Claudio Bassi

In Brief Background and Aims: The lack of consensus on how to define and grade adverse postoperative events has greatly hampered the evaluation of surgical procedures. A new classification of complications, initiated in 1992, was updated 5 years ago. It is based on the type of therapy needed to correct the complication. The principle of the classification was to be simple, reproducible, flexible, and applicable irrespective of the cultural background. The aim of the current study was to critically evaluate this classification from the perspective of its use in the literature, by assessing interobserver variability in grading complex complication scenarios and to correlate the classification grades with patients', nurses', and doctors’ perception. Material and Methods: Reports from the literature using the classification system were systematically analyzed. Next, 11 scenarios illustrating difficult cases were prepared to develop a consensus on how to rank the various complications. Third, 7 centers from different continents, having routinely used the classification, independently assessed the 11 scenarios. An agreement analysis was performed to test the accuracy and reliability of the classification. Finally, the perception of the severity was tested in patients, nurses, and physicians by presenting 30 scenarios, each illustrating a specific grade of complication. Results: We noted a dramatic increase in the use of the classification in many fields of surgery. About half of the studies used the contracted form, whereas the rest used the full range of grading. Two-thirds of the publications avoided subjective terms such as minor or major complications. The study of 11 difficult cases among various centers revealed a high degree of agreement in identifying and ranking complications (89% agreement), and enabled a better definition of unclear situations. Each grade of complications significantly correlated with the perception by patients, nurses, and physicians (P < 0.05, Kruskal-Wallis test). Conclusions: This 5-year evaluation provides strong evidence that the classification is valid and applicable worldwide in many fields of surgery. No modification in the general principle of classification is warranted in view of the use in ongoing publications and trials. Subjective, inaccurate, or confusing terms such as “minor or major” should be removed from the surgical literature. A critical appraisal 5 years after introducing a new system to rank postoperative complications has shown a rapid and wide acceptance in the literature. To further support the use of this system, we documented an excellent correlation between the various grades of severity and perception by patients and health care providers, and obtained consensus among experts to rank difficult cases. The grades are sufficiently self explanatory that subjective terms such as minor and major complications should be avoided.

Background Postoperative pancreatic fistula (POPF) is still regarded as a major complication. The incidence of POPF varies greatly in different reports, depending on the definition applied at each surgical center. Our aim was to agree upon an objective and internationally accepted definition to allow comparison of different surgical experiences. Methods An international panel of pancreatic surgeons, working in well-known, high-volume centers, reviewed the literature on the topic and worked together to develop a simple, objective, reliable, and easy-to-apply definition of POPF, graded primarily on clinical impact. Results A POPF represents a failure of healing/sealing of a pancreatic-enteric anastomosis or a parenchymal leak not directly related to an anastomosis. An all-inclusive definition is a drain output of any measurable volume of fluid on or after postoperative day 3 with an amylase content greater than 3 times the serum amylase activity. Three different grades of POPF (grades A, B, C) are defined according to the clinical impact on the patient's hospital course. Conclusions The present definition and clinical grading of POPF should allow realistic comparisons of surgical experiences in the future when new techniques, new operations, or new pharmacologic agents that may impact surgical treatment of pancreatic disorders are addressed. Postoperative pancreatic fistula (POPF) is still regarded as a major complication. The incidence of POPF varies greatly in different reports, depending on the definition applied at each surgical center. Our aim was to agree upon an objective and internationally accepted definition to allow comparison of different surgical experiences. An international panel of pancreatic surgeons, working in well-known, high-volume centers, reviewed the literature on the topic and worked together to develop a simple, objective, reliable, and easy-to-apply definition of POPF, graded primarily on clinical impact. A POPF represents a failure of healing/sealing of a pancreatic-enteric anastomosis or a parenchymal leak not directly related to an anastomosis. An all-inclusive definition is a drain output of any measurable volume of fluid on or after postoperative day 3 with an amylase content greater than 3 times the serum amylase activity. Three different grades of POPF (grades A, B, C) are defined according to the clinical impact on the patient's hospital course. The present definition and clinical grading of POPF should allow realistic comparisons of surgical experiences in the future when new techniques, new operations, or new pharmacologic agents that may impact surgical treatment of pancreatic disorders are addressed.

<h3>Background</h3> In 2005, the International Study Group of Pancreatic Fistula developed a definition and grading of postoperative pancreatic fistula that has been accepted universally. Eleven years later, because postoperative pancreatic fistula remains one of the most relevant and harmful complications of pancreatic operation, the International Study Group of Pancreatic Fistula classification has become the gold standard in defining postoperative pancreatic fistula in clinical practice. The aim of the present report is to verify the value of the International Study Group of Pancreatic Fistula definition and grading of postoperative pancreatic fistula and to update the International Study Group of Pancreatic Fistula classification in light of recent evidence that has emerged, as well as to address the lingering controversies about the original definition and grading of postoperative pancreatic fistula. <h3>Methods</h3> The International Study Group of Pancreatic Fistula reconvened as the International Study Group in Pancreatic Surgery in order to perform a review of the recent literature and consequently to update and revise the grading system of postoperative pancreatic fistula. <h3>Results</h3> Based on the literature since 2005 investigating the validity and clinical use of the original International Study Group of Pancreatic Fistula classification, a clinically relevant postoperative pancreatic fistula is now redefined as a drain output of any measurable volume of fluid with an amylase level >3 times the upper limit of institutional normal serum amylase activity, associated with a clinically relevant development/condition related directly to the postoperative pancreatic fistula. Consequently, the former "grade A postoperative pancreatic fistula" is now redefined and called a "biochemical leak," because it has no clinical importance and is no longer referred to a true pancreatic fistula. Postoperative pancreatic fistula grades B and C are confirmed but defined more strictly. In particular, grade B requires a change in the postoperative management; drains are either left in place >3 weeks or repositioned through endoscopic or percutaneous procedures. Grade C postoperative pancreatic fistula refers to those postoperative pancreatic fistula that require reoperation or lead to single or multiple organ failure and/or mortality attributable to the pancreatic fistula. <h3>Conclusion</h3> This new definition and grading system of postoperative pancreatic fistula should lead to a more universally consistent evaluation of operative outcomes after pancreatic operation and will allow for a better comparison of techniques used to mitigate the rate and clinical impact of a pancreatic fistula. Use of this updated classification will also allow for more precise comparisons of surgical quality between surgeons and units who perform pancreatic surgery.

The effect of adjuvant treatment on survival in pancreatic cancer is unclear. We report the final results of the European Study Group for Pancreatic Cancer 1 Trial and update the interim results.In a multicenter trial using a two-by-two factorial design, we randomly assigned 73 patients with resected pancreatic ductal adenocarcinoma to treatment with chemoradiotherapy alone (20 Gy over a two-week period plus fluorouracil), 75 patients to chemotherapy alone (fluorouracil), 72 patients to both chemoradiotherapy and chemotherapy, and 69 patients to observation.The analysis was based on 237 deaths among the 289 patients (82 percent) and a median follow-up of 47 months (interquartile range, 33 to 62). The estimated five-year survival rate was 10 percent among patients assigned to receive chemoradiotherapy and 20 percent among patients who did not receive chemoradiotherapy (P=0.05). The five-year survival rate was 21 percent among patients who received chemotherapy and 8 percent among patients who did not receive chemotherapy (P=0.009). The benefit of chemotherapy persisted after adjustment for major prognostic factors.Adjuvant chemotherapy has a significant survival benefit in patients with resected pancreatic cancer, whereas adjuvant chemoradiotherapy has a deleterious effect on survival.

Delayed gastric emptying (DGE) is one of the most common complications after pancreatic resection. In the literature, the reported incidence of DGE after pancreatic surgery varies considerably between different surgical centers, primarily because an internationally accepted consensus definition of DGE is not available. Several surgical centers use a different definition of DGE. Hence, a valid comparison of different study reports and operative techniques is not possible.After a literature review on DGE after pancreatic resection, the International Study Group of Pancreatic Surgery (ISGPS) developed an objective and generally applicable definition with grades of DGE based primarily on severity and clinical impact.DGE represents the inability to return to a standard diet by the end of the first postoperative week and includes prolonged nasogastric intubation of the patient. Three different grades (A, B, and C) were defined based on the impact on the clinical course and on postoperative management.The proposed definition, which includes a clinical grading of DGE, should allow objective and accurate comparison of the results of future clinical trials and will facilitate the objective evaluation of novel interventions and surgical modalities in the field of pancreatic surgery.

Pancreatic cancer remains one of the most lethal of malignancies and a major health burden. We performed whole-genome sequencing and copy number variation (CNV) analysis of 100 pancreatic ductal adenocarcinomas (PDACs). Chromosomal rearrangements leading to gene disruption were prevalent, affecting genes known to be important in pancreatic cancer (TP53, SMAD4, CDKN2A, ARID1A and ROBO2) and new candidate drivers of pancreatic carcinogenesis (KDM6A and PREX2). Patterns of structural variation (variation in chromosomal structure) classified PDACs into 4 subtypes with potential clinical utility: the subtypes were termed stable, locally rearranged, scattered and unstable. A significant proportion harboured focal amplifications, many of which contained druggable oncogenes (ERBB2, MET, FGFR1, CDK6, PIK3R3 and PIK3CA), but at low individual patient prevalence. Genomic instability co-segregated with inactivation of DNA maintenance genes (BRCA1, BRCA2 or PALB2) and a mutational signature of DNA damage repair deficiency. Of 8 patients who received platinum therapy, 4 of 5 individuals with these measures of defective DNA maintenance responded.

Background Postoperative hemorrhage is one of the most severe complications after pancreatic surgery. Due to the lack of an internationally accepted, universal definition of postpancreatectomy hemorrhage (PPH), the incidences reported in the literature vary considerably, even in reports from randomized controlled trials. Because of these variations in the definition of what constitutes a PPH, the incidences of its occurrence are not comparable. Methods The International Study Group of Pancreatic Surgery (ISGPS) developed an objective, generally applicable definition of PPH based on a literature review and consensus clinical experience. Results Postpancreatectomy hemorrhage is defined by 3 parameters: onset, location, and severity. The onset is either early (≤24 hours after the end of the index operation) or late (>24 hours). The location is either intraluminal or extraluminal. The severity of bleeding may be either mild or severe. Three different grades of PPH (grades A, B, and C) are defined according to the time of onset, site of bleeding, severity, and clinical impact. Conclusions An objective, universally accepted definition and clinical grading of PPH is important for the appropriate management and use of interventions in PPH. Such a definition also would allow comparisons of results from future clinical trials. Such standardized definitions are necessary to compare, in a nonpartisan manner, the outcomes of studies and the evaluation of novel operative treatment modalities in pancreatic surgery. Postoperative hemorrhage is one of the most severe complications after pancreatic surgery. Due to the lack of an internationally accepted, universal definition of postpancreatectomy hemorrhage (PPH), the incidences reported in the literature vary considerably, even in reports from randomized controlled trials. Because of these variations in the definition of what constitutes a PPH, the incidences of its occurrence are not comparable. The International Study Group of Pancreatic Surgery (ISGPS) developed an objective, generally applicable definition of PPH based on a literature review and consensus clinical experience. Postpancreatectomy hemorrhage is defined by 3 parameters: onset, location, and severity. The onset is either early (≤24 hours after the end of the index operation) or late (>24 hours). The location is either intraluminal or extraluminal. The severity of bleeding may be either mild or severe. Three different grades of PPH (grades A, B, and C) are defined according to the time of onset, site of bleeding, severity, and clinical impact. An objective, universally accepted definition and clinical grading of PPH is important for the appropriate management and use of interventions in PPH. Such a definition also would allow comparisons of results from future clinical trials. Such standardized definitions are necessary to compare, in a nonpartisan manner, the outcomes of studies and the evaluation of novel operative treatment modalities in pancreatic surgery.

<h3>Context</h3>Adjuvant fluorouracil has been shown to be of benefit for patients with resected pancreatic cancer. Gemcitabine is known to be the most effective agent in advanced disease as well as an effective agent in patients with resected pancreatic cancer.<h3>Objective</h3>To determine whether fluorouracil or gemcitabine is superior in terms of overall survival as adjuvant treatment following resection of pancreatic cancer.<h3>Design, Setting, and Patients</h3>The European Study Group for Pancreatic Cancer (ESPAC)-3 trial, an open-label, phase 3, randomized controlled trial conducted in 159 pancreatic cancer centers in Europe, Australasia, Japan, and Canada. Included in ESPAC-3 version 2 were 1088 patients with pancreatic ductal adenocarcinoma who had undergone cancer resection; patients were randomized between July 2000 and January 2007 and underwent at least 2 years of follow-up.<h3>Interventions</h3>Patients received either fluorouracil plus folinic acid (folinic acid, 20 mg/m², intravenous bolus injection, followed by fluorouracil, 425 mg/m² intravenous bolus injection given 1-5 days every 28 days) (n = 551) or gemcitabine (1000 mg/m² intravenous infusion once a week for 3 of every 4 weeks) (n = 537) for 6 months.<h3>Main Outcome Measures</h3>Primary outcome measure was overall survival; secondary measures were toxicity, progression-free survival, and quality of life.<h3>Results</h3>Final analysis was carried out on an intention-to-treat basis after a median of 34.2 (interquartile range, 27.1-43.4) months' follow-up after 753 deaths (69%). Median survival was 23.0 (95% confidence interval [CI], 21.1-25.0) months for patients treated with fluorouracil plus folinic acid and 23.6 (95% CI, 21.4-26.4) months for those treated with gemcitabine (χ²₁ = 0.7; P = .39; hazard ratio, 0.94 [95% CI, 0.81-1.08]). Seventy-seven patients (14%) receiving fluorouracil plus folinic acid had 97 treatment-related serious adverse events, compared with 40 patients (7.5%) receiving gemcitabine, who had 52 events (P &lt; .001). There were no significant differences in either progression-free survival or global quality-of-life scores between the treatment groups.<h3>Conclusion</h3>Compared with the use of fluorouracil plus folinic acid, gemcitabine did not result in improved overall survival in patients with completely resected pancreatic cancer.<h3>Trial Registration</h3>clinicaltrials.gov Identifier: NCT00058201

The role of adjuvant treatment in pancreatic cancer remains uncertain. The European Study Group for Pancreatic Cancer (ESPAC) assessed the roles of chemoradiotherapy and chemotherapy in a randomised study.After resection, patients were randomly assigned to adjuvant chemoradiotherapy (20 Gy in ten daily fractions over 2 weeks with 500 mg/m(2) fluorouracil intravenously on days 1-3, repeated after 2 weeks) or chemotherapy (intravenous fluorouracil 425 mg/m(2) and folinic acid 20 mg/m(2) daily for 5 days, monthly for 6 months). Clinicians could randomise patients into a two-by-two factorial design (observation, chemoradiotherapy alone, chemotherapy alone, or both) or into one of the main treatment comparisons (chemoradiotherapy versus no chemoradiotherapy or chemotherapy versus no chemotherapy). The primary endpoint was death, and all analyses were by intention to treat. Findings 541 eligible patients with pancreatic ductal adenocarcinoma were randomised: 285 in the two-by-two factorial design (70 chemoradiotherapy, 74 chemotherapy, 72 both, 69 observation); a further 68 patients were randomly assigned chemoradiotherapy or no chemoradiotherapy and 188 chemotherapy or no chemotherapy. Median follow-up of the 227 (42%) patients still alive was 10 months (range 0-62). Overall results showed no benefit for adjuvant chemoradiotherapy (median survival 15.5 months in 175 patients with chemoradiotherapy vs 16.1 months in 178 patients without; hazard ratio 1.18 [95% CI 0.90-1.55], p=0.24). There was evidence of a survival benefit for adjuvant chemotherapy (median survival 19.7 months in 238 patients with chemotherapy vs 14.0 months in 235 patients without; hazard ratio 0.66 [0.52-0.83], p=0.0005). Interpretation This study showed no survival benefit for adjuvant chemoradiotherapy but revealed a potential benefit for adjuvant chemotherapy, justifying further randomised controlled trials of adjuvant chemotherapy in pancreatic cancer.

This position statement was developed to expedite a consensus on definition and treatment for borderline resectable pancreatic ductal adenocarcinoma (BRPC) that would have worldwide acceptability.An international panel of pancreatic surgeons from well-established, high-volume centers collaborated on a literature review and development of consensus on issues related to borderline resectable pancreatic cancer.The International Study Group of Pancreatic Surgery (ISGPS) supports the National Comprehensive Cancer Network criteria for the definition of BRPC. Current evidence supports operative exploration and resection in the case of involvement of the mesentericoportal venous axis; in addition, a new classification of extrahepatic mesentericoportal venous resections is proposed by the ISGPS. Suspicion of arterial involvement should lead to exploration to confirm the imaging-based findings. Formal arterial resections are not recommended; however, in exceptional circumstances, individual therapeutic approaches may be evaluated under experimental protocols. The ISGPS endorses the recommendations for specimen examination and the definition of an R1 resection (tumor within 1 mm from the margin) used by the British Royal College of Pathologists. Standard preoperative diagnostics for BRPC may include: (1) serum levels of CA19-9, because CA19-9 levels predict survival in large retrospective series; and also (2) the modified Glasgow Prognostic Score and the neutrophil/lymphocyte ratio because of the prognostic relevance of the systemic inflammatory response. Various regimens of neoadjuvant therapy are recommended only in the setting of prospective trials at high-volume centers.Current evidence justifies portomesenteric venous resection in patients with BRPC. Basic definitions were identified, that are currently lacking but that are needed to obtain further evidence and improvement for this important patient subgroup. A consensus for each topic is given.

The diagnosis of pancreatic neuroendocrine tumours (PanNETs) is increasing owing to more sensitive detection methods, and this increase is creating challenges for clinical management. We performed whole-genome sequencing of 102 primary PanNETs and defined the genomic events that characterize their pathogenesis. Here we describe the mutational signatures they harbour, including a deficiency in G:C > T:A base excision repair due to inactivation of MUTYH, which encodes a DNA glycosylase. Clinically sporadic PanNETs contain a larger-than-expected proportion of germline mutations, including previously unreported mutations in the DNA repair genes MUTYH, CHEK2 and BRCA2. Together with mutations in MEN1 and VHL, these mutations occur in 17% of patients. Somatic mutations, including point mutations and gene fusions, were commonly found in genes involved in four main pathways: chromatin remodelling, DNA damage repair, activation of mTOR signalling (including previously undescribed EWSR1 gene fusions), and telomere maintenance. In addition, our gene expression analyses identified a subgroup of tumours associated with hypoxia and HIF signalling. The genomes of 102 primary pancreatic neuroendocrine tumours have been sequenced, revealing mutations in genes with functions such as chromatin remodelling, DNA damage repair, mTOR activation and telomere maintenance, and a greater-than-expected contribution from germ line mutations. Pancreatic neuroendocrine tumours (PanNETs) are the second most common epithelial neoplasm of the pancreas. Aldo Scarpa, Sean Grimmond and colleagues report whole-genome sequencing of 102 primary PanNETs and present analysis of their mutational signatures as part of the International Cancer Genome Consortium. They find frequent mutations in genes with functions that include chromatin remodelling, DNA damage repair, activation of mTOR signalling, and telomere maintenance. They also identify mutational signatures, including one resulting from inactivation of the DNA repair gene MUTYH, and report a larger than expected germline contribution to PanNET development.

In Brief Objective: To describe clinical characteristics and outcomes of a large cohort of intraductal papillary mucinous neoplasms (IPMNs) of the pancreas affecting the main pancreatic duct. Summary Background Data: IPMNs are being diagnosed with increasing frequency. Preoperative determination of malignancy remains problematic, and reported results of long-term survival following resection are conflicting. Methods: The combined databases from the Massachusetts General Hospital and the Pancreatic Unit of the University of Verona were analyzed. To avoid confusing overlap with mucinous cystic neoplasms, only patients with tumors of the main pancreatic duct (with or without side branch involvement) were included. A total of 140 tumors consecutively resected between 1990 and 2002 were classified as either benign (adenoma and borderline tumors) or malignant (carcinoma in situ or invasive cancer) to compare their characteristics and survival. Results: Men and women were equally affected (mean age 65 years). Seven patients (12%) had adenomas, 40 (28%) borderline tumors, 25 (18%) carcinoma in situ, and 58 (42%) invasive carcinoma. The median age of patients with benign IPMN was 6.4 years younger than those with malignant tumors (P = 0.04). The principal symptoms were abdominal pain (65%), weight loss (44%), acute pancreatitis (23%), jaundice (17%), and onset or worsening of diabetes (12%); 27% of patients were asymptomatic. Jaundice and diabetes were significantly associated with malignant tumors. Five- and 10-year cancer-specific survival for patients with noninvasive tumors was 100%, and comparable survival of the 58 patients with invasive carcinoma was 60% and 50%. Conclusions: Cancer is found in 60% of patients with main-duct IPMNs. Patients with malignant tumors are 6 years older than their benign counterparts and have a higher likelihood of presenting with jaundice or new onset diabetes. No patients with benign tumors or carcinoma in situ died of their disease following resection, and those with invasive cancer had a markedly better survival (60% at 5 years) than pancreatic ductal adenocarcinoma. These findings support both the concept of progression of benign IPMNs to invasive cancer and an aggressive policy of resection at diagnosis. Sixty percent of resected main-duct intraductal papillary mucinous neoplasms of the pancreas harbor either carcinoma in situ or invasive cancer. Compared with patients with benign tumors, these patients are older and have a higher likelihood of presenting with jaundice or diabetes, but 29% of them are asymptomatic. Resection can be done safely and long-term survival is excellent, with a low likelihood of recurrence in the remaining pancreas.

Screening individuals at increased risk for pancreatic cancer (PC) detects early, potentially curable, pancreatic neoplasia.To develop consortium statements on screening, surveillance and management of high-risk individuals with an inherited predisposition to PC.A 49-expert multidisciplinary international consortium met to discuss pancreatic screening and vote on statements. Consensus was considered reached if ≥ 75% agreed or disagreed.There was excellent agreement that, to be successful, a screening programme should detect and treat T1N0M0 margin-negative PC and high-grade dysplastic precursor lesions (pancreatic intraepithelial neoplasia and intraductal papillary mucinous neoplasm). It was agreed that the following were candidates for screening: first-degree relatives (FDRs) of patients with PC from a familial PC kindred with at least two affected FDRs; patients with Peutz-Jeghers syndrome; and p16, BRCA2 and hereditary non-polyposis colorectal cancer (HNPCC) mutation carriers with ≥ 1 affected FDR. Consensus was not reached for the age to initiate screening or stop surveillance. It was agreed that initial screening should include endoscopic ultrasonography (EUS) and/or MRI/magnetic resonance cholangiopancreatography not CT or endoscopic retrograde cholangiopancreatography. There was no consensus on the need for EUS fine-needle aspiration to evaluate cysts. There was disagreement on optimal screening modalities and intervals for follow-up imaging. When surgery is recommended it should be performed at a high-volume centre. There was great disagreement as to which screening abnormalities were of sufficient concern to for surgery to be recommended.Screening is recommended for high-risk individuals, but more evidence is needed, particularly for how to manage patients with detected lesions. Screening and subsequent management should take place at high-volume centres with multidisciplinary teams, preferably within research protocols.

The clinicopathological features of 56 patients with mucinous cystic tumors (MCTs) of the pancreas were studied. Particular attention was paid to the prognosis of MCTs and the relationship to their ovarian, hepatic, and retroperitoneal counterparts. To distinguish MCTs from pancreatic intraductal papillary-mucinous tumors, MCTs were defined as tumors lacking communication with the duct system and containing mucin-producing epithelium, usually supported by ovarian-like stroma. All 56 tumors occurred in women (mean age 48.2 years) and were preferentially (93%) located in the body and tail of the pancreas. In accordance with the WHO classification, MCTs were divided into adenomas (n = 22), borderline tumors (n= 12), and noninvasive and invasive carcinomas (n = 22). Survival analysis revealed the extent of invasion to be the most significant prognostic factor (p<0.0001). Malignancy correlated with multilocularity and presence of papillary projections or mural nodules, loss of ovarian-like stroma, and p53 immunoreactivity. Stromal luteinization with expression of tyrosine hydroxylase, calretinin, or alpha inhibin was found in 66% of the cases. We conclude that the biologic behavior of MCTs is predictable on the basis of the extent of invasion. The similarities (i.e. gender, morphology, stromal luteinization) between pancreatic MCT and its ovarian, hepatobiliary, and retroperitoneal counterparts suggest a common pathway for their development.

To assess the influence of resection margins on survival for patients with resected pancreatic cancer treated within the context of the adjuvant European Study Group for Pancreatic Cancer-1 (ESPAC-1) study.Pancreatic cancer is associated with a poor long-term survival rate of only 10% to 15% after resection. Patients with positive microscopic resection margins (R1) have a worse survival, but it is not known how they fare in adjuvant studies.ESPAC-1, the largest randomized adjuvant study of resectable pancreatic cancer ever performed, set out to look at the roles of chemoradiation and chemotherapy. Randomization was stratified prospectively by resection margin status.Of 541 patients with a median follow-up of 10 months, 101 (19%) had R1 resections. Resection margin status was confirmed as an influential prognostic factor, with a median survival of 10.9 months for R1 versus 16.9 months months for patients with R0 margins. Resection margin status remained an independent factor in a Cox proportional hazards model only in the absence of tumor grade and nodal status. There was a survival benefit for chemotherapy but not chemoradiation, irrespective of R0/R1 status. The median survival was 19.7 months with chemotherapy versus 14.0 months without. For patients with R0 margins, chemotherapy produced longer survival compared with to no chemotherapy. This difference was less apparent for the smaller subgroup of R1 patients, but there was no significant heterogeneity between the R0 and R1 groups.Resection margin-positive pancreatic tumors represent a biologically more aggressive cancer; these patients benefit from resection and adjuvant chemotherapy but not chemoradiation. The magnitude of benefit for chemotherapy treatment is reduced for patients with R1 margins versus those with R0 margins. Patients with R1 tumors should be included in future trials of adjuvant treatments and randomization and analysis should be stratified by this significant prognostic factor.

The lymph node (Ln) status of patients with resectable pancreatic ductal adenocarcinoma is an important predictor of survival. The survival benefit of extended lymphadenectomy during pancreatectomy is, however, disputed, and there is no true definition of the optimal extent of the lymphadenectomy. The aim of this study was to formulate a definition for standard lymphadenectomy during pancreatectomy.During a consensus meeting of the International Study Group on Pancreatic Surgery, pancreatic surgeons formulated a consensus statement based on available literature and their experience.The nomenclature of the Japanese Pancreas Society was accepted by all participants. Extended lymphadenectomy during pancreatoduodenectomy with resection of Ln's along the left side of the superior mesenteric artery (SMA) and around the celiac trunk, splenic artery, or left gastric artery showed no survival benefit compared with a standard lymphadenectomy. No level I evidence was available on prognostic impact of positive para-aortic Ln's. Consensus was reached on selectively removing suspected Ln's outside the resection area for frozen section. No consensus was reached on continuing or terminating resection in cases where these nodes were positive.Extended lymphadenectomy cannot be recommended. Standard lymphadenectomy for pancreatoduodenectomy should strive to resect Ln stations no. 5, 6, 8a, 12b1, 12b2, 12c, 13a, 13b, 14a, 14b, 17a, and 17b. For cancers of the body and tail of the pancreas, removal of stations 10, 11, and 18 is standard. Furthermore, lymphadenectomy is important for adequate nodal staging. Both pancreatic resection in relatively fit patients or nonresectional palliative treatment were accepted as acceptable treatment in cases of positive Ln's outside the resection plane. This consensus statement could serve as a guide for surgeons and researchers in future directives and new clinical studies.

This statement was developed to promote international consensus on the definition of borderline resectable pancreatic ductal adenocarcinoma (BR-PDAC) which was adopted by the National Comprehensive Cancer Network (NCCN) in 2006, but which has changed yearly and become more complicated. Based on a symposium held during the 20th meeting of the International Association of Pancreatology (IAP) in Sendai, Japan, in 2016, the presenters sought consensus on issues related to BR-PDAC. We defined patients with BR-PDAC according to the three distinct dimensions: anatomical (A), biological (B), and conditional (C). Anatomic factors include tumor contact with the superior mesenteric artery and/or celiac artery of less than 180° without showing stenosis or deformity, tumor contact with the common hepatic artery without showing tumor contact with the proper hepatic artery and/or celiac artery, and tumor contact with the superior mesenteric vein and/or portal vein including bilateral narrowing or occlusion without extending beyond the inferior border of the duodenum. Biological factors include potentially resectable disease based on anatomic criteria but with clinical findings suspicious for (but unproven) distant metastases or regional lymph nodes metastases diagnosed by biopsy or positron emission tomography-computed tomography. This also includes a serum carbohydrate antigen (CA) 19–9 level more than 500 units/ml. Conditional factors include the patients with potentially resectable disease based on anatomic and biologic criteria and with Eastern Cooperative Oncology Group (ECOG) performance status of 2 or more. The definition of BR-PDAC requires one or more positive dimensions (e.g. A, B, C, AB, AC, BC or ABC). The present definition acknowledges that resectability is not just about the anatomic relationship between the tumor and vessels, but that biological and conditional dimensions are also important. The aim in presenting this consensus definition is also to highlight issues which remain controversial and require further research.

(1) Mild acute pancreatitis is not an indication for pancreatic surgery. (2) The use of prophylactic broad-spectrum antibiotics reduces infection rates in computed tomography-proven necrotizing pancreatitis but may not improve survival. (3) Fine-needle aspiration for bacteriology should be performed to differentiate between sterile and infected pancreatic necrosis in patients with sepsis syndrome. (4) Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention including surgery and radiological drainage. (5) Patients with sterile pancreatic necrosis (with negative fine-needle aspiration for bacteriology) should be managed conservatively and only undergo intervention in selected cases. (6) Early surgery within 14 days after onset of the disease is not recommended in patients with necrotizing pancreatitis unless there are specific indications. (7) Surgical and other forms of interventional management should favor an organ-preserving approach, which involves de-bridement or necrosectomy combined with a postoperative management concept that maximizes postoperative evacuation of retroperitoneal debris and exudate. (8) Cholecystectomy should be performed to avoid recurrence of gallstone-associated acute pancreatitis. (9) In mild gallstone-associated acute pancreatitis, cholecys-tectomy should be performed as soon as the patient has recovered and ideally during the same hospital admission. (10) In severe gallstone-associated acute pancreatitis, cholecystectomy should be delayed until there is sufficient resolution of the inflammatory response and clinical recovery. (11) Endoscopic sphincterotomy is an alternative to cholecystectomy in those who are not fit to undergo surgery in order to lower the risk of recurrence of gallstone-associated acute pancreatitis. There is however a theoretical risk of introducing infection into sterile pancreatic necrosis. These guidelines should now form the basis for audit studies in order to determine the quality of patient care delivery.

In Brief Objective: Mucinous cystic neoplasms (MCNs) of the pancreas have often been confused with intraductal papillary mucinous neoplasms. We evaluated the clinicopathologic characteristics, prevalence of cancer, and prognosis of a large series of well-characterized MCNs in 2 tertiary centers. Methods: Analysis of 163 patients with resected MCNs, defined by the presence of ovarian stroma and lack of communication with the main pancreatic duct. Results: MCNs were seen mostly in women (95%) and in the distal pancreas (97%); 25% were incidentally discovered. Symptomatic patients typically had mild abdominal pain, but 9% presented with acute pancreatitis. One hundred eighteen patients (72%) had adenoma, 17 (10.5%) borderline tumors, 9 (5.5%) in situ carcinoma, and 19 (12%) invasive carcinoma. Patients with invasive carcinoma were significantly older than those with noninvasive neoplasms (55 vs. 44 years, P = 0.01). Findings associated with malignancy were presence of nodules (P = 0.0001) and diameter ≥60 mm (P = 0.0001). All neoplasms with cancer were either ≥40 mm in size or had nodules. There was no operative mortality and postoperative morbidity was 49%. Median follow-up was 57 months (range, 4–233); only patients with invasive carcinoma had recurrence. The 5-year disease-specific survival for noninvasive MCNs was 100%, and for those with invasive cancer, 57%. Conclusions: This series, the largest with MCNs defined by ovarian stroma, shows a prevalence of cancer of only 17.5%. Patients with invasive carcinoma are older, suggesting progression from adenoma to carcinoma. Although resection should be considered for all cases, in low-risk MCNs (≤4 cm/no nodules), nonradical resections are appropriate. The clinicopathologic characteristics and survival in 163 patients affected by mucinous cystic neoplasms (MCNs) defined by ovarian stroma were evaluated. Prevalence of invasive cancer was only 12%, and these patients were significantly older, had larger tumors, and had a higher prevalence of nodules. Five-year disease-specific survival was 100% and 57% for noninvasive and invasive MCNs, respectively. Surgery should be considered for all cases, but in low-risk MCNs (≤ 4 cm/no nodules), nonradical resections are appropriate.

The role of surgically placed intra-abdominal drainages after pancreatic resections has not been clearly established. In particular, their effect on morbidity rates and the optimal timing for their removal remains controversial.A total of 114 eligible patients who underwent standard pancreatic resections and at low risk of postoperative pancreatic fistula according to our institutional protocol (amylase value in drains < or =5000 U/L on postoperative day [POD] 1) were randomized on POD 3 to receive either early (POD 3) or standard drain removal (POD 5 or beyond). The primary end point of the study was the incidence of pancreatic fistula. Secondary endpoints included abdominal complications, pulmonary complications, in-hospital stay, and perioperative mortality. Cost-analysis between the 2 groups was also made.Early drain removal was associated with a decreased rate of pancreatic fistula (P = 0.0001), abdominal complications (P = 0.002), and pulmonary complications (P = 0.007). Median in-hospital stay was shorter (P = 0.018), and hospital costs decreased (P = 0.02). Mortality was nil. A significant association with pancreatic fistula was found for timing of drain removal (P < 0.001), unintentional weight decrease before surgery (P = 0.022), type of pancreas texture (P = 0.015), serum amylase levels on POD 1 (P = 0.001), and albumin levels on POD 1 (P = 0.039). Multivariate analysis showed that timing of drain removal (P = 0.0003) and unintentional weight decrease before surgery (P = 0.02) were independent risk factors of pancreatic fistula.In patients at low risk of pancreatic fistula, intra-abdominal drains can be safely removed on POD 3 after standard pancreatic resections. A prolonged period of drain insertion is associated with a higher rate of postoperative complications with increased hospital stay and costs. The manuscript is a randomized trial, registered in the NLM database as NCT00931554.

(1) Mild acute pancreatitis is not an indication for pancreatic surgery. (2) The use of prophylactic broad-spectrum antibiotics reduces infection rates in computed tomography-proven necrotizing pancreatitis but may not improve survival. (3) Fine-needle aspiration for bacteriology should be performed to differentiate between sterile and infected pancreatic necrosis in patients with sepsis syndrome. (4) Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention including surgery and radiological drainage. (5) Patients with sterile pancreatic necrosis (with negative fine-needle aspiration for bacteriology) should be managed conservatively and only undergo intervention in selected cases. (6) Early surgery within 14 days after onset of the disease is not recommended in patients with necrotizing pancreatitis unless there are specific indications. (7) Surgical and other forms of interventional management should favor an organ-preserving approach, which involves de-bridement or necrosectomy combined with a postoperative management concept that maximizes postoperative evacuation of retroperitoneal debris and exudate. (8) Cholecystectomy should be performed to avoid recurrence of gallstone-associated acute pancreatitis. (9) In mild gallstone-associated acute pancreatitis, cholecys-tectomy should be performed as soon as the patient has recovered and ideally during the same hospital admission. (10) In severe gallstone-associated acute pancreatitis, cholecystectomy should be delayed until there is sufficient resolution of the inflammatory response and clinical recovery. (11) Endoscopic sphincterotomy is an alternative to cholecystectomy in those who are not fit to undergo surgery in order to lower the risk of recurrence of gallstone-associated acute pancreatitis. There is however a theoretical risk of introducing infection into sterile pancreatic necrosis. These guidelines should now form the basis for audit studies in order to determine the quality of patient care delivery.

Intraductal papillary mucinous neoplasms (IPMNs) of the pancreas arising in branch ducts are thought to be less aggressive than their main-duct counterparts, and guidelines for their conservative management were recently proposed. This study describes the combined experience of 2 tertiary centers with branch-duct IPMNs aiming to validate these recommendations.A review of 145 patients with resected, pathologically confirmed, branch-duct IPMNs between 1990 and 2005 was conducted.Sixty-six patients (45.5%) had adenoma, 47 (32%) borderline tumors, 16 (11%) carcinoma in situ, and 16 (11%) invasive carcinoma. Median age was similar between benign and malignant subgroups (66 vs 67.5 years, respectively). Jaundice was more frequent in patients with cancer (12.5% vs 1.8%, respectively, P = .022) and abdominal pain in patients with benign tumors (45% vs 25%, respectively, P = .025). Forty percent of tumors were discovered incidentally. Findings associated with malignancy were the presence of a thick wall (P < .001), nodules (P < .001), and tumor diameter >or=30 mm (P < .001). All neoplasms with cancer were larger than 30 mm in size or had nodules or caused symptoms. After a mean follow-up of 45 months, the 5-year disease-specific survival for branch-duct IPMNs with noninvasive neoplasms was 100% and, for invasive cancer, was 63%.This large cohort of resected branch-duct IPMNs shows that cancer is present in 22% of cases and validates the recent guidelines that indicate absence of malignancy in tumors <30 mm, without symptoms or mural nodules.

To compare the results of pancreaticogastrostomy versus pancreaticojejunostomy following pancreaticoduodenectomy in a prospective and randomized setting.While several techniques have been proposed for reconstructing pancreatico-digestive continuity, only a limited number of randomized studies have been carried out.A total of 151 patients undergoing pancreaticoduodenectomy with soft residual tissue were randomized to receive either pancreaticogastrostomy (group PG) or end-to-side pancreaticojejunostomy (group PJ).The 2 treatment groups showed no differences in vital statistics or underlying disease, mean duration of surgery, and need for intraoperative blood transfusion. Overall, the incidence of surgical complications was 34% (29% in PG, 39% in PJ, P = not significant). Patients receiving PG showed a significantly lower rate of multiple surgical complications (P = 0.002). Pancreatic fistula was the most frequent complication, occurring in 14.5% of patients (13% in PG and 16% in PJ, P = not significant). Five patients in each treatment arm required a second surgical intervention; the postoperative mortality rate was 0.6%. PG was favored over PJ due to significant differences in postoperative collections (P = 0.01), delayed gastric emptying (P = 0.03), and biliary fistula (P = 0.01). The mean postoperative hospitalization period stay was comparable in both groups.When compared with PJ, PG did not show any significant differences in the overall postoperative complication rate or incidence of pancreatic fistula. However, biliary fistula, postoperative collections and delayed gastric emptying are significantly reduced in patients treated by PG. In addition, pancreaticogastrostomy is associated with a significantly lower frequency of multiple surgical complications.

The reported experience with laparoscopic pancreatic resections (LPR) remains limited to case reports or small series of patients.A retrospective multicenter study was conducted in 25 European surgical centers concerning their experience with LPR. Detailed questionnaires were used, focusing on patients, tumors, operative data, and late outcome.During the study period, 127 patients with presumed pancreatic neoplasms were enrolled in this series. Final diagnoses included benign pancreatic diseases in 111 patients (87%; insulinoma: 22, neuroendocrine neoplasm: 20, mucinous cystadenoma: 26, serous cystadenoma: 21, chronic pancreatitis: 11, others: 11), and 16 patients (13%) had malignant pancreatic diseases (insulinoma: 3, neuroendocrine neoplasm: 5, ductal adenocarcinoma: 4, cystadenocarcinoma: 2, renal metastases: 2). Five patients with presumed benign pancreatic disease had malignancy at final pathology. The median tumor size was 30 mm (range, 5-120 mm); 89% of tumors were located in the left pancreas. Laparoscopically successful procedures included 21 enucleations, 24 distal splenopancreatectomies, 58 distal pancreatectomies with splenic preservation, and 3 pancreatoduodenal resections. The overall conversion rate was 14%. There were no postoperative deaths. The rate of overall postoperative pancreatic-related complications was 31%, including a 17% rate of clinical pancreatic fistula. The surgical reoperation rate was 6.3%. In laparoscopically successful operations, the median postoperative hospital stay was 7 days (range, 3-67 days), decreased compared with patients requiring conversion to open pancreatectomy. During a median follow-up of 15 months (range, 3-47 months), 23% of the patients with pancreatic malignancies had tumor recurrence. Late outcome was satisfactory in all patients with benign diseases.LPR is feasible and safe in selected patients with presumed benign and distal pancreatic tumors. The management of the pancreatic stump remains a challenge. The role of LPR for pancreatic malignancies remains controversial.

The diagnosis, early assessment, and management of severe acute pancreatitis remain difficult clinical problems. This article presents the consensus obtained at a meeting convened to consider the evidence in these areas. The aim of the article is to provide outcome statements to guide clinical practice, with an assessment of the supporting evidence for each statement.Working groups considered the published evidence in the areas of diagnosis, assessment of severity, nonoperative treatment, and surgical treatment of severe acute pancreatitis. Outcome statements were defined to summarize the conclusions on each point considered. The findings were discussed and agreed on by all participants. A careful assessment was made of the strength of the available evidence (proven, probable, possible, unproven, or inappropriate).There is reliable evidence to support much current practice. Clear guidance can be given in most areas examined, and several areas were identified where further investigation would be helpful. Diagnosis using plasma concentrations of pancreatic enzymes is reliable. Rapid advances are taking place in the assessment of severity. Several new therapeutic strategies show real promise for the reduction of morbidity and mortality rates. Surgical debridement is required for infected pancreatic necrosis, but is less often necessary for sterile necrosis.

Journal of Gastroenterology and HepatologyVolume 17, Issue s1 p. S15-S39 Guidelines for the management of acute pancreatitis J TOOULI, J TOOULI Flinders University, Adelaide, Australia,Search for more papers by this authorM BROOKE-SMITH, M BROOKE-SMITH Flinders University, Adelaide, Australia,Search for more papers by this authorC BASSI, C BASSI Universita di Verona, Verona, Italy,Search for more papers by this authorD CARR-LOCKE, D CARR-LOCKE Brigham and Women’s Hospital, Massachusetts, USA,Search for more papers by this authorJ TELFORD, J TELFORD Brigham and Women’s Hospital, Massachusetts, USA,Search for more papers by this authorP FREENY, P FREENY University of Washington, Washington, USA,Search for more papers by this authorC IMRIE, C IMRIE Royal Infirmary, Glasgow, UK andSearch for more papers by this authorR TANDON, R TANDON All India Institnte of Medical Sciences, New Delhi, IndiaSearch for more papers by this author J TOOULI, J TOOULI Flinders University, Adelaide, Australia,Search for more papers by this authorM BROOKE-SMITH, M BROOKE-SMITH Flinders University, Adelaide, Australia,Search for more papers by this authorC BASSI, C BASSI Universita di Verona, Verona, Italy,Search for more papers by this authorD CARR-LOCKE, D CARR-LOCKE Brigham and Women’s Hospital, Massachusetts, USA,Search for more papers by this authorJ TELFORD, J TELFORD Brigham and Women’s Hospital, Massachusetts, USA,Search for more papers by this authorP FREENY, P FREENY University of Washington, Washington, USA,Search for more papers by this authorC IMRIE, C IMRIE Royal Infirmary, Glasgow, UK andSearch for more papers by this authorR TANDON, R TANDON All India Institnte of Medical Sciences, New Delhi, IndiaSearch for more papers by this author First published: 08 May 2002 https://doi.org/10.1046/j.1440-1746.17.s1.2.xCitations: 270 J. 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Radiology 1984; 150: 51– 5. Citing Literature Volume17, Issues1February 2002Pages S15-S39 ReferencesRelatedInformation

The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals).A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statements. Consensus was considered reached if ≥75% agreed or disagreed.Consensus was reached on 55 statements. The main goals of surveillance (to identify high-grade dysplastic precursor lesions and T1N0M0 pancreatic cancer) remained unchanged. Experts agreed that for those with familial risk, surveillance should start no earlier than age 50 or 10 years earlier than the youngest relative with pancreatic cancer, but were split on whether to start at age 50 or 55. Germline ATM mutation carriers with one affected first-degree relative are now considered eligible for surveillance. Experts agreed that preferred surveillance tests are endoscopic ultrasound and MRI/magnetic retrograde cholangiopancreatography, but no consensus was reached on how to alternate these modalities. Annual surveillance is recommended in the absence of concerning lesions. Main areas of disagreement included if and how surveillance should be performed for hereditary pancreatitis, and the management of indeterminate lesions.Pancreatic surveillance is recommended for selected high-risk individuals to detect early pancreatic cancer and its high-grade precursors, but should be performed in a research setting by multidisciplinary teams in centres with appropriate expertise. Until more evidence supporting these recommendations is available, the benefits, risks and costs of surveillance of pancreatic surveillance need additional evaluation.

Purpose Adjuvant chemotherapy improves patient survival rates after resection for pancreatic adenocarcinoma, but the optimal duration and time to initiate chemotherapy is unknown. Patients and Methods Patients with pancreatic ductal adenocarcinoma treated within the international, phase III, European Study Group for Pancreatic Cancer–3 (version 2) study were included if they had been randomly assigned to chemotherapy. Overall survival analysis was performed on an intention-to-treat basis, retaining patients in their randomized groups, and adjusting the overall treatment effect by known prognostic variables as well as the start time of chemotherapy. Results There were 985 patients, of whom 486 (49%) received gemcitabine and 499 (51%) received fluorouracil; 675 patients (68%) completed all six cycles of chemotherapy (full course) and 293 patients (30%) completed one to five cycles. Lymph node involvement, resection margins status, tumor differentiation, and completion of therapy were all shown by multivariable Cox regression to be independent survival factors. Overall survival favored patients who completed the full six courses of treatment versus those who did not (hazard ratio [HR], 0.516; 95% CI, 0.443 to 0.601; P &lt; .001). Time to starting chemotherapy did not influence overall survival rates for the full study population (HR, 0.985; 95% CI, 0.956 to 1.015). Chemotherapy start time was an important survival factor only for the subgroup of patients who did not complete therapy, in favor of later treatment (P &lt; .001). Conclusion Completion of all six cycles of planned adjuvant chemotherapy rather than early initiation was an independent prognostic factor after resection for pancreatic adenocarcinoma. There seems to be no difference in outcome if chemotherapy is delayed up to 12 weeks, thus allowing adequate time for postoperative recovery.

The aim of this study was to investigate the worldwide evidence of the roles of adjuvant chemoradiation and adjuvant chemotherapy on survival in potentially curative resected pancreatic cancer. Five randomised controlled trials of adjuvant treatment in patients with histologically proven pancreatic ductal adenocarcinoma were identified, of which the four most recent trials provided individual patient data (875 patients). This meta-analysis includes previously unpublished follow-up data on 261 patients. The pooled estimate of the hazard ratio (HR) indicated a 25% significant reduction in the risk of death with chemotherapy (H = 0.75, 95% confidence interval (CI): 0.64, 0.90, P-values(stratified) (Pstrat) = 0.001) with median survival estimated at 19.0 (95% CI: 16.4, 21.1) months with chemotherapy and 13.5 (95% CI: 12.2, 15.8) without. The 2- and 5-year survival rates were estimated at 38 and 19%, respectively, with chemotherapy and 28 and 12% without. The pooled estimate of the HR indicated no significant difference in the risk of death with chemoradiation (HR = 1.09, 95% CI: 0.89, 1.32, Pstrat = 0.43) with median survivals estimated at 15.8 (95% CI: 13.9, 18.1) months with chemoradiation and 15.2 (95% CI: 13.1, 18.2) without. The 2- and 5-year survival rates were estimated at 30 and 12%, respectively, with chemoradiation and 34 and 17% without. Subgroup analyses estimated that chemoradiation was more effective and chemotherapy less effective in patients with positive resection margins. These results show that chemotherapy is effective adjuvant treatment in pancreatic cancer but not chemoradiation. Further studies with chemoradiation are warranted in patients with positive resection margins, as chemotherapy appeared relatively ineffective in this patient subgroup.

Intraductal neoplasms are important precursors to invasive pancreatic cancer and provide an opportunity to detect and treat pancreatic neoplasia before an invasive carcinoma develops. The diagnostic evaluation of these lesions is challenging, as diagnostic imaging and cytological sampling do not provide accurate information on lesion classification, the grade of dysplasia or the presence of invasion. Moreover, the molecular driver gene mutations of these precursor lesions have yet to be fully characterized. Fifty-two intraductal papillary neoplasms, including 48 intraductal papillary mucinous neoplasms (IPMNs) and four intraductal tubulopapillary neoplasms (ITPNs), were subjected to the mutation assessment in 51 cancer-associated genes, using ion torrent semiconductor-based next-generation sequencing. P16 and Smad4 immunohistochemistry was performed on 34 IPMNs and 17 IPMN-associated carcinomas. At least one somatic mutation was observed in 46/48 (96%) IPMNs; 29 (60%) had multiple gene alterations. GNAS and/or KRAS mutations were found in 44/48 (92%) of IPMNs. GNAS was mutated in 38/48 (79%) IPMNs, KRAS in 24/48 (50%) and these mutations coexisted in 18/48 (37.5%) of IPMNs. RNF43 was the third most commonly mutated gene and was always associated with GNAS and/or KRAS mutations, as were virtually all the low-frequency mutations found in other genes. Mutations in TP53 and BRAF genes (10% and 6%) were only observed in high-grade IPMNs. P16 was lost in 7/34 IPMNs and 9/17 IPMN-associated carcinomas; Smad4 was lost in 1/34 IPMNs and 5/17 IPMN-associated carcinomas. In contrast to IPMNs, only one of four ITPNs had detectable driver gene (GNAS and NRAS) mutations. Deep sequencing DNA from seven cyst fluid aspirates identified 10 of the 13 mutations detected in their associated IPMN. Using next-generation sequencing to detect cyst fluid mutations has the potential to improve the diagnostic and prognostic stratification of pancreatic cystic neoplasms.

The correlation of the amylase value in drains (AVD) with the development of pancreatic fistula (PF) is still unclear.The purpose of this study was to identify within the first postoperative day (POD1) the predictive role of different risks factors, including AVD, in the development of PF.We prospectively investigated 137 patients who underwent major pancreatic resections. PF was defined and graded in accordance with the International Study Group on PF.We considered 101 pancreaticoduodenectomies and 36 distal resections. The overall incidence of PF (A, B, and C grades) was 19.7% and it was 14.8% after pancreaticoduodenectomy and 33.3% after distal resection. All PF occurred in "soft" remnant pancreas. The PF developed in patients with a POD1 median AVD of 10,000 U/L, whereas patients without PF had a median AVD of 1222 U/L (P < 0.001). We established a cut-off of 5000 U/L POD1 AVD for univariate and multivariate analysis. The area under the receiver operating characteristic (ROC) curve was 0.922 (P < 0.001). The predicting risk factors selected in the univariate setting were "soft" pancreas (P = 0.005; odds ratio [OR]: 1.54; 95% CI: 1.32-1.79) and AVD (P < 0.001; OR: 5.66; 95% CI: 3.6-8.7; positive predictive value 59%; negative predictive value 98%), whereas in multivariate analysis the predicting risk factor was the POD1 AVD (P < 0.001; OR: 68.4; 95% CI: 14.8-315). Only 2 PFs were detected with AVD <5000 U/L and both were in pancreatogastric anastomosis (P = 0.053).AVD in POD1 > or =5000 U/L is the only significant predictive factor of PF development.

Mucin-producing neoplasms (MPNs) of the pancreas include mucinous cystic neoplasms (MCNs) and main-duct, branch-duct, and combined intraductal papillary mucinous neoplasms (IPMNs). MCNs and branch-duct IPMNs are frequently confused; it is unclear whether main-duct, combined, and branch-duct IPMNs are a different spectrum of the same disease. We evaluated their clinical and epidemiologic characteristics.Patients who underwent resection for histologically confirmed MPNs were identified (N = 557); specimens were reviewed and eventually reclassified.One hundred sixty-eight patients (30%) had MCNs, 159 (28.5%) had branch-duct IPMNs, 149 (27%) had combined IPMNs, and 81 (14.5%) had main-duct IPMNs. Patients with MCNs were significantly younger and almost exclusively women; 44% of patients with main-duct or combined IPMNs and 57% of those with branch-duct IPMNs were women. MCNs were single lesions located in the distal pancreas (95%); 11% were invasive. IPMNs were more frequently found in the proximal pancreas; invasive cancer was found in 11%, 42%, and 48% of branch-duct, combined, and main-duct IPMNs, respectively (P = .001). Patients with invasive MCN and those with combined and main-duct IPMNs were older than those with noninvasive tumors. The 5-year disease-specific survival rate approached 100% for patients with noninvasive MPNs. The rates for those with invasive cancer were 58%, 56%, 51%, and 64% for invasive MCNs, branch-duct IPMNs, main-duct IPMNs, and combined IPMNs, respectively.MPNs comprise 3 different neoplasms: MCNs, branch-duct IPMNs, and main-duct IPMNs, including the combined type. These tumors have specific clinical, epidemiologic, and morphologic features that allow a reasonable degree of accuracy in preoperative diagnosis.

<h3>Objectives</h3> Serous cystic neoplasm (SCN) is a cystic neoplasm of the pancreas whose natural history is poorly known. The purpose of the study was to attempt to describe the natural history of SCN, including the specific mortality. <h3>Design</h3> Retrospective multinational study including SCN diagnosed between 1990 and 2014. <h3>Results</h3> 2622 patients were included. Seventy-four per cent were women, and median age at diagnosis was 58 years (16–99). Patients presented with non-specific abdominal pain (27%), pancreaticobiliary symptoms (9%), diabetes mellitus (5%), other symptoms (4%) and/or were asymptomatic (61%). Fifty-two per cent of patients were operated on during the first year after diagnosis (median size: 40 mm (2–200)), 9% had resection beyond 1 year of follow-up (3 years (1–20), size at diagnosis: 25 mm (4–140)) and 39% had no surgery (3.6 years (1–23), 25.5 mm (1–200)). Surgical indications were (not exclusive) uncertain diagnosis (60%), symptoms (23%), size increase (12%), large size (6%) and adjacent organ compression (5%). In patients followed beyond 1 year (n=1271), size increased in 37% (growth rate: 4 mm/year), was stable in 57% and decreased in 6%. Three serous cystadenocarcinomas were recorded. Postoperative mortality was 0.6% (n=10), and SCN9s related mortality was 0.1% (n=1). <h3>Conclusions</h3> After a 3-year follow-up, clinical relevant symptoms occurred in a very small proportion of patients and size slowly increased in less than half. Surgical treatment should be proposed only for diagnosis remaining uncertain after complete workup, significant and related symptoms or exceptionally when exists concern with malignancy. This study supports an initial conservative management in the majority of patients with SCN. <h3>Trial registration number</h3> IRB 00006477.

The aim of this study was to develop an alternative fistula risk score (a-FRS) for postoperative pancreatic fistula (POPF) after pancreatoduodenectomy, without blood loss as a predictor.Blood loss, one of the predictors of the original-FRS, was not a significant factor during 2 recent external validations.The a-FRS was developed in 2 databases: the Dutch Pancreatic Cancer Audit (18 centers) and the University Hospital Southampton NHS. Primary outcome was grade B/C POPF according to the 2005 International Study Group on Pancreatic Surgery (ISGPS) definition. The score was externally validated in 2 independent databases (University Hospital of Verona and University Hospital of Pennsylvania), using both 2005 and 2016 ISGPS definitions. The a-FRS was also compared with the original-FRS.For model design, 1924 patients were included of whom 12% developed POPF. Three predictors were strongly associated with POPF: soft pancreatic texture [odds ratio (OR) 2.58, 95% confidence interval (95% CI) 1.80-3.69], small pancreatic duct diameter (per mm increase, OR: 0.68, 95% CI: 0.61-0.76), and high body mass index (BMI) (per kg/m increase, OR: 1.07, 95% CI: 1.04-1.11). Discrimination was adequate with an area under curve (AUC) of 0.75 (95% CI: 0.71-0.78) after internal validation, and 0.78 (0.74-0.82) after external validation. The predictive capacity of a-FRS was comparable with the original-FRS, both for the 2005 definition (AUC 0.78 vs 0.75, P = 0.03), and 2016 definition (AUC 0.72 vs 0.70, P = 0.05).The a-FRS predicts POPF after pancreatoduodenectomy based on 3 easily available variables (pancreatic texture, duct diameter, BMI) without blood loss and pathology, and was successfully validated for both the 2005 and 2016 POPF definition. The online calculator is available at www.pancreascalculator.com.

Human equilibrative nucleoside transporter 1 (hENT1) levels in pancreatic adenocarcinoma may predict survival in patients who receive adjuvant gemcitabine after resection.Microarrays from 434 patients randomized to chemotherapy in the ESPAC-3 trial (plus controls from ESPAC-1/3) were stained with the 10D7G2 anti-hENT1 antibody. Patients were classified as having high hENT1 expression if the mean H score for their cores was above the overall median H score (48). High and low hENT1-expressing groups were compared using Kaplan-Meier curves, log-rank tests, and Cox proportional hazards models. All statistical tests were two-sided.Three hundred eighty patients (87.6%) and 1808 cores were suitable and included in the final analysis. Median overall survival for gemcitabine-treated patients (n = 176) was 23.4 (95% confidence interval [CI] = 18.3 to 26.0) months vs 23.5 (95% CI = 19.8 to 27.3) months for 176 patients treated with 5-fluorouracil/folinic acid (χ(2) 1=0.24; P = .62). Median survival for patients treated with gemcitabine was 17.1 (95% CI = 14.3 to 23.8) months for those with low hENT1 expression vs 26.2 (95% CI = 21.2 to 31.4) months for those with high hENT1 expression (χ(2)₁= 9.87; P = .002). For the 5-fluorouracil group, median survival was 25.6 (95% CI = 20.1 to 27.9) and 21.9 (95% CI = 16.0 to 28.3) months for those with low and high hENT1 expression, respectively (χ(2)₁ = 0.83; P = .36). hENT1 levels were not predictive of survival for the 28 patients of the observation group (χ(2)₁ = 0.37; P = .54). Multivariable analysis confirmed hENT1 expression as a predictive marker in gemcitabine-treated (Wald χ(2) = 9.16; P = .003) but not 5-fluorouracil-treated (Wald χ(2) = 1.22; P = .27) patients.Subject to prospective validation, gemcitabine should not be used for patients with low tumor hENT1 expression.

Complete macroscopic tumor resection is one of the most relevant predictors of long-term survival in pancreatic ductal adenocarcinoma. Because locally advanced pancreatic tumors can involve adjacent organs, "extended" pancreatectomy that includes the resection of additional organs may be needed to achieve this goal. Our aim was to develop a common consistent terminology to be used in centers reporting results of pancreatic resections for cancer.An international panel of pancreatic surgeons working in well-known, high-volume centers reviewed the literature on extended pancreatectomies and worked together to establish a consensus on the definition and the role of extended pancreatectomy in pancreatic cancer.Macroscopic (R1) and microscopic (R0) complete tumor resection can be achieved in patients with locally advanced disease by extended pancreatectomy. Operative time, blood loss, need for blood transfusions, duration of stay in the intensive care unit, and hospital morbidity, and possibly also perioperative mortality are increased with extended resections. Long-term survival is similar compared with standard resections but appears to be better compared with bypass surgery or nonsurgical palliative chemotherapy or chemoradiotherapy. It was not possible to identify any clear prognostic criteria based on the specific additional organ resected.Despite increased perioperative morbidity, extended pancreatectomy is warranted in locally advanced disease to achieve long-term survival in pancreatic ductal adenocarcinoma if macroscopic clearance can be achieved. Definitions of extended pancreatectomies for locally advanced disease (and not distant metastatic disease) are established that are crucial for comparison of results of future trials across different practices and countries, in particular for those using neoadjuvant therapy.

There are no established guidelines for pathologic diagnosis/reporting of intraductal papillary mucinous neoplasms (IPMNs).An international multidisciplinary group, brought together by the Verona Pancreas Group in Italy-2013, was tasked to devise recommendations.(1) Crucial to rule out invasive carcinoma with extensive (if not complete) sampling. (2) Invasive component is to be documented in a full synoptic report including its size, type, grade, and stage. (3) The term "minimally invasive" should be avoided; instead, invasion size with stage and substaging of T1 (1a, b, c; ≤ 0.5, > 0.5-≤ 1, > 1 cm) is to be documented. (4) Largest diameter of the invasion, not the distance from the nearest duct, is to be used. (5) A category of "indeterminate/(suspicious) for invasion" is acceptable for rare cases. (6) The term "malignant" IPMN should be avoided. (7) The highest grade of dysplasia in the non-invasive component is to be documented separately. (8) Lesion size is to be correlated with imaging findings in cysts with rupture. (9) The main duct diameter and, if possible, its involvement are to be documented; however, it is not required to provide main versus branch duct classification in the resected tumor. (10) Subtyping as gastric/intestinal/pancreatobiliary/oncocytic/mixed is of value. (11) Frozen section is to be performed highly selectively, with appreciation of its shortcomings. (12) These principles also apply to other similar tumoral intraepithelial neoplasms (mucinous cystic neoplasms, intra-ampullary, and intra-biliary/cholecystic).These recommendations will ensure proper communication of salient tumor characteristics to the management teams, accurate comparison of data between analyses, and development of more effective management algorithms.

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. 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. 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. 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. 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.

The aim of this study was to compare oncological outcomes after minimally invasive distal pancreatectomy (MIDP) with open distal pancreatectomy (ODP) in patients with pancreatic ductal adenocarcinoma (PDAC).Cohort studies have suggested superior short-term outcomes of MIDP vs. ODP. Recent international surveys, however, revealed that surgeons have concerns about the oncological outcomes of MIDP for PDAC.This is a pan-European propensity score matched study including patients who underwent MIDP (laparoscopic or robot-assisted) or ODP for PDAC between January 1, 2007 and July 1, 2015. MIDP patients were matched to ODP patients in a 1:1 ratio. Main outcomes were radical (R0) resection, lymph node retrieval, and survival.In total, 1212 patients were included from 34 centers in 11 countries. Of 356 (29%) MIDP patients, 340 could be matched. After matching, the MIDP conversion rate was 19% (n = 62). Median blood loss [200 mL (60-400) vs 300 mL (150-500), P = 0.001] and hospital stay [8 (6-12) vs 9 (7-14) days, P < 0.001] were lower after MIDP. Clavien-Dindo grade ≥3 complications (18% vs 21%, P = 0.431) and 90-day mortality (2% vs 3%, P > 0.99) were comparable for MIDP and ODP, respectively. R0 resection rate was higher (67% vs 58%, P = 0.019), whereas Gerota's fascia resection (31% vs 60%, P < 0.001) and lymph node retrieval [14 (8-22) vs 22 (14-31), P < 0.001] were lower after MIDP. Median overall survival was 28 [95% confidence interval (CI), 22-34] versus 31 (95% CI, 26-36) months (P = 0.929).Comparable survival was seen after MIDP and ODP for PDAC, but the opposing differences in R0 resection rate, resection of Gerota's fascia, and lymph node retrieval strengthen the need for a randomized trial to confirm the oncological safety of MIDP.

The recently released eighth edition of the American Joint Committee on Cancer TNM staging system for pancreatic cancer seeks to improve prognostic accuracy but lacks international validation.To validate the eighth edition of the American Joint Committee on Cancer TNM staging system in an international cohort of patients with resected pancreatic ductal adenocarcinoma.This international multicenter cohort study took place in 5 tertiary centers in Europe and the United States from 2000 to 2015. Patients who underwent pancreatoduodenectomy for nonmetastatic pancreatic ductal adenocarcinoma were eligible. Data analysis took place from December 2017 to April 2018.Patients were retrospectively staged according to the seventh and eighth editions of the TNM staging system.Prognostic accuracy on survival rates, assessed by Kaplan-Meier and multivariate Cox proportional hazards analyses and concordance statistics.A total of 1525 consecutive patients were included (median [IQR] age, 66 (58-72) years; 802 (52.6%) male). Distribution among stages via the seventh edition was stage IA in 41 patients (2.7%), stage IB in 42 (2.8%), stage IIA in 200 (13.1%), stage IIB in 1229 (80.6%), and stage III in 12 (0.8%); this changed with use of the eighth edition to stage IA in 118 patients (7.7%), stage IB in 144 (9.4%), stage IIA in 22 (1.4%), stage IIB in 643 (42.2%), and stage III in 598 (39.2%). With the eighth edition, 774 patients (50.8%) migrated to a different stage; 183 (12.0%) were reclassified to a lower stage and 591 (38.8%) to a higher stage. Median overall survival for the entire cohort was 24.4 months (95% CI, 23.4-26.2 months). On Kaplan-Meier analysis, 5-year survival rates changed from 38.2% for patients in stage IA, 34.7% in IB, 35.3% in IIA, 16.5% in IIB, and 0% in stage III (log-rank P < .001) via classification with the seventh edition to 39.2% for patients in stage IA, 33.9% in IB, 27.6% in IIA, 21.0% in IIB, and 10.8% in stage III (log-rank P < .001) with the eighth edition. For patients who were node negative, the T stage was not associated with prognostication of survival in either edition. In the eighth edition, the N stage was associated with 5-year survival rates of 35.6% in N0, 20.8% in N1, and 10.9% in N2 (log-rank P < .001). The C statistic improved from 0.55 (95% CI, 0.53-0.57) for the seventh edition to 0.57 (95% CI, 0.55-0.60) for the eighth edition.The eighth edition of the TNM staging system demonstrated a more equal distribution among stages and a modestly increased prognostic accuracy in patients with resected pancreatic ductal adenocarcinoma compared with the seventh edition. The revised T stage remains poorly associated with survival, whereas the revised N stage is highly prognostic.

Objective: To use the concept of benchmarking to establish robust and standardized outcome references after pancreatico-duodenectomy (PD). Background: Best achievable results after PD are unknown. Consequently, outcome comparisons among different cohorts, centers or with novel surgical techniques remain speculative. Methods: This multicenter study analyzes consecutive patients (2012–2015) undergoing PD in 23 international expert centers in pancreas surgery. Outcomes in patients without significant comorbidities and major vascular resection (benchmark cases) were analyzed to establish 20 outcome benchmarks for PD. These benchmarks were tested in a cohort with a poorer preoperative physical status (ASA class ≥3) and a cohort treated by minimally invasive approaches. Results: Two thousand three hundred seventy-five (38%) low-risk cases out of a total of 6186 PDs were analyzed, disclosing low in-hospital mortality (≤1.6%) but high morbidity, with a 73% benchmark morbidity rate cumulated within 6 months following surgery. Benchmark cutoffs for pancreatic fistulas (B-C), severe complications (≥ grade 3), and failure-to-rescue rate were 19%, 30%, and 9%, respectively. The ASA ≥3 cohort showed comparable morbidity but a higher in hospital-mortality (3% vs 1.6%) and failure-to-rescue rate (16% vs 9%) than the benchmarks. The proportion of benchmark cases performed varied greatly across centers and continents for both open (9%–93%) and minimally invasive (11%–62%) PD. Centers operating mostly on complex PD cases disclosed better results than those with a majority of low-risk cases. Conclusion: The proposed outcome benchmarks for PD, established in a large-scale international patient cohort and tested in 2 different cohorts, may allow for meaningful comparisons between different patient cohorts, centers, countries, and surgical techniques.

Objective To evaluate mid-term outcomes and predictors of survival in non-operated patients with pancreatic intraductal papillary mucinous neoplasms (IPMNs) with worrisome features or high-risk stigmata as defined by International Consensus Guidelines for IPMN. Reasons for non-surgical options were physicians’ recommendation, patient personal choice or comorbidities precluding surgery. Methods In this retrospective, multicentre analysis, IPMNs were classified as branch duct (BD) and main duct (MD), the latter including mixed IPMNs. Univariate and multivariate analysis for overall survival (OS) and disease-specific survival (DSS) were obtained. Results Of 281 patients identified, 159 (57%) had BD-IPMNs and 122 (43%) had MD-IPMNs; 50 (18%) had high-risk stigmata and 231 (82%) had worrisome features. Median follow-up was 51 months. The 5-year OS and DSS for the entire cohort were 81% and 89.9%. An invasive pancreatic malignancy developed in 34 patients (12%); 31 had invasive IPMNs (11%) and 3 had IPMN-distinct pancreatic ductal adenocarcinoma (1%). Independent predictors of poor DSS in the entire cohort were age &gt;70 years, atypical/malignant cyst fluid cytology, jaundice and MD &gt;15 mm. Compared with MD-IPMNs, BD-IPMNs had significantly better 5-year OS (86% vs 74.1%, p=0.002) and DSS (97% vs 81.2%, p&lt;0.0001). Patients with worrisome features had better 5-year DSS compared with those with high-risk stigmata (96.2% vs 60.2%, p&lt;0.0001). Conclusions In elderly patients with IPMNs that have worrisome features, the 5-year DSS is 96%, suggesting that conservative management is appropriate. By contrast, presence of high-risk stigmata is associated with a 40% risk of IPMN-related death, reinforcing that surgical resection should be offered to fit patients.

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. 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. 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. 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. 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.

One-hundred-fifty-three biliary cancers, including 70 intrahepatic cholangiocarcinomas (ICC), 57 extrahepatic cholangiocarcinomas (ECC) and 26 gallbladder carcinomas (GBC) were assessed for mutations in 56 genes using multigene next-generation sequencing.Expression of EGFR and mTOR pathway genes was investigated by immunohistochemistry.At least one mutated gene was observed in 118/153 (77%) cancers.The genes most frequently involved were KRAS (28%), TP53 (18%), ARID1A (12%), IDH1/2 (9%), PBRM1 (9%), BAP1 (7%), and PIK3CA (7%).IDH1/2 (p=0.0005) and BAP1 (p=0.0097)mutations were characteristic of ICC, while KRAS (p=0.0019) and TP53 (p=0.0019) were more frequent in ECC and GBC.Multivariate analysis identified tumour stage and TP53 mutations as independent predictors of survival.Alterations in chromatin remodeling genes (ARID1A, BAP1, PBRM1, SMARCB1) were seen in 31% of cases.Potentially actionable mutations were seen in 104/153 (68%) cancers: i) KRAS/NRAS/BRAF mutations were found in 34% of cancers; ii) mTOR pathway activation was documented by immunohistochemistry in 51% of cases and by mutations in mTOR pathway genes in 19% of cancers; iii) TGF-ß/Smad signaling was altered in 10.5% cancers; iv) mutations in tyrosine kinase receptors were found in 9% cases.Our study identified molecular subgroups of cholangiocarcinomas that can be explored for specific drug targeting in clinical trials.www.impactjournals.com/oncotarget

Background The optimal nutritional therapy in the field of pancreatic surgery is still debated. Methods An international panel of recognized pancreatic surgeons and pancreatologists decided that the topic of nutritional support was of importance in pancreatic surgery. Thus, they reviewed the best contemporary literature and worked to develop a position paper to provide evidence supporting the integration of appropriate nutritional support into the overall management of patients undergoing pancreatic resection. Strength of recommendation and quality of evidence were based on the approach of the grading of recommendations assessment, development and evaluation Working Group. Results The measurement of nutritional status should be part of routine preoperative assessment because malnutrition is a recognized risk factor for surgery-related complications. In addition to patient's weight loss and body mass index, measurement of sarcopenia and sarcopenic obesity should be considered in the preoperative evaluation because they are strong predictors of poor short-term and long-term outcomes. The available data do not show any definitive nutritional advantages for one specific type of gastrointestinal reconstruction technique after pancreatoduodenectomy over the others. Postoperative early resumption of oral intake is safe and should be encouraged within enhanced recovery protocols, but in the case of severe postoperative complications or poor tolerance of oral food after the operation, supplementary artificial nutrition should be started at once. At present, there is not enough evidence to show the benefit of avoiding oral intake in clinically stable patients who are complicated by a clinically irrelevant postoperative pancreatic fistula (a so-called biochemical leak), while special caution should be given to feeding patients with clinically relevant postoperative pancreatic fistula orally. When an artificial nutritional support is needed, enteral nutrition is preferred whenever possible over parenteral nutrition. After the operation, regardless of the type of pancreatic resection or technique of reconstruction, patients should be monitored carefully to assess for the presence of endocrine and exocrine pancreatic insufficiency. Although fecal elastase-1 is the most readily available clinical test for detection of pancreatic exocrine insufficiency, its sensitivity and specificity are low. Pancreatic enzyme replacement therapy should be initiated routinely after pancreatoduodenectomy and in patients with locally advanced disease and continued for at least 6 months after surgery, because untreated pancreatic exocrine insufficiency may result in severe nutritional derangement. Conclusion The importance of this position paper is the consensus reached on the topic. Concentrating on nutritional support and therapy is of utmost value in pancreatic surgery for both short- and long-term outcomes. The optimal nutritional therapy in the field of pancreatic surgery is still debated. An international panel of recognized pancreatic surgeons and pancreatologists decided that the topic of nutritional support was of importance in pancreatic surgery. Thus, they reviewed the best contemporary literature and worked to develop a position paper to provide evidence supporting the integration of appropriate nutritional support into the overall management of patients undergoing pancreatic resection. Strength of recommendation and quality of evidence were based on the approach of the grading of recommendations assessment, development and evaluation Working Group. The measurement of nutritional status should be part of routine preoperative assessment because malnutrition is a recognized risk factor for surgery-related complications. In addition to patient's weight loss and body mass index, measurement of sarcopenia and sarcopenic obesity should be considered in the preoperative evaluation because they are strong predictors of poor short-term and long-term outcomes. The available data do not show any definitive nutritional advantages for one specific type of gastrointestinal reconstruction technique after pancreatoduodenectomy over the others. Postoperative early resumption of oral intake is safe and should be encouraged within enhanced recovery protocols, but in the case of severe postoperative complications or poor tolerance of oral food after the operation, supplementary artificial nutrition should be started at once. At present, there is not enough evidence to show the benefit of avoiding oral intake in clinically stable patients who are complicated by a clinically irrelevant postoperative pancreatic fistula (a so-called biochemical leak), while special caution should be given to feeding patients with clinically relevant postoperative pancreatic fistula orally. When an artificial nutritional support is needed, enteral nutrition is preferred whenever possible over parenteral nutrition. After the operation, regardless of the type of pancreatic resection or technique of reconstruction, patients should be monitored carefully to assess for the presence of endocrine and exocrine pancreatic insufficiency. Although fecal elastase-1 is the most readily available clinical test for detection of pancreatic exocrine insufficiency, its sensitivity and specificity are low. Pancreatic enzyme replacement therapy should be initiated routinely after pancreatoduodenectomy and in patients with locally advanced disease and continued for at least 6 months after surgery, because untreated pancreatic exocrine insufficiency may result in severe nutritional derangement. The importance of this position paper is the consensus reached on the topic. Concentrating on nutritional support and therapy is of utmost value in pancreatic surgery for both short- and long-term outcomes.

Objective: To identify a clinical fistula risk score following distal pancreatectomy. Background: Clinically relevant pancreatic fistula (CR-POPF) following distal pancreatectomy (DP) is a dominant contributor to procedural morbidity, yet risk factors attributable to CR-POPF and effective practices to reduce its occurrence remain elusive. Methods: This multinational, retrospective study of 2026 DPs involved 52 surgeons at 10 institutions (2001–2016). CR-POPFs were defined by 2016 International Study Group criteria, and risk models generated using stepwise logistic regression analysis were evaluated by c-statistic. Mitigation strategies were assessed by regression modeling while controlling for identified risk factors and treating institution. Results: CR-POPF occurred following 306 (15.1%) DPs. Risk factors independently associated with CR-POPF included: age (&lt;60 yrs: OR 1.42, 95% CI 1.05–1.82), obesity (OR 1.54, 95% CI 1.19–2.12), hypoalbuminenia (OR 1.63, 95% CI 1.06–2.51), the absence of epidural anesthesia (OR 1.59, 95% CI 1.17–2.16), neuroendocrine or nonmalignant pathology (OR 1.56, 95% CI 1.18–2.06), concomitant splenectomy (OR 1.99, 95% CI 1.25–3.17), and vascular resection (OR 2.29, 95% CI 1.25–3.17). After adjusting for inherent risk between cases by multivariable regression, the following were not independently associated with CR-POPF: method of transection, suture ligation of the pancreatic duct, staple size, the use of staple line reinforcement, tissue patches, biologic sealants, or prophylactic octreotide. Intraoperative drainage was associated with a greater fistula rate (OR 2.09, 95% CI 1.51–3.78) but reduced fistula severity ( P &lt; 0.001). Conclusions: From this large analysis of pancreatic fistula following DP, CR-POPF occurrence cannot be reliably predicted. Opportunities for developing a risk score model are limited for performing risk-adjusted analyses of mitigation strategies and surgeon performance.

This multicenter study sought to prospectively evaluate a drain management protocol for pancreatoduodenectomy (PD).Recent evidence suggests value for both selective drain placement and early drain removal for PD. Both strategies have been associated with reduced rates of clinically relevant pancreatic fistula (CR-POPF)-the most common and morbid complication after PD.The protocol was applied to 260 consecutive PDs performed at two institutions over 17 months. Risk for ISGPF CR-POPF was determined intraoperatively using the Fistula Risk Score (FRS); drains were omitted in negligible/low risk patients and drain fluid amylase (DFA) was measured on postoperative day 1 (POD 1) for moderate/high risk patients. Drains were removed early (POD 3) in patients with POD 1 DFA ≤5,000 U/L, whereas patients with POD 1 DFA >5,000 U/L were managed by clinical discretion. Outcomes were compared with a historical cohort (N = 557; 2011-2014).Fistula risk did not differ between cohorts (median FRS: 4 vs 4; P = 0.933). No CR-POPFs developed in the 70 (26.9%) negligible/low risk patients. Overall CR-POPF rates were significantly lower after protocol implementation (11.2 vs 20.6%, P = 0.001). The protocol cohort also demonstrated lower rates of severe complication, any complication, reoperation, and percutaneous drainage (all P < 0.05). These patients also experienced reduced hospital stay (median: 8 days vs 9 days, P = 0.001). There were no differences between cohorts in the frequency of bile or chyle leaks.Drains can be safely omitted for one-quarter of PDs. Drain amylase analysis identifies which moderate/high risk patients benefit from early drain removal. This data-driven, risk-stratified approach significantly decreases the occurrence of clinically relevant pancreatic fistula.

<h3>Background</h3> Pancreatic ductal adenocarcinoma (PDAC) is a highly devastating disease with an overall 5-year survival rate of less than 8%. New evidence indicates that PDAC cells release pro-inflammatory metabolites that induce a marked alteration of normal hematopoiesis, favoring the expansion and accumulation of myeloid-derived suppressor cells (MDSCs). We report here that PDAC patients show increased levels of both circulating and tumor-infiltrating MDSC-like cells. <h3>Methods</h3> The frequency of MDSC subsets in the peripheral blood was determined by flow cytometry in three independent cohorts of PDAC patients (total analyzed patients, <i>n</i> = 117). Frequency of circulating MDSCs was correlated with overall survival of PDAC patients. We also analyzed the frequency of tumor-infiltrating MDSC and the immune landscape in fresh biopsies. Purified myeloid cell subsets were tested in vitro for their T-cell suppressive capacity. <h3>Results</h3> Correlation with clinical data revealed that MDSC frequency was significantly associated with a shorter patients' overall survival and metastatic disease. However, the immunosuppressive activity of purified MDSCs was detectable only in some patients and mainly limited to the monocytic subset. A transcriptome analysis of the immunosuppressive M-MDSCs highlighted a distinct gene signature in which STAT3 was crucial for monocyte re-programming. Suppressive M-MDSCs can be characterized as circulating STAT3/arginase1-expressing CD14⁺ cells. <h3>Conclusion</h3> MDSC analysis aids in defining the immune landscape of PDAC patients for a more appropriate diagnosis, stratification and treatment.

The aim of this study was to develop a classification system for pancreas-associated risk factors in pancreatoduodenectomy (PD).Postoperative pancreatic fistula (POPF) is the most relevant PD-associated complication. A simple standardized surgical reporting system based on pancreas-associated risk factors is lacking.A systematic literature search was conducted to identify studies investigating clinically relevant (CR) POPF (CR-POPF) and pancreas-associated risk factors after PD. A meta-analysis of CR-POPF rate for texture of the pancreas (soft vs not-soft) and main pancreatic duct (MPD) diameter was performed using the Mantel-Haenszel method. Based on the results, the International Study Group of Pancreatic Surgery (ISGPS) proposes the following classification: A, not-soft (hard) texture and MPD >3 mm; B, not-soft (hard) texture and MPD ≤3 mm; C, soft texture and MPD >3 mm; D, soft texture and MPD ≤3 mm. The classification was evaluated in a multi-institutional, international cohort.Of the 2917 articles identified, 108 studies were included in the analyses. Soft pancreatic texture was significantly associated with the development of CR-POPF [odds ratio (OR) 4.24, 95% confidence interval (CI) 3.67-4.89, P < 0.01) following PD. Similarly, MPD diameter ≤3 mm significantly increased CR-POPF risk compared with >3 mm diameter MPDs (OR 3.66, 95% CI 2.62-5.12, P < 0.01). The proposed 4-stage system was confirmed in an independent cohort of 5533 patients with CR-POPF rates of 3.5%, 6.2%, 16.6%, and 23.2% for type A-D, respectively ( P < 0.001).For future pancreatic surgical outcomes studies, the ISGPS recommends reporting these risk factors according to the proposed classification system for better comparability of results.

Myeloid cells can restrain antitumor immunity by metabolic pathways, such as the degradation of l -arginine, whose concentrations are regulated by the arginase 1 (ARG1) enzyme. Results from preclinical studies indicate the important role of arginine metabolism in pancreatic ductal adenocarcinoma (PDAC) progression, suggesting a potential for clinical application; however, divergent evolution in ARG1 expression and function in rodents and humans has restricted clinical translation. To overcome this dichotomy, here, we show that neutrophil extracellular traps (NETs), released by spontaneously activated neutrophils isolated from patients with PDAC, create a microdomain where cathepsin S (CTSS) cleaves human (h)ARG1 into different molecular forms endowed with enhanced enzymatic activity at physiological pH. NET-associated hARG1 suppresses T lymphocytes whose proliferation is restored by either adding a hARG1-specific monoclonal antibody (mAb) or preventing CTSS-mediated cleavage, whereas small-molecule inhibitors are not effective. We show that ARG1 blockade, combined with immune checkpoint inhibitors, can restore CD8 + T cell function in ex vivo PDAC tumors. Furthermore, anti-hARG1 mAbs increase the frequency of adoptively transferred tumor-specific CD8 + T cells in tumor and enhance the effectiveness of immune checkpoint therapy in humanized mice. Thus, this study shows that extracellular ARG1, released by activated myeloid cells, localizes in NETs, where it interacts with CTSS that in turn cleaves ARG1, producing major molecular forms endowed with different enzymatic activity at physiological pH. Once exocytosed, ARG1 activity can be targeted by mAbs, which bear potential for clinical application for the treatment of PDAC and require further exploration.

&lt;i&gt;Background:&lt;/i&gt; Pancreatic fistula (PF) is still regarded as a serious complication both in terms of frequency and sequelae. The incidence varies greatly in different reports because of the different definitions used. The aim of this study was to compare several definitions of PF encountered in the current literature and to demonstrate that the PF rate in the same group of patients treated in a high volume center is dependent upon the definition applied. &lt;i&gt;Methods:&lt;/i&gt; A Medline search of the last 10 years was performed as regards the definition of PF. A score was assigned to the reproducible definitions based upon two basic parameters: daily output (cm&lt;sup&gt;3&lt;/sup&gt;) and duration of the fistula represented by the number of days between the postoperative day of onset and the duration of the complication. Four definitions were formulated and were then applied to a group of 242 patients that underwent pancreatic head or intermediate resections with pancreatico-jejunal anastomosis in our Pancreatic Unit between November 1996 and December 2000. Statistical analysis was carried out using the Yates correct χ&lt;sup&gt;2&lt;/sup&gt; test with statistical significance set at p &lt; 0.05. &lt;i&gt;Results:&lt;/i&gt; Among 26 different definitions identified, 14 were found suitable for the applied score. We formulated four final definitions summarizing the current concepts of PF. The incidence of PF ranged between 9.9 and 28.5% according to the different definitions applied with highly statistical differences between them. &lt;i&gt;Conclusions:&lt;/i&gt; The PF rate after pancreatic resections is strictly dependent upon the definition used. An overall general agreement for an internationally accepted definition is urgently needed to correctly compare different experiences.

Anastomotic failure is still a significant problem that affects the outcome of pancreaticoduodenectomy. There have been many techniques proposed for the reconstruction of pancreatic digestive continuity, but there have been few prospective and randomized studies that compare their efficacy.In the current work, 144 patients who underwent a pancreaticoduodenectomy with soft residual tissue were assigned randomly to receive either a duct-to-mucosa anastomosis (group A) or a 1-layer end-to-side pancreaticojejunostomy (group B).The 2 treatment groups were found not to have any differences in regards to vital statistics, underlying disease, or operative techniques. The postoperative course was complicated in 54% of the 144 patients, with a comprehensive incidence of abdominal complications in 36% (group A, 35%; group B, 38%; P=not significant). The principal complication was pancreatic fistulas, which occurred in 14% of patients (group A, 13%; group B, 15%; P=not significant). Two patients (2%) required reoperation; the postoperative mortality rate was 1%.The 2 methods that were studied revealed no significant difference the rate of complications.

<b>Background:</b> Branch-duct intraductal papillary mucinous neoplasms (BD-IPMNs) of the pancreas are reported to be less aggressive than the main-duct type. Hence, less aggressive treatment has been proposed for the former. <b>Aim:</b> To evaluate the effectiveness of a follow-up protocol for BD-IPMNs. <b>Design:</b> Prospective study. <b>Setting:</b> An academic tertiary referral centre. <b>Patients:</b> From 2000 to 2003, 109 patients with BD-IPMNs underwent trans-abdominal ultrasound and magnetic resonance cholangiopancreatography with secretin. Patients who presented malignancy-related parameters (size &gt;3.5 cm, nodules, thick walls, carbohydrate antigen 19.9 level &gt;25 U/l, recent-onset or worsened diabetes) and/or complained of symptoms were submitted to surgery (arm A). All asymptomatic patients without suspicion of malignancy were followed up according to a 6-month clinical–radiological protocol (arm B). <b>Main outcome measures:</b> The effectiveness of conservative management of BD-IPMNs. <b>Results:</b> 20 (18.3%) patients underwent surgery (arm A); pathological diagnosis of BD-IPMNs was always confirmed. 89 (81.7%) patients were followed up for a median of 32 months (arm B); of these, 57 (64%) patients had multifocal disease. After a mean follow-up of 18.2 months, 5 (5.6%) patients showed an increase in lesion size and underwent surgery. The pathological diagnosis was branch-duct adenoma in three patients and borderline adenoma in two. <b>Conclusions:</b> Surgery is indicated in &lt;20% of cases of BD-IPMNs, and, in the absence of malignancy-related parameters, careful non-operative management seems to be safe and effective in asymptomatic patients. Although observation for a longer time is needed to confirm these results, our findings support the guidelines recently recommended by the International Association of Pancreatology.

In Brief Objective: To describe the clinical characteristics, indications, technical procedures, and outcome of a consecutive series of laparoscopic distal pancreatic resections performed by the same surgical team. Summary Background Data: Laparoscopic distal pancreatic resection has increasingly been described as a feasible and safe procedure, although accompanied by a high rate of conversion and morbidity. Methods: A consecutive series of patients affected by solid and cystic tumors were selected prospectively to undergo laparoscopic distal pancreatectomy performed by the same surgical team. Clinical characteristics as well as diagnostic preoperative assessment and intra- and postoperative data were prospectively recorded. A follow-up of at least 3 months was available for all patients. Results: Fifty-eight patients underwent laparoscopic resection between May 1999 and November 2005. All procedures were successfully performed laparoscopically, and no patient required intraoperative blood transfusion. Splenic vessel preservation was possible in 84.4% of spleen-preserving procedures. There were no mortalities. The overall median hospital stay was 9 days, while it was 10.5 days for patients with postoperative pancreatic fistulae (27.5% of all cases). Follow-up was available for all patients. Conclusions: Our experience in 58 consecutive patients was characterized by the lack of conversions and by acceptable rates of postoperative pancreatic fistulae and morbidity. Laparoscopy proved especially beneficial in patients with postoperative complications as they had a relatively short hospital stay. Solid and cystic tumors of the distal pancreas represent a good indication for laparoscopic resection whenever possible. Laparocopic distal pancreatectomy is increasingly used by many surgical teams. The major issues related to the technique are the conversion rate and postoperative complications. The authors describe their experience and discuss the indications, techniques, and results of 58 consecutive operations performed by the same surgical team with no conversions.

Pancreaticoduodenectomy (PD) is still a difficult procedure with significant morbidity. We report 150 consecutive PDs performed during a 3-year period. All the cases have been prospectively evaluated with regard to the surgical outcome. Mortality in this series was 3/150 (2%) with a re-operation rate of 5/150 (3.3%); surgical complications were experienced in 57/150 (38%). The most frequent complications were collections in 25/150 (16.6%) and pancreatic fistulas in 16/150 (10.7%). The majority of these complications were conservatively managed: only one abscess and one fistula due to an anastomotic dehiscence required re-operation. The complication most responsible for mortality was haemorrhage secondary to arterial pseudoaneurysms in patients with severe post-operative pancreatitis. The continued high morbidity of PDs is compensated by the ability to treat complications non-operatively, resulting in a surgical risk that should now be considered medium to low in high volume centres.

In Brief Objective: To evaluate the indications, perioperative, and long-term outcomes of a large cohort of patients who underwent middle pancreatectomy (MP). Summary Background Data: MP is a parenchyma-sparing technique aimed to reduce the risk of postoperative exocrine and endocrine insufficiency. Reported outcomes after MP are conflicting. Methods: Patients who underwent MP between 1990 and 2005 at the Massachusetts General Hospital and at the University of Verona were identified. The outcomes after MP were compared with a control group that underwent extended left pancreatectomy (ELP) for neoplasms in the mid pancreas. Results: A total of 100 patients underwent MP. The most common indications were neuroendocrine neoplasms, serous cystadenoma, and branch-duct IPMNs. Comparison with 45 ELP showed that intraoperative blood loss and transfusions were significantly higher for ELP. The 2 groups showed no differences in overall morbidity, abdominal complications, overall pancreatic fistula, and grade B/C pancreatic fistula rate (17% in MP and 13% in ELP), but the mean hospital-stay was longer for MP patients (P = 0.005). Mortality was zero. In the MP group, 5 patients affected by IPMNs had positive resection margins and 3 had recurrence. After a median follow-up of 54 months, incidence of new endocrine and exocrine insufficiency were significantly higher in the ELP group (4% vs. 38%, P = 0.0001 and 5% vs. 15.6%, P = 0.039, respectively). Conclusions: MP is a safe and effective procedure for treatment of benign and low-grade malignant neoplasms of the mid pancreas and is associated with a low risk of development of exocrine and endocrine insufficiency. MP should be avoided in patients affected by main-duct IPMN. We evaluated indications, perioperative, and long-term outcomes of 100 patients who underwent middle pancreatectomy (MP) at 2 high-volume centers. The outcomes after MP were compared with a control group that underwent extended left pancreatectomy (ELP) for neoplasms in the mid pancreas. The incidence of new endocrine and exocrine insufficiency was significantly higher in the ELP group compared with MP one, with a 9-fold increase of new-onset diabetes (38% vs. 4%, P = 0.0001) and a 3-fold increase in exocrine insufficiency (15.6% vs. 5%, P = 0.039).

Recent evidence of pancreatic penetration of several antibiotics active against the usual flora found in pancreatic sepsis, at therapeutic minimal inhibitory concentration, prompted the authors to perform a randomized, multicenter, clinical trial on imipenem prophylaxis in acute pancreatitis. Seventy-four patients with computed tomographic (CT) scans demonstrating necrotizing pancreatitis within 72 hours of onset were randomly assigned to two groups receiving no antibiotic treatment or 0.5 gram of prophylactic imipenem administered intravenously every eight hours for two weeks. Pancreatic sepsis was always detected by means of cultures (percutaneous CT or ultrasound-guided needle aspiration and intraoperative samples). The incidence of pancreatic sepsis was much less in treated patients (12.2 versus 30.3 percent, p < 0.01). Therefore, the authors recommend prophylactic use of imipenem in patients with acute necrotizing pancreatitis.

There is overwhelming consensus that quality of life assessment is urgently required in pancreatic cancer, yet little research has been conducted. We report on the development of a disease specific questionnaire module to supplement the EORTC core cancer module, the QLQ-C30 in patients with pancreatic cancer, using EORTC quality of life study group guidelines for module development. Relevant QoL issues were generated from literature searches and interviews with health professionals and patients with pancreatic cancer. Issues were constructed into items and provisionally translated. The provisional module was pretested in patients in 8 European centres. The resulting module the QLQ-PAN26 includes 26 items related to disease symptoms, treatment side-effects and emotional issues specific to pancreatic cancer. This should ensure that the module will be sensitive to assess the small but important disease and treatment related QoL changes in pancreatic cancer. The use of the QLQ-C30 and QLQ-PAN26 will provide a comprehensive system of QoL assessment in international trials of pancreatic cancer.

Assessment of the severity of acute pancreatitis (AP), together with the patient's nutritional status is crucial in the decision making process that determines the need for artificial nutrition. Both should be done on admission and at frequent intervals thereafter. The indication for nutritional support in AP is actual or anticipated inadequate oral intake for 5-7 days. This period may be shorter in those with pre-existing malnutrition. Substrate metabolism in severe AP is similar to that in severe sepsis or trauma. Parenteral amino acids, glucose and lipid infusion do not affect pancreatic secretion and function. If lipids are administered, serum triglycerides must be monitored regularly. The use of intravenous lipids as part of parenteral nutrition (PN) is safe and feasible when hypertriglyceridemia is avoided. PN is indicated only in those patients who are unable to tolerate targeted requirements by the enteral route. As rates of EN tolerance increase then volumes of PN should be decreased. When PN is administered, particular attention should be given to avoid overfeeding. When PN is indicated, a parenteral glutamine supplementation should be considered. In chronic pancreatitis PN may, on rare occasions, be indicated in patients with gastric outlet obstruction secondary to duodenal stenosis or those with complex fistulation, and in occasional malnourished patients prior to surgery.

Abstract Background In a randomized double-blind study the efficacy of neurolytic coeliac plexus block (NCPB) was compared with pharmacological therapy in the treatment of pain from pancreatic cancer. Methods Twenty-four patients were divided into two groups: 12 patients underwent NCPB (group 1) and 12 were treated with pharmacological therapy (group 2). Immediate and long-term efficacy, mean analgesic consumption, mortality and morbidity were evaluated at follow-up. Statistical analysis was performed with the unpaired t test, Mann–Whitney U test and Fisher's exact test. Results Immediately after the block, patients in group 1 reported significant pain relief compared with those in group 2 (P &amp;lt; 0·05), but long-term results did not differ between the groups. Mean analgesic consumption was lower in group 1. There were no deaths. Complications related to NCPB were transient diarrhoea and hypotension (P not significant between groups). Drug-related adverse effects were constipation (five of 12 patients in group 1 versus12 of 12 in group 2), nausea and/or vomiting (four of 12 patients in group 1 versus 12 of 12 in group 2) (P &amp;lt; 0·05), one gastric ulcer and one gluteal abscess in group 2. Conclusion NCPB was associated with a reduction in analgesic drug administration and drug-related adverse effects, representing an effective tool in the treatment of pancreatic cancer pain.

In Brief Background: Pancreatic infections and sepsis are major complications in severe acute pancreatitis (AP) with significant impact on management and outcome. We investigated the value of Procalcitonin (PCT) for identifying patients at risk to develop pancreatic infections in severe AP. Methods: A total of 104 patients with predicted severe AP were enrolled in five European academic surgical centers within 96 hours of symptom onset. PCT was measured prospectively by a semi-automated immunoassay in each center, C-reactive protein (CRP) was routinely assessed. Both parameters were monitored over a maximum of 21 consecutive days and in weekly intervals thereafter. Results: In contrast to CRP, PCT concentrations were significantly elevated in patients with pancreatic infections and associated multiorgan dysfunction syndrome (MODS) who all required surgery (n = 10) and in nonsurvivors (n = 8) early after onset of symptoms. PCT levels revealed only a moderate increase in patients with pancreatic infections in the absence of MODS (n = 7), all of whom were managed nonoperatively without mortality. A PCT value of ≥3.5 ng/mL on 2 consecutive days was superior to CRP ≥430 mg/L for the assessment of infected necrosis with MODS or nonsurvival as determined by ROC analysis with a sensitivity and specificity of 93% and 88% for PCT and 40% and 100% for CRP, respectively (P < 0.01). The single or combined prediction of the two major complications was already possible on the third and fourth day after onset of symptoms with a sensitivity and specificity of 79% and 93% for PCT ≥3.8 ng/mL compared with 36% and 97% for CRP ≥430 mg/L, respectively (P = 0.002). Conclusion: Monitoring of PCT allows early and reliable assessment of clinically relevant pancreatic infections and overall prognosis in AP. This single test parameter significantly contributes to an improved stratification of patients at risk to develop major complications. Early and reliable assessment of pancreatic infections is of major importance for timely goal-directed treatment in acute pancreatitis. The results of our prospective international multicenter study in patients with predicted severe disease has shown that a single laboratory test, Procalcitonin, significantly contributes to an early stratification of patients at risk to develop clinically relevant pancreatic infections or death.

Non-functioning pancreatic endocrine tumours (NF-PETs) are an aggressive gastroenteropancreatic neoplasm. The present study assessed survival, value of World Health Organisation (WHO) classification and prognostic utility of clinicopathological parameters at diagnosis.From 1990 to 2004, 180 patients with NF-PETs were entered in a prospective database, and predictors of prognosis were tested in uni- and multivariate models.There were 25 (14%) benign lesions, 38 (21%) neoplasms of uncertain behaviour, 100 well-differentiated carcinomas (56%) and 17 poorly differentiated carcinomas (9%). Radical resection was possible in 93 cases (51.6%). Overall 5-, 10- and 15-year survival rates were 67%, 49.3% and 32.8%, respectively, and were significantly higher in radically resected patients (93%, 80.8% and 65.2%, respectively; P < 0.00001). By multivariate analysis, poor differentiation [hazard ratio (HR) 7.3; P = 0.0001], nodal metastases (HR 3.05; P = 0.02), liver metastases (HR 3.29; P = 0.003), K(i)-67 >5% (HR 2.5; P = 0.012) and weight loss (HR 3.06; P = 0.001) were significantly associated with mortality.This study confirms the good long-term survival of patients with NF-PETs and the prognostic value of WHO classification, liver metastases, poor differentiation, Ki-67, nodal metastases and weight loss. These latter two parameters have a prognostic value similar to that of liver metastases and Ki-67.

Gene expression studies were undertaken in normal pancreas and pancreatic adenocarcinomas to determine new candidate genes that can potentially be used as markers of the disease. The characteristic desmoplastic stromal reaction of pancreatic adenocarcinoma greatly hampers expression studies in this tumour type, and usually necessitates time-consuming tissue microdissection for enrichment of the tumour cell population. We show that fine needle aspiration of cancer provides a fast and efficient way of obtaining samples highly enriched in tumour cells with sufficient yields of RNA. Using Atlas cancer cDNA arrays with 588 cancer-related genes, we describe gene expression profiles of normal pancreas, bulk pancreatic tumour tissues and pancreatic tumour aspirates containing more than 95% tumour cells. Analysis of bulk tissue specimens revealed differentially expressed genes belonging predominantly to the stromal component of the tumour. This contrasted with the results obtained from tumour-cell enriched samples. Several genes already described in pancreatic cancer (caspase 8, TIMP1, CD9, IL-13) were also differentially expressed in our study. Furthermore, we found dysregulated expression of genes not previously associated with pancreatic adenocarcinoma, such as Rac 1, GLG1, NEDD5, RPL-13a, RPS9 and members of the Wnt5A gene family. In summary, we present a panel of genes newly identified in the pathogenesis of pancreatic adenocarcinoma and demonstrate that fine needle aspirates of the tumour mass are a convenient source of material for gene expression studies in tumours accompanied by desmoplastic reactions.

Antibiotic prophylaxis in severe pancreatitis has recently yielded promising clinical results, with imipenem significantly reducing the incidence of infected necrosis compared with an untreated control group. On the bases of pefloxacin's spectrum of action and pancreatic penetration, we investigated whether such drugs represent a valid alternative to imipenem.In a multicenter study, 60 patients with severe acute pancreatitis with necrosis affecting at least 50% of the pancreas were randomly allocated to receive intravenous treatment for 2 weeks with pefloxacin, 400 mg twice daily (30 patients), or imipenem, 500 mg three times daily (30 patients), within 120 hours of onset of symptoms. Age, sex, body weight, Ranson and Apache II scores, C-reactive protein, etiology, and time from onset of symptoms to treatment were well matched in the two groups.The incidences of infected necrosis and extrapancreatic infections were 34% and 44%, respectively, in the pefloxacin group and 10% and 20% in the imipenem group. Imipenem proved significantly more effective in prevention of pancreatic infections (P </= 0.05). Mortality was not significantly different in the two groups.Despite its theoretical potential, pefloxacin is inferior to imipenem in the prevention of infections associated with severe pancreatitis.

Alterations of K-ras, p53, p16 and DPC4/Smad4 characterize pancreatic ductal cancer (PDC). Reports of inactivation of these latter two genes in pancreatic endocrine tumours (PET) suggest that common molecular pathways are involved in the tumorigenesis of pancreatic exocrine and endocrine epithelia. We characterized 112 primary pancreatic tumours for alterations in p16 and DPC4 and immunohistochemical expression of DPC4. The cases included 34 PDC, 10 intraductal papillary-mucinous tumours (IPMT), 6 acinar carcinomas (PAC), 5 solid-pseudopapillary tumours (SPT), 16 ampulla of Vater cancers (AVC) and 41 PET. All tumours were also presently or previously analysed for K-ras and p53 mutations and allelic loss at 9p, 17p and 18q. Alterations in K-ras, p53, p16 and DPC4 were found in 82%, 53%, 38% and 9% of PDC, respectively and in 47%, 60%, 25% and 6% of AVC. Alterations in these genes were virtually absent in PET, PAC or SPT, while in IPMT only K-ras mutations were present (30%). Positive immunostaining confirmed the absence of DPC4 alterations in all IPMT, SPT, PAC and PET, while 47% of PDC and 38% of AVC were immunonegative. These data suggest that pancreatic exocrine and endocrine tumourigenesis involves different genetic targets and that among exocrine pancreatic neoplasms, only ductal and ampullary cancers share common molecular events. © 2001 Cancer Research Campaign http://www.bjcancer.com

Chronic pancreatitis patients appear to present an increased incidence of pancreatic cancer. The aim of the study was to compare the incidence of cancer, whether pancreatic or extrapancreatic, in our chronic pancreatitis cases with that in the population of our region.We analyzed 715 cases of chronic pancreatitis with a median follow-up of 10 yr (7287 person-years); during this observation period they developed 61 neoplasms, 14 of which were pancreatic cancers. The cancer incidence rates were compared, after correction for age and gender, with those of a tumour registry.We documented a significant increase in incidence of both extrapancreatic (Standardized Incidence Ratio [SIR], 1.5; 95% confidence interval [CI], 1.1-2.0; p <0.003) and pancreatic cancer (SIR, 18.5; 95% CI, 10-30; p <0.0001) in chronic pancreatitis patients. Even when excluding from the analysis the four cases of pancreatic cancer that occurred within 4 yr of clinical onset of chronic pancreatitis, the SIR is 13.3 (95% CI, 6.4-24.5; p <0.0001). If we exclude these early-onset cancers, there would appear to be no increased risk of pancreatic cancer in nonsmokers, whereas in smokers this risk increases 15.6-fold.The risks of pancreatic and nonpancreatic cancers are increased in the course of chronic pancreatitis, the former being significantly higher than the latter. The very high incidence of pancreatic cancer in smokers probably suggests that, in addition to cigarette smoking, some other factor linked to chronic inflammation of the pancreas may be responsible for the increased risk.

The ESPAC-1, ESPAC-1 plus, and early ESPAC-3(v1) results (458 randomized patients; 364 deaths) were used to estimate the effectiveness of adjuvant 5FU/FA vs resection alone for pancreatic cancer using meta-analysis. The pooled hazard ratio of 0.70 (95% CI=0.55-0.88) P=0.003, and the median survival of 23.2 (95% CI=20.1-26.5) months with 5FU/FA vs 16.8 (95% CI=14.3-19.2) months with resection alone supports the use of adjuvant 5FU/FA in pancreatic cancer.

Abstract A placebo-controlled double-blind multicentre study, with randomization into parallel groups, was performed to determine whether perioperative subcutaneous administration of octreotide 0·1 mg every 8 h reduces the rate of complications specifically related to pancreatic surgery. In all, 252 patients were evaluated (153 men, 99 women; mean(s.e.m.) age 53·1(0·8) years) who had pancreatic or periampullary tumour or other duodenal disease (157 patients) or chronic pancreatitis (95) and were undergoing elective pancreatic resection (100 Whipple's procedure, 60 distal resection, 12 others), pancreaticojejunostomy (66) or enucleation of pancreatic lesions (14). The proportion of patients with complications was significantly lower in the group treated with octreotide than in the placebo group (15·6 versus 29·2 per cent, P = 0·01). Octreotide thus appears to reduce substantially the risk of complications related to elective pancreatic surgery. Moreover, treatment acceptability was high.

Abstract Background Radiofrequency ablation (RFA) may be a valuable treatment option for locally advanced pancreatic cancer. The present study examined its feasibility and safety. Methods Fifty patients with locally advanced pancreatic cancer were studied prospectively. Ultrasound-guided RFA was performed during laparotomy. The main outcome measures were short-term morbidity and mortality. Results The tumour was located in the pancreatic head or uncinate process in 34 patients and in the body or tail in 16; median diameter was 40 (interquartile range 30–50) mm. RFA was the only treatment in 19 patients. RFA was combined with biliary and gastric bypass in 19 patients, gastric bypass alone in eight, biliary bypass alone in three and pancreaticojejunostomy in one. The 30-day mortality rate was 2 per cent. Abdominal complications occurred in 24 per cent of patients; in half they were directly associated with RFA and treated conservatively. Three patients with surgery-related complications needed reoperation. Reduction of RFA temperature from 105 °C to 90 °C resulted in a significant reduction in complications (ten versus two of 25 patients; P = 0·028). Median postoperative hospital stay was 10 (range 7–31) days. Conclusion RFA of locally advanced pancreatic cancer is feasible and relatively well tolerated, with a 24 per cent complication rate.

The surgical strategy in patients with a pancreatic intraductal papillary mucinous tumour (IPMT) is still controversial. In this study the pathological findings in a series of patients were used to rationalize surgical choice.Fifty-one patients with IPMT were observed between 1988 and 1998 and treated by pancreatic resection. Factors evaluated included symptoms, tumour site, type of operation, histological findings and resection margins, tumour stage, follow-up and survival.Pancreaticoduodenectomy was the most frequent surgical treatment (33 patients; 65 per cent), followed by left pancreatectomy (ten), total pancreatectomy (five) and middle pancreatectomy (three). Histological assessment revealed the tumour to be an adenoma in 13 patients (25 per cent), a borderline tumour in ten (20 per cent) and a carcinoma in 28 (55 per cent), 19 of which were invasive. Mild to moderate dysplasia was present at the resection margin in 20 specimens (41 per cent), and carcinoma in one. Local recurrence was observed in four patients (8 per cent), all of whom underwent a second resection. The 3-year actuarial survival rate for benign and malignant disease was 94 and 69 per cent respectively (P = 0.03).These results suggest that resection should be the treatment for IPMT. Management of the resection margin could be crucial in avoiding tumour recurrence.

Chronic pancreatitis (CP) produces disabling symptoms and requires major clinical interventions over a number of years. There is consensus that quality-of-life (QoL) assessment should be part of assessing the treatment and outcome of CP. These symptoms and treatments resemble those of pancreatic cancer, for which there are validated QoL assessment instruments. The aim of our study was to assess the appropriateness of using the EORTC QoL assessment system for pancreatic cancer (the EORTC QLQ-C30 and QLQ-PAN26) for patients with CP, and to document important issues that affect QoL in these patients.A structured literature review was undertaken to determine current approaches to QoL in pancreatic disease. Sixty-six patients with newly diagnosed or treated CP were asked to complete the EORTC QLQ-C30 and QLQ-PAN26 in four countries (Germany, Italy, South Africa, and United Kingdom). Patients were asked to review the appropriateness of the content and structure of the instruments, during a directed interview. Standard psychometric tests were used to assess the reliability and validity of the instruments. Peer review was undertaken to review findings and adapt the QLQ-PAN26 on the basis of the responses obtained.The literature review highlighted the potential value of the EORTC QLQ-C30 and identified the lack of a CP-specific instrument, which had been appropriately developed. There was overwhelming consensus among experts that the EORTC assessment system appeared suitable for use in CP patients. This was endorsed by all patients. Patients identified additional issues related to guilt about the use of alcohol and the burden of trying to abstain. All but one scale (jaundice) exhibited adequate internal consistency (r > 0.70) Construct validity of the QLQ-C30 and QLQ-PAN26 showed strong associations between conceptually related scales (r > 0.6, p < 0.001) and significantly discriminated between patients on the basis of performance status and requirement for opiate analgesia. Significant issues affecting QoL in CP patients, in addition to recognized symptoms of the disease, were fear of future health problems, difficulty sleeping, and fatigue.The EORTC QLQ-C30 and QLQ-PAN26 appear to be an appropriate assessment system for CP, with the addition of items to cover guilt about alcohol consumption, and the burden of abstention. Patients' QoL is adversely affected by the fear of future health problems, difficulty sleeping, and fatigue.

Standard resections for benign and borderline neoplasms of the pancreas are associated with a significant risk of long-term functional impairment, whereas enucleation preserves healthy parenchyma and pancreatic function. The aim of this study was to evaluate postoperative and long-term oncological and functional results after pancreatic enucleation.Data collected prospectively from 61 consecutive patients who underwent pancreatic enucleation were analysed.There were no deaths. A clinically significant pancreatic fistula was reported in 14 patients (23 per cent), and five patients (8 per cent) had a further operation for fistula-related complications. The most common indication for surgery was endocrine neoplasm (38 patients; 62 per cent) and two patients (3 per cent) had a final histopathological diagnosis of malignant neoplasm. At a median follow-up of 61 months no patient had developed tumour recurrence or exocrine insufficiency. Two elderly patients developed non-insulin-dependent diabetes.Enucleation is an effective procedure for the radical treatment of benign and borderline neoplasms of the pancreas, with good long-term outcomes.

Intraductal papillary mucinous neoplasms (IPMNs) are the most common cystic precursor lesions of invasive pancreatic cancer. The recent identification of activating GNAS mutations at codon 201 in IPMNs is a promising target for early detection and therapy. The purpose of this study was to explore clinicopathological correlates of GNAS mutational status in resected IPMNs.Clinical and pathologic characteristics were retrieved on 54 patients in whom GNAS codon 201 mutational status was previously reported ("historical group", Wu et al. Sci Transl Med 3:92ra66, 2011). In addition, a separate cohort of 32 patients (validation group) was included. After microdissection and DNA extraction, GNAS status was determined in the validation group by pyrosequencing.GNAS activating mutations were found in 64% of the 32 IPMNs included in the validation group, compared with a previously reported prevalence of 57% in the historical group. Overall, 52 of 86 (61%) of IPMNs demonstrated GNAS mutations in the two studies combined. Analysis of both groups confirmed that demographic characteristics, tumor location, ductal system involvement, focality, size, grade of dysplasia, presence of an associated cancer, and overall survival were not correlated with GNAS mutational status. Stratified by histological subtype, 100% of intestinal type IPMNs demonstrated GNAS mutations compared to 51% of gastric IPMN, 71% of pancreatobiliary IPMNs, and 0% of oncocytic IPMNs.GNAS activating mutations can be reliably detected in IPMNs by pyrosequencing. In terms of clinicopathological parameters, only histological subtype was correlated with mutational frequency, with the intestinal phenotype always associated with GNAS mutations.

Purpose Gemcitabine requires transporter proteins to cross cell membranes. Low expression of human equilibrative nucleoside transporter-1 (hENT1) may result in gemcitabine resistance in pancreatic ductal adenocarcinoma (PDAC). CO-101, a lipid-drug conjugate of gemcitabine, was rationally designed to enter cells independently of hENT1. We conducted a randomized controlled trial to determine whether CO-101 improved survival versus gemcitabine in patients with metastatic PDAC (mPDAC) with low hENT1. The study also tested the hypothesis that gemcitabine is more active in patients with mPDAC tumors with high versus low hENT1 expression. Patients and Methods Patients were randomly assigned to CO-101 or gemcitabine, after providing a metastasis sample for blinded hENT1 assessment. An immunohistochemistry test measuring tumor hENT1 was developed. To dichotomize the population, an hENT1 cutoff value was defined using primary PDAC samples from an adjuvant trial, and a high/low cutoff was applied. The primary end point was overall survival (OS) in the low hENT1 subgroup. Results Of 367 patients enrolled, hENT1 status was measured in 358 patients (97.5%). Two hundred thirty-two (64.8%) of 358 patients were hENT1 low. There was no difference in OS between treatments in the low hENT1 subgroup or overall, with hazard ratios (HRs) of 0.994 (95% CI, 0.746 to 1.326) and 1.072 (95% CI, 0.856 to 1.344), respectively. The toxicity profiles in both arms were similar. Within the gemcitabine arm, there was no difference in survival between the high and low hENT1 subgroups (HR, 1.147; 95% CI, 0.809 to 1.626). Conclusion CO-101 is not superior to gemcitabine in patients with mPDAC and low tumor hENT1. Metastasis hENT1 expression did not predict gemcitabine outcome.

Purpose Individuals with adenocarcinoma of the ampulla of Vater demonstrate a broad range of outcomes, presumably because these cancers may arise from any one of the three epithelia that converge at that location. This variability poses challenges for clinical decision making and the development of novel therapeutic strategies. Patients and Methods We assessed the potential clinical utility of histomolecular phenotypes defined using a combination of histopathology and protein expression (CDX2 and MUC1) in 208 patients from three independent cohorts who underwent surgical resection for adenocarcinoma of the ampulla of Vater. Results Histologic subtype and CDX2 and MUC1 expression were significant prognostic variables. Patients with a histomolecular pancreaticobiliary phenotype (CDX2 negative, MUC1 positive) segregated into a poor prognostic group in the training (hazard ratio [HR], 3.34; 95% CI, 1.69 to 6.62; P &lt; .001) and both validation cohorts (HR, 5.65; 95% CI, 2.77 to 11.5; P &lt; .001 and HR, 2.78; 95% CI, 1.25 to 7.17; P = .0119) compared with histomolecular nonpancreaticobiliary carcinomas. Further stratification by lymph node (LN) status defined three clinically relevant subgroups: one, patients with histomolecular nonpancreaticobiliary (intestinal) carcinoma without LN metastases who had an excellent prognosis; two, those with histomolecular pancreaticobiliary carcinoma with LN metastases who had a poor outcome; and three, the remainder of patients (nonpancreaticobiliary, LN positive or pancreaticobiliary, LN negative) who had an intermediate outcome. Conclusion Histopathologic and molecular criteria combine to define clinically relevant histomolecular phenotypes of adenocarcinoma of the ampulla of Vater and potentially represent distinct diseases with significant implications for current therapeutic strategies, the ability to interpret past clinical trials, and future trial design.

Introduction: The following is a summary of the official guidelines of the Italian Association for the Study of the Pancreas regarding the medical, endoscopic and surgical management of acute pancreatitis. Statements: Clinical features together with elevation of the plasma concentrations of pancreatic enzymes are the cornerstones of diagnosis (recommendation A). Contrast-enhanced computed tomography (CT) provides good evidence for the presence of pancreatitis (recommendation C) and it should be carried out 48–72 h after the onset of symptoms in patients with predicted severe pancreatitis. Severity assessment is essential for the selection of the proper initial treatment in the management of acute pancreatitis (recommendation A) and should be done using the APACHE II score, serum C-reactive protein and CT assessment (recommendation C). The etiology of acute pancreatitis should be able to be determined in at least 80% of cases (recommendation B). An adequate volume of intravenous fluid should be administered promptly to correct the volume deficit and maintain basal fluid requirements (recommendation A); analgesia is crucial for the correct treatment of the disease (recommendation A). Enteral feeding is indicated in severe necrotizing pancreatitis and it is better than total parenteral nutrition (recommendation A). The use of prophylactic broad-spectrum antibiotics reduces infection rates in CT-proven necrotizing pancreatitis (recommendation A). Infected pancreatic necrosis in patients with clinical signs and symptoms of sepsis is an indication for intervention, including surgery and radiological drainage (recommendation B). Conclusions: The participants agreed to revise the guidelines every 3 years in order to re-evaluate each question on the management of acute pancreatitis patients according to the most recent literature.

OBJECTIVES: Autoimmune pancreatitis (AIP) is thought to be an immune-mediated inflammatory process, directed against the epithelial components of the pancreas. The objective was to identify novel markers of disease and to unravel the pathogenesis of AIP. METHODS: To explore key targets of the inflammatory process, we analyzed the expression of proteins at the RNA and protein level using genomics and proteomics, immunohistochemistry, western blot, and immunoassay. An animal model of AIP with LP-BM5 murine leukemia virus-infected mice was studied in parallel. RNA microarrays of pancreatic tissue from 12 patients with AIP were compared with those of 8 patients with non-AIP chronic pancreatitis. RESULTS: Expression profiling showed 272 upregulated genes, including those encoding for immunoglobulins, chemokines and their receptors, and 86 downregulated genes, including those for pancreatic proteases such as three trypsinogen isoforms. Protein profiling showed that the expression of trypsinogens and other pancreatic enzymes was greatly reduced. Immunohistochemistry showed a near-loss of trypsin-positive acinar cells, which was also confirmed by western blotting. The serum of AIP patients contained high titers of autoantibodies against the trypsinogens PRSS1 and PRSS2 but not against PRSS3. In addition, there were autoantibodies against the trypsin inhibitor PSTI (the product of theSPINK1gene). In the pancreas of AIP animals, we found similar protein patterns and a reduction in trypsinogen. CONCLUSIONS: These data indicate that the immune-mediated process characterizing AIP involves pancreatic acinar cells and their secretory enzymes such as trypsin isoforms. Demonstration of trypsinogen autoantibodies may be helpful for the diagnosis of AIP.

Background Current guidelines for the management of pancreatic cystic neoplasms are based on the assumption that these lesions can be classified correctly on the basis of features of cross-sectional imaging. However, a certain degree of overlap between different lesions exists, and little is known about the rate of inaccurate preoperative diagnoses. To address this issue, preoperative and final pathologic diagnoses of patients resected for a presumed pancreatic cystic neoplasm were compared. Methods Retrospective analysis was undertaken of patients managed operatively between 2000 and 2010. Preoperative workup was reviewed to identify diagnostic pitfalls and potential risk factors for incorrect preoperative characterization of cystic lesions presumed to be neoplastic. Results We analyzed 476 patients. Final pathologic diagnosis matched the preoperative diagnosis in 78% of cases. The highest accuracy was reached for solid pseudopapillary neoplasms (95%) and for main duct/mixed duct intraductal papillary mucinous neoplasms (81%). Surprisingly, 23 cysts (5%) were found to be ductal adenocarcinoma, whereas 45 patients (9%) underwent a pancreatic resection for a non-neoplastic condition. The use of a routine radiologic workup, including contrast-enhanced ultrasonography and magnetic resonance imaging, was associated with a favorably correct characterization of the cystic lesion. Endoscopic ultrasonography did not seem to improve diagnostic accuracy. Increased levels of serum carbohydrate antigen (CA)19-9 resulted as risk factors for an incorrect diagnosis as well as for a final diagnosis of a ductal adenocarcinoma. Conclusion The overall rate of inaccurate preoperative diagnoses in a tertiary care center with a broad experience in pancreatology approached 22%. Serum CA19-9 is an important complementary tool within the context of preoperative investigation of cystic neoplasms of the pancreas. Current guidelines for the management of pancreatic cystic neoplasms are based on the assumption that these lesions can be classified correctly on the basis of features of cross-sectional imaging. However, a certain degree of overlap between different lesions exists, and little is known about the rate of inaccurate preoperative diagnoses. To address this issue, preoperative and final pathologic diagnoses of patients resected for a presumed pancreatic cystic neoplasm were compared. Retrospective analysis was undertaken of patients managed operatively between 2000 and 2010. Preoperative workup was reviewed to identify diagnostic pitfalls and potential risk factors for incorrect preoperative characterization of cystic lesions presumed to be neoplastic. We analyzed 476 patients. Final pathologic diagnosis matched the preoperative diagnosis in 78% of cases. The highest accuracy was reached for solid pseudopapillary neoplasms (95%) and for main duct/mixed duct intraductal papillary mucinous neoplasms (81%). Surprisingly, 23 cysts (5%) were found to be ductal adenocarcinoma, whereas 45 patients (9%) underwent a pancreatic resection for a non-neoplastic condition. The use of a routine radiologic workup, including contrast-enhanced ultrasonography and magnetic resonance imaging, was associated with a favorably correct characterization of the cystic lesion. Endoscopic ultrasonography did not seem to improve diagnostic accuracy. Increased levels of serum carbohydrate antigen (CA)19-9 resulted as risk factors for an incorrect diagnosis as well as for a final diagnosis of a ductal adenocarcinoma. The overall rate of inaccurate preoperative diagnoses in a tertiary care center with a broad experience in pancreatology approached 22%. Serum CA19-9 is an important complementary tool within the context of preoperative investigation of cystic neoplasms of the pancreas.

Pancreatoduodenectomy (PD) provides the best chance for cure in the treatment of patients with localized pancreatic head cancer. In patients with a suspected, clinically resectable pancreatic head malignancy, the need for histologic confirmation before proceeding with PD has not historically been required, but remains controversial.An international panel of pancreatic surgeons working in well-known, high-volume centers reviewed the literature and worked together to establish a consensus on when to perform a PD in the absence of positive histology.The incidence of benign disease after PD for a presumed malignancy is 5-13%. Diagnosis by endoscopic cholangiopancreatography brushings and percutaneous fine-needle aspiration are highly specific, but poorly sensitive. Aspiration biopsy guided by endoscopic ultrasonography (EUS) has greater sensitivity, but it is highly operator dependent and increases expense. The incidence of autoimmune pancreatitis (AIP) in the benign resected specimens is 30-43%. EUS-guided Trucut biopsy, serum levels of immunoglobulin G4, and HISORt (Histology, Imaging, Serology, Other organ involvement, and Response to therapy) are used for diagnosis. If AIP is suspected but not confirmed, the response to a short course of steroids is helpful for diagnosis.In the presence of a solid mass suspicious for malignancy, consensus was reached that biopsy proof is not required before proceeding with resection. Confirmation of malignancy, however, is mandatory for patients with borderline resectable disease to be treated with neoadjuvant therapy before exploration for resection. When a diagnosis of AIP is highly suspected, a biopsy is recommended, and a short course of steroid treatment should be considered if the biopsy does not reveal features suspicious for malignancy.

Objective: The aim of this study was to identify the optimal fistula mitigation strategy following pancreaticoduodenectomy. Background: The utility of technical strategies to prevent clinically relevant postoperative pancreatic fistula (CR-POPF) following pancreatoduodenectomy (PD) may vary by the circumstances of the anastomosis. The Fistula Risk Score (FRS) identifies a distinct high-risk cohort (FRS 7 to 10) that demonstrates substantially worse clinical outcomes. The value of various fistula mitigation strategies in these particular high-stakes cases has not been previously explored. Methods: This multinational study included 5323 PDs performed by 62 surgeons at 17 institutions. Mitigation strategies, including both technique related (ie, pancreatogastrostomy reconstruction; dunking; tissue patches) and the use of adjuvant strategies (ie, intraperitoneal drains; anastomotic stents; prophylactic octreotide; tissue sealants), were evaluated using multivariable regression analysis and propensity score matching. Results: A total of 522 (9.8%) PDs met high-risk FRS criteria, with an observed CR-POPF rate of 29.1%. Pancreatogastrostomy, prophylactic octreotide, and omission of externalized stents were each associated with an increased rate of CR-POPF (all P < 0.001). In a multivariable model accounting for patient, surgeon, and institutional characteristics, the use of external stents [odds ratio (OR) 0.45, 95% confidence interval (95% CI) 0.25–0.81] and the omission of prophylactic octreotide (OR 0.49, 95% CI 0.30–0.78) were independently associated with decreased CR-POPF occurrence. In the propensity score matched cohort, an “optimal” mitigation strategy (ie, externalized stent and no prophylactic octreotide) was associated with a reduced rate of CR-POPF (13.2% vs 33.5%, P < 0.001). Conclusions: The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes.

In Brief Objective: To evaluate the role of an absorbable fibrin sealant patch (TachoSil) in reducing postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP). Background: POPF remains the main complication after DP. Methods: This was a prospective, open, randomized, study in which patients undergoing elective DP were randomized to standard surgical suturing or stapling with or without TachoSil. The primary end point was the incidence of POPF according to International Study Group on Pancreatic Fistula criteria. Amylase level in drainage fluid, number of days until removal of drain, and duration of hospital stay were secondary end points. Results: A total of 275 patients were enrolled at 19 centers over a 2-year period (TachoSil, n = 145; standard, n = 130). Twenty percent of procedures were laparoscopic and 21% were spleen-preserving resections. The incidence of POPF was not significantly different between groups (TachoSil, 62%; standard 68%; P = 0.267). Grade A fistula rate was similar in both groups (TachoSil 54%; standard 55%), whereas the grade B + C fistula rate was 8% with TachoSil versus 14% without (P = 0.139). Amylase drainage level on postoperative day 1 was significantly reduced with TachoSil (P = 0.025). Median number of days until drainage removal and length of hospital stay were similar in both groups (7 and 10 days, respectively). Conclusions: The POPF rate was higher than expected when International Study Group on Pancreatic Fistula criteria were strictly applied, although the majority were biochemical fistulas. TachoSil had no significant effect on the rate of POPF, although there was a significant reduction of amylase level in drainage fluid on postoperative day 1. Patients undergoing distal pancreatectomy were randomized to standard surgical suturing or stapling with (n = 145) or without (n = 130) TachoSil. The incidence of postoperative pancreatic fistula was not significantly different between groups (TachoSil, 62%; standard 68%; P = 0.267). Amylase level in drainage fluid on postoperative day 1 was reduced with TachoSil P = 0.025).

To evaluate the safety of the NanoKnife Low Energy Direct Current (LEDC) System (Irreversible Electroporation, IRE) in order to treat patients with unresectable pancreatic adenocarcinoma.Prospective, nonrandomized, single-center clinical evaluation of ten patients with a cytohystological diagnosis of unresectable locally advanced pancreatic cancer (LAPC) that was no further responsive to standard treatments. The primary outcome was the rate of procedure-related abdominal complications. The secondary endpoints included the evaluation of the short-term efficacy of IRE through the evaluation of tumor reduction at imaging and biological tumor response as shown by CA 19-9, clinical assessments and patient quality of life.Ten patients (5 males, 5 females) were enrolled, with a median age of 66 and median tumor size of 30 mm. All patients were treated successfully with a median procedure time of 79.5 min. Two procedure-related complications were described in one patient (10%): a pancreatic abscess with a pancreoduodenal fistula. Three patients had early progression of disease: one patient developed pulmonary metastases 30 days post-IRE and two patients had liver metastases 60 days after the procedure. We registered an overall survival of 7.5 months (range: 2.9-15.9).IRE is a safe procedure in patients with LAPC and may represent a new technological option in the treatment and multimodality management of this disease.

International Study Group of Pancreatic Fistula (ISGPF) grade C postoperative pancreatic fistulas (POPF) are the greatest contributor to major morbidity and mortality following pancreatoduodenectomy (PD); however, their infrequent occurrence has hindered deeper analysis. This study sought to develop a predictive algorithm, which could facilitate effective management of this challenging complication.Data were accrued from 4301 PDs worldwide. Demographics, postoperative management, and microbiological characteristics of grade C POPFs were evaluated. American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) preoperative and intraoperative variables were compared between grade C POPFs and a 639-case sample of non-grade C POPFs. Risk factors for grade C POPF formation were identified using regression analysis.Grade C POPFs developed in 79 patients (1.8 %). Deaths (90 days) occurred in 2.0 % (N = 88) of the overall series, with 35 % (N = 25) occurring in the presence of a grade C POPF. Reoperations occurred 72.2 % of the time. The rates of single- and multi-system organ failure were 28.2 and 39.7 %, respectively. Mortality rates escalated with pulmonary, renal, and neurologic organ failure, but they were unaffected by reoperation(s). The median number of complications incurred was four (IQR: 2-5), and the median duration of hospital stay was 32 (IQR: 21-54) days. Warning signs for impending grade C POPFs most often presented on postoperative day (POD) 6. Adjuvant chemotherapy might have benefited 55.7 % of grade C POPF patients, yet it was delayed in 25.6 % and never delivered in 67.4 % of these patients. Predictive models for grade C POPF occurrence based on preoperative factors alone and preoperative and intraoperative factors yielded areas under the receiver operating characteristic curve of 0.73 and 0.84 (both P < 0.000001), respectively.This global study represents the largest analysis of grade C POPFs following PD. It describes the severe burden that grade C POPFs incur on patients, with high rates of reoperation and infection, while also potentially worsening overall survival by causing death and delay/omission of adjuvant therapy. Additionally, aggressive clinical management for these POPFs did not improve or worsen 90-day mortality. Predictive tools developed through these data may provide value in managing this difficult complication.

Background Total pancreatectomy (TP) has been performed rarely in the past because of its high morbidity and mortality. Because outcomes of pancreatic surgery as well as management of pancreatic insufficiency have improved markedly, enthusiasm for TP has an increased. Methods Between 1996 and 2008, 65 patients (33 females, 32 males; median age, 63 years) underwent TP at a single, high-volume center. Indications, timing, and perioperative and long-term results were analyzed. Results Twenty-five patients (38.5%) underwent a planned, elective TP and 25 patients underwent a single-stage unplanned TP after an initial partial pancreatectomy that required TP because of intraoperative hemorrhage (n = 1) or positive pancreatic resection margin (n = 24). The remaining 15 patients (23%) underwent a 2-stage pancreatectomy for tumor recurrence in the remnant. No completion TP for postoperative complications were performed. There was no mortality; the overall morbidity was 39% and the reoperation rate was 5%. Overall, 48% of patients had intraductal papillary mucinous neoplasms, and 29% pancreatic ductal adenocarcinoma. The R1 resection rate was 12%. Four of 23 patients (17%) who underwent single-stage, unplanned TP for positive resection margin had R1 resection (positive retroperitoneal margin). The median follow-up was 34 months. The overall 5-year survival was 71%. No deaths owing to hypoglycemia were observed. Median insulin was 32 U/d, and the median lipase was 80,000 U/d. Conclusion TP can be performed safely with no mortality and acceptable morbidity. Postoperative pancreatic insufficiency can be managed safely. To achieve an R0 during TP, both the resection and retroperitoneal margin should be evaluated intraoperatively. TP is an effective operation in selected patients. Total pancreatectomy (TP) has been performed rarely in the past because of its high morbidity and mortality. Because outcomes of pancreatic surgery as well as management of pancreatic insufficiency have improved markedly, enthusiasm for TP has an increased. Between 1996 and 2008, 65 patients (33 females, 32 males; median age, 63 years) underwent TP at a single, high-volume center. Indications, timing, and perioperative and long-term results were analyzed. Twenty-five patients (38.5%) underwent a planned, elective TP and 25 patients underwent a single-stage unplanned TP after an initial partial pancreatectomy that required TP because of intraoperative hemorrhage (n = 1) or positive pancreatic resection margin (n = 24). The remaining 15 patients (23%) underwent a 2-stage pancreatectomy for tumor recurrence in the remnant. No completion TP for postoperative complications were performed. There was no mortality; the overall morbidity was 39% and the reoperation rate was 5%. Overall, 48% of patients had intraductal papillary mucinous neoplasms, and 29% pancreatic ductal adenocarcinoma. The R1 resection rate was 12%. Four of 23 patients (17%) who underwent single-stage, unplanned TP for positive resection margin had R1 resection (positive retroperitoneal margin). The median follow-up was 34 months. The overall 5-year survival was 71%. No deaths owing to hypoglycemia were observed. Median insulin was 32 U/d, and the median lipase was 80,000 U/d. TP can be performed safely with no mortality and acceptable morbidity. Postoperative pancreatic insufficiency can be managed safely. To achieve an R0 during TP, both the resection and retroperitoneal margin should be evaluated intraoperatively. TP is an effective operation in selected patients.

The aim of the study is to characterize postoperative acute pancreatitis (POAP).A standardized definition of POAP after pancreaticoduodenectomy (PD) has been recently proposed, but specific studies are lacking.The patients were extracted from the prospective database of The Pancreas Institute of Verona. POAP was defined as an elevation of the serum pancreatic amylase levels above the upper limit of normal (52 U/L) on postoperative day (POD) 0 or 1. The endpoints included defining the incidence and predictors of POAP and investigating the association of POAP with postoperative pancreatic fistula (POPF).The study population consisted of 292 patients who underwent PD. The POAP and POPF rates were 55.8% and 22.3%, respectively. POAP was an independent predictor of POPF (OR 3.8), with a 92% sensitivity and 53.7% specificity (AUC 0.79). Preoperative exocrine insufficiency (OR 0.39), neoadjuvant therapy (OR 0.29) additional resection of the pancreatic stump margin (OR 0.25), soft pancreatic texture (OR 4.38), and Main Pancreatic Duct (MPD) diameter ≤3 mm (OR 2.86) were independent predictors of POAP. In high-risk patients, an intraoperative fluid administration of ≤3 ml/kg/h was associated with an increased incidence of POAP (24.6 vs. 0%, P = 0.04) and POPF (27.6 vs. 11.4%, P = 0.05).This study represents the first clinical application of the only available definition of POAP as a specific complication of pancreatic surgery. POAP is associated with an increased occurrence of POPF and overall morbidity and could potentially be avoided through a specific intraoperative fluid regimen in high-risk pancreas.

OBJECTIVES: To investigate environmental, personal, and hereditary risk factors associated with the occurrence of intraductal papillary mucinous neoplasms of the pancreas (IPMNs). METHODS: Multicentre case–control study. Risk factors were identified from a questionnaire collecting data on family and medical history, and environmental factors. Cases were prevalent IPMNs seen at the participating units within an 18-month timeframe. Matched controls were enrolled alongside patients seen at outpatient clinics. RESULTS: Three-hundred and ninety patients with IPMN and 390 matched controls (166 males, mean age 65 in each group) were enrolled. Of the IPMNs, 310 had branch-duct involvement and 80 main-duct involvement. The only cancer with a 1st degree family history significantly higher in IPMN was pancreatic ductal adenocarcinoma (PDAC) (5.4% vs. 1.5%). Previous history of diabetes (13.6% vs. 7.5%), chronic pancreatitis (CP) (3.1% vs. 0.3%), peptic ulcer (7.2% vs. 4.3%), and insulin use (4.9% vs. 1.1%) were all more frequent with IPMNs. Logistic regression multivariate analysis revealed that history of diabetes (odds ratio (OR): 1.79, confidence interval (CI) 95%: 1.08–2.98), CP (OR: 10.10, CI 95%: 1.30–78.32), and family histories of PDAC (OR: 2.94, CI 95%: 1.17–7.39) were all independent risk factors. However, when analysis was restricted to diabetics who had taken insulin, risk of IPMN became stronger (OR: 6.03, CI 95%: 1.74–20.84). The association with all these risk factors seemed stronger for the subgroup with main duct involvement. CONCLUSIONS: A previous history of diabetes, especially with insulin use, CP, and family history of PDAC are all relevant risk factors for the development of IPMN. These results suggest an overlap between certain risk factors for PDAC and IPMN.

The aim of this study was to characterize patterns of local progression following resection for pancreatic intraductal papillary mucinous neoplasms (IPMN) using targeted next-generation sequencing (NGS).Progression of neoplastic disease in the remnant pancreas following resection of IPMN may include development of a new IPMN or ductal adenocarcinoma (PDAC). However, it is not clear whether this progression represents recurrence of the same neoplasm or an independent second neoplasm.Targeted-NGS on genes commonly mutated in IPMN and PDAC was performed on tumors from (1) 13 patients who developed disease progression in the remnant pancreas following resection of IPMN; and (2) 10 patients who underwent a resection for PDAC and had a concomitant IPMN. Mutations in the tumors were compared in order to determine the relationship between neoplasms. In parallel, clinical and pathological characteristics of 260 patients who underwent resection of noninvasive IPMN were reviewed to identify risk factors associated with local progression.We identified 3 mechanisms underlying local progression in the remnant pancreas: (1) residual microscopic disease at the resection margin, (2) intraparenchymal spread of neoplastic cells, leading to an anatomically separate but genetically related recurrence, and (3) multifocal disease with genetically distinct lesions. Analysis of the 260 patients with noninvasive IPMNs showed that family history of pancreatic cancer (P = 0.027) and high-grade dysplasia (HGD) (P = 0.003) were independent risk factors for the development of an IPMN with HGD or an invasive carcinoma in the remnant pancreas.Using NGS, we identify distinct mechanisms for development of metachronous or synchronous neoplasms in patients with IPMN. Patients with a primary IPMN with HGD or with positive family history are at an increased risk to develop subsequent high-risk neoplasms in the remnant pancreas.

Background A recent randomized trial used the Fistula Risk Score (FRS) to develop guidelines for selective drainage based on clinically relevant fistula (CR-POPF) risk. Additionally, postoperative day (POD) 1 drain and serum amylase have been identified as accurate postoperative predictors of CR-POPF. This study sought to identify patients who may benefit from selective drainage, as well as the optimal timing for drain removal after pancreatoduodenectomy. Study Design One hundred six pancreatoduodenectomies from a previously reported RCT were assessed using risk-adjustment. The incidence of CR-POPF was compared between FRS risk cohorts. Drain and serum amylase values from POD 1 were evaluated using receiver operating characteristic (ROC) analysis to establish cut-offs predictive of CR-POPF occurrence. A regression analysis compared drain removal randomizations (POD 3 vs POD 5). Results Three-quarters of patients had moderate/high CR-POPF risk. This group had a CR-POPF rate of 36.3% vs 7.7% among negligible/low risk patients (p = 0.005). The areas under the ROC curve for CR-POPF prediction using POD 1 drain and serum amylase values were 0.800 (p = 0.000001; 95% CI 0.70–0.90) and 0.655 (p = 0.012; 95% CI 0.55–0.77), respectively. No significant serum amylase cut-offs were identified. Moderate/high risk patients with POD 1 drain amylase ≤5,000 U/L had significantly lower rates of CR-POPF when randomized to POD 3 drain removal (4.2% vs 38.5%; p = 0.003); moreover, these patients experienced fewer complications and shorter hospital stays. Conclusions A clinical care protocol is proposed whereby drains are recommended for moderate/high FRS risk patients, but may be omitted in patients with negligible/low risk. Drain amylase values in moderate/high risk patients should then be evaluated on POD 1 to determine the optimal timing for drain removal. Moderate/high risk patients with POD 1 drain amylase ≤5,000 U/L have lower rates of CR-POPF with POD 3 (vs POD ≥ 5) drain removal; early drain removal is recommended for these patients.

The natural history and growth pattern of pancreatic serous cystic neoplasms (SCNs) are not well understood. This study was designed in order to get insight into the growth rate of SCNs and to suggest recommendations for their management.Patients with well-documented incidentally discovered or minimally symptomatic SCNs who underwent yearly surveillance MRI were analysed using a linear mixed model. The growth rate and the effects of different fixed factors (sex, personal history of other non-pancreatic malignancies, radiological pattern, clinical presentation, tumour site) and random factors (age and tumour diameter at the time of diagnosis) on tumour growth were investigated.Study population consisted of 145 patients. Estimated overall mean growth rate was 0.28 cm/year, but the growth curve analysis showed a different trend between the first 7 years after the baseline evaluation (growth rate of 0.1 cm/year) and the subsequent period (years 7 to 10, growth rate of 0.6 cm/year, p<0.0001). Tests for fixed effects demonstrated that an oligocystic/macrocystic pattern and a personal history of other tumours are significant predictors of a more rapid mean tumour growth (p<0.0001 and 0.022, growth rates of 0.34 cm/year). Furthermore, tumour growth significantly increased with age (p = 0.0001).Overall, SCNs grow slowly, and an initial non-operative approach is feasible in all the asymptomatic or minimally symptomatic patients. The oligocystic/macrocystic variant, a history of other non-pancreatic malignancies and patients' age impact on tumour growth. In any case, a significant growth is unlikely to occur before 7 years from the baseline evaluation. Tumour size at the time of diagnosis should not be used for decisional purposes.

This is a medical position statement developed by the Exocrine Pancreatic Insufficiency collaborative group which is a part of the Italian Association for the Study of the Pancreas (AISP). We covered the main diseases associated with exocrine pancreatic insufficiency (EPI) which are of common interest to internists/gastroenterologists, oncologists and surgeons, fully aware that EPI may also occur together with many other diseases, but less frequently. A preliminary manuscript based on an extended literature search (Medline/PubMed, Cochrane Library and Google Scholar) of published reports was prepared, and key recommendations were proposed. The evidence was discussed at a dedicated meeting in Bologna during the National Meeting of the Association in October 2012. Each of the proposed recommendations and algorithms was discussed and an initial consensus was reached. The final draft of the manuscript was then sent to the AISP Council for approval and/or modification. All concerned parties approved the final version of the manuscript in June 2013.