Risk of metachronous peritoneal metastases in patients with pT4a versus pT4b colon cancer: An international multicentre cohort study.

INTRODUCTION: With evolving treatment strategies aiming at prevention or early detection of metachronous peritoneal metastases (PM), identification of high-risk colon cancer patients becomes increasingly important. This study aimed to evaluate differences between pT4a (peritoneal penetration) and pT4b (invasion of other organs/structures) subcategories regarding risk of PM and other oncological outcomes. MATERIALS AND METHODS: From eight databases deriving from four countries, patients who underwent curative intent treatment for pT4N0-2M0 primary colon cancer were included. Primary outcome was the 5-year metachronous PM rate assessed by Kaplan-Meier analysis. Independent predictors for metachronous PM were identified by Cox regression analysis. Secondary endpoints included 5-year local and distant recurrence rates, and 5-year disease free and overall survival (DFS, OS). RESULTS: In total, 665 patients with pT4a and 187 patients with pT4b colon cancer were included. Median follow-up was 38 months (IQR 23-60). Five-year PM rate was 24.7% and 12.2% for pT4a and pT4b categories, respectively (p = 0.005). Independent predictors for metachronous PM were female sex, right-sided colon cancer, peritumoral abscess, pT4a, pN2, R1 resection, signet ring cell histology and postoperative surgical site infections. Five-year local recurrence rate was 14% in both pT4a and pT4b cancer (p = 0.138). Corresponding five-year distant metastases rates were 35% and 28% (p = 0.138). Five-year DFS and OS were 54% vs. 62% (p = 0.095) and 63% vs. 68% (p = 0.148) for pT4a vs. pT4b categories, respectively. CONCLUSION: Patients with pT4a colon cancer have a higher risk of metachronous PM than pT4b patients. This observation has important implications for early detection and future adjuvant treatment strategies.

Bile leakage after loop closure vs clip closure of the cystic duct during laparoscopic cholecystectomy: A retrospective analysis of a prospective cohort.

BACKGROUND: Laparoscopic cholecystectomy (LC) is one of the most frequently performed surgical procedures. Cystic stump leakage is an underestimated, potentially life threatening complication that occurs in 1%-6% of the patients. With a secure cystic duct occlusion technique during LC, bile leakage becomes a preventable complication. AIM: To investigate the effect of polydioxanone (PDS) loop closure of the cystic duct on bile leakage rate in LC patients. METHODS: In this retrospective analysis of a prospective cohort, the effect of PDS loop closure of the cystic duct on bile leakage complication was compared to patients with conventional clip closure. Logistic regression analysis was used to develop a risk score to identify bile leakage risk. Leakage rate was assessed for categories of patients with increasing levels of bile leakage risk. RESULTS: Of the 4359 patients who underwent LC, 136 (3%) underwent cystic duct closure by a PDS loop. Preoperatively, loop closure patients had significantly more complicated biliary disease compared to the clipped closure patients. In the loop closure cohort, zero (0%) bile leakage occurred compared to 59 of 4223 (1.4%) clip closure patients. For patients at increased bile leakage risk (risk score ≥ 1) rates were 1.6% and up to 13% (4/30) for clip closure patients with a risk score ≥ 4. This risk increase paralleled a stepwise increase of actual bile leakage complication for clip closure patients, which was not observed for loop closure patients. CONCLUSION: Cystic duct closure with a PDS loop during LC may reduce bile leakage in patients at increased risk for bile leakage.

Laparoscopic surgery facilitates administration of adjuvant chemotherapy in locally advanced colon cancer: propensity score analyses.

PURPOSE: The aim of this study was to evaluate the impact of a laparoscopic approach on long-term oncological outcomes in curative intent surgery for pT4 colon cancer, in both overall and stratified subgroups with distinct clinical entities. PATIENTS AND METHODS: Patients with a pT4N0-2M0 colon cancer from four centers between 2000 and 2014 were included. Laparoscopic and open approaches were compared according to the intention-to-treat principle. Propensity scores were used to adjust for baseline differences between the groups in three manners: i) as a linear predictor in a Cox regression model, ii) to create a 1:1 matched cohort, and iii) to stratify patients into four groups with an increasing chance of receiving laparoscopy. RESULTS: In total, 424 patients were included. After 1:1 matching, a laparoscopic approach correlated with higher rates of radical resection, lower morbidity, and a higher percentage of patients receiving adjuvant chemotherapy. This translated into better 5-year disease-free survival (52% vs 40%, HR 0.70; 95% CI 0.50-0.96) and 5-year overall survival (68% vs 57%, HR 0.66; 95% CI 0.43-0.99). These results were confirmed in the other two propensity score analyses. In the multivariable models, adjuvant chemotherapy remained independently associated with better survival, whereas surgical approach lost significance. CONCLUSIONS: In locally advanced colon cancer, an intentional laparoscopic approach in experienced hands seems to decrease morbidity and to increase the proportion of patients receiving adjuvant chemotherapy. Receiving adjuvant chemotherapy was independently associated with improved survival.

Systematic Review and Meta-Analysis of Liver Resection for Colorectal Metastases in Elderly Patients.

BACKGROUND: This systematic review and meta-analysis evaluated the short- and long-term outcomes of liver resection for colorectal liver metastases (CRLM) in elderly patients. METHODS: A PubMed, EMBASE, and Cochrane Library search was performed from January 1995 to April 2017, for studies comparing both short- and long-term outcomes in younger and elderly patients undergoing liver resection for CRLM. RESULTS: Eleven studies comparing patients aged <70 years with patients aged >70 years and 4 studies comparing patients aged <75 years with patients aged >75 years were included. Postoperative morbidity was similar in patients aged >70 years (27 vs. 30%; p = 0.35) but higher in patients aged >75 years (21 vs. 32%; p = 0.001). Postoperative mortality was higher in both patients aged >70 years (2 vs. 4%; p = 0.01) and in patients aged >75 years (1 vs. 6%; p = 0.02). Mean 5-year overall survival was lower in patients aged >70 years (40 vs. 32%; p < 0.001) but equal in patients aged >75 years (42 vs. 32%; p = 0.06). CONCLUSION: Although postoperative morbidity and mortality were increased with higher age, liver resection for CRLM seems justified in selected elderly patients.

Superiority of Step-up Approach vs Open Necrosectomy in Long-term Follow-up of Patients With Necrotizing Pancreatitis.

BACKGROUND & AIMS: In a 2010 randomized trial (the PANTER trial), a surgical step-up approach for infected necrotizing pancreatitis was found to reduce the composite endpoint of death or major complications compared with open necrosectomy; 35% of patients were successfully treated with simple catheter drainage only. There is concern, however, that minimally invasive treatment increases the need for reinterventions for residual peripancreatic necrotic collections and other complications during the long term. We therefore performed a long-term follow-up study. METHODS: We reevaluated all the 73 patients (of the 88 patients randomly assigned to groups) who were still alive after the index admission, at a mean 86 months (±11 months) of follow-up. We collected data on all clinical and health care resource utilization endpoints through this follow-up period. The primary endpoint was death or major complications (the same as for the PANTER trial). We also measured exocrine insufficiency, quality of life (using the Short Form-36 and EuroQol 5 dimensions forms), and Izbicki pain scores. RESULTS: From index admission to long-term follow-up, 19 patients (44%) died or had major complications in the step-up group compared with 33 patients (73%) in the open-necrosectomy group (P = .005). Significantly lower proportions of patients in the step-up group had incisional hernias (23% vs 53%; P = .004), pancreatic exocrine insufficiency (29% vs 56%; P = .03), or endocrine insufficiency (40% vs 64%; P = .05). There were no significant differences between groups in proportions of patients requiring additional drainage procedures (11% vs 13%; P = .99) or pancreatic surgery (11% vs 5%; P = .43), or in recurrent acute pancreatitis, chronic pancreatitis, Izbicki pain scores, or medical costs. Quality of life increased during follow-up without a significant difference between groups. CONCLUSIONS: In an analysis of long-term outcomes of trial participants, we found the step-up approach for necrotizing pancreatitis to be superior to open necrosectomy, without increased risk of reinterventions.

Postoperative abdominal infections after resection of T4 colon cancer increase the risk of intra-abdominal recurrence.

INTRODUCTION: Patients with pT4 colon cancer are at risk of developing intra-abdominal recurrence. Infectious complications have shown to negatively influence disease free survival (DFS) and overall survival (OS) in stage I-III colon cancer. The aim of this study was to determine whether surgical site infections (SSIs) also increase the risk of intra-abdominal recurrence in pT4 colon cancer patients. METHODS: All consecutive patients with pT4N0-2M0 colon cancer from four centres between January 2000 and December 2014 were included. Patients were categorized into 2 groups; with and without a postoperative (<30 days) SSIs. SSIs included both deep incisional as well as organ/space SSIs. The primary outcome was intra-abdominal recurrence (including local/incisional recurrence, peritoneal metastases) and was assessed using Kaplan-Meier and Cox regression analyses. Secondary outcome measures were DFS and OS. RESULTS: Out of 420 patients, 62 (15%) developed a SSI. The 5-year intra-abdominal recurrence rates were 44% and 27% for patients with and without a SSI, respectively (p = 0.011). After multivariate analysis, SSI was independently associated with intra-abdominal recurrence (HR 1.807 (1.091-2.992)), worse DFS (HR 1.788 (1.226-2.607)), and worse OS (HR 1.837 (1.135-2.973)). Other independent risk factors for intra-abdominal recurrence were a R1 resection (HR 2.616 (1.264-5.415)) and N2-stage (HR 2.096 (1.318-3.332)). CONCLUSION: SSIs after resection of a pT4N0-2M0 colon cancer are associated with an increased risk of intra-abdominal recurrence and worse survival. This finding supports the hypothesis that infection-based immunologic pathways play a role in colon cancer cell dissemination and outgrowth.

The First Year After Colorectal Surgery in the Elderly.

PURPOSE: Surgery for colorectal malignancy is increasingly being performed in the elderly. Little is known about the impact of complications on late mortality. This study aimed to analyze whether a complicated postoperative course affects the 1-year survival in elderly patients. METHODS: All consecutive patients older than 75 years of age who underwent colorectal cancer surgery between January 2009 and April 2013 were included in this study. The main outcome was mortality at 1 year after surgery. Logistic regression analyses were performed to determine risk factors for a poor outcome (mortality) after survival of the early postoperative course of surgery at 1-year follow-up. Patients who died within 30 days postoperatively were excluded from analysis. RESULTS: The early mortality rate was 6.3% (n = 15), and 2 patients died during follow-up as a result of complications after a second surgery. A total of 223 patients survived the perioperative period and were included in this study. Twenty-two patients (9.9%) died during the first year of follow-up. Stage IV disease (P = 0.002), complications of primary surgery (P = 0.016), and comorbidity (P = 0.050) were risk factors for 1-year mortality. Intensive care unit stay, reoperation and readmission were not associated with a worse 1-year outcome. CONCLUSION: Elderly patients with stage IV disease at the time of surgery, comorbidity, and postoperative complications are at risk for mortality during the first year after surgery. A patient-tailored approach with special attention to perioperative care should be considered in the elderly.

Treatment of Peritoneal Dissemination in Stomach Cancer Patients With Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC): Rationale and Design of the PERISCOPE Study.

BACKGROUND: Patients with gastric cancer and peritoneal carcinomatosis have a very poor prognosis; median survival is 3 to 4 months. Palliative systemic chemotherapy is currently the only treatment available in the Netherlands. Intraoperative hyperthermic intraperitoneal chemotherapy (HIPEC) has an established role in the treatment of peritoneal carcinomatosis originating from colorectal cancer, appendiceal cancer, and pseudomyxoma peritonei; its role in gastric cancer is uncertain. Currently, there is no consensus on the choice of chemotherapeutic agents used in HIPEC for gastric cancer. OBJECTIVE: The main objectives of this study are (1) to investigate the safety, tolerability, and feasibility of gastrectomy combined with cytoreductive surgery and HIPEC after systemic chemotherapy, as a primary treatment option for patients with advanced gastric cancer with tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis; and (2) to determine the maximum tolerated dose (MTD) of intraperitoneal docetaxel in combination with a fixed dose of intraperitoneal oxaliplatin. METHODS: The PERISCOPE study is a multicenter, open label, phase I-II dose-escalation study. The MTD of docetaxel will be studied using a 3+3 design. Patients with locally advanced (cT3-cT4) gastric adenocarcinoma are eligible for inclusion if the primary gastric tumor is considered resectable, tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis is confirmed by diagnostic laparoscopy/ laparotomy, and prior systemic chemotherapy was without disease progression. At laparotomy, cytoreductive surgery (complete removal of all macroscopically visible tumor deposits) and a total or partial gastrectomy with a D2 lymph node dissection is performed. An open HIPEC technique is used with 460mg/m2 hyperthermic oxaliplatin for 30 minutes (41°C to 42°C) followed by normothermic docetaxel for 90 minutes (37°C) in a dose that will be escalated per 3 patients (0, 50, 75, 100, 125, 150 mg/m2). The primary endpoint is treatment related toxicity. RESULTS: Patient accrual is ongoing and the first results are expected in 2017. CONCLUSIONS: The PERISCOPE study will determine the safety, tolerability, and feasibility of gastrectomy combined with cytoreduction and HIPEC using oxaliplatin in combination with docetaxel after systemic chemotherapy as primary treatment option for gastric cancer patients with tumor positive peritoneal cytology and/or limited peritoneal carcinomatosis. This study will provide pharmacokinetic data on the intraperitoneal administration of oxaliplatin and docetaxel, including the MTD of intraperitoneal-administered docetaxel. These data are a prerequisite for the safe conduct of future HIPEC studies in patients with gastric cancer. TRIAL REGISTRATION: Netherlands Trial Registration (NTR): NTR4250; http://www.trialregister.nl/trialreg/admin/ rctview.asp?TC=4250 (Archived by WebCite at http://www.webcitation.org/6rWJONgkt).

Influence of Morbid Obesity on the Pharmacokinetics of Morphine, Morphine-3-Glucuronide, and Morphine-6-Glucuronide.

INTRODUCTION: Obesity is associated with many pathophysiological changes that may result in altered drug metabolism. The aim of this study is to investigate the influence of obesity on the pharmacokinetics of morphine, morphine-3-glucuronide (M3G), and morphine-6-glucuronide (M6G) through a combined analysis in morbidly obese patients and non-obese healthy volunteers. METHODS: In this analysis, data from 20 morbidly obese patients [mean body mass index 49.9 kg/m2 (range 37.6-78.6 kg/m2) and weight 151.3 kg (range 112-251.9 kg)] and 20 healthy volunteers [mean weight 70.6 kg (range 58-85 kg)] were included. Morbidly obese patients received 10 mg of intravenous (I.V.) morphine after gastric bypass surgery, with additional morphine I.V. doses as needed. Healthy volunteers received an I.V. bolus of morphine of 0.1 mg/kg followed by an infusion of 0.030 mg kg-1 h-1 for 1 h. Population pharmacokinetic modeling was performed using NONMEM 7.2. RESULTS: In morbidly obese patients, elimination clearance of M3G and M6G was decreased substantially compared with healthy volunteers (p < 0.001). Regarding glucuronidation, only a slight decrease in the formation of M6G and a delay in the formation of M3G was found (both p < 0.001). Obesity was also identified as a covariate for the peripheral volume of distribution of morphine (p < 0.001). CONCLUSION: Metabolism of morphine is not altered in morbidly obese patients. However, decreased elimination of both M3G and M6G is evident, resulting in a substantial increase in exposure to these two metabolites. A rational explanation of this finding is that it results from alterations in membrane transporter function and/or expression in the liver. ClinicalTrials.gov identifier: NCT01097148.

Early Cholecystectomy for Acute Cholecystitis in the Elderly Population: A Systematic Review and Meta-Analysis.

BACKGROUND: In the era of advanced surgical techniques and improved perioperative care, the willingness to perform emergency operations in elderly patients continues to increase. This systematic review aimed at assessing the clinical outcomes of early cholecystectomy in elderly patients with acute cholecystitis. METHODS: Medline, Embase, and Cochrane Library databases were systematically searched for studies reporting on early cholecystectomy for acute cholecystitis in patients aged ≥70 years. The conversion rate, perioperative morbidity, and mortality were calculated using a random-effects model. RESULTS: Eight articles fell within the scope of this study. In total, 592 patients were identified. The mean age was 81 years. Early cholecystectomy was performed laparoscopically in 316 patients (53%) and open in 276 patients (47%). The procedure was associated with a conversion rate of 23% (95% CI 18.6-28.3), a perioperative morbidity of 24% (95% CI 20.5-27.5), and a mortality of 3.5% (95% CI 2.3-5.4). CONCLUSION: Early cholecystectomy seems to be a feasible treatment in elderly patients with acute cholecystitis. To reduce morbidity, patients who may benefit from surgery ought to be selected carefully. Future prospective studies should compare early cholecystectomy with alternative treatments to select the treatment that is most appropriate for elderly patients.

The optimal treatment of patients with mild and moderate acute cholecystitis: time for a revision of the Tokyo Guidelines.

INTRODUCTION: According to the Tokyo Guidelines, severity of acute cholecystitis is divided into three grades based on the degree of inflammation and the presence of organ dysfunction. These guidelines recommend grade I (mild) acute cholecystitis to be treated with early laparoscopic cholecystectomy and grade II (moderate) acute cholecystitis with delayed cholecystectomy. Yet, several studies have shown that, for acute cholecystitis in general, early cholecystectomy is superior to delayed cholecystectomy in terms of complication rate, duration of hospital stay and costs. The aim of this study was to determine the clinical outcomes of emergency cholecystectomy in patients with grade II acute cholecystitis. Based on our findings, we propose a revision of the Tokyo Guidelines. METHODS: We performed a retrospective observational cohort study of 589 consecutive patients undergoing emergency cholecystectomy for acute calculous cholecystitis in a large teaching hospital between January 2002 and January 2015. Patients were classified according to the severity assessment criteria of the Tokyo Guidelines. Patients with grade I and grade II acute cholecystitis were compared for perioperative outcomes. RESULTS: Emergency cholecystectomy was performed in 270 patients with grade I acute cholecystitis and 187 patients with grade II acute cholecystitis. There was no difference in conversion rate (6 vs. 6%, p = 0.985) and operating time (60 min [25-255] vs. 70 min [30-255], p = 0.421). Also the perioperative complication rate (7 vs. 9%, p = 0.517), 30-day mortality (1 vs. 1%, p = 0.648) and length of hospital stay (4 days [1-42] vs. 4 days [1-62], p = 0.327) were similar between grade I and grade II acute cholecystitis. CONCLUSION: The clinical outcomes of emergency cholecystectomy did not differ between patients with grade I and grade II acute cholecystitis. The findings support a revision of the Tokyo Guidelines with respect to the recommendation of performing emergency cholecystectomy in both grade I and grade II acute cholecystitis.

Conservative treatment of acute cholecystitis: a systematic review and pooled analysis.

BACKGROUND: In medical practice, the tendency to remove an inflamed gallbladder is deeply rooted. Cholecystectomy, however, is associated with relatively high complication rates, and therefore the decision whether or not to perform surgery should be well considered. For some patients, the surgical risk-benefit profile may favour conservative treatment. The objective of this study was to examine the short- and long-term outcome of conservative treatment of patients with acute calculous cholecystitis. METHODS: A systematic search of MEDLINE, Embase and Cochrane Library databases was performed. Prospective studies reporting on the success rate of conservative treatment (i.e. non-invasive treatment) of acute cholecystitis during index admission were included, as well as prospective and retrospective studies reporting on the recurrence rate of gallstone-related disease during long-term follow-up (i.e. ≥12 months) after initial non-surgical management. Study selection was undertaken independently by two reviewers using predefined criteria. The risk of bias was assessed. The pooled success and mortality rate during index admission and the pooled recurrence rate of gallstone-related disease during long-term follow-up were calculated using a random-effects model. RESULTS: A total of 1841 patients were included in 10 randomized controlled trials and 14 non-randomized studies. Conservative treatment during index admission was successful in 87 % of patients with acute calculous cholecystitis and in 96 % of patients with mild disease. In the long term, 22 % of the patients developed recurrent gallstone-related disease. Pooled analysis showed a success rate of 86 % (95 % CI 0.8-0.9), a mortality rate of 0.5 % (95 % CI 0.001-0.009) and a recurrence rate of 20 % (95 % CI 0.1-0.3). DISCUSSION: Conservative treatment of acute calculous cholecystitis during index admission seems feasible and safe, especially in patients with mild disease. During long-term follow-up, less than a quarter of the patients appear to develop recurrent gallstone-related disease, although this outcome is based on limited data.

Use of an Image Acquisition Stabilizer Improves Sidestream Dark Field Imaging of the Serosa during Open Gastrointestinal Surgery.

AIM: To investigate whether an image acquisition stabilizer (IAS) mounted on the sidestream dark field camera (SDF) during gastrointestinal surgery improves image stability and acquisition. METHODS: Serosal SDF imaging was compared with SDF imaging combined with an IAS (SDF + IAS) during gastrointestinal surgery. Stability was assessed as the image drift in pixels and the time to obtain stable images. The success rate was determined as the percentage of analyzable images after recording. The effect of negative pressure from the IAS was determined during single-spot measurements and by comparing microvascular parameters between groups. Data are presented as mean ± SD. RESULTS: Sixty serosal measurements were performed per group; 87% were successful in the SDF group and 100% in the SDF + IAS group (p = 0.003). Image drift in the SDF group was 148 ± 36 versus 55 ± 15 pixels in the SDF + IAS group; p < 0.001. Time to stable image was 96 ± 60 s in the SDF group versus 57 ± 31 s in the SDF + IAS group; p = 0.03. No effect of negative pressure was seen. CONCLUSION: The use of an IAS mounted on an SDF camera during serosal microvascular assessment improves the success rate of image acquisition and stability and reduces the time to stable image with no effect on the microcirculation.

Cytoreductive surgery and HIPEC offers similar outcomes in patients with rectal peritoneal metastases compared to colon cancer patients: a matched case control study.

BACKGROUND & OBJECTIVES: The effect of cytoreduction and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with rectal peritoneal metastases (PM) is unclear. This case-control study aims to assess the results of cytoreduction and HIPEC in patients with rectal PM compared to colon PM patients. METHODS: Colorectal PM patients treated with complete macroscopic cytoreduction and HIPEC were included. Two colon cancer patients were case-matched for each rectal cancer patient, based on prognostic factors (T stage, N stage, histology type, and extent of PM). Short- and long-term outcomes were compared between both groups. RESULTS: From 317 patients treated with complete macroscopic cytoreduction and HIPEC, 29 patients (9.1%) had rectal PM. Fifty-eight colon cases were selected as control patients. Baseline characteristics were similar between groups. Major morbidity was 27.6% and 34.5% in the rectal and colon group, respectively (P = 0.516). Median disease-free survival was 13.5 months in the rectal group and 13.6 months in the colon group (P = 0.621). Two- and five-year overall survival rates were 54%/32% in rectal cancer patients, and 61%/24% in colon cancer patients (P = 0.987). CONCLUSIONS: Cytoreduction and HIPEC in selected patients with rectal PM is feasible and provides similar outcomes as in colon cancer patients. Rectal PM should not be regarded a contra-indication for cytoreduction and HIPEC in selected patients. J. Surg. Oncol. 2016;113:548-553. © 2016 Wiley Periodicals, Inc.

Morbidly Obese Patients Exhibit Increased CYP2E1-Mediated Oxidation of Acetaminophen.

INTRODUCTION: Acetaminophen (paracetamol) is mainly metabolized via glucuronidation and sulphation, while the minor pathway through cytochrome P450 (CYP) 2E1 is held responsible for hepatotoxicity. In obese patients, CYP2E1 activity is reported to be induced, thereby potentially worsening the safety profile of acetaminophen. The aim of this study was to determine the pharmacokinetics of acetaminophen and its metabolites (glucuronide, sulphate, cysteine and mercapturate) in morbidly obese and non-obese patients. METHODS: Twenty morbidly obese patients (with a median total body weight [TBW] of 140.1 kg [range 106-193.1 kg] and body mass index [BMI] of 45.1 kg/m(2) [40-55.2 kg/m(2)]) and eight non-obese patients (with a TBW of 69.4 kg [53.4-91.7] and BMI of 21.8 kg/m(2) [19.4-27.4]) received 2 g of intravenous acetaminophen. Fifteen blood samples were collected per patient. Population pharmacokinetic modelling was performed using NONMEM. RESULTS: In morbidly obese patients, the median area under the plasma concentration-time curve from 0 to 8 h (AUC0-8h) of acetaminophen was significantly smaller (P = 0.009), while the AUC0-8h ratios of the glucuronide, sulphate and cysteine metabolites to acetaminophen were significantly higher (P = 0.043, 0.004 and 0.010, respectively). In the model, acetaminophen CYP2E1-mediated clearance (cysteine and mercapturate) increased with lean body weight [LBW] (population mean [relative standard error] 0.0185 L/min [15 %], P < 0.01). Moreover, accelerated formation of the cysteine and mercapturate metabolites was found with increasing LBW (P < 0.001). Glucuronidation clearance (0.219 L/min [5 %]) and sulphation clearance (0.0646 L/min [6 %]) also increased with LBW (P < 0.001). CONCLUSION: Obesity leads to lower acetaminophen concentrations and earlier and higher peak concentrations of acetaminophen cysteine and mercapturate. While a higher dose may be anticipated to achieve adequate acetaminophen concentrations, the increased CYP2E1-mediated pathway may preclude this dose adjustment.

Risk of Recurrent Pancreatitis and Progression to Chronic Pancreatitis After a First Episode of Acute Pancreatitis.

BACKGROUND & AIMS: Patients with a first episode of acute pancreatitis can develop recurrent or chronic pancreatitis (CP). However, little is known about the incidence or risk factors for these events. METHODS: We performed a cross-sectional study of 669 patients with a first episode of acute pancreatitis admitted to 15 Dutch hospitals from December 2003 through March 2007. We collected information on disease course, outpatient visits, and hospital readmissions, as well as results from imaging, laboratory, and histology studies. Standardized follow-up questionnaires were sent to all available patients to collect information on hospitalizations and interventions for pancreatic disease, abdominal pain, steatorrhea, diabetes mellitus, medications, and alcohol and tobacco use. Patients were followed up for a median time period of 57 months. Primary end points were recurrent pancreatitis and CP. Risk factors were evaluated using regression analysis. The cumulative risk was assessed using Kaplan-Meier analysis. RESULTS: Recurrent pancreatitis developed in 117 patients (17%), and CP occurred in 51 patients (7.6%). Recurrent pancreatitis developed in 12% of patients with biliary disease, 24% of patients with alcoholic etiology, and 25% of patients with disease of idiopathic or other etiologies; CP occurred in 3%, 16%, and 10% of these patients, respectively. Etiology, smoking, and necrotizing pancreatitis were independent risk factors for recurrent pancreatitis and CP. Acute Physiology and Chronic Health Evaluation II scores at admission also were associated independently with recurrent pancreatitis. The cumulative risk for recurrent pancreatitis over 5 years was highest among smokers at 40% (compared with 13% for nonsmokers). For alcohol abusers and current smokers, the cumulative risks for CP were similar-approximately 18%. In contrast, the cumulative risk of CP increased to 30% in patients who smoked and abused alcohol. CONCLUSIONS: Based on a retrospective analysis of patients admitted to Dutch hospitals, a first episode of acute pancreatitis leads to recurrent pancreatitis in 17% of patients, and almost 8% of patients progress to CP within 5 years. Progression was associated independently with alcoholic etiology, smoking, and a history of pancreatic necrosis. Smoking is the predominant risk factor for recurrent disease, whereas the combination of alcohol abuse and smoking produces the highest cumulative risk for chronic pancreatitis.

Early complication detection after colorectal surgery (CONDOR): study protocol for a prospective clinical diagnostic study.

PURPOSE: Anastomotic leakage is one of the most feared complications following colorectal surgery with a high morbidity and mortality rate. Multiple risk factors have been identified, but leakage still occurs. Early detection is crucial in order to reduce morbidity and mortality. The aim of this study is to create a decision algorithm for early detection of anastomotic leakage. METHODS: All patients who undergo elective colorectal surgery for benign or malignant disease are enrolled in this multicenter study. The primary endpoint is the accuracy of the prediction of anastomotic leakage. The main study parameter is the occurrence of postoperative anastomotic leakage. Secondary study parameters are clinical (vital) parameters, additional laboratory or radiology examination, other complications, mortality, re-intervention, duration of hospital and intensive care stay, emergency room visits, readmission to the hospital and total costs. Daily physical examination and each step in clinical decision making will be evaluated prospectively in a standardized manner. The focus of the analysis will be on the added value of diagnostic tools, such as laboratory results and imaging studies, over physical examination by using logistic regression and decision tree analysis. CONCLUSION: This study aims to develop an optimal diagnostic algorithm that can act as a guideline for surgeons or surgical residents to early identify patients with anastomotic leakage after colorectal surgery.

Treatment-Related Mortality After Cytoreductive Surgery and HIPEC in Patients with Colorectal Peritoneal Carcinomatosis is Underestimated by Conventional Parameters.

BACKGROUND: Cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) as treatment for patients with colorectal peritoneal carcinomatosis (PC) is regarded as an extensive procedure. The risk of postoperative mortality after major abdominal surgery might be substantially higher than described by the 30-day mortality. This study aims to identify causes of 1-year mortality, thereby assessing a more accurate treatment-related mortality rate after CRS + HIPEC. METHODS: All subsequent patients with colorectal PC treated with CRS + HIPEC with complete macroscopic cytoreduction in two tertiary hospitals between April 2005 and April 2013 were included in this study. Causes of 1-year mortality were carefully analyzed and patient data were compared between patients who died or did not die within 12 months after CRS + HIPEC. RESULTS: Of the 245 included patients, 34 (13.9 %) died within 12 months after CRS + HIPEC. The overall treatment-related mortality rate was 4.9 % (n = 12), and the 30-day and in-hospital mortality rates were 1.6 % (n = 4) and 2.4 % (n = 6), respectively. Furthermore, 18 patients (7.3 %) died due to early recurrent disease. Three patients (1.2 %) died of cardiovascular events, unrelated to CRS + HIPEC. The 1-year mortality group had more extensive peritoneal disease (p = 0.02) and the operative time in this group was longer (p < 0.001). CONCLUSIONS: Overall treatment-related mortality was considerably higher than described by the 30-day and in-hospital mortality rate. However, even though complete macroscopic cytoreduction was achieved in every patient, the main cause of 1-year mortality was early recurrent disease. Both findings are valuable in preoperative patient selection, as well as in preoperative counseling of patients undergoing a CRS + HIPEC procedure.

Same-admission versus interval cholecystectomy for mild gallstone pancreatitis (PONCHO): a multicentre randomised controlled trial.

BACKGROUND: In patients with mild gallstone pancreatitis, cholecystectomy during the same hospital admission might reduce the risk of recurrent gallstone-related complications, compared with the more commonly used strategy of interval cholecystectomy. However, evidence to support same-admission cholecystectomy is poor, and concerns exist about an increased risk of cholecystectomy-related complications with this approach. In this study, we aimed to compare same-admission and interval cholecystectomy, with the hypothesis that same-admission cholecystectomy would reduce the risk of recurrent gallstone-related complications without increasing the difficulty of surgery. METHODS: For this multicentre, parallel-group, assessor-masked, randomised controlled superiority trial, inpatients recovering from mild gallstone pancreatitis at 23 hospitals in the Netherlands (with hospital discharge foreseen within 48 h) were assessed for eligibility. Adult patients (aged ≥18 years) were eligible for randomisation if they had a serum C-reactive protein concentration less than 100 mg/L, no need for opioid analgesics, and could tolerate a normal oral diet. Patients with American Society of Anesthesiologists (ASA) class III physical status who were older than 75 years of age, all ASA class IV patients, those with chronic pancreatitis, and those with ongoing alcohol misuse were excluded. A central study coordinator randomly assigned eligible patients (1:1) by computer-based randomisation, with varying block sizes of two and four patients, to cholecystectomy within 3 days of randomisation (same-admission cholecystectomy) or to discharge and cholecystectomy 25-30 days after randomisation (interval cholecystectomy). Randomisation was stratified by centre and by whether or not endoscopic sphincterotomy had been done. Neither investigators nor participants were masked to group assignment. The primary endpoint was a composite of readmission for recurrent gallstone-related complications (pancreatitis, cholangitis, cholecystitis, choledocholithiasis needing endoscopic intervention, or gallstone colic) or mortality within 6 months after randomisation, analysed by intention to treat. The trial was designed to reduce the incidence of the primary endpoint from 8% in the interval group to 1% in the same-admission group. Safety endpoints included bile duct leakage and other complications necessitating re-intervention. This trial is registered with Current Controlled Trials, number ISRCTN72764151, and is complete. FINDINGS: Between Dec 22, 2010, and Aug 19, 2013, 266 inpatients from 23 hospitals in the Netherlands were randomly assigned to interval cholecystectomy (n=137) or same-admission cholecystectomy (n=129). One patient from each group was excluded from the final analyses, because of an incorrect diagnosis of pancreatitis in one patient (in the interval group) and discontinued follow-up in the other (in the same-admission group). The primary endpoint occurred in 23 (17%) of 136 patients in the interval group and in six (5%) of 128 patients in the same-admission group (risk ratio 0·28, 95% CI 0·12-0·66; p=0·002). Safety endpoints occurred in four patients: one case of bile duct leakage and one case of postoperative bleeding in each group. All of these were serious adverse events and were judged to be treatment related, but none led to death. INTERPRETATION: Compared with interval cholecystectomy, same-admission cholecystectomy reduced the rate of recurrent gallstone-related complications in patients with mild gallstone pancreatitis, with a very low risk of cholecystectomy-related complications. FUNDING: Dutch Digestive Disease Foundation.

The Pharmacokinetics of the CYP3A Substrate Midazolam in Morbidly Obese Patients Before and One Year After Bariatric Surgery.

PURPOSE: Bariatric surgery is nowadays commonly applied as treatment for morbid obesity (BMI > 40 kg/m(2)). As information about the effects of this procedure on a drug's pharmacokinetics is limited, we aimed to evaluate the pharmacokinetics of CYP3A probe substrate midazolam after oral and intravenous administration in a cohort of morbidly obese patients that was studied before and 1 year post bariatric surgery. METHODS: Twenty morbidly obese patients (aged 26-58 years) undergoing bariatric surgery participated in the study of which 18 patients returned 1 year after surgery. At both occasions, patients received 7.5 mg oral and 5 mg intravenous midazolam separated by 160 ± 48 min. Per patient and occasion, a mean of 22 blood samples were collected. Midazolam concentrations were analyzed using population pharmacokinetic modeling. RESULTS: One year after bariatric surgery, systemic clearance of midazolam was higher [0.65 (7%) versus 0.39 (11%) L/min, mean ± RSE (P < 0.01), respectively] and mean oral transit time (MTT) was faster [23 (20%) versus 51 (15%) minutes (P < 0.01)], while oral bioavailability was unchanged (0.54 (9%)). Central and peripheral volumes of distribution were overall lower (P < 0.05). CONCLUSIONS: In this cohort study in morbidly obese patients, systemic clearance was 1.7 times higher 1 year after bariatric surgery, which may potentially result from an increase in hepatic CYP3A activity per unit of liver weight. Although MTT was found to be faster, oral bioavailability remained unchanged, which considering the increased systemic clearance implies an increase in the fraction escaping intestinal first pass metabolism.