2.4, CI: 1.12‐5.16) and LVEF (OR: 3.83,CI: 1.37‐10.8) were associated with failure to convert with the first dose. Female sex and LVEF also were associated with increased risk of failure to convert at all. Concomitant use of CCB associated with decreased risk of failure to convert to SR. In Cox proportional model, female sex, age <63 years and CAD were associated with increased AF readmission within 1 year.ConclusionsDyslipidemia and LVEF <40% were associated with failure to cardiovert after first dose, and female sex and LVEF 40% were related to failure to convert at all on dofetilide in persistent AF patients. After 1‐year follow‐up, female sex, known CAD, and age <63 years were associated with increased AF readmissions.

Background: Oblique injuries are known to be a common cause of time out of play for professional baseball players, and prior work has suggested that injury rates may be on the rise in Major League Baseball (MLB). Purpose: To better understand the current incidence of oblique injuries, determine their impact based on time out of play, and to identify common injury patterns that may guide future injury prevention programs. Study Design: Descriptive epidemiological study. Methods: Using the MLB Health and Injury Tracking System, all oblique injuries that resulted in time out of play in MLB and Minor League Baseball (MiLB) during the 2011 to 2015 seasons were identified. Player demographics such as age, position/role, and handedness were included. Injury-specific factors analyzed included the following: date of injury, timing during season, days missed, mechanism, side, treatment, and reinjury status. Results: A total of 996 oblique injuries occurred in 259 (26%) MLB and 737 (74%) MiLB players. Although the injury rate was steady in MiLB, the MLB injury rate declined ( P = .037). A total of 22,064 days were missed at a mean rate of 4413 days per season and 22.2 days per injury. The majority of these occurred during batting (n = 455, 46%) or pitching (n = 348, 35%), with pitchers losing 5 days more per injury than batters ( P < .001). The leading side was injured in 77% of cases and took 5 days longer to recover from than trailing side injuries ( P = .009). Seventy-nine (7.9%) players received either a corticosteroid or platelet-rich plasma injection, and the mean recovery time was 11 days longer compared with those who did not receive an injection ( P < .001). Conclusion: Although the rate of abdominal oblique injuries is on the decline in MLB, this is not the case for MiLB, and these injuries continue to represent a significant source of time out of play in professional baseball. The vast majority of injuries occur on the lead side, and these injuries result in the greatest amount time out of play. The benefit of injections for the treatment of oblique injuries remains unknown.