Citations

Abstract Background: The existence, etiology, diagnosis, and treatment of median arcuate ligament syndrome (MALS) have long been subjects of debate. To our knowledge, there have not been any studies assessing the effectiveness of surgical treatment in improving physical and psychological quality of life in pediatric patients. Subjects and Methods: This is an Institutional Review Board–approved prospective study including all patients undergoing surgical treatment of MALS between 2009 and 2012 at our institution. Demographic information, presenting symptoms, radiological imaging, procedure duration, hospital length of stay, and perioperative complications were gathered for analysis. Patients and their parents were asked to complete the Child Health Questionnaire, a physical and psychological health survey, both within 1 week prior to and at least 3 months following their surgery. Results: Six patients underwent laparoscopic release for MALS. The majority of patients were female ( n =5 [83.3%]), with an average age of 15.7±1.5 years. Presenting symptoms lasted on average 16.5±12.7 months prior to treatment. Average pre- and postsurgical ultrasound celiac artery peak velocities with inspiration were 332.0±34.1 cm/second and 224.3±31.2 cm/second, respectively, with a statistically significant decrease of 107.67 cm/second ( P =.03). The average follow-up period from time of surgery to time of quality of life survey completion was 13±11.3 months, with a range of 3–29 months. A significant improvement from pre- to postsurgical scores was observed in the physical functioning ( P =.03), mental health ( P =.03), and self-esteem categories ( P =.03) of the child assessment. Similarly, there was a significant postsurgical improvement in all categories pertaining to the parent's quality of life ( P =.03). Improvement was also seen in the parents' perception of their child's physical functioning ( P =.03), bodily pain/discomfort ( P =.03), mental health ( P =.03), and general health perceptions ( P =.03). No intraoperative or postoperative complications occurred. Conclusions: Our preliminary results demonstrate that laparoscopic median arcuate ligament release for MALS in the pediatric population is safe and effective and improves overall quality of life for the patients and their parents. In carefully selected patients, laparoscopic release for MALS without additional celiac artery reconstruction normalizes blood flow in the celiac artery and improves physical and psychosocial quality of life for the child and his or her parents.

BACKGROUNDOveruse of inpatient stat laboratory orders (“stat” is an abbreviation of the Latin word “statim,” meaning immediately, without delay) is a major problem in the modern healthcare system.OBJECTIVETo understand patterns of stat laboratory ordering practices at our institution and to assess the effectiveness of individual feedback in reducing these orders.INTERVENTIONMedicine and General Surgery residents were given a teaching session about appropriate stat ordering practice in January 2010. Individual feedback was given to providers who were the highest utilizers of stat laboratory orders by their direct supervisors from February through June of 2010.MEASUREMENTSThe proportion of stat orders out of total laboratory orders per provider was the main outcome measure. All inpatient laboratory orders from September 2009 to June 2010 were analyzed.RESULTSThe median proportion of stat orders out of total laboratory orders was 41.6% for nontrainee providers (N = 500), 38.7% for Medicine residents (N = 125), 80.2% for General Surgery residents (N = 32), and 24.2% for other trainee providers (N = 150). Among 27 providers who received feedback (7 nontrainees, 16 Medicine residents, and 4 General Surgery residents), the proportion of stat laboratory orders per provider decreased by 15.7% (95% confidence interval: 5.6%‐25.9%, P = 0.004) after feedback, whereas the decrease among providers who were high utilizers but did not receive feedback (N = 39) was not significant (4.5%; 95% confidence interval: 2.1%‐11.0%, P = 0.18). Monthly trends showed reduction in the proportion of stat orders among Medicine and General Surgery residents, but not among other trainee providers.CONCLUSIONSThe frequency of stat ordering was highly variable among providers. Individual feedback to the highest utilizers of stat orders was effective in decreasing these orders. Journal of Hospital Medicine 2014;9:13–18. © 2013 Society of Hospital Medicine

Directional mesenchymal cell invasion in vivo is understood to be a stimulated event and to be regulated by cytokines, chemokines, and types of extracellular matrix (ECM). Instead, by focusing on the cellular response to ECM stiffness, we found that soft ECM (low stiffness) itself is sufficient to prevent stable cell-to-cell adherens junction formation, up-regulate matrix metalloproteinase (MMP) secretion, promote MMP activity, and induce invadosome-like protrusion (ILP) formation. Consistently, similar ILP formation was also detected in a three-dimensional directional invasion assay in soft matrix. Primary human fibroblasts spontaneously form ILPs in a very narrow range of ECM stiffness (0.1–0.4 kPa), and such ILP formation is Src family kinase dependent. In contrast, spontaneous ILP formation in malignant cancer cells and fibrosarcoma cells occurs across a much wider range of ECM stiffness, and these tumor cell ILPs are also more prominent at lower stiffness. These findings suggest that ECM softness is a natural stimulator for cellular invasiveness.

Abstract Glycogen synthase kinase-3 (GSK-3), a constitutively active serine/threonine kinase, is a key regulator of numerous cellular processes ranging from glycogen metabolism to cell-cycle regulation and proliferation. Consistent with its involvement in many pathways, it has also been implicated in the pathogenesis of various human diseases, including type II diabetes, Alzheimer disease, bipolar disorder, inflammation, and cancer. Consequently, it is recognized as an attractive target for the development of new drugs. In the present study, we investigated the effect of both pharmacologic and genetic inhibition of GSK-3 in two different renal cancer cell lines. We have shown potent antiproliferative activity of 9-ING-41, a maleimide-based GSK-3 inhibitor. The antiproliferative activity is most likely caused by G0–G1 and G2–M phase arrest as evident from cell-cycle analysis. We have established that inhibition of GSK-3 imparted a differentiated phenotype in renal cancer cells. We have also shown that GSK-3 inhibition induced autophagy, likely as a result of imbalanced energy homeostasis caused by impaired glucose metabolism. In addition, we have demonstrated the antitumor activity of 9-ING-41 in two different subcutaneous xenograft renal cell carcinoma tumor models. To our knowledge, this is the first report describing autophagy induction due to GSK-3 inhibition in renal cancer cells. Mol Cancer Ther; 13(2); 285–96. ©2013 AACR.

AbstractIn cancer clinical trials, patients often experience a recurrence of disease prior to the outcome of interest, overall survival. Additionally, for many cancers, there is a cured fraction of the population who will never experience a recurrence. There is often interest in how different covariates affect the probability of being cured of disease and the time to recurrence, time to death, and time to death after recurrence. We propose a multi‐state Markov model with an incorporated cured fraction to jointly model recurrence and death in colon cancer. A Bayesian estimation strategy is used to obtain parameter estimates. The model can be used to assess how individual covariates affect the probability of being cured and each of the transition rates. Checks for the adequacy of the model fit and for the functional forms of covariates are explored. The methods are applied to data from 12 randomized trials in colon cancer, where we show common effects of specific covariates across the trials. Copyright © 2013 John Wiley & Sons, Ltd.

Context: The BRAF V600E mutation (BRAF-MUT) confers an aggressive phenotype in papillary thyroid carcinoma, but unidentified additional genomic abnormalities may be required for full phenotypic expression. Objective: RNA sequencing (RNA-Seq) was performed to identify genes differentially expressed between BRAF-MUT and BRAF wild-type (BRAF-WT) tumors and to correlate changes to patient clinical status. Design: BRAF-MUT and BRAF-WT tumors were identified in patients with T1N0 and T2–3N1 tumors evaluated in a referral medical center. Gene expression levels were determined (RNA-Seq) and fusion transcripts were detected. Multiplexed capture/detection and digital counting of mRNA transcripts (nCounter, NanoString Technologies) validated RNA-Seq data for immune system-related genes. Patients: BRAF-MUT patients included nine women, three men; nine were TNM stage I and three were stage III. Three (25%) had tumor infiltrating lymphocytes. BRAF-WT included five women, three men; all were stage I, and five (62.5%) had tumor infiltrating lymphocytes. Results: RNA-Seq identified 560 of 13 085 genes differentially expressed between BRAF-MUT and BRAF-WT tumors. Approximately 10% of these genes were related to MetaCore immune function pathways; 51 were underexpressed in BRAF-MUT tumors, whereas 4 (HLAG, CXCL14, TIMP1, IL1RAP) were overexpressed. The four most differentially overexpressed immune genes in BRAF-WT tumors (IL1B; CCL19; CCL21; CXCR4) correlated with lymphocyte infiltration. nCounter confirmed the RNA-Seq expression level data. Eleven different high-confidence fusion transcripts were detected (four interchromosomal; seven intrachromosomal) in 13 of 20 tumors. All in-frame fusions were validated by RT-PCR. Conclusion: BRAF-MUT papillary thyroid cancers have reduced expression of immune/inflammatory response genes compared with BRAF-WT tumors and correlate with lymphocyte infiltration. In contrast, HLA-G and CXCL14 are overexpressed in BRAF-MUT tumors. Sixty-five percent of tumors had between one and three fusion transcripts. Functional studies will be required to determine the potential role of these newly identified genomic abnormalities in contributing to the aggressiveness of BRAF-MUT and BRAF-WT tumors.

Background Dabigatran is a novel oral anticoagulant approved for thromboprophylaxis in atrial fibrillation. Adoption patterns of this new agent in community practice are unknown. Methods and Results We studied patterns of dabigatran use among patients enrolled in the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT‐AF) Registry between June 2010 and August 2011 and followed for 12 months. Among 9974 atrial fibrillation patients included, 1217 (12%) were treated with dabigatran during the study. Overall, patients receiving dabigatran were younger (median age 72 versus 75 years, P <0.0001), more likely to be white (92% versus 89%, P =0.005), more likely to have private insurance (33% versus 25%, P <0.0001), and less likely to have prior cardiovascular disease (4% versus 33%, P <0.0001). They had more new‐onset atrial fibrillation (8.8% versus 4.1%, P <0.0001), lower CHADS 2 scores (estimated risk based on the presence of congestive heart failure, hypertension, aged ≥75 years, diabetes mellitus, and prior stroke or transient ischemic attack; mean 2.0 versus 2.3, P <0.0001), and lower Anticoagulation and Risk Factors in Atrial Fibrillation scores (mean 2.4 versus 2.8, P <0.0001). More than half (n=14/25, 56%) of patients with severe kidney disease were not prescribed reduced dosing, whereas 10% (n=91/920) with preserved renal function received lower dosing. Among patients not on dabigatran at baseline, 8% had dabigatran initiated during follow‐up. Patient education was significantly associated with switching from warfarin to dabigatran (adjusted odds ratio for postgraduate 1.73, P =0.007), whereas antiarrhythmic drug use significantly correlated with de novo adoption of dabigatran (adjusted odds ratio 2.4, P <0.0001). Conclusions Patients receiving dabigatran were younger and at a lower risk of stroke and bleeding. Patients appeared to drive switching from warfarin, whereas clinical characteristics influenced de novo start of dabigatran. These data suggest cautious early uptake of dabigatran, and more careful attention to dosing adjustments is warranted. Clinical Trial Registration URL : Clinicaltrials.gov. Unique identifier: NCT 01165710.