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.

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.

Early versus on-demand nasoenteric tube feeding in acute pancreatitis.

BACKGROUND: Early enteral feeding through a nasoenteric feeding tube is often used in patients with severe acute pancreatitis to prevent gut-derived infections, but evidence to support this strategy is limited. We conducted a multicenter, randomized trial comparing early nasoenteric tube feeding with an oral diet at 72 hours after presentation to the emergency department in patients with acute pancreatitis. METHODS: We enrolled patients with acute pancreatitis who were at high risk for complications on the basis of an Acute Physiology and Chronic Health Evaluation II score of 8 or higher (on a scale of 0 to 71, with higher scores indicating more severe disease), an Imrie or modified Glasgow score of 3 or higher (on a scale of 0 to 8, with higher scores indicating more severe disease), or a serum C-reactive protein level of more than 150 mg per liter. Patients were randomly assigned to nasoenteric tube feeding within 24 hours after randomization (early group) or to an oral diet initiated 72 hours after presentation (on-demand group), with tube feeding provided if the oral diet was not tolerated. The primary end point was a composite of major infection (infected pancreatic necrosis, bacteremia, or pneumonia) or death during 6 months of follow-up. RESULTS: A total of 208 patients were enrolled at 19 Dutch hospitals. The primary end point occurred in 30 of 101 patients (30%) in the early group and in 28 of 104 (27%) in the on-demand group (risk ratio, 1.07; 95% confidence interval, 0.79 to 1.44; P=0.76). There were no significant differences between the early group and the on-demand group in the rate of major infection (25% and 26%, respectively; P=0.87) or death (11% and 7%, respectively; P=0.33). In the on-demand group, 72 patients (69%) tolerated an oral diet and did not require tube feeding. CONCLUSIONS: This trial did not show the superiority of early nasoenteric tube feeding, as compared with an oral diet after 72 hours, in reducing the rate of infection or death in patients with acute pancreatitis at high risk for complications. (Funded by the Netherlands Organization for Health Research and Development and others; PYTHON Current Controlled Trials number, ISRCTN18170985.).

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.

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.

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.

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.

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.

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.

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.

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.

Skeletal Muscle Depletion is Associated with Severe Postoperative Complications in Patients Undergoing Cytoreductive Surgery with Hyperthermic Intraperitoneal Chemotherapy for Peritoneal Carcinomatosis of Colorectal Cancer.

BACKGROUND: In patients undergoing colorectal cancer surgery, skeletal muscle depletion (sarcopenia) is associated with impaired postoperative recovery and decreased survival. This study aimed to determine whether skeletal muscle depletion can predict postoperative complications for patients undergoing cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS-HIPEC) for peritoneal carcinomatosis of colorectal cancer. METHODS: All consecutive patients with an available preoperative computed tomography (CT) scan who underwent CRS-HIPEC for peritoneal carcinomatosis of colorectal cancer in two centers were analyzed. Skeletal muscle mass was determined using the L3 muscle index on the preoperative CT scan. The cutoff values defined by Prado et al. were used to classify the patients as sarcopenic or nonsarcopenic. RESULTS: Of the study's 206 patients, 90 (43.7 %) were classified as sarcopenic. The sarcopenic patients underwent significantly more reoperations than the nonsarcopenic patients (25.6 vs. 12.1 %; p = 0.012). The mean L3 muscle index was significantly lower for the patients who experienced severe postoperative complications than for the patients without severe postoperative complications (85.6 vs. 110.2 cm(2)/m(2); p = 0.008). In a multivariable logistic regression model, L3 muscle index was the only parameter independently associated with the risk of severe postoperative complications (odds ratio 0.93; 95 % confidence interval 0.87-0.99; p = 0.018). CONCLUSION: Skeletal muscle mass depletion, assessed using CT-based muscle mass measurements, is associated with an increased risk of severe postoperative complications in patients undergoing CRS-HIPEC for colorectal peritoneal carcinomatosis and could therefore be used in preoperative risk assessment.

Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with colon cancer at high risk of peritoneal carcinomatosis; the COLOPEC randomized multicentre trial.

BACKGROUND: The peritoneum is the second most common site of recurrence in colorectal cancer. Early detection of peritoneal carcinomatosis (PC) by imaging is difficult. Patients eventually presenting with clinically apparent PC have a poor prognosis. Median survival is only about five months if untreated and the benefit of palliative systemic chemotherapy is limited. Only a quarter of patients are eligible for curative treatment, consisting of cytoreductive surgery and hyperthermic intraperitoneal chemotherapy (CR/HIPEC). However, the effectiveness depends highly on the extent of disease and the treatment is associated with a considerable complication rate. These clinical problems underline the need for effective adjuvant therapy in high-risk patients to minimize the risk of outgrowth of peritoneal micro metastases. Adjuvant hyperthermic intraperitoneal chemotherapy (HIPEC) seems to be suitable for this purpose. Without the need for cytoreductive surgery, adjuvant HIPEC can be performed with a low complication rate and short hospital stay. METHODS/DESIGN: The aim of this study is to determine the effectiveness of adjuvant HIPEC in preventing the development of PC in patients with colon cancer at high risk of peritoneal recurrence. This study will be performed in the nine Dutch HIPEC centres, starting in April 2015. Eligible for inclusion are patients who underwent curative resection for T4 or intra-abdominally perforated cM0 stage colon cancer. After resection of the primary tumour, 176 patients will be randomized to adjuvant HIPEC followed by routine adjuvant systemic chemotherapy in the experimental arm, or to systemic chemotherapy only in the control arm. Adjuvant HIPEC will be performed simultaneously or shortly after the primary resection. Oxaliplatin will be used as chemotherapeutic agent, for 30 min at 42-43 °C. Just before HIPEC, 5-fluorouracil and leucovorin will be administered intravenously. Primary endpoint is peritoneal disease-free survival at 18 months. Diagnostic laparoscopy will be performed routinely after 18 months postoperatively in both arms of the study in patients without evidence of disease based on routine follow-up using CT imaging and CEA. DISCUSSION: Adjuvant HIPEC is assumed to reduce the expected 25 % absolute risk of PC in patients with T4 or perforated colon cancer to a risk of 10 %. This reduction is likely to translate into a prolonged overall survival. TRIAL REGISTRATION NUMBER: NCT02231086 (Clinicaltrials.gov).

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.

Population pharmacodynamic model for low molecular weight heparin nadroparin in morbidly obese and non-obese patients using anti-Xa levels as endpoint.

PURPOSE: In absence of specific dosing guidelines, the optimal dose of low molecular weight heparins for thrombosis prophylaxis in morbidly obese patients (BMI>40 kg/m(2)) remains unknown. In order to guide dosing in this patient group, a pharmacodynamics model is developed for nadroparin in morbidly obese and non-obese patients using anti-Xa levels as an endpoint, thereby characterizing the influence of excessive body weight on different pharmacodynamic model parameters. METHODS: Twenty-eight morbidly obese and seven non-obese patients receiving 5700 IU and 2850 IU subcutaneous (s.c.) nadroparin for surgery, respectively, were included with a mean total body weight (TBW) of 135 kg (range 72-252 kg). Up to 11 anti-Xa levels were collected from the start until 24 h after nadroparin administration. Population pharmacodynamic modelling with covariate analysis was performed using NONMEM. RESULTS: In a two-compartment pharmacodynamic model with baseline endogenous anti-Xa levels, the effect of nadroparin was found to be delayed and could be best described using a transit compartment. TBW was the most predictive covariate for clearance (CL=23.0 mL/min × (TBW/70)), while lean body weight (LBW) proved the most predictive covariate for central volume of distribution (V1=7.0 L × (LBW/60)). CONCLUSIONS: A pharmacodynamic model was developed characterizing anti-Xa levels after s.c. administration of nadroparin in patients weighing between 72 and 252 kg with TBW and LBW as the major determinants for clearance and volume of distribution, respectively.

Implementation of a standardized HIPEC protocol improves outcome for peritoneal malignancy.

BACKGROUND: Experience with Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) in a pioneer hospital resulted in a treatment protocol that has become the standard in the Netherlands. Outcome of CRS and HIPEC was reviewed to assure differences between the pioneer phase and the period wherein the Dutch HIPEC protocol was clinically implemented. METHODS: The first consecutive 100 CRS and HIPEC procedures performed in the Netherlands were included as pioneer cohort (1995-1999). Two-hundred and seventy-two procedures that were performed in three participating HIPEC centres after the implementation of the Dutch HIPEC protocol were included as the implementation cohort (2005-2012). Another 100 recent patients of the first centre were included as a control group (2009-2011). Indications for the CRS and HIPEC treatment were peritoneal carcinomatosis (PC) from colorectal carcinoma and pseudomyxoma peritonei (PMP). RESULTS: Of the 472 included procedures, 327 (69 %) procedures were performed for PC from colorectal carcinoma and 145 for PMP (31 %). Compared with the implementation phase, the pioneer phase was characterized by more affected abdominal regions (mean 4.3 vs. 3.5, p < 0.001), more resections (mean 3.8 vs. 3.4, p < 0.001), less macroscopic radical cytoreductions (66 vs. 86 %, p < 0.001) and more patients with major morbidity (grade III-V) (64 vs. 32 %, p < 0.001). Other determinants of morbidity were high tumour load and multiple organ resections. Outcome of the implementation phase was similar to the control group. CONCLUSIONS: This study determined that outcome had improved ever since the Dutch HIPEC protocol has been implemented based on completeness of cytoreduction and decreasing morbidity.

Cytoreductive surgery and HIPEC in treatment of colorectal peritoneal carcinomatosis: experiment or standard care? A survey among oncologic surgeons and medical oncologists.

BACKGROUND: Controversy still exists regarding the position of cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) in patients with peritoneal metastasis of colorectal carcinoma. The goal of the current study was to evaluate the opinions about this treatment among Dutch oncologic surgeons and medical oncologists. METHODS: An online survey was sent to all known Dutch oncologic surgeons (n = 459) and medical oncologists (n = 363) representing the respective departments of 84 hospitals. A comparison was made between surgeons and oncologists. RESULTS: 185 eligible responses were received from 71 hospitals, resulting in a response rate of 23 % for individuals and a response rate of 85 % for hospitals. Overall, 65 % of respondents regarded CRS+HIPEC as effective with sufficient evidence, 29 % responded that CRS+HIPEC is probably effective without sufficient evidence, and 7 % of respondents regards HIPEC as probably ineffective. Medical oncologists were less convinced of the effectiveness of CRS+HIPEC than surgeons (P = 0.006). Of all the respondents, 68 % indicated that they regard CRS+HIPEC as a standard treatment for patients with peritoneal dissemination of colorectal carcinoma (77 % of surgeons vs 54 % of oncologists, P = 0.001). Additionally, 68 % of respondents regard CRS+HIPEC as potentially curative (77 % of surgeons vs 54 % of oncologists, P = 0.001). CONCLUSIONS: Approximately 30 % of physicians who treat colorectal carcinoma do not regard CRS+HIPEC as standard care. Surgeons appear to be significantly more in favor of this treatment than medical oncologists. This study shows that efforts should be made to improve knowledge and increase acceptance of CRS and HIPEC in colorectal cancer treatment among medical oncologists and surgeons.

Downregulation of the acetyl-CoA metabolic network in adipose tissue of obese diabetic individuals and recovery after weight loss.

AIMS/HYPOTHESIS: Not all obese individuals develop type 2 diabetes. Why some obese individuals retain normal glucose tolerance (NGT) is not well understood. We hypothesise that the biochemical mechanisms that underlie the function of adipose tissue can help explain the difference between obese individuals with NGT and those with type 2 diabetes. METHODS: RNA sequencing was used to analyse the transcriptome of samples extracted from visceral adipose tissue (VAT) and subcutaneous adipose tissue (SAT) of obese women with NGT or type 2 diabetes who were undergoing bariatric surgery. The gene expression data was analysed by bioinformatic visualisation and statistical analyses techniques. RESULTS: A network-based approach to distinguish obese individuals with NGT from obese individuals with type 2 diabetes identified acetyl-CoA metabolic network downregulation as an important feature in the pathophysiology of type 2 diabetes in obese individuals. In general, genes within two reaction steps of acetyl-CoA were found to be downregulated in the VAT and SAT of individuals with type 2 diabetes. Upon weight loss and amelioration of metabolic abnormalities three months following bariatric surgery, the expression level of these genes recovered to levels seen in individuals with NGT. We report four novel genes associated with type 2 diabetes and recovery upon weight loss: ACAT1 (encoding acetyl-CoA acetyltransferase 1), ACACA (encoding acetyl-CoA carboxylase α), ALDH6A1 (encoding aldehyde dehydrogenase 6 family, member A1) and MTHFD1 (encoding methylenetetrahydrofolate dehydrogenase). CONCLUSIONS/INTERPRETATION: Downregulation of the acetyl-CoA network in VAT and SAT is an important feature in the pathophysiology of type 2 diabetes in obese individuals. ACAT1, ACACA, ALDH6A1 and MTHFD1 represent novel biomarkers in adipose tissue associated with type 2 diabetes in obese individuals.

Peritoneal carcinomatosis of gastric origin: a population-based study on incidence, survival and risk factors.

Peritoneal carcinomatosis (PC) is an important cause of morbidity and mortality among patients with gastric cancer. The aim of the current study was to provide reliable population-based data on the incidence, risk factors and prognosis of PC of gastric origin. All patients diagnosed with gastric cancer in the area of the Eindhoven Cancer Registry between 1995 and 2011 were included. Incidence and survival were computed and risk factors for peritoneal carcinomatosis were determined using multivariate logistic regression analysis. In total, 5,220 patients were diagnosed with gastric cancer, of whom 2,029 (39%) presented with metastatic disease. PC was present in 706 patients (14%) of whom 491 patients (9%) had PC as the only metastatic site. Younger age (<60 years), female gender, advanced T- and N-stage, primary tumor of signet ring cells or linitis plastica and primary tumors covering multiple anatomical locations of the stomach were all associated with a higher odds ratios of developing PC. Median survival of patients without metastases was 14 months, but only 4 months for patients with PC. PC is a frequent condition in patients presenting with gastric cancer, especially in younger patients with advanced tumor stages. Given the detrimental influence of PC on survival, efforts should be undertaken to further explore the promising results that were obtained in preventing or treating this condition with multimodality strategies.