Joris J. Scheepers

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.

Prolonged continuous or intermittent vascular inflow occlusion during hemihepatectomy in pigs.

OBJECTIVE To assess ischemia and reperfusion (I/R) injury in a hemihepatectomy model in pigs after prolonged continuous or intermittent vascular inflow occlusion in the liver. SUMMARY BACKGROUND DATA Massive intraoperative blood loss during liver resections can be prevented by temporary vascular inflow occlusion, consequently leading to ischemia and reperfusion injury in the remnant liver. Previously, in a pig liver resection model in which only limited I/R injury was induced during brief (90 min) vascular inflow occlusion, the authors demonstrated reduced I/R injury after continuous (CNT) occlusion, compared to intermittent (INT). This liver resection study on pigs was undertaken to assess I/R injury after prolonged (120 min) CNT or INT occlusion. METHODS In pigs (37.0 +/- 1.5 kg), liver ischemia during 2 hours was CNT (n = 6) or INT (n = 6) (eight subsequent periods of 12 min ischemia and 3 min recirculation), followed by 6 hours of reperfusion. A left hemihepatectomy (45.5% +/- 1.4%) was performed within the first 12 minutes of ischemia. No hepatic pedicle clamping or liver resection was performed in control experiments (n = 6). Microvascular damage was assessed by hyaluronic acid (HA) uptake capacity of the liver (parameter of early sinusoidal endothelial cell damage) and restoration of intrahepatic tissue pO2 during reperfusion. Hepatocellular damage was tested by plasma concentrations of aspartate aminotransferase (AST), alanine aminotransferase, and lactate dehydrogenase (LDH). RESULTS Hyaluronic acid uptake after 6 hours of reperfusion, compared to preischemic uptake, was unaltered in the control group, but was significantly reduced in both resection groups. However, more HA was taken up after INT occlusion, compared to CNT (60.4% +/- 5.6% and 39.5% +/- 3.7%, respectively; ANOVA: p = 0.001). Intrahepatic tissue pO2 distribution after 6 hours of reperfusion more closely returned to preischemic configuration in the INT group than in the CNT group, indicating reduced microcirculatory disturbances after INT occlusion. Release of AST and LDH after 6 hours of reperfusion was significantly increased in both CNT and INT groups. Lower AST levels, however, were found after INT occlusion than after CNT occlusion (267.0 +/- 74.7 U/l and 603.3 +/- 132.4 U/l, respectively; p = 0.06). CONCLUSIONS Intermittent hepatic vascular inflow occlusion during prolonged liver ischemia in pigs resulted in less microcirculatory and hepatocellular injury, compared to continuous occlusion. Intermittent clamping is preferable when prolonged periods of vascular inflow occlusion are applied during liver resections.

Influence of circumferential resection margin on prognosis in distal esophageal and gastroesophageal cancer approached through the transhiatal route

We studied the influence of circumferential resection margin (CRM) involvement on survival in patients with malignancies of the distal esophagus and gastroesophageal junction. One hundred ten consecutive patients undergoing a laparoscopic or open transhiatal esophagectomy for malignancy of the distal 5 cm of the esophagus, or a Siewert I gastroesophageal junction tumor were analyzed, retrospectively. Only patients with potentially resectable tumors were included. CRM status was defined as clear or involved (microscopic tumor within 1 mm of the resection margin). Statistical analysis was done by means of univariate and multivariate analysis using the Kaplan-Meier method and Cox proportional hazard model. One hundred ten patients were analyzed. Sixty patients underwent open transhiatal esophagectomy, and 50 patients underwent laparoscopic transhiatal esophagectomy. There were 6 (5%) T(1), 18 (16%) T(2), and 86 (89%) T(3) tumors. CRM was clear in 68 (62%) patients and involved in 42 (38%) patients. Median survival in these groups was 50 vs. 20 months (P = 0.000). Since CRM involvement was only seen in T(3) tumors, this group was analyzed in detail. Median survival in the T(3)CRM(-) and T(3)CRM(+) group was 33 vs. 19 months (P = 0.004). For T(3)N(0) tumors, median survival in CRM(-) and CRM(+) was 40 and 22 months, respectively (P = 0.036). Median survival for T(3)N(1) tumors in CRM(-) and CRM(+) was 22 and 13 months, respectively (P = 0.049). Involvement of the circumferential resection margin was found to be an independent prognostic factor on survival in our study. It predicts a poor prognosis in patients with potentially resectable malignancies of the distal 5 cm of the esophagus and Siewert I adenocarcinomas of the gastro esophageal junction.

Pancreatitis of biliary origin, optimal timing of cholecystectomy (PONCHO trial): study protocol for a randomized controlled trial.

BackgroundAfter an initial attack of biliary pancreatitis, cholecystectomy minimizes the risk of recurrent biliary pancreatitis and other gallstone-related complications. Guidelines advocate performing cholecystectomy within 2 to 4 weeks after discharge for mild biliary pancreatitis. During this waiting period, the patient is at risk of recurrent biliary events. In current clinical practice, surgeons usually postpone cholecystectomy for 6 weeks due to a perceived risk of a more difficult dissection in the early days following pancreatitis and for logistical reasons. We hypothesize that early laparoscopic cholecystectomy minimizes the risk of recurrent biliary pancreatitis or other complications of gallstone disease in patients with mild biliary pancreatitis without increasing the difficulty of dissection and the surgical complication rate compared with interval laparoscopic cholecystectomy.Methods/DesignPONCHO is a randomized controlled, parallel-group, assessor-blinded, superiority multicenter trial. Patients are randomly allocated to undergo early laparoscopic cholecystectomy, within 72 hours after randomization, or interval laparoscopic cholecystectomy, 25 to 30 days after randomization. During a 30-month period, 266 patients will be enrolled from 18 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite endpoint of mortality and acute re-admissions for biliary events (that is, recurrent biliary pancreatitis, acute cholecystitis, symptomatic/obstructive choledocholithiasis requiring endoscopic retrograde cholangiopancreaticography including cholangitis (with/without endoscopic sphincterotomy), and uncomplicated biliary colics) occurring within 6 months following randomization. Secondary endpoints include the individual endpoints of the composite endpoint, surgical and other complications, technical difficulty of cholecystectomy and costs.DiscussionThe PONCHO trial is designed to show that early laparoscopic cholecystectomy (within 72 hours) reduces the combined endpoint of mortality and re-admissions for biliary events as compared with interval laparoscopic cholecystectomy (between 25 and 30 days) after recovery of a first episode of mild biliary pancreatitis.Trial registrationCurrent Controlled Trials: ISRCTN72764151

Endoscopic or surgical step-up approach for infected necrotising pancreatitis: a multicentre randomised trial

BACKGROUND Infected necrotising pancreatitis is a potentially lethal disease and an indication for invasive intervention. The surgical step-up approach is the standard treatment. A promising alternative is the endoscopic step-up approach. We compared both approaches to see whether the endoscopic step-up approach was superior to the surgical step-up approach in terms of clinical and economic outcomes. METHODS In this multicentre, randomised, superiority trial, we recruited adult patients with infected necrotising pancreatitis and an indication for invasive intervention from 19 hospitals in the Netherlands. Patients were randomly assigned to either the endoscopic or the surgical step-up approach. The endoscopic approach consisted of endoscopic ultrasound-guided transluminal drainage followed, if necessary, by endoscopic necrosectomy. The surgical approach consisted of percutaneous catheter drainage followed, if necessary, by video-assisted retroperitoneal debridement. The primary endpoint was a composite of major complications or death during 6-month follow-up. Analyses were by intention to treat. This trial is registered with the ISRCTN registry, number ISRCTN09186711. FINDINGS Between Sept 20, 2011, and Jan 29, 2015, we screened 418 patients with pancreatic or extrapancreatic necrosis, of which 98 patients were enrolled and randomly assigned to the endoscopic step-up approach (n=51) or the surgical step-up approach (n=47). The primary endpoint occurred in 22 (43%) of 51 patients in the endoscopy group and in 21 (45%) of 47 patients in the surgery group (risk ratio [RR] 0·97, 95% CI 0·62-1·51; p=0·88). Mortality did not differ between groups (nine [18%] patients in the endoscopy group vs six [13%] patients in the surgery group; RR 1·38, 95% CI 0·53-3·59, p=0·50), nor did any of the major complications included in the primary endpoint. INTERPRETATION In patients with infected necrotising pancreatitis, the endoscopic step-up approach was not superior to the surgical step-up approach in reducing major complications or death. The rate of pancreatic fistulas and length of hospital stay were lower in the endoscopy group. The outcome of this trial will probably result in a shift to the endoscopic step-up approach as treatment preference. FUNDING The Dutch Digestive Disease Foundation, Fonds NutsOhra, and the Netherlands Organization for Health Research and Development.

Alpha glutathione S-transferase as novel parameter for hepatocellular damage in the isolated perfused rat liver

A LPHA glutathione S-transferase (alpha-GST) is a cytosolic enzyme predominantly located in hepatocytes with a uniform distribution in the liver.’ Several clinical and experimental studies have shown that alphaGST is an early and sensitive parameter for hepatocellular membrane damage.2-4 Liver damage during hypothermic &hernia and reperfusion has been demonstrated to occur first at the microvascular level, especially in the sinusoidal endothelial cells (SEC).5 In a previous study from our laboratory it was shown that uptake capacity of exogenous hyaluronic acid (HA) is a sensitive parameter to detect SEC damage during reperfusion of isolated rat livers.6 Parameters of hepatocellular damage, such as release of transaminases, were increased later on in the process of ischemia and reperfusion (I/R).7,8 The aim of this study was to compare release of alpha-GST with the release of conventional enzymes that serve as parameters of hepatocellular injury in isolated perfused rat livers. In literature, a beneficial effect of preflush with an albumin-containing solution of cold-preserved livers prior to reperfusion is suggested. 9-1’ The effect of albumin preflush was therefore studied in reperfusion-induced liver injury.

Impact of a Nationwide Training Program in Minimally Invasive Distal Pancreatectomy (LAELAPS)

Objective: To study the feasibility and impact of a nationwide training program in minimally invasive distal pancreatectomy (MIDP). Summary of Background Data: Superior outcomes of MIDP compared with open distal pancreatectomy have been reported. In the Netherlands (2005 to 2013) only 10% of distal pancreatectomies were in a minimally invasive fashion and 85% of surgeons welcomed MIDP training. The feasibility and impact of a nationwide training program is unknown. Methods: From 2014 to 2015, 32 pancreatic surgeons from 17 centers participated in a nationwide training program in MIDP, including detailed technique description, video training, and proctoring on-site. Outcomes of MIDP before training (2005–2013) were compared with outcomes after training (2014–2015). Results: In total, 201 patients were included; 71 underwent MIDP in 9 years before training versus 130 in 22 months after training (7-fold increase, P < 0.001). The conversion rate (38% [n = 27] vs 8% [n = 11], P < 0.001) and blood loss were lower after training and more pancreatic adenocarcinomas were resected (7 [10%] vs 28 [22%], P = 0.03), with comparable R0-resection rates (4/7 [57%] vs 19/28 [68%], P = 0.67). Clavien-Dindo score ≥III complications (15 [21%] vs 19 [15%], P = 0.24) and pancreatic fistulas (20 [28%] vs 41 [32%], P = 0.62) were not significantly different. Length of hospital stay was shorter after training (9 [7–12] vs 7 [5–8] days, P < 0.001). Thirty-day mortality was 3% vs 0% (P = 0.12). Conclusion: A nationwide MIDP training program was feasible and followed by a steep increase in the use of MIDP, also in patients with pancreatic cancer, and decreased conversion rates. Future studies should determine whether such a training program is applicable in other settings.

Systematic approach of postoperative gastric conduit complications after esophageal resection.

Complications after esophagectomy related to ischemia of the graft are dreaded. Prompt assessment of the situation is essential. The series presented describes our experience regarding the evaluation of gastric tube complications. A score is presented classifying flexible endoscopy and CT-scan findings. A retrospective analysis from the charts of 47 consecutive patients who underwent esophagectomy for cancer was conducted. Patients who underwent upper endoscopy during admittance were entered in this study. Findings on flexible endoscopy and CT scan were systematic scored. According to the findings, different attitudes were taken. Between January 2006 and December 2007, 47 patients underwent esophagectomy for cancer. Eleven (23%) out of 47 patients were suspected to have complications related to the viability of the anastomosis. Median period to deterioration was 5 days. In 3 (27%) patients, stent placement was the only intervention necessary. In 2 (18%) patients, stent placement was combined with drainage of abscesses in the upper mediastinum. Five (46%) patients required a new right thoracotomy, with drainage of mediastinal abscesses and empyema. In 2 patients a limited resection and a new cervical anastomosis with a stent was created. Mean intensive care admission and hospital admittance was 30.2 days and 67.9 days, respectively. Two patients (18%) died during hospital admittance. All cervical anastomosis required postoperative dilatation. No complications related to the use of flexible endoscopy were seen. An aggressive policy is adopted in patients deteriorating following esophagectomy. CT-scanning of the thorax and a flexible endoscopy of the gastric conduit should always be performed. Direct therapy should be adopted without delay.

Continuous or Intermittent Vascular Clamping during Hemihepatectomy in Pigs: Hyaluronic Acid Kinetics in the Assessment of Early Microvascular Liver Damage

OBJECTIVE To assess the uptake of hyaluronic acid (HA) as a marker of microvascular damage in a model of hemihepatectomy in pigs having continuous or intermittent vascular inflow occlusion. DESIGN Prospective, animal study. SETTING Laboratory for experimental surgery, University hospital, The Netherlands. INTERVENTIONS Total liver ischaemia was achieved during 90 minutes by continuous (n = 5) or intermittent (n = 5) occlusion of the portal vein and hepatic artery followed by 120 minutes of reperfusion. In a second series of pigs (n = 8) a left hemihepatectomy was added to the protocol. MAIN OUTCOME MEASURES Uptake of exogenous HA was assessed before ischaemia and after 120 minutes of reperfusion, together with the galactose elimination capacity. Plasma activities of aspartate aminotransferase (AST), alanine amino transferase, and lactate dehydrogenase were measured and specimens of liver were obtained for histopathological examination. RESULTS HA uptake was slightly reduced after reperfusion in unresected livers compared with uptake before ischaemia. After hemihepatectomy HA uptake after reperfusion was significantly reduced after both continuous and intermittent occlusion, but more HA was taken up after continuous occlusion (p = 0.02). Release of AST after reperfusion was increased only after hemihepatectomy. CONCLUSIONS Microvascular damage, as assessed by HA uptake capacity, significantly contributed to normothermic ischaemia and reperfusion injury in porcine liver. Vascular inflow occlusion during 90 minutes in combination with hemihepatectomy resulted in less liver damage when vascular occlusion was continuous rather than intermittent.

Minimally invasive oesophageal resection for distal oesophageal cancer: A review of the literature

Oesophagus resection is adequate treatment for some benign oesophageal diseases, especially caustic and peptic stenosis and end-stage motility dysfunction. However, the most frequent indications for oesophageal resection are the high-grade dysplasia of Barrett oesophagus and non-metastasized oesophageal cancer. Different procedures have been developed for performing oesophageal resection given the 5-year survival rate of only 18% among patients operated on. A disadvantage of the conventional approach is the high morbidity rate, especially with pulmonary complications. Minimally invasive oesophageal resections, which were first performed in 1991, may reduce this important morbidity and preserve the oncologic outcome. The first reports of morbidity and respiratory complications with this approach were disappointing and it seemed likely that the procedure would have to be abandoned. However, in the past 5 years, Japanese groups and the group of Luketich in Pittsburgh have given these techniques an important impetus. The outcomes of the new series are different from those in the beginning period, and are leading to an enormous expansion worldwide. Important factors behind the change are standardization of the operative technique, the experience of many surgeons with more advanced laparoscopic procedures, important improvements in instruments for dissection and division of tissues, a better technique in use of anaesthesia, and a better selection of patients for operation. Two minimally invasive techniques are being perfected: the three-stage operation by right thoracoscopy and laparoscopy, and the transhiatal laparoscopic approach. The former may be applied successfully for any tumour in the oesophagus, whereas the latter seems ideal for distal oesophageal and oesophagogastric junction tumours. This review article discusses all these aspects, giving special attention to indications and operative technique.