Citations

BACKGROUND Recombinant interleukin‐2 (rIL‐2) induces cellular cytotoxicity against leukemia blasts. Patients with acute myeloid leukemia (AML) in first complete remission (CR) may harbor minimal residual disease that is susceptible to rIL‐2–activated effector cells. METHODS In the Cancer and Leukemia Group B (CALGB) 19808 study, patients with AML in first CR were randomly assigned after all planned chemotherapy to receive a 90‐day course of subcutaneously administered rIL‐2 or no further therapy. The primary objective was to compare disease‐free survival (DFS) between the 2 treatment arms. A total of 534 patients achieved a CR, 214 of whom were randomized. Six courses of low‐dose daily rIL‐2 were given for the expansion of cytotoxic effector cells, each followed by 3‐day high‐dose boluses given to trigger cytotoxicity against minimal residual disease. RESULTS On the protocol‐specified intention‐to‐treat analysis, the hazards ratio for DFS was 0.75 (95% confidence interval, 0.52‐1.09; P = .13); the 5‐year DFS rate was 42% in the observation arm and 53% in the rIL‐2 treatment arm. The hazards ratio for overall survival (OS) was 0.88 (95% confidence interval, 0.54‐1.23; P = .34); the 5‐year OS rate was 58% for the observation arm and 63% for the rIL‐2 treatment arm. Twenty‐five of the 107 patients randomized to treatment with rIL‐2 either refused or were unable to initiate therapy and 30 patients did not complete their assigned therapy. However, significant toxicities were not commonly observed. The trial design did not anticipate the difficulties patients would encounter with protocol compliance. CONCLUSIONS The efficacy of immunotherapy with rIL‐2 administered after intensive postremission treatment was not assessed as planned because of unexpected refusals by patients and/or their physicians to comply with protocol‐directed therapy. Neither DFS nor OS was found to be significantly improved. Cancer 2014;120:1010–1017 . © 2013 American Cancer Society .

ABSTRACTRare variants have recently garnered an immense amount of attention in genetic association analysis. However, unlike methods traditionally used for single marker analysis in GWAS, rare variant analysis often requires some method of aggregation, since single marker approaches are poorly powered for typical sequencing study sample sizes. Advancements in sequencing technologies have rendered next‐generation sequencing platforms a realistic alternative to traditional genotyping arrays. Exome sequencing in particular not only provides base‐level resolution of genetic coding regions, but also a natural paradigm for aggregation via genes and exons. Here, we propose the use of penalized regression in combination with variant aggregation measures to identify rare variant enrichment in exome sequencing data. In contrast to marginal gene‐level testing, we simultaneously evaluate the effects of rare variants in multiple genes, focusing on gene‐based least absolute shrinkage and selection operator (LASSO) and exon‐based sparse group LASSO models. By using gene membership as a grouping variable, the sparse group LASSO can be used as a gene‐centric analysis of rare variants while also providing a penalized approach toward identifying specific regions of interest. We apply extensive simulations to evaluate the performance of these approaches with respect to specificity and sensitivity, comparing these results to multiple competing marginal testing methods. Finally, we discuss our findings and outline future research.

BACKGROUND The majority of patients diagnosed with clear cell renal cell carcinoma (ccRCC) have low‐risk disease with a < 10% chance of ccRCC‐specific death. DNA sequencing revealed that mutations in BAP1 (BRCA1 associated protein‐1) occur in 5% to 15% of ccRCC cases and are associated with poor outcomes. The vast majority of BAP1 mutations abolish protein expression. In this study, we used a highly sensitive and specific immunohistochemistry (IHC) assay to test whether BAP1 expression is an independent marker of ccRCC‐specific survival, particularly in patients with low‐risk disease. METHODS BAP1 expression was assessed, using IHC, in 1479 patients who underwent nephrectomy to treat clinically localized ccRCC. A centralized pathologist dichotomized patients as either BAP1‐positive or BAP1‐negative. The authors employed Kaplan‐Meier and Cox regression models to associate BAP1 expression with cancer‐specific survival. RESULTS A total of 10.5% of tumors were BAP1‐negative, 84.8% of tumors were BAP1‐positive, and 4.6% of tumors had ambiguous staining for BAP1. Patients with BAP1‐negative tumors have an increased risk of ccRCC‐related death (hazard ratio [HR] = 3.06; 95% confidence interval [CI] = 2.28‐4.10; P = 6.77 × 10 −14 ). BAP1 expression remained an independent marker of prognosis after adjusting for the UCLA integrated staging system (UISS) (HR = 1.67; 95% CI = 1.24‐2.25; P < .001). Finally, BAP1 was an independent prognostic marker in low‐risk patients with a Mayo Clinic stage, size, grade, and necrosis (SSIGN) score of ≤ 3 (HR = 3.24; 95% CI = 1.26‐8.33; P = .015). CONCLUSIONS This study used a large patient cohort to demonstrate that BAP1 expression is an independent marker of prognosis in patients with low‐risk (SSIGN≤ 3) ccRCC. Cancer 2014;1059–1067 . © 2014 American Cancer Society .

Insulin deprivation in type 1 diabetes (T1D) individuals increases lipolysis and plasma free fatty acids (FFA) concentration, which can stimulate synthesis of intramyocellular bioactive lipids such as ceramides (Cer) and long-chain fatty acid-CoAs (LCFa-CoAs). Ceramide was shown to decrease muscle insulin sensitivity, and at mitochondrial levels it stimulates reactive oxygen species production. Here, we show that insulin deprivation in streptozotocin diabetic C57BL/6 mice increases quadriceps muscle Cer content, which was correlated with a concomitant decrease in the body fat and increased plasma FFA, glycosylated hemoglobin level (%Hb A1c), and muscular LCFa-CoA content. The alternations were accompanied by an increase in protein expression in LCFa-CoA and Cer synthesis (FATP1/ACSVL5, CerS1, CerS5), a decrease in the expression of genes implicated in muscle insulin sensitivity (GLUT4, GYS1), and inhibition of insulin signaling cascade by Aktα and GYS3β phosphorylation under acute insulin stimulation. Both the content and composition of sarcoplasmic fraction sphingolipids were most affected by insulin deprivation, whereas mitochondrial fraction sphingolipids remained stable. The observed effects of insulin deprivation were reversed, except for content and composition of LCFa-CoA, CerS protein expression, GYS1 gene expression, and phosphorylation status of Akt and GYS3β when exogenous insulin was provided by subcutaneous insulin implants. Principal component analysis and Pearson's correlation analysis revealed close relationships between the features of the diabetic phenotype, the content of LCFa-CoAs and Cers containing C18-fatty acids in sarcoplasm, but not in mitochondria. Insulin replacement did not completely rescue the phenotype, especially regarding the content of LCFa-CoA, or proteins implicated in Cer synthesis and muscle insulin sensitivity. These persistent changes might contribute to muscle insulin resistance observed in T1D individuals.

Abstract Introduction: With an expanding population of patients requiring ventricular assist devices, it is inevitable that these patients will require noncardiac surgery. Ventricular assist devices provide mechanical support for a failing heart either as a bridge to transplant or now as a long-term support if transplant is not available, so-called destination therapy. These devices can add significant technical challenges to abdominal surgery, in that the power supply and drivelines crossing the abdomen can potentially be damaged. The use of preoperative or intraoperative imaging may aid in locating these devices and increase patient safety. Materials and Methods: We describe a laparoscopic cholecystectomy in two patients supported with HeartMate ® II (Thoratec Corp., Pleasanton, CA) left ventricular assist devices. Our use of fluoroscopic guidance in port placement is also described. A literature review was performed to assess the frequency of laparoscopic procedures performed on patients with similar ventricular assist devices and of complications associated with the device and other comorbidities. Results: Laparoscopic cholecystectomy was performed without significant intraoperative hemodynamic changes. The use of imaging, such as fluoroscopy, can identify the location of the ventricular assist device and its associated drive wires to assure they are not damaged intraoperatively. Conclusions: Laparoscopic cholecystectomy can be performed safely on patients with ventricular assist devices. Complications due to damage to the device can be avoided with the assistance of fluoroscopy to identify the implanted abdominal portions of the ventricular assist device. Each laparoscopic procedure performed on these patients presents the surgeon with unique obstacles in which careful operative planning and intraoperative monitoring are essential.

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.