CCL20 is up-regulated in non-alcoholic fatty liver disease fibrosis and is produced by hepatic stellate cells in response to fatty acid loading.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is a prevalent complication of extreme obesity. Loading of the liver with fat can progress to inflammation and fibrosis including cirrhosis. The molecular factors involved in the progression from simple steatosis to fibrosis remain poorly understood. METHODS: Gene expression profiling using microarray, PCR array, and RNA sequencing was performed on RNA from liver biopsy tissue from patients with extreme obesity. Patients were grouped based on histological findings including normal liver histology with no steatosis, lobular inflammation, or fibrosis, and grades 1, 2, 3, and 4 fibrosis with coexistent steatosis and lobular inflammation. Validation of expression was conducted using quantitative PCR. Serum analysis was performed using ELISA. Expression analysis of hepatocytes and hepatic stellate cells in response to lipid loading were conducted in vitro using quantitative PCR and ELISA. RESULTS: Three orthogonal methods to profile human liver biopsy RNA each identified the chemokine CCL20 (CC chemokine ligand 20 or MIP-3 alpha) gene as one of the most up-regulated transcripts in NAFLD fibrosis relative to normal histology, validated in a replication group. CCL20 protein levels in serum measured in 224 NAFLD patients were increased in severe fibrosis (p < 0.001), with moderate correlation of hepatic transcript levels and serum levels. Expression of CCL20, but not its cognate receptor CC chemokine receptor 6, was significantly (p < 0.001) increased in response to fatty acid loading in LX-2 hepatic stellate cells, with relative increases greater than those in HepG2 hepatocyte cells. CONCLUSIONS: These results suggest that expression of CCL20, an important inflammatory mediator, is increased in NAFLD fibrosis. CCL20 serves as a chemoattractant molecule for immature dendritic cells, which have been shown to produce many of the inflammatory molecules that mediate liver fibrosis. These data also point to hepatic stellate cells as a key cell type that may respond to lipid loading of the liver.

All-Cause and Specific-Cause Mortality Risk After Roux-en-Y Gastric Bypass in Patients With and Without Diabetes.

OBJECTIVE: This study assessed all-cause and specific-cause mortality after Roux-en-Y gastric bypass (RYGB) and in matched control subjects, stratified by diabetes status. RESEARCH DESIGN AND METHODS: RYGB patients were matched by age, BMI, sex, and diabetes status at time of surgery to nonsurgical control subjects using data from the electronic health record. Kaplan-Meier curves and Cox regression were used to assess differences in all-cause and specific-cause mortality between RYGB patients and control subjects with and without diabetes. RESULTS: Of the 3,242 eligible RYGB patients enrolled from January 2004 to December 2015, control subjects were identified for 2,428 (n = 625 with diabetes and n = 1,803 without diabetes). Median postoperative follow-up was 5.8 years for patients with diabetes and 6.7 years for patients without diabetes. All-cause mortality was reduced in RYGB patients compared with control subjects only for those with diabetes at the time of surgery (adjusted hazard ratio 0.44; P < 0.0001). Mortality was not significantly improved in RYGB patients without diabetes compared with control subjects without diabetes (adjusted hazard ratio 0.84; P = 0.37). Deaths from cardiovascular diseases (P = 0.011), respiratory conditions (P = 0.017), and diabetes P = 0.011) were more frequent in control subjects with diabetes than in RYGB patients with diabetes. RYGB patients without diabetes were less likely to die of cancer (P = 0.0038) and respiratory diseases (P = 0.046) than control subjects without diabetes but were at higher risk of death from external causes (P = 0.012), including intentional self-harm (P = 0.025), than control subjects without diabetes. CONCLUSIONS: All-cause mortality benefits of RYGB are driven predominantly by patients with diabetes at the time of surgery. RYGB patients with diabetes were less likely to die of cardiovascular diseases, diabetes, and respiratory conditions than their counterparts without RYGB.

Nutrient Transporter Expression in the Jejunum in Relation to Body Mass Index in Patients Undergoing Bariatric Surgery.

Nutrient tranters (NT) facilitate nutrient absorption and contribute to the regulation of circulating nutrients. In this cross-sectional study, we determined the associations between the level of obesity; mRNA abundance for NTs; and serum concentrations of amino acids, short-chain fatty acids, and glucose in patients with morbid obesity undergoing a Roux-en-Y gastric bypass. Proximal jejunal samples were obtained at the time of surgery from 42 patients (90% female, age = 42.6 ± 11.9 years, pre-operative body mass index (BMI) = 55.5 ± 11.3 kg/m²) undergoing a Roux-en-Y gastric bypass. RNA was extracted from the jejunal mucosa and quantitative real-time-PCR was performed for the NTs studied. BMI negatively correlated with jejunal mRNA abundance of the amino acid NTs TauT (r = -0.625, p < 0.0001), ASCT2 (r = -0.320, p = 0.039), LAT1 (r = -0.304, p = 0.05). BMI positively correlated with jejunal mRNA abundance of the lactate/short-chain fatty acid NT SMCT1 (r = 0.543, p = 0.0002). Serum concentrations of the short-chain fatty acids, butyric, valeric, and isocaproic acid correlated positively with BMI (n = 30) (r = 0.45, r = 0.44, r = 0.36, p ≤ 0.05; respectively). Lower jejunal mRNA abundance for the amino acid NTs TauT, ASCT2, and LAT1 could protect against further obesity-related elevations in circulating amino acids. The positive correlation between BMI and the jejunal mRNA abundance of the high-affinity short-chain fatty acid/monocarboxylate transporter SMCT1 is intriguing and requires further investigation.

Utility of Ultrasound, Transaminases, and Visual Inspection to Assess Nonalcoholic Fatty Liver Disease in Bariatric Surgery Patients.

BACKGROUND: Nonalcoholic fatty liver disease (NAFLD) is common in adults with extreme obesity and can impact long-term health and survival. Liver biopsy is the only accurate test for diagnosis and staging, but is invasive and costly. Non-invasive testing offers an attractive alternate, but the overall accuracy remains a significant issue. This study was conducted to determine the accuracy and clinical utility of pre-operative ultrasound and liver transaminase levels, as well as intra-operative hepatic visual inspection, for assessing presence of NAFLD as confirmed by hepatic histology. METHODS: Data was collected prospectively from 580 morbidly obese adult patients who underwent Roux-en-Y gastric bypass surgery with intraoperative wedge biopsy between January 2004 and February 2009. Complete data for ultrasound, ALT and AST levels, and documented visual inspection was available for 513 patients. RESULTS: The prevalence of NAFLD was 69 % and that of NASH was 32 %. The individual non-invasive clinical assessments demonstrated low sensitivity, specificity, and accuracy for detecting the presence of steatosis, steatohepatitis, or fibrosis. The combination of normal or abnormal results for all tests improved predictive utility. Abnormal tests with all three assessments had a sensitivity of 95-98 % and a specificity of 28-48 % for major histologic findings in NAFLD/NASH. Normal tests with all three assessments had a sensitivity of 12-22 % and a specificity of 89-97 % for major histologic findings in NAFLD/NASH. CONCLUSIONS: Although individual clinical tests for NAFLD have limited accuracy, the use of combined clinical tests may prove useful.

Feasibility and impact of an evidence-based program for gastric bypass surgery.

BACKGROUND: Health care in the United States is expensive and quality is variable. The aim of this study was to investigate whether our integrated health system, composed of academic hospitals, a practice plan, and a managed care payer, could reliably implement an evidence-based program for gastric bypass surgery. A secondary aim was to evaluate the impact of the program on clinical outcomes. STUDY DESIGN: A standardized program for delivery of clinical best-practice elements for patients undergoing initial open or laparoscopic Roux-en-Y gastric bypass was implemented in 2008. Best-practice elements were embedded into the workflow. The best-practice elements were refined after reviewing failures observed during the early implementation period. The study period was divided into 3 groups: group α = year preceding program implementation (control), group ß = first year of implementation (unreliable), and group Ω = 2nd to 4th years of implementation (reliable). Outcomes data were collected for all patients who had undergone Roux-en-Y gastric bypass between May 2008 and April 2012 and were compared with a control group from the preceding year using multiple logistic regression analysis. RESULTS: Two thousand and sixty-one patients were studied, with no significant demographic differences between study groups. Best-practice elements delivery was 40% in group ß, but was >90% for group Ω (p < 0.001). Length of stay for group α was 3.5 days and improved to 2.2 days (p < 0.001) for group Ω. Complications and readmission rates improved considerably with reliable delivery of best-practice elements. CONCLUSIONS: Standardization of evidence-based care delivery for Roux-en-Y gastric bypass was feasible and reliable delivery of this pathway improved clinical outcomes.

Perturbations of fibroblast growth factors 19 and 21 in type 2 diabetes.

Fibroblast growth factors 19 and 21 (FGF19 and FGF21) have been implicated, independently, in type 2 diabetes (T2D) but it is not known if their circulating levels correlate with each other or whether the associated hepatic signaling mechanisms that play a role in glucose metabolism are dysregulated in diabetes. We used a cross-sectional, case/control, experimental design involving Class III obese patients undergoing Roux-en-Y bariatric surgery (RYGB), and measured FGF19 and FGF21 serum levels and hepatic gene expression (mRNA) in perioperative liver wedge biopsies. We found that T2D patients had lower FGF19 and higher FGF21 serum levels. The latter was corroborated transcriptionally, whereby, FGF21, as well as CYP7A1, ß-Klotho, FGFR4, HNF4α, and glycogen synthase, but not of SHP or FXR mRNA levels in liver biopsies were higher in T2D patients that did not remit diabetes after RYGB surgery, compared to T2D patients that remitted diabetes after RYGB surgery or did not have diabetes. In a Phenome-wide association analysis using 205 clinical variables, higher FGF21 serum levels were associated with higher glucose levels and various cardiometabolic disease phenotypes. When serum levels of FGF19 were < 200 mg/mL and FGF21 > 500 mg/mL, 91% of patients had diabetes. These data suggest that FGF19/FGF21 circulating levels and hepatic gene expression of the associated signaling pathway are significantly dysregulated in type 2 diabetes.

Same-day combined endoscopic retrograde cholangiopancreatography and cholecystectomy: Achievable and minimizes costs.

BACKGROUND: It is estimated that choledocholithiasis is present in 5% to 20% of patients at the time of laparoscopic cholecystectomy (LC). Several European studies have found decreased length of stay (LOS) when performing LC and intraoperative endoscopic retrograde cholangiopancreatography (ERCP) on the same day for choledocholithiasis. In the United States, common bile duct stones are usually managed preoperatively and typically on a day separate from the day LC was performed. Our aim was to evaluate LOS and total hospital cost for separate-day versus same-day ERCP/cholecystectomy. METHODS: This was a retrospective study of patients undergoing ERCP and cholecystectomy during the same admission for the management of choledocholithiasis from 2010 to 2014 at Geisinger Medical Center. The separate-day group underwent ERCP at least 1 day before cholecystectomy and often underwent two separate anesthesia events, while the same-day group had ERCP and cholecystectomy performed on the same day under one general anesthesia event. The primary outcome measured was LOS. RESULTS: The study population included 240 patients. There were 175 patients in the separate-day group and 65 patients in the same-day group. Median age was similar between the two groups. The separate-day group had a median of one minor comorbidity compared with zero within the same-day group using the Charlson Comorbidity Index. Overall, LOS for the separate-day group was 5 days compared with 3 days in the same-day group (p < 0.0001). There was no difference in conversion rates to open cholecystectomy between the two groups (14% in the separate-day vs. 12% in the same-day group). Total median hospital cost for the separate-day group was $102,537 compared with $90,269 in the same-day group (p < 0.0001). CONCLUSION: Same-day ERCP and cholecystectomy is feasible and minimizes costs. Same-day procedures decreased hospital LOS by 2 days and had approximately $12,000 in cost savings. Future goals include a multidisciplinary protocol to study outcomes in larger numbers. LEVEL OF EVIDENCE: Therapeutic study, level IV. Economic study, level III.

Preoperative use of incretins is associated with increased diabetes remission after RYGB surgery among patients taking insulin: a retrospective cohort analysis.

OBJECTIVE: The main goal of this study was to determine the effects of incretins on type 2 diabetes (T2D) remission after Roux-en-Y gastric bypass (RYGB) surgery for patients taking insulin. BACKGROUND: Type 2 diabetes is a chronic disease with potentially debilitating consequences. RYGB surgery is one of the few interventions that can remit T2D. Preoperative use of insulin, however, predisposes to significantly lower T2D remission rates. METHODS: A retrospective cohort of 690 T2D patients with at least 12 months follow-up and available electronic medical records was used to identify 37 T2D patients who were actively using a Glucagon-like peptide 1 (GLP-1) agonist in addition to another antidiabetic medication, during the preoperative period. RESULTS: Here, we report that use of insulin, along with other antidiabetic medications, significantly diminished overall T2D remission rates 14 months after RYGB surgery (9%) compared with patients not taking insulin (56%). Addition of the GLP-1 agonist, however, increased significantly T2D early remission rates (22%), compared with patients not taking the GLP-1 agonist (4%). Moreover, the 6-year remission rates were also significantly higher for the former group of patients. The GLP-1 agonist did not improve the remission rates of diabetic patients not taking insulin as part of their pharmacotherapy. CONCLUSIONS: Preoperative use of antidiabetic medication, coupled with an incretin agonist, could significantly improve the odds of T2D remission after RYGB surgery in patients also using insulin.

Preoperative prediction of type 2 diabetes remission after Roux-en-Y gastric bypass surgery: a retrospective cohort study.

BACKGROUND: About 60% of patients with type 2 diabetes achieve remission after Roux-en-Y gastric bypass (RYGB) surgery. No accurate method is available to preoperatively predict the probability of remission. Our goal was to develop a way to predict probability of diabetes remission after RYGB surgery on the basis of preoperative clinical criteria. METHODS: In a retrospective cohort study, we identified individuals with type 2 diabetes for whom electronic medical records were available from a primary cohort of 2300 patients who underwent RYGB surgery at the Geisinger Health System (Danville, PA, USA) between Jan 1, 2004, and Feb 15, 2011. Partial and complete remission were defined according to the American Diabetes Association criteria. We examined 259 clinical variables for our algorithm and used multiple logistic regression models to identify independent predictors of early remission (beginning within first 2 months after surgery and lasting at least 12 months) or late remission (beginning more than 2 months after surgery and lasting at least 12 months). We assessed a final Cox regression model with a consistent subset of variables that predicted remission, and used the resulting hazard ratios (HRs) to guide creation of a weighting system to produce a score (DiaRem) to predict probability of diabetes remission within 5 years. We assessed the validity of the DiaRem score with data from two additional cohorts. FINDINGS: Electronic medical records were available for 690 patients in the primary cohort, of whom 463 (63%) had achieved partial or complete remission. Four preoperative clinical variables were included in the final Cox regression model: insulin use, age, HbA1c concentration, and type of antidiabetic drugs. We developed a DiaRem score that ranges from 0 to 22, with the greatest weight given to insulin use before surgery (adding ten to the score; HR 5·90, 95% CI 4·41­7·90; p<0·0001). Kaplan-Meier analysis showed that 88% (95% CI 83­92%) of patients who scored 0­2, 64% (58­71%) of those who scored 3­7, 23% (13­33%) of those who scored 8­12, 11% (6­16%) of those who scored 13­17, and 2% (0­5%) of those who scored 18­22 achieved early remission (partial or complete). As in the primary cohort, the proportion of patients achieving remission in the replication cohorts was highest for the lowest scores, and lowest for the highest scores. INTERPRETATION: The DiaRem score is a novel preoperative method to predict the probability of remission of type 2 diabetes after RYGB surgery. FUNDING: Geisinger Health System and the US National Institutes of Health.

Clinical factors associated with weight loss outcomes after Roux-en-Y gastric bypass surgery.

OBJECTIVE: Gastric bypass surgery is an effective therapy for extreme obesity. However, substantial variability in weight loss outcomes exists that remains largely unexplained. Our objective was to determine whether any commonly collected preoperative clinical variables were associated with weight loss following Roux-en-Y gastric bypass (RYGB) surgery. METHODS: The analysis was based on a prospectively recruited observational cohort of 2,365 patients who underwent Roux-en-Y gastric bypass surgery from 2004 to 2009. Weight loss was stratified into three major phases, early (0-6 months), nadir, and long-term (>36 months). Multivariate regression models were constructed using a database of over 350 variables. RESULTS: A total of 12-14 preoperative variables were independently associated (P < 0.05) with each of the temporal weight loss phases. Preoperative variables associated with poorer nadir and long-term weight loss included higher baseline BMI, higher preoperative weight loss, iron deficiency, use of any diabetes medication, nonuse of bupropion medication, no history of smoking, age >50 years, and the presence of fibrosis on liver biopsy. CONCLUSIONS: Several variables previously associated with poorer weight loss after RYGB surgery including age, baseline BMI, and type 2 diabetes were replicated. Several others suggest possible clinical interventions for postoperative management of RYGB patients to improve weight loss outcomes.

Identification of novel clinical factors associated with hepatic fat accumulation in extreme obesity.

OBJECTIVES: The accumulation of lipids stored as excess triglycerides in the liver (steatosis) is highly prevalent in obesity and has been associated with several clinical characteristics, but most studies have been based on relatively small sample sizes using a limited set of variables. We sought to identify clinical factors associated with liver fat accumulation in a large cohort of patients with extreme obesity. METHODS: We analyzed 2929 patients undergoing intraoperative liver biopsy during a primary bariatric surgery. Univariate and multivariate regression modeling was used to identify associations with over 200 clinical variables with the presence of any fat in the liver and with moderate to severe versus mild fat accumulation. RESULTS: A total of 19 data elements were associated with the presence of liver fat and 11 with severity of liver fat including ALT and AST, plasma lipid, glucose, and iron metabolism variables, several medications and laboratory measures, and sleep apnea. The accuracy of a multiple logistic regression model for presence of liver fat was 81% and for severity of liver fat accumulation was 77%. CONCLUSIONS: A limited set of clinical factors can be used to model hepatic fat accumulation with moderate accuracy and may provide potential mechanistic insights in the setting of extreme obesity.

Next-generation sequence analysis of genes associated with obesity and nonalcoholic fatty liver disease-related cirrhosis in extreme obesity.

OBJECTIVES: Genome-wide association studies (GWAS) have led to the identification of single nucleotide polymorphisms in or near several loci that are associated with the risk of obesity and nonalcoholic fatty liver disease (NAFLD). We hypothesized that missense variants in GWAS and related candidate genes may underlie cases of extreme obesity and NAFLD-related cirrhosis, an extreme manifestation of NAFLD. METHODS: We performed whole-exome sequencing on 6 Caucasian patients with extreme obesity [mean body mass index (BMI) 84.4] and 4 obese Caucasian patients (mean BMI 57.0) with NAFLD-related cirrhosis. RESULTS: Sequence analysis was performed on 24 replicated GWAS and selected candidate obesity genes and 5 loci associated with NAFLD. No missense variants were identified in 19 of the 29 genes analyzed, although all patients carried at least 2 missense variants in the remaining genes without excess homozygosity. One patient with extreme obesity carried 2 novel damaging mutations in BBS1 and was homozygous for benign and damaging MC3R variants. In addition, 1 patient with NAFLD-related cirrhosis was compound heterozygous for rare damaging mutations in PNPLA3. CONCLUSIONS: These results indicate that analyzing candidate loci previously identified by GWAS analyses using whole-exome sequencing is an effective strategy to identify potentially causative missense variants underlying extreme obesity and NAFLD-related cirrhosis.

A role for fibroblast growth factor 19 and bile acids in diabetes remission after Roux-en-Y gastric bypass.

OBJECTIVE: Roux-en-Y gastric bypass (RYGB) in humans can remit type 2 diabetes, but the operative mechanism is not completely understood. In mice, fibroblast growth factor (FGF) 15 (FGF19 in humans) regulates hepatic bile acid (BA) production and can also resolve diabetes. In this study, we tested the hypothesis that the FGF19-BA pathway plays a role in the remission of human diabetes after RYGB surgery. RESEARCH DESIGN AND METHODS: Cohorts of diabetic and nondiabetic individuals of various body weights were used. In addition, RYGB patients without diabetes (No-Diabetes), RYGB patients with diabetes who experienced remission for at least 12 months after surgery (Diabetes-R), and RYGB patients with diabetes who did not go into remission after surgery (Diabetes-NoR) were studied. Circulating FGF19 and BA levels, hepatic glycogen content, and expression levels of genes regulating the FGF19-BA pathway were compared among these groups of patients using pre- and postoperative serum samples and intraoperative liver biopsies. RESULTS: Preoperatively, patients with diabetes had lower FGF19 and higher BA levels than nondiabetic patients, irrespective of body weight. In diabetic patients undergoing RYGB, lower FGF19 levels were significantly correlated with increased hepatic expression of the cholesterol 7alpha-hydroxylase 1 (CYP7A1) gene, which modulates BA production. Following RYGB surgery, however, FGF19 and BA levels (particularly cholic and deoxycholic acids) exhibited larger increases in Diabetic-R patients compared with nondiabetic and Diabetic-NoR patients. CONCLUSIONS: Taken together, the baseline and postoperative data implicate the FGF19-CYP7A1-BA pathway in the etiology and remission of type 2 diabetes following RYGB surgery.

An electronic health record-enabled obesity database.

BACKGROUND: The effectiveness of weight loss therapies is commonly measured using body mass index and other obesity-related variables. Although these data are often stored in electronic health records (EHRs) and potentially very accessible, few studies on obesity and weight loss have used data derived from EHRs. We developed processes for obtaining data from the EHR in order to construct a database on patients undergoing Roux-en-Y gastric bypass (RYGB) surgery. METHODS: Clinical data obtained as part of standard of care in a bariatric surgery program at an integrated health delivery system were extracted from the EHR and deposited into a data warehouse. Data files were extracted, cleaned, and stored in research datasets. To illustrate the utility of the data, Kaplan-Meier analysis was used to estimate length of post-operative follow-up. RESULTS: Demographic, laboratory, medication, co-morbidity, and survey data were obtained from 2028 patients who had undergone RYGB at the same institution since 2004. Pre-and post-operative diagnostic and prescribing information were available on all patients, while survey laboratory data were available on a majority of patients. The number of patients with post-operative laboratory test results varied by test. Based on Kaplan-Meier estimates, over 74% of patients had post-operative weight data available at 4 years. CONCLUSION: A variety of EHR-derived data related to obesity can be efficiently obtained and used to study important outcomes following RYGB.

High allelic burden of four obesity SNPs is associated with poorer weight loss outcomes following gastric bypass surgery.

Genome-wide association and linkage studies have identified multiple susceptibility loci for obesity. We hypothesized that such loci may affect weight loss outcomes following dietary or surgical weight loss interventions. A total of 1,001 white individuals with extreme obesity (BMI >35 kg/m(2)) who underwent a preoperative diet/behavioral weight loss intervention and Roux-en-Y gastric bypass surgery were genotyped for single-nucleotide polymorphisms (SNPs) in or near the fat mass and obesity-associated (FTO), insulin induced gene 2 (INSIG2), melanocortin 4 receptor (MC4R), and proprotein convertase subtilisin/kexin type 1 (PCSK1) obesity genes. Association analysis was performed using recessive and additive models with pre- and postoperative weight loss data. An increasing number of obesity SNP alleles or homozygous SNP genotypes was associated with increased BMI (P < 0.0006) and excess body weight (P < 0.0004). No association between the amounts of weight lost from a short-term dietary intervention and any individual obesity SNP or cumulative number of obesity SNP alleles or homozygous SNP genotypes was observed. Linear mixed regression analysis revealed significant differences in postoperative weight loss trajectories across groups with low, intermediate, and high numbers of obesity SNP alleles or numbers of homozygous SNP genotypes (P < 0.0001). Initial BMI interacted with genotype to influence weight loss with initial BMI <50 kg/m(2), with evidence of a dosage effect, which was not present in individuals with initial BMI ≥50 kg/m(2). Differences in metabolic rate, binge eating behavior, and other clinical parameters were not associated with genotype. These data suggest that response to a surgical weight loss intervention is influenced by genetic susceptibility and BMI.

Preoperative weight loss before bariatric surgery.

HYPOTHESIS: Preoperative weight loss reduces the frequency of surgical complications in patients undergoing bariatric surgery. DESIGN: Review of records of patients undergoing open or laparoscopic gastric bypass. SETTING: A comprehensive, multidisciplinary obesity treatment center at a tertiary referral center that serves central Pennsylvania. PATIENTS: A total of 881 patients undergoing open or laparoscopic gastric bypass from May 31, 2002, through February 24, 2006. INTERVENTION: All preoperative patients completed a 6-month multidisciplinary program that encouraged a 10% preoperative weight loss. MAIN OUTCOME MEASURES: Loss of excess body weight (EBW) and total and major complication rates. RESULTS: Of the 881 patients, 592 (67.2%) lost 5% or more EBW and 423 (48.0%) lost more than 10% EBW. Patients referred for open gastric bypass (n = 466) were generally older (P < .001), had a higher body mass index (P < .001), and were more often men (P < .001) than those undergoing laparoscopic gastric bypass (n = 415). Total and major complication rates were higher in patients undergoing open gastric bypass (P < .001 and P = .03, respectively). Univariate analysis revealed that increasing preoperative weight loss is associated with reduced complication frequencies for the entire group for total complications (P =.004) and most likely for major complications (P = .06). Controlling for age, sex, baseline body mass index, and type of surgery in a multiple logistic regression model, increased preoperative weight loss was a predictor of reduced complications for any (P =.004) and major (P = .03) complications. CONCLUSION: Preoperative weight loss is associated with fewer complications after gastric bypass surgery.

Downregulation of PAR-4, a pro-apoptotic gene, in pancreatic tumors harboring K-ras mutation.

Oncogenic ras is known to inhibit cell death and growth inhibitory genes and activate prosurvival genes. Proapoptotic gene PAR-4, has been found to be downregulated by oncogenic ras. Since pancreatic tumors harbor a high incidence of K-ras point mutations, we hypothesized that oncogenic K-ras might influence the function and expression of PAR-4. PAR-4 expression levels were analyzed in 4 established pancreatic tumor cell lines, 10 normal pancreatic tissues, 44 frozen tumor tissues and 25 paraffin-embedded pancreatic adenocarcinoma samples by Real Time RT-PCR, Western blot analysis and immunohistochemistry. K-ras mutational status was analyzed by allele-specific oligonucleotide-hybridization. Expression levels of PAR-4 were correlated with the K-ras mutational status and clinical characteristics. Further, modulation of endogenous PAR-4 was tested by transiently expressing oncogenic ras in a wild-type K-ras pancreatic cancer cell line, BxPC-3. Three cell lines with K-ras mutations showed low levels of PAR-4 when compared to a normal pancreatic tissue. Of 44 frozen tumors, 16 showed appreciable upregulation of Par mRNA and 27 showed significant downregulation of PAR-4 mRNA when compared to normal pancreatic tissue and 1 had levels equivalent to normal pancreatic tissue. Of 25 paraffin-embedded tumors, 9 showed downregulation of PAR-4 protein and this downregulation of PAR-4 correlated significantly with K-ras mutational status (p < 0.00002). In addition, the presence of PAR-4 mRNA or protein expression in pancreatic tumors correlated with prolonged survival. Transient overexpression of oncogenic ras in wild-type K-ras BxPC-3 cells significantly downregulated the endogenous PAR-4 protein levels and conferred accelerated growth. Thus, downregulation or loss of PAR-4 expression by oncogenic ras may provide a selective survival advantage for pancreatic tumors, through inhibition of proapoptotic pathway mediated by PAR-4.

Outcomes of preoperative weight loss in high-risk patients undergoing gastric bypass surgery.

HYPOTHESIS: Modest, preoperative weight loss will improve perioperative outcomes among high-risk, morbidly obese patients undergoing Roux-en-Y gastric bypass. DESIGN: A prospective, longitudinal assessment of characteristics and outcomes of gastric bypass patients. SETTING: All patients undergoing open or laparoscopic Roux-en-Y gastric bypass surgery for morbid obesity or its comorbid medical problems at Geisinger Medical Center in Danville, Pennsylvania, during a 3-year period from May 31, 2002, to February 24, 2006, were included in this analysis. Patients were required to participate in a standardized multidisciplinary preoperative program that encompasses medical, psychological, nutritional, and surgical interventions and education. In addition, patients were encouraged to achieve a 10% loss of excess body weight prior to surgical intervention. RESULTS: Of the 884 subjects, 425 (48%) lost more than 10% of their excess body weight prior to the operation. After surgery (mean follow-up, 12 months), this group was more likely to achieve 70% loss of excess body weight (P < .001). Those who lost more than 5% of excess body weight prior to surgery were statistically less likely to have a length of stay of greater than 4 days (P = .03). CONCLUSIONS: This study shows that high-risk morbidly obese candidates for bariatric surgery who are able to achieve a loss of 5% to 10% excess body weight prior to surgery have a higher probability of a shorter length of hospital stay and more rapid postoperative weight loss.