Citations

AbstractAcinar‐to‐ductal metaplasia (ADM) is a reversible epithelial transdifferentiation process that occurs in the pancreas in response to acute inflammation. ADM can rapidly progress towards pre‐malignant pancreatic intraepithelial neoplasia (PanIN) lesions in the presence of mutant KRas and ultimately pancreatic adenocarcinoma (PDAC). In the present work, we elucidate the role and related mechanism of glycogen synthase kinase‐3beta (GSK‐3β) in ADM development using in vitro 3D cultures and genetically engineered mouse models. We show that GSK‐3β promotes TGF‐α‐induced ADM in 3D cultured primary acinar cells, whereas deletion of GSK‐3β attenuates caerulein‐induced ADM formation and PanIN progression in KrasG12D transgenic mice. Furthermore, we demonstrate that GSK‐3β ablation influences ADM formation and PanIN progression by suppressing oncogenic KRas‐driven cell proliferation. Mechanistically, we show that GSK‐3β regulates proliferation by increasing the activation of S6 kinase. Taken together, these results indicate that GSK‐3β participates in early pancreatitis‐induced ADM and thus could be a target for the treatment of chronic pancreatitis and the prevention of PDAC progression. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Purpose The purpose of this pilot feasibility project was to examine the potential effectiveness of a digital storytelling intervention designed through a community-based participatory research (CBPR) approach for immigrants and refugees with type 2 diabetes mellitus (T2DM). Methods The intervention was a 12-minute culturally and linguistically tailored video consisting of an introduction, 4 stories, and a concluding educational message. A structured interview was used to assess the intervention for acceptability, interest level, and usefulness among 25 participants with T2DM (15 Latino, 10 Somali) across 5 primary care clinical sites. After watching the video, participants rated their confidence and motivation about managing T2DM as a result of the intervention. Baseline A1C and follow-up values (up to 6 months) were abstracted from medical records. Results All participants reported that the intervention got their attention, was interesting, and was useful; 96% reported that they were more confident about managing their T2DM than before they watched the video, and 92% reported that the video motivated them to change a specific behavior related to T2DM self-management. The mean baseline A1C level for the intervention participants was 9.3% (78 mmol/mol). The change from baseline to first follow-up A1C level was −0.8% (−10 mmol/mol) ( P < .05). Conclusions Implementation of a digital storytelling intervention for T2DM among immigrant populations in primary care settings is feasible and resulted in self-rated improvement in psychosocial constructs that are associated with healthy T2DM self-management behaviors, and there was some evidence of improvement in glycemic control. A large-scale efficacy trial of the intervention is warranted.

Abstract BACKGROUND Cerebrospinal fluid (CSF) leak is a well-recognized complication after surgical resection of vestibular schwannomas and is associated with a number of secondary complications, including readmission and meningitis. OBJECTIVE To identify risk factors for and timing of 30-d readmission with CSF leak. METHODS Patients who had undergone surgical resection of a vestibular schwannoma from 1995 to 2010 were identified in the California Office of Statewide Health Planning and Development database. The most common admission diagnoses were identified by International Classification of Disease, ninth Revision, diagnosis codes, and predictors of readmission with CSF leak were determined using logistic regression. RESULTS A total of 6820 patients were identified. CSF leak, though a relatively uncommon cause of admission after discharge (3.52% of all patients), was implicated in nearly half of 490 readmissions (48.98%). Significant independent predictors of readmission with CSF leak were male sex (odds ratio [OR] 1.72, 95% confidence interval [CI] 1.32-2.25), first admission at a teaching hospital (OR 3.32, 95% CI 1.06-10.39), CSF leak during first admission (OR 1.84, 95% CI 1.33-2.55), obesity during first admission (OR 2.10, 95% CI 1.20-3.66), and case volume of first admission hospital (OR of log case volume 0.82, 95% CI 0.70-0.95). Median time to readmission was 6 d from hospital discharge. CONCLUSION This study has quantified CSF leak as an important contributor to nearly half of all readmissions following vestibular schwannoma surgery. We propose that surgeons should focus on technical factors that may reduce CSF leakage and take advantage of potential screening strategies for the detection of CSF leakage prior to first admission discharge.

PEComas represent a family of uncommon mesenchymal tumors composed of “perivascular epithelioid cells” with a distinct immunophenotype that typically shows both myogenic and melanocytic differentiation. The PEComa family includes angiomyolipoma (AML), clear cell “sugar” tumor of the lung and extra pulmonary sites, lymphangioleiomyomatosis and clear cell myomelanocytic tumor of the falciform ligament/ligamentum teres. Very rarely, PEComas may arise in the skin. Primary cutaneous PEComas typically display a dermal proliferation of epithelioid cells with pale, clear, or granular pink cytoplasm arranged in nests and trabecula with an intervening arborizing network of delicate capillaries. Primary cutaneous PEComas have a lower frequency of myogenic marker expression than their deep soft tissue and visceral counterparts. They also often express strong diffuse CD10, leading to potential confusion with metastatic renal cell carcinoma. Most cases behave indolently. We report 5 additional cases of this rare entity. All showed classic histologic features and expression of either HMB‐45 and/or Melan‐A/MART‐1. Four cases were tested for myogenic markers (2 were positive & 2 were negative). Three cases were tested for CD10 (all 3 were positive). All of our cases with clinical follow‐up behaved indolently. Table 1 provides a summary of findings for all 5 cases in our series.

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.

ObjectivesCurrently, there are no cardiovascular (CV) preprocedure screening parameters for patients undergoing in‐office laryngeal procedures (IOLP). Studies have shown significant changes in CV measures for IOLP. The aim was to develop and evaluate a pre‐IOLP CV screening protocol.MethodsReview of IOLP literature and consultation with an anesthesiologist and cardiologist led to the development of CV parameters and questions related to four metabolic equivalents (METS) of work as a patient‐screening tool before IOLP. A separate cohort was screened with only a modified CV protocol. All patients were screened for heart rate (HR) and blood pressure (BP) elevation prior to the procedure. Need for further CV evaluation was characterized as systolic blood pressure BP >160, diastolic BP >100, and/or HR >110 beats/minute. Patients whose BP/HR exceeded these values were referred to their primary care physician (PCP) before re‐screening. If parameters were exceeded again at the second screen, then the procedure was done under monitored anesthesia care.ResultsThe first study phase included 56 patients. The fail rate was 40% largely related to four METS of work. The second study phase included 440 patients. The screen fail rate was 15 patients of 572 (2.6%). Of these, 12 patients of 132 (9.1%) failed the initial screen and were sent to their PCP for further evaluation, and five of 440 (1.4%) patients failed on the day of the procedure. Overall, five of 440 (1.5%) patients would qualify to have their site of service changed for their laryngology procedure from an unmonitored to a monitored setting due to the prescreening criteria.ConclusionFew patients needed further workup based upon the in‐office CV parameters set in this study. Patients with CV risk factors were identified by the screening protocol. Having established hemodynamic parameters in place may improve the safety of IOLP with a very low physician burden.Level of Evidence2b Laryngoscope, 127:1845–1849, 2017