Profiling of Adipose and Skeletal Muscle in Human Pancreatic Cancer Cachexia Reveals Distinct Gene Profiles with Convergent Pathways.

The vast majority of patients with pancreatic ductal adenocarcinoma (PDAC) suffer cachexia. Although cachexia results from concurrent loss of adipose and muscle tissue, most studies focus on muscle alone. Emerging data demonstrate the prognostic value of fat loss in cachexia. Here we sought to identify the muscle and adipose gene profiles and pathways regulated in cachexia. Matched rectus abdominis muscle and subcutaneous adipose tissue were obtained at surgery from patients with benign conditions (n = 11) and patients with PDAC (n = 24). Self-reported weight loss and body composition measurements defined cachexia status. Gene profiling was done using ion proton sequencing. Results were queried against external datasets for validation. 961 DE genes were identified from muscle and 2000 from adipose tissue, demonstrating greater response of adipose than muscle. In addition to known cachexia genes such as FOXO1, novel genes from muscle, including PPP1R8 and AEN correlated with cancer weight loss. All the adipose correlated genes including SCGN and EDR17 are novel for PDAC cachexia. Pathway analysis demonstrated shared pathways but largely non-overlapping genes in both tissues. Age related muscle loss predominantly had a distinct gene profiles compared to cachexia. This analysis of matched, externally validate gene expression points to novel targets in cachexia.

Novel Preoperative Patient-centered Surgical Wellness Program Impacts Length of Stay Following Pancreatectomy.

BACKGROUND/AIM: We created a novel, preoperative wellness program (WP) that promotes recovery. This study assessed its impact on patient outcomes after pancreatectomy. PATIENTS AND METHODS: Pancreatoduodenectomies (PD) and distal pancreatectomies (DP) performed from 2015 to 2018 were reviewed using our institutional NSQIP database. Patients in the WP had their medical conditions optimized and were provided with the following: chlorhexidine, topical mupirocin, incentive spirometer, and immune-nutrition supplements. RESULTS: Out of a total of 669 pancreatectomy patients (411 PD, 258 DP), 308 were enrolled in the WP (188 PD, 120 DP). In the PD subgroup, on multivariable analysis (MVA), the WP patients had shorter lengths of hospital stay (LOS) (12 vs. 10 days, p<0.001). On MVA, WP patients had less post-op transfusion (20 vs. 10%, p=0.027). For the combined groups on MVA, LOS continued to be significant (OR=0.89, 95%CI=0.82-0.97, p<0.007). CONCLUSION: A preoperative patient centered WP may reduce the length of stay.

Surgical Transgastric Necrosectomy for Necrotizing Pancreatitis: A Single-stage Procedure for Walled-off Pancreatic Necrosis.

OBJECTIVE: The aim of this study was to evaluate the role of surgical transgastric necrosectomy (TGN) for walled-off pancreatic necrosis (WON) in selected patients. BACKGROUND: WON is a common consequence of severe pancreatitis and typically occurs 3 to 5 weeks after the onset of acute pancreatitis. When symptomatic, it can require intervention. METHODS: A retrospective review of patients with WON undergoing surgical management at 3 high-volume pancreatic institutions was performed. Surgical indications, intervention timing, technical methodology, and patient outcomes were evaluated. Patients undergoing intervention <30 days were excluded. Differences across centers were evaluated using a P value of <0.05 as significant. RESULTS: One hundred seventy-eight total patients were analyzed (mean WON diameter = 14 cm, 64% male, mean age = 51 years) across 3 centers. The majority required inpatient admission with a median preoperative length of hospital stay of 29 days (25% required preoperative critical care support). Most (96%) patients underwent a TGN. The median duration of time between the onset of pancreatitis symptoms and operative intervention was 60 days. Thirty-nine percent of the necrosum was infected. Postoperative morbidity and mortality were 38% and 2%, respectively. The median postoperative length of hospital length of stay was 8 days, with the majority of patients discharged home. The median length of follow-up was 21 months, with 91% of patients having complete clinical resolution of symptoms at a median of 6 weeks. Readmission to hospital and/or a repeat intervention was also not infrequent (20%). CONCLUSION: Surgical TGN is an excellent 1-stage surgical option for symptomatic WON in a highly selected group of patients. Precise surgical technique and long-term outpatient follow-up are mandatory for optimal patient outcomes.

Indication for en bloc pancreatectomy with colectomy: when is it safe?

INTRODUCTION: Aggressive en bloc resection of adjacent organs is often necessary to resect pancreatic or colonic lesions. However, it is debated whether simultaneous pancreatectomy with colectomy (P+C) is warranted as it potentially increases morbidity and mortality (MM). We hypothesized that MM would be increased in P+C, especially in cases of pancreatitis. METHODS: All patients who underwent pancreatectomy (P) and simultaneous pancreatectomy with colectomy (P+C) at a high-volume center from November 2006 to 2015 were prospectively collected using ACS-NSQIP at our institution. Patients with additional multivisceral or enucleation procedures were excluded. Data were augmented to 90-day outcomes using our institutional database. RESULTS: Forty-three patients with a mean age of 62 years (27:16 male: female) underwent P+C, accounting for 2.39% (43/1797) of pancreatectomies performed. Pancreatoduodenectomy (PD) was performed in 61% (n = 26), distal pancreatectomy (DP) in 37% (n = 16), and total pancreatectomy (TP) in 2% (n = 1) of patients. The 30- and 90-day MM were higher in P+C than P (30-day: 54 vs. 37%, p = 0.037 and 9 vs. 2%, p = 0.022; 90-day: 61 vs. 42%, p = 0.019 and 14 vs. 3%, p = 0.002). Logistical regression modeling revealed an association between 90-day mortality and colectomy (p = 0.013, OR = 3.556). When P+C MM were analyzed according to intraoperative factors, there was no significant difference according to type of pancreatectomy (PD vs. DP vs. TP), origin of primary lesion (pancreas vs. colon), surgical indication (malignant vs. non-malignant), or case status (planned colectomy vs. intraoperative decision). CONCLUSIONS: Addition of colectomy to pancreatectomy substantially increased MM. Subanalysis revealed that type of resection performed, etiology, and planning status did not account for increased risk when performing P+C. However, colectomy was found to be an independent risk factor for mortality. Therefore, patients should be informed of the risk of increased postoperative complications until a further study can identify potential patients or perioperative factors that can be used for risk stratification.

International Consensus Guidelines parameters for the prediction of malignancy in intraductal papillary mucinous neoplasm are not properly weighted and are not cumulative.

BACKGROUND: The International Consensus Guidelines (ICG) stratify risk for malignancy in patients with intraductal papillary mucinous neoplasm (IPMN) into three progressive categories according to whether patients show 'no criteria', 'worrisome features' (WFs) or 'high-risk stigmata' (HRS). OBJECTIVES: This study was conducted to test the hypothesis that type (clinical versus radiological) and quantity of ICG WFs and HRS carry unequal weight and are not cumulative in the prediction of risk for malignancy or invasiveness in IPMN. METHODS: A retrospective review of a prospectively maintained database of patients who underwent surgical resection for IPMN at a single, university-based medical centre during 1992-2012 was performed. Differences that achieved a P-value of <0.05 were considered significant. RESULTS: Of 362 patients, 340 were eligible for entry into the study and were categorized as demonstrating no criteria (n = 70), WFs (n = 185) or HRS (n = 85). Patients in the WFs group had higher rates of malignant and invasive IPMN than those in the no-criteria group [26.5% versus 4.3% (P < 0.0001) and 15.7% versus 4.3% (P = 0.02), respectively]. Patients in the HRS group had higher rates of malignant and invasive IPMN than those in the WFs group [56.5% versus 26.5% (P = 0.0001) and 42.4% versus 15.7% (P = 0.0001), respectively]. When radiological parameters only were considered for WFs versus HRS, no difference was found in rates of malignant or invasive IPMN. By contrast, when clinical parameters only were considered, patients in the HRS group had higher rates of malignant or invasive IPMN [66.7% versus 8.1% (P = 0.04) and 66.7% versus 2.7% (P = 0.01), respectively]. There was no stepwise increase in rates of malignant or invasive IPMN with the number of WFs. However, patients with only one WF had a lower risk for malignancy than patients with two or more WFs. CONCLUSIONS: The type and quantity of ICG WFs and HRS carry unequal weight and are not cumulative in the prediction of risk for malignancy or invasiveness in IPMN.

Does the interval from imaging to operation affect the rate of unanticipated metastasis encountered during operation for pancreatic adenocarcinoma?

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy with a propensity for early metastasis that is often encountered unexpectedly at operation. Our objective was to examine the effect of the time interval between preoperative imaging and attempted resection and the venue in which imaging was performed on the frequency of unanticipated metastasis (UM) encountered at operation. We hypothesize that imaging obtained locally at our hospital and within 4 weeks of operation will result in a lesser frequency of UM encountered at operation. METHODS: Between January 2004 and December 2009, records of patients undergoing planned pancreatic resection for PDAC at a high volume pancreatic surgery center were compiled. Exclusion criteria included neoadjuvant therapy, prior pancreatic resection, or evidence of metastasis on imaging. Review and analysis of clinical, radiographic, operative, and pathologic data were undertaken. Frequency of UM and outcome of resection was compared with the interval between most recent cross-sectional imaging (dual-phase contrast-enhanced CT or MRI) and operation defined as imaging-to-operation interval (IOI). RESULTS: Four-hundred eighty-seven patients met eligibility requirements for the study: 431 (88%) proximal and 56 (12%) distal PDAC. 202 (41%) patients had their most recent imaging performed at an outside institution, and no difference in the rates of UM was observed whether imaging was conducted at our institution or at an outside institution (P > .05). Of 329 with complete imaging information for analysis, UM were discovered in 60 (18%): 52 (18%) of 293 proximal PDAC and 8 (22%) of 36 distal PDAC. In proximal PDAC, there was a linear relationship in the frequency of UM as a function of the weekly IOI (R(2) = .99; P = .006). For distal PDAC, no significant difference in the frequency of UM as a function of IOI was observed. CONCLUSION: For proximally located PDAC, the frequency of UM increases with greater imaging-to-operation interval. Performing imaging at a high volume, pancreatic surgery center compared with elsewhere was not associated with a decrease in the rate of UM. Obtaining timely diagnostic imaging for proximal PDAC may improve the accuracy of preoperative staging, and thereby reduce the number of operations not producing oncologic benefit.

Radiation dose from computed tomography in patients with necrotizing pancreatitis: how much is too much?

OBJECTIVES: Low-dose ionizing radiation from medical imaging has been indirectly linked with subsequent cancer. Computed tomography (CT) is the gold standard for defining pancreatic necrosis. The primary goal was to identify the frequency and effective radiation dose of CT imaging for patients with necrotizing pancreatitis. METHODS: All patients with necrotizing pancreatitis (2003-2007) were retrospectively analyzed for CT-related radiation exposure. RESULTS: Necrosis was identified in 18% (238/1290) of patients with acute pancreatitis (mean age = 53 years; hospital/ICU length of stay = 23/7 days; mortality = 9%). A median of five CTs/patient [interquartile range (IQR) = 4] were performed during a median 2.6-month interval. The average effective dose was 40 mSv per patient (equivalent to 2,000 chest X-rays; 13.2 years of background radiation; one out of 250 increased risk of fatal cancer). The actual effective dose was 63 mSv considering various scanner technologies. CTs were infrequently (20%) followed by direct intervention (199 interventional radiology, 118 operative, 12 endoscopic) (median = 1; IQR = 2). Magnetic resonance imaging did not have a CT-sparing effect. Mean direct hospital costs increased linearly with CT number (R = 0.7). CONCLUSIONS: The effective radiation dose received by patients with necrotizing pancreatitis is significant. Management changes infrequently follow CT imaging. The ubiquitous use of CT in necrotizing pancreatitis raises substantial public health concerns and mandates a careful reassessment of its utility.

Effect of hospital volume, surgeon experience, and surgeon volume on patient outcomes after pancreaticoduodenectomy: a single-institution experience.

OBJECTIVE: To determine the importance of hospital volume, surgeon experience, and surgeon volume in performing pancreaticoduodenectomy (PD). DESIGN, SETTING, AND PATIENTS: From 1980 through 2007, 1003 patients underwent PD by 19 surgeons at a university hospital. MAIN OUTCOME MEASURES: Patient morbidity and mortality, quality of resection, and learning curve were examined according to hospital volume (period 1: 1980-2003 vs period 2: 2004-2007), surgeon experience (total number of PDs), and surgeon volume (number of PDs per year). RESULTS: Perioperative morbidity and mortality for all 1003 PDs were 41% and 3%, respectively. Differences existed between period 1 and period 2 in percentage of PDs performed in elderly patients (7% vs 17%), mortality (4% vs 2%), estimated blood loss (1817 mL vs 780 mL), length of stay (18 days vs 12 days), and proportion of International Study Group on Pancreatic Fistula grade C pancreatic fistulae (29% vs 12%). Surgeons with less experience (<50 PDs) performed PD with higher morbidity (53% vs 39%), pancreatic fistula rate (20% vs 10%), estimated blood loss (1918 mL vs 1101 mL), and operative time (458 minutes vs 335 minutes) compared with surgeons with more experience (> or =50 PDs). Experienced surgeons had comparable outcomes irrespective of annual volume. Mortality, margins, and number of lymph nodes resected were not affected by surgeon experience or surgeon volume. Learning curves projected that less experienced surgeons would achieve morbidity and mortality rates equivalent to those of experienced surgeons when they reached 20 and 60 PDs, respectively. CONCLUSIONS: Improvement in PD outcomes, including mortality, occurred with increased PD volume at a pancreatic center. Surgeon experience remained an important determinant of overall morbidity. Experienced surgeons, however, had comparable outcomes irrespective of annual volume.

Laparoscopic left pancreatectomy: complication risk score correlates with morbidity and risk for pancreatic fistula.

BACKGROUND: Surgeons are performing laparoscopic left pancreatectomy (LLP) with increasing frequency; however, determinants of perioperative outcome after LLP are not well defined. We evaluated factors contributing to morbidity after LLP. METHODS: Records from patients undergoing LLP from 2000 to 2008 from nine academic medical centers were evaluated to assess risk factors for perioperative complications. Extent of pancreatic resection was determined by the length of the gross pancreatic specimen. Complications and pancreatic fistula rates were assessed, and a model was developed to identify those at risk of postoperative adverse events. RESULTS: Among the 219 LLP cases, indications were cystic neoplasms in 122 (56%), solid neoplasms in 83 (38%), and chronic pancreatitis in 14 (6%). Thirty-day morbidity and mortality were 39% and 0, respectively. Major complications occurred in 11%. Pancreatic fistulae were detected in 23%, with clinically important fistulae (International Study Group on Pancreatic Fistula Definition grade B/C) seen in 10%. On multivariate analysis, only greater estimated blood loss (EBL), higher body mass index (BMI), and longer length of resected pancreas were associated with major complications. A complication risk score consisting of 1 point each for BMI >27, pancreatic specimen length >8 cm, or EBL > or =150 mL predicted an increased risk of complications and pancreatic fistulae. CONCLUSIONS: The risk of major complications after LLP is 11%, with clinically important pancreatic fistulae occurring in 10%. A complication risk score incorporating BMI, extent of pancreatic resection, and EBL correlates with all end points evaluated. The complication risk score should be used when quality outcome measures are evaluated.

Does type of pancreaticojejunostomy after pancreaticoduodenectomy decrease rate of pancreatic fistula? A randomized, prospective, dual-institution trial.

BACKGROUND: Pancreatic fistula (PF) is one of the most common complications after pancreaticoduodenectomy. There have been no large prospective randomized trials evaluating PF rates comparing invagination versus duct to mucosa pancreaticojejunostomy. We tested the hypothesis that a duct to mucosa pancreaticojejunostomy would reduce the PF rate. STUDY DESIGN: Between August 2006 and May 2008, 197 patients at two institutions underwent pancreaticoduodenectomy by a total of 8 experienced pancreatic surgeons as part of this prospective randomized trial (clinical trial no. NCT00359320). All patients were stratified by pancreatic texture and randomized to either an invagination or a duct to mucosa pancreaticojejunal anastomosis. Recorded variables included pancreatic duct diameter, operative time, blood loss, complications, and pathology. Primary end point was PF rate, as defined by the International Study Group on Pancreatic Fistula. Secondary end points included PF grade, postoperative length of hospital stay, other morbidities, and mortality. RESULTS: Rate of PF for the entire cohort was 17.8%. There were 23 fistulas (24%) in the duct to mucosa cohort and 12 fistulas (12%) in the invagination cohort (p < 0.05). The greatest risk factor for a PF was pancreas texture: PF developed in only 8 patients (8%) with hard glands, and in 27 patients (27%) with a soft gland. There were two perioperative deaths (both in the duct to mucosa group), with the proximate causes of death being PF, followed by bleeding and sepsis. CONCLUSIONS: This dual-institution prospective randomized trial reveals considerably fewer fistulas with invagination compared with duct to mucosa pancreaticojejunostomy after pancreaticoduodenectomy. Results confirm increased PF rates in soft as compared with hard glands. Additional studies are needed to define the optimal technique of pancreatic reconstruction after pancreaticoduodenectomy.

Adjuvant chemoradiation therapy for pancreatic adenocarcinoma: who really benefits?

BACKGROUND: The role of adjuvant chemoradiation therapy (CRT) in pancreatic cancer remains controversial. The primary aim of this study was to determine if CRT improved survival in patients with resected pancreatic cancer in a large, multiinstitutional cohort of patients. STUDY DESIGN: Patients undergoing resection for pancreatic adenocarcinoma from seven academic medical institutions were included. Exclusion criteria included patients with T4 or M1 disease, R2 resection margin, preoperative therapy, chemotherapy alone, or if adjuvant therapy status was unknown. RESULTS: There were 747 patients included in the initial evaluation. Primary analysis was performed between patients that had surgery alone (n=374) and those receiving adjuvant CRT (n=299). Median followup time was 12.2 months and 14.5 months for survivors. Median overall survival for patients receiving adjuvant CRT was significantly longer than for those undergoing operation alone (20.0 months versus 14.5 months, p=0.001). On subset and multivariate analysis, adjuvant CRT demonstrated a significant survival advantage only among patients who had lymph node (LN)-positive disease (hazard ratio 0.477, 95% CI 0.357 to 0.638) and not for LN-negative patients (hazard ratio 0.810, 95% CI 0.556 to 1.181). Disease-free survival in patients with LN-negative disease who received adjuvant CRT was significantly worse than in patients who had surgery alone (14.5 months versus 18.6 months, p=0.034). CONCLUSIONS: This large multiinstitutional study emphasizes the importance of analyzing subsets of patients with pancreas adenocarcinoma who have LN metastasis. Benefit of adjuvant CRT is seen only in patients with LN-positive disease, regardless of resection margin status. CRT in patients with LN-negative disease may contribute to reduced disease-free survival.

Middle segment pancreatectomy can be safely incorporated into a pancreatic surgeon's clinical practice.

Middle segment pancreatectomy (MSP) is a new operation where the advantages of parenchymal preservation are counterbalanced by a high postoperative complication rate and unease among surgeons with adopting a new technique. This study reviews our experience incorporating MSP into our clinical practice focusing on the initial 34 consecutive patients operated on by one surgeon at a single institution between 1998 and 2007. Patients were divided into early (initial 17 operations) and late (subsequent 17 operations) groups for analysis. Thirty-one reconstructions were by Roux-en-y pancreaticojejunostomy and three were by pancreaticogastrostomy. Using multiple linear regression and logistic regression, we found no significant differences in performance outcomes (operative time, blood loss, tumor size, margin negative resection rate, pancreatic fistula rate, hospital length of stay, postoperative complications, and hospital readmission rate) between our early and late experience even after adjusting for potential confounding variables (patient demographics, co-morbidities, neoplasm, pancreatitis). The pancreatic fistula rate in this series was 29.4% (10/34) and they were all International Study Group on Pancreatic Fistula (ISGPF) Grade A (60%) or B (40%). In summary, MSP is an operation with a flat learning curve and acceptable morbidity rate that can be safely incorporated as a parenchymal preserving option by pancreatic surgeons in their clinical practice.

Total pancreatectomy (R0 resection) improves survival over subtotal pancreatectomy in isolated neck margin positive pancreatic adenocarcinoma.

UNLABELLED: In patients undergoing pancreaticoduodenectomy (PD) for pancreatic adenocarcinoma (PC), conversion to total pancreatectomy (TP) may be necessary to achieve R0 resection. HYPOTHESIS: We sought to examine the oncologic benefit of conversion of PD to TP to achieve an R0 resection in patients with an isolated positive neck margin. METHODS: We conducted a retrospective analysis of prospectively collected data at Indiana University and Johns Hopkins Medical Institutions. A review of 1,579 patients who underwent PD or TP for PC at these institutions between 1992 and 2006 was performed. Sixty-one patients were eligible. RESULTS: Twenty-eight patients underwent PD with an isolated positive neck margin found on pathologic examination; 33 patients had conversion to TP for isolated neck margin involvement to achieve R0 resection. Patients undergoing TP versus PD had a greater median survival (18 vs 10 months; P = .04). Mortality (6% vs 7%) and morbidity (36% vs 54%; P = .20) for TP versus PD were comparable. Multivariate analysis revealed PD and greater tumor size as the only independent predictors of poor long-term survival (hazard ratio [HR], 2.2; P = .01 and HR, 1.3; P = .005). CONCLUSIONS: Conversion of PD to TP to achieve an R0 resection in patients with pancreatic adenocarcinoma is associated with a survival benefit.

Intraductal papillary mucinous neoplasms: predictors of malignant and invasive pathology.

OBJECTIVE: Determine whether size and other preoperative parameters predict malignant or invasive intraductal papillary mucinous neoplasia (IPMN). SUMMARY BACKGROUND DATA: From 1991 to 2006, 150 patients underwent 156 operations for IPMN. METHODS: Prospectively collected, retrospective review of a single academic institution's experience. All preoperative parameters including a detailed radiologic-based classification of IPMN type, location, distribution, size, number, cytology, and mural nodularity were correlated with IPMN pathology. RESULTS: Malignant IPMN was present in 32% of cases, whereas 19% of cases were invasive. IPMN type and main pancreatic duct diameter were significant predictors of malignant IPMN (P<0.001). Side-branch lesion number was negatively associated with invasive IPMN (P=0.03). Side-branch size, location, and distribution did not predict IPMN pathology. The presence of mural nodules was associated with malignant and invasive IPMN (P<0.001; P<0.02). Atypical cytopathology was significantly associated with malignant and invasive IPMN (P<0.001; P<0.001). Multivariate analysis demonstrated mural nodularity and atypical cytopathology were predictive of malignancy and/or invasion in branch-type IPMN. CONCLUSIONS: To lower the rate of invasive pathology, surgery should be recommended for fit patients with main-duct IPMN and for branch-duct IPMN with mural nodularity or positive cytology irrespective of location, distribution, or size.

Declining morbidity and mortality rates in the surgical management of pancreatic necrosis.

Surgical management of patients with pancreatic necrosis (PN) has evolved over the last two decades to include prophylactic antibiotics, initial medical management, and delayed surgical intervention. The purpose of this study is to identify changes in morbidity and mortality rates as our methods of surgical management have evolved. One hundred two consecutive patients (59 males and 43 females, mean age 53 +/- 16 years) with PN managed surgically were classified as group I (1993-2001), after the routine use of prophylactic antibiotics (N = 55), and group II (2002-2005), after the use of International Association of Pancreatology (IAP) guidelines for intervention (N = 47). Age, sex, etiology of pancreatitis, percent of necrosis, infected necrosis, and acute physiology and chronic health evaluation II scores were similar between groups. Despite a significant worsening of Balthazar computed tomography scoring in group II patients (p < 0.0001), operative morbidity (49 [89%] vs 34 [72%], p = 0.03), mortality (10 [18%] vs 2 [4%], p = 0.03), and hospital length of stay (38 +/- 33 days vs 26 +/- 23 days, p = 0.04) were significantly less in group II patients. Current methods of surgical management utilizing IAP guidelines have resulted in a decreased operative morbidity, mortality, and hospital length of stay in patients with PN.

Perioperative antibiotic prophylaxis in the gastric bypass patient: do we achieve therapeutic levels?

BACKGROUND: Perioperative surgical antibiotic prophylaxis requires that therapeutically effective drug concentrations be present in the tissues. METHODS: Patients undergoing Roux-en-Y gastric bypass for morbid obesity were given 2 g cefazolin preoperatively, followed by a second dose at 3 hours. Thirty-eight patients were each assigned to 1 of 3 body mass index (BMI) groups: (A) BMI=40-49 (N = 17); (B) BMI=50-59 (N=11); (C) BMI > or= 60 (N=10). Multiple timed serum (baseline; incision, 15, 30, 60 minutes; prior to second prophylactic dose; and closure) and tissue (skin, subcutaneous fat, and omentum) specimens were collected and cefazolin concentration analyzed by microbiological assay. RESULTS: No significant difference was observed in intraoperative fluid replacement or blood loss among BMI groups. Serum antimicrobial concentrations exceeded resistance breakpoint (32 microg/mL) in 73%, 68%, and 52% of BMI groups A, B, and C, respectively. No significant difference in cefazolin concentration was observed in mean incisional skin and closure tissue specimens in groups A, B, and C. A significant decrease in cefazolin concentration was noted in closure adipose (p=.04), initial (p=.03) and closure omentum (p=.05) tissues in groups B and C compared with A. Over 90% of serum samples exhibited therapeutic concentrations covering 53.8% of gram-positive and 78.6% of gram-negative surgical pathogens. However, therapeutic tissue levels were achieved in only 48.1%, 28.6%, and 10.2% of groups A, B, and C, respectively. CONCLUSIONS: Pharmacokinetic analysis suggests that present dosing strategies may fail to provide adequate perioperative prophylaxis in gastric bypass patients.

In vitro activities of moxifloxacin against 900 aerobic and anaerobic surgical isolates from patients with intra-abdominal and diabetic foot infections.

The in vitro activities of moxifloxacin, ciprofloxacin, levofloxacin, gatifloxacin, imipenem, piperacillin-tazobactam, clindamycin, and metronidazole against 900 surgical isolates were determined using NCCLS testing methods. Moxifloxacin exhibited good to excellent antimicrobial activity against most aerobic (90.8%) and anaerobic (97.1%) microorganisms, suggesting that it may be effective for the treatment of polymicrobial surgical infections.

Decreased gallbladder response in leptin-deficient obese mice.

Obesity is a major risk factor for gallstone formation, but the pathogenesis of this phenomenon remains unclear. Human data on gallbladder emptying are conflicting, and no animal data exist on the effect of obesity on gallbladder motility. Leptin, a hormone produced by adipocytes, is known to have central effects on neuropeptide Y and cholecystokinin, but the influence of leptin on the biliary effects of these hormones is unknown. Therefore we tested the hypothesis that leptin-deficient C57BL/6J-lep(ob) obese mice would have decreased gallbladder responses to excitatory stimuli. Twelve-week-old lean control (C57BL/6J) (n = 22) and C57BL/6J-lep(ob) obese (n = 20) female mice were fed a nonlithogenic diet. The mice were fasted overnight and underwent cholecystectomy. Whole gallbladders were placed in 3 ml muscle baths. After optimal length was determined with acetylcholine (10(-5) mol/L, responses to increasing doses of neuropeptide Y (10(-8) to 10(-6) mol/L) and cholecystokinin-8 (10(-10) to 10(-7) mol/L) were measured. Student's t test and two-way analysis of variance were used where appropriate. Results were expressed as Newtons per cross-sectional area. The lean control mice had significantly greater excitatory responses to acetylcholine than the obese mice (0.37 +/- 0.05 vs. 0.16 +/- 0.02, P < 0.01). The gallbladder responses were also greater when mice were treated with neuropeptide Y (10(-8) mol/L: 0.00 +/- 0.00 vs. 0.00 +/- 0.00, NS; 10(-7) mol/L: 0.12 +/- 0.02 vs. 0.05 +/- 0.01, P < 0.01; 10(-6) mol/L: 0.26 +/- 0.08 vs. 0.06 +/- 0.01, P < 0.01) and cholecystokinin (10(-10) mol/L: 0.27 +/- 0.04 vs. 0.13 +/- 0.02, P < 0.01; 10(-9) mol/L: 0.59 +/- 0.08 vs. 0.27 +/- 0.04, P < 0.01; 10(-8) mol/L: 0.80 +/- 0.11 vs. 0.37 +/- 0.05, P < 0.01; 10(-7) mol/L: 0.86 +/- 0.11 vs. 0.44 +/- 0.06, P < 0.01). These data suggest that genetically obese, leptin-deficient mice have decreased responses to acetylcholine, neuropeptide Y, and cholecystokinin. We conclude that decreased gallbladder motility contributes to the increased incidence of gallstones associated with obesity.