Marc G. Besselink

Interventions for Necrotizing Pancreatitis Summary of a Multidisciplinary Consensus Conference

Abstract Pancreatic and peripancreatic necrosis may result in significant morbidity and mortality in patients with acute pancreatitis. Many recommendations have been made for management of necrotizing pancreatitis, but no published guidelines have incorporated the many recent developments in minimally invasive techniques for necrosectomy. Hence, a multidisciplinary conference was convened to develop a consensus on interventions for necrotizing pancreatitis. Participants included most international experts from multiple disciplines. The evidence for efficacy of interventions was reviewed, presentations were given by experts, and a consensus was reached on each topic. In summary, intervention is primarily indicated for infected necrosis, less often for symptomatic sterile necrosis, and should ideally be delayed as long as possible, preferably 4 weeks or longer after the onset of disease, for better demarcation and liquefaction of the necrosis. Both the step-up approach using percutaneous drainage followed by minimally invasive video-assisted retroperitoneal debridement and per-oral endoscopic necrosectomy have been shown to have superior outcomes to traditional open necrosectomy with respect to short-term and long-term morbidity and are emerging as treatments of choice. Applicability of these techniques depends on the availability of specialized expertise and a multidisciplinary team dedicated to the management of severe acute pancreatitis and its complications.

Transluminal endoscopic step-up approach versus minimally invasive surgical step-up approach in patients with infected necrotising pancreatitis (TENSION trial): design and rationale of a randomised controlled multicenter trial [ISRCTN09186711]

BackgroundInfected necrotising pancreatitis is a potentially lethal disease that nearly always requires intervention. Traditionally, primary open necrosectomy has been the treatment of choice. In recent years, the surgical step-up approach, consisting of percutaneous catheter drainage followed, if necessary, by (minimally invasive) surgical necrosectomy has become the standard of care. A promising minimally invasive alternative is the endoscopic transluminal step-up approach. This approach consists of endoscopic transluminal drainage followed, if necessary, by endoscopic transluminal necrosectomy. We hypothesise that the less invasive endoscopic step-up approach is superior to the surgical step-up approach in terms of clinical and economic outcomes.Methods/DesignThe TENSION trial is a randomised controlled, parallel-group superiority multicenter trial. Patients with (suspected) infected necrotising pancreatitis with an indication for intervention and in whom both treatment modalities are deemed possible, will be randomised to either an endoscopic transluminal or a surgical step-up approach. During a 4xa0year study period, 98 patients will be enrolled from 24 hospitals of the Dutch Pancreatitis Study Group. The primary endpoint is a composite of death and major complications within 6xa0months following randomisation. Secondary endpoints include complications such as pancreaticocutaneous fistula, exocrine or endocrine pancreatic insufficiency, need for additional radiological, endoscopic or surgical intervention, the need for necrosectomy after drainage, the number of (re-)interventions, quality of life, and total direct and indirect costs.DiscussionThe TENSION trial will answer the question whether an endoscopic step-up approach reduces the combined primary endpoint of death and major complications, as well as hospital stay and related costs compared with a surgical step-up approach in patients with infected necrotising pancreatitis.

Laparoscopic pancreatic surgery for benign and malignant disease

Laparoscopic surgery for benign and malignant pancreatic lesions has slowly been gaining acceptance over the past decade and is being introduced in many centres. Some studies suggest that this approach is equivalent to or better than open surgery, but randomized data are needed to assess outcomes. In this Review, we aim to provide a comprehensive overview of the state of the art in laparoscopic pancreatic surgery by aggregating high-quality published evidence. Various aspects, including the benefits, limitations, oncological efficacy, learning curve and latest innovations, are discussed. The focus is on laparoscopic Whipple procedure and laparoscopic distal pancreatectomy for both benign and malignant disease, but robot-assisted surgery is also addressed. Surgical and oncological outcomes are discussed as well as quality of life parameters and the cost efficiency of laparoscopic pancreatic surgery. We have also included decision-aid algorithms based on the literature and our own expertise; these algorithms can assist in the decision to perform a laparoscopic or open procedure.

Pancreatic anastomosis after pancreatoduodenectomy: A position statement by the International Study Group of Pancreatic Surgery (ISGPS).

Background. Clinically relevant postoperative pancreatic fistula (grades B and C of the ISGPS definition) remains the most troublesome complication after pancreatoduodenectomy. The approach to management of the pancreatic remnant via some form of pancreatico‐enteric anastomosis determines the incidence and severity of clinically relevant postoperative pancreatic fistula. Despite numerous trials comparing diverse pancreatico‐enteric anastomosis techniques and other adjunctive strategies (pancreatic duct stenting, somatostatin analogues, etc), currently, there is no clear consensus regarding the ideal method of pancreatico‐enteric anastomosis. Methods. An international panel of pancreatic surgeons working in well‐known, high‐volume centers reviewed the best contemporary literature concerning pancreatico‐enteric anastomosis and worked to develop a position statement on pancreatic anastomosis after pancreatoduodenectomy. Results. There is inherent risk assumed by creating a pancreatico‐enteric anastomosis based on factors related to the gland (eg, parenchymal texture, disease pathology). None of the technical variations of pancreaticojejunal or pancreaticogastric anastomosis, such as duct‐mucosa, invagination method, and binding technique, have been found to be consistently superior to another. Randomized trials and meta‐analyses comparing pancreaticogastrostomy versus pancreaticojejunostomy yield conflicting results and are inherently prone to bias due to marked heterogeneity in the studies. The benefit of stenting the pancreatico‐enteric anastomosis to decrease clinically relevant postoperative pancreatic fistula is not supported by high‐level evidence. While controversial, somatostatin analogues appear to decrease perioperative complications but not mortality, although consistent data across the more than 20 studies addressing this topic are lacking. The Fistula Risk Score is useful for predicting postoperative pancreatic fistula as well as for comparing outcomes of pancreatico‐enteric anastomosis across studies. Conclusion. Currently, no specific technique can eliminate development of clinically relevant postoperative pancreatic fistula. While consistent practice of any standardized technique may decrease the rate of clinically relevant postoperative pancreatic fistula, experienced surgeons can have lower postoperative pancreatic fistula rates performing a variety of techniques depending on the clinical situation. There is no clear evidence on the benefit of internal or external stenting after pancreatico‐enteric anastomosis. The use of somatostatin analogues may be important in decreasing morbidity after pancreatoduodenectomy, but it remains controversial. Future studies should focus on novel approaches to decrease the rate of clinically relevant postoperative pancreatic fistula with appropriate risk adjustment.

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

BACKGROUNDnInfected 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.nnnMETHODSnIn 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.nnnFINDINGSnBetween 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.nnnINTERPRETATIONnIn 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.nnnFUNDINGnThe Dutch Digestive Disease Foundation, Fonds NutsOhra, and the Netherlands Organization for Health Research and Development.

Trends in worldwide volume and methodological quality of surgical randomized controlled trials

Objective: To assess worldwide trends in volume and methodological quality of published surgical randomized controlled trials (RCTs) over the past decade. Background: Randomized controlled trials are essential for clinical decision making. It has repeatedly been suggested that surgical RCTs are scarce and of mediocre quality. Methods: We systematically searched PubMed for surgical RCTs published in 1999 and 2009. Characteristics and risks of bias were extracted. Trials where compared between study years and geographical regions. Primary outcome was “low risk of bias,” defined by all of the following: adequate allocation generation and concealment, intention-to-treat analysis, and adequate dropout handling. Results: The volume of published surgical RCTs increased by 50%, from 300 in 1999 to 450 in 2009. Volume increased in Europe (27% increase), Asia/Oceania (160% increase), and Africa/South America (416% increase) but decreased in North America (23% decrease), although the United States remained the country with the highest number of published RCTs. In 2009, methodological quality of surgical trials improved in terms of sample size calculation, adequate generation of randomization sequence, concealment of randomization sequence, and use of intention-to-treat analysis as compared with 1999 (P < 0.001 for all). The proportion of low risk of bias trials increased from 6% to 14% (prevalence ratio 2.59; 95% confidence interval 1.55–4.32). In 2009, the highest proportion of low risk of bias trials was from Europe (23%), whereas the lowest was from Asia/Oceania (5%). Conclusions: Volume and quality of surgical RCTs improved although striking differences exist between continents and countries. Structured education in trial methodology, enforced adherence to existing guidelines, and improved research infrastructure may guide further improvements.

Training in Minimally Invasive Pancreatic Resections: A paradigm shift away from "See one, Do one, Teach one"

BACKGROUNDnIncreased incorporation of minimally invasive pancreatic resections (MIPR) has emerged into hepato-pancreato-biliary practice, however, no standardization exists for its safe adoption. Novel strategies are presented for dissemination of safe MIPR.nnnMETHODSnAn international State-of-the-Art conference evaluating multiple aspects of MIPR was conducted by a panel of pancreas experts in Sao Paulo, Brazil on April 20, 2016. Training and education issues were discussed regarding the introduction of novel strategies for safe dissemination of MIPR.nnnRESULTSnThe low volume of pancreatic resections per institution poses a challenge for surgeons to overcome their MIPR learning curve without deliberate training. A mastery-based simulation and biotissue curriculum can improve technical proficiency and allow for training of surgeons before the operating room. Video-based platforms allow for performance reporting and feedback necessary for coaching and surgical quality improvement. Centers of excellence with training involving a standardized approach and proctorship are important concepts that can be utilized in various formats internationally.nnnDISCUSSIONnSurgical volume is not sufficient to ensure quality and patient safety in MIPR. Safe adoption of these complex procedures should consider innovative mastery-based training outside of the operating room, novel video based coaching techniques and prospective reporting of patient data and outcomes using standardized definitions.

Definition and classification of chyle leak after pancreatic operation: A consensus statement by the International Study Group on Pancreatic Surgery.

BACKGROUND Recent literature suggests that chyle leak may complicate up to 10% of pancreatic resections. Treatment depends on its severity, which may include chylous ascites. No international consensus definition or grading system of chyle leak currently is available. METHODS The International Study Group on Pancreatic Surgery, an international panel of pancreatic surgeons working in well‐known, high‐volume centers, reviewed the literature and worked together to establish a consensus on the definition and classification of chyle leak after pancreatic operation. RESULTS Chyle leak was defined as output of milky‐colored fluid from a drain, drain site, or wound on or after postoperative day 3, with a triglyceride content ≥110 mg/dL (≥1.2 mmol/L). Three different grades of severity were defined according to the management needed: grade A, no specific intervention other than oral dietary restrictions; grade B, prolongation of hospital stay, nasoenteral nutrition with dietary restriction, total parenteral nutrition, octreotide, maintenance of surgical drains, or placement of new percutaneous drains; and grade C, need for other more invasive in‐hospital treatment, intensive care unit admission, or mortality. CONCLUSION This classification and grading system for chyle leak after pancreatic resection allows for comparison of outcomes between series. As with the other the International Study Group on Pancreatic Surgery consensus statements, this classification should facilitate communication and evaluation of different approaches to the prevention and treatment of this complication.

Irreversible electroporation in locally advanced pancreatic cancer: A call for standardization of energy delivery

Irreversible Electroporation (IRE) is used to treat locally advanced cancers, commonly of the pancreas, liver, kidney, and other soft tissues. Precise eligibility for IRE should be established in each individual patient by a multidisciplinary team based on comprehensive clinical, imaging, and laboratory assessment. Standardization of IRE technique and protocols is expected to improve safety, lead to reproducible outcomes, and facilitate further research into IRE. The present article provides a set of technical recommendations for the use of IRE in the treatment of locally advanced pancreatic cancer. J. Surg. Oncol. 2016;114:865–871.

Proceedings of the first international state-of-the-art conference on minimally-invasive pancreatic resection (MIPR)

The application of minimally-invasive techniques to major pancreatic resection (MIPR) has occurred steadily, but slowly, over the last two decades. Questions linger regarding its safety, efficacy, and broad applicability. On April 20th, 2016, the first International State-of-the-Art Conference on Minimally Invasive Pancreatic Resection convened in Sao Paulo, Brazil in conjunction with the International Hepato-Pancreato-Biliary Associations (IHPBA) 10th World Congress. This report describes the genesis, preparation, execution and output from this seminal event. Major themes explored include: (i) scrutiny of best-level evidence outcomes of both MIPR Distal Pancreatectomy (DP) and pancreatoduodenectomy (PD), (ii) Cost/Value/Quality of Life assessment of MIPR, (iii) topics in training, education and credentialing, and (iv) development of best approaches to analyze results of MIPR - including clinical trial design and registry development. Results of a worldwide survey of over 400 surgeons on the practice of MIPR were presented. The proceedings of this event serve as a platform for understanding the role of MIPR in pancreatic resection. Data and concepts presented at this meeting form the basis for further study, application and dissemination of MIPR.