Genetic and functional analysis of chymotrypsin-like protease (CTRL) in chronic pancreatitis.

BACKGROUND: Genetic predisposition is crucial in the pathogenesis of early-onset chronic pancreatitis (CP). So far, several genetic alterations have been identified as risk factors, predominantly in genes encoding digestive enzymes. However, many early-onset CP cases have no identified underlying cause. Chymotrypsins are a family of serine proteases that can cleave trypsinogen and lead to its degradation. Because genetic alterations in the chymotrypsins CTRC, CTRB1, and CTRB2 are associated with CP, we genetically and functionally investigated chymotrypsin-like protease (CTRL) as a potential risk factor. METHODS: We screened 1005 non-alcoholic CP patients and 1594 controls for CTRL variants by exome sequencing. We performed Western blots and activity assays to analyse secretion and proteolytic activity. We measured BiP mRNA expression to investigate the potential impact of identified alterations on endoplasmic reticulum (ER) stress. RESULTS: We identified 13 heterozygous non-synonymous CTRL variants: five exclusively in patients and three only in controls. Functionality was unchanged in 6/13 variants. Four alterations showed normal secretion but reduced (p.G20S, p.G56S, p.G61S) or abolished (p.S208F) activity. Another three variants (p.C201Y, p.G215R and p.C220G) were not secreted and already showed reduced or no activity intracellularly. However, intracellular retention did not lead to ER stress. CONCLUSION: We identified several CTRL variants, some showing potent effects on protease function and secretion. We observed these effects in variants found in patients and controls, and CTRL loss-of-function variants were not significantly more common in patients than controls. Therefore, CTRL is unlikely to play a relevant role in the development of CP.

Chemotherapy-induced infiltration of neutrophils promotes pancreatic cancer metastasis via Gas6/AXL signalling axis.

OBJECTIVE: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease and cytotoxic chemotherapy is the standard of care treatment for patients with advanced disease. Here, we investigate how the microenvironment in PDAC liver metastases reacts to chemotherapy and its role in metastatic disease progression post-treatment, an area which is poorly understood. DESIGN: The impact of chemotherapy on metastatic disease progression and immune cell infiltrates was characterised using flow and mass cytometry combined with transcriptional and histopathological analysis in experimental PDAC liver metastases mouse models. Findings were validated in patient derived liver metastases and in an autochthonous PDAC mouse model. Human and murine primary cell cocultures and ex vivo patient-derived liver explants were deployed to gain mechanistical insights on whether and how chemotherapy affects the metastatic tumour microenvironment. RESULTS: We show that in vivo, chemotherapy induces an initial infiltration of proinflammatory macrophages into the liver and activates cytotoxic T cells, leading only to a temporary restraining of metastatic disease progression. However, after stopping treatment, neutrophils are recruited to the metastatic liver via CXCL1 and 2 secretion by metastatic tumour cells. These neutrophils express growth arrest specific 6 (Gas6) which leads to AXL receptor activation on tumour cells enabling their regrowth. Disruption of neutrophil infiltration or inhibition of the Gas6/AXL signalling axis in combination with chemotherapy inhibits metastatic growth. Chemotherapy increases Gas6 expression in circulating neutrophils from patients with metastatic pancreatic cancer and recombinant Gas6 is sufficient to promote tumour cell proliferation ex vivo, in patient-derived metastatic liver explants. CONCLUSION: Combining chemotherapy with Gas6/AXL or neutrophil targeted therapy could provide a therapeutic benefit for patients with metastatic pancreatic cancer.

Postpancreatectomy Acute Pancreatitis (PPAP): Definition and Grading From the International Study Group for Pancreatic Surgery (ISGPS).

OBJECTIVE: The ISGPS aimed to develop a universally accepted definition for PPAP for standardized reporting and outcome comparison. BACKGROUND: PPAP is an increasingly recognized complication after partial pancreatic resections, but its incidence and clinical impact, and even its existence are variable because an internationally accepted consensus definition and grading system are lacking. METHODS: The ISGPS developed a consensus definition and grading of PPAP with its members after an evidence review and after a series of discussions and multiple revisions from April 2020 to May 2021. RESULTS: We defined PPAP as an acute inflammatory condition of the pancreatic remnant beginning within the first 3 postoperative days after a partial pancreatic resection. The diagnosis requires (1) a sustained postoperative serum hyperamylasemia (POH) greater than the institutional upper limit of normal for at least the first 48 hours postoperatively, (2) associated with clinically relevant features, and (3) radiologic alterations consistent with PPAP. Three different PPAP grades were defined based on the clinical impact: (1) grade postoperative hyperamylasemia, biochemical changes only; (2) grade B, mild or moderate complications; and (3) grade C, severe life-threatening complications. DISCUSSIONS: The present definition and grading scale of PPAP, based on biochemical, radiologic, and clinical criteria, are instrumental for a better understanding of PPAP and the spectrum of postoperative complications related to this emerging entity. The current terminology will serve as a reference point for standard assessment and lend itself to developing specific treatments and prevention strategies.

Early infection is an independent risk factor for increased mortality in patients with culture-confirmed infected pancreatic necrosis.

BACKGROUND: Mortality in infected pancreatic necrosis (IPN) is dynamic over the course of the disease, with type and timing of interventions as well as persistent organ failure being key determinants. The timing of infection onset and how it pertains to mortality is not well defined. OBJECTIVES: To determine the association between mortality and the development of early IPN. METHODS: International multicenter retrospective cohort study of patients with IPN, confirmed by a positive microbial culture from (peri) pancreatic collections. The association between timing of infection onset, timing of interventions and mortality were assessed using Cox regression analyses. RESULTS: A total of 743 patients from 19 centers across 3 continents with culture-confirmed IPN from 2000 to 2016 were evaluated, mortality rate was 20.9% (155/734). Early infection was associated with a higher mortality, when early infection occurred within the first 4 weeks from presentation with acute pancreatitis. After adjusting for comorbidity, advanced age, organ failure, enteral nutrition and parenteral nutrition, early infection (≤4 weeks) and early open surgery (≤4 weeks) were associated with increased mortality [HR: 2.45 (95% CI: 1.63-3.67), p < 0.001 and HR: 4.88 (95% CI: 1.70-13.98), p = 0.003, respectively]. There was no association between late open surgery, early or late minimally invasive surgery, early or late percutaneous drainage with mortality (p > 0.05). CONCLUSION: Early infection was associated with increased mortality, independent of interventions. Early surgery remains a strong predictor of excess mortality.

SARS-CoV-2 infection in acute pancreatitis increases disease severity and 30-day mortality: COVID PAN collaborative study.

OBJECTIVE: There is emerging evidence that the pancreas may be a target organ of SARS-CoV-2 infection. This aim of this study was to investigate the outcome of patients with acute pancreatitis (AP) and coexistent SARS-CoV-2 infection. DESIGN: A prospective international multicentre cohort study including consecutive patients admitted with AP during the current pandemic was undertaken. Primary outcome measure was severity of AP. Secondary outcome measures were aetiology of AP, intensive care unit (ICU) admission, length of hospital stay, local complications, acute respiratory distress syndrome (ARDS), persistent organ failure and 30-day mortality. Multilevel logistic regression was used to compare the two groups. RESULTS: 1777 patients with AP were included during the study period from 1 March to 23 July 2020. 149 patients (8.3%) had concomitant SARS-CoV-2 infection. Overall, SARS-CoV-2-positive patients were older male patients and more likely to develop severe AP and ARDS (p<0.001). Unadjusted analysis showed that SARS-CoV-2-positive patients with AP were more likely to require ICU admission (OR 5.21, p<0.001), local complications (OR 2.91, p<0.001), persistent organ failure (OR 7.32, p<0.001), prolonged hospital stay (OR 1.89, p<0.001) and a higher 30-day mortality (OR 6.56, p<0.001). Adjusted analysis showed length of stay (OR 1.32, p<0.001), persistent organ failure (OR 2.77, p<0.003) and 30-day mortality (OR 2.41, p<0.04) were significantly higher in SARS-CoV-2 co-infection. CONCLUSION: Patients with AP and coexistent SARS-CoV-2 infection are at increased risk of severe AP, worse clinical outcomes, prolonged length of hospital stay and high 30-day mortality.

The in situ near-total pancreatectomy (LIVOCADO procedure) for end-staged chronic pancreatitis.

PURPOSE: Total pancreatectomy for severe pain in end-stage chronic pancreatitis may be the only option, but with vascular involvement, this is usually too high risk and/or technically not feasible. The purpose of the study was to present the clinical outcomes of a novel procedure in severe chronic pancreatitis complicated by uncontrollable pain and vascular involvement. METHODS: We describe an in situ near-total pancreatectomy that avoids peripancreatic vascular dissection (Livocado procedure) and report on surgical and clinical outcomes. RESULTS: The Livocado procedure was carried out on 18 (3.9%) of 465 patients undergoing surgery for chronic pancreatitis. There were 13 men and 5 women with a median (IQR) age of 48.5 (42.4-57) years and weight of 60.7 (58.0-75.0) kg. All had severe pain and vascular involvement; 17 had pancreatic parenchymal calcification; the median (IQR) oral morphine equivalent dose requirement was 86 (33-195) mg/day. The median (IQR) maximal pain scores were 9 (9-10); the average pain score was 6 (IQR 4-7). There was no peri-operative or 90-day mortality. At a median (IQR) follow-up of 32.5 (21-45.75) months, both maximal and average pain scores were significantly improved post-operatively, and at 12 months, two-thirds of patients were completely pain free. Six (33%) patients had employment pre-operatively versus 13 (72%) post-operatively (p = 0.01). CONCLUSIONS: The Livocado procedure was safe and carried out successfully in patients with chronic pancreatitis with vascular involvement where other procedures would be contraindicated. Perioperative outcomes, post-operative pain scores, and employment rehabilitation were comparable with other procedures carried out in patients without vascular involvement.

International consensus guidelines on surveillance for pancreatic cancer in chronic pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with the International Association of Pancreatology, the American Pancreatic Association, the Japan Pancreas Society, and European Pancreatic Club.

BACKGROUND: Patients with chronic pancreatitis (CP) have an increased risk of pancreatic cancer. We present the international consensus guidelines for surveillance of pancreatic cancer in CP. METHODS: The international group evaluated 10 statements generated from evidence on 5 questions relating to pancreatic cancer in CP. The GRADE approach was used to evaluate the level of evidence available per statement. The working group voted on each statement for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: In the following domains there was strong consensus: (1) the risk of pancreatic cancer in affected individuals with hereditary pancreatitis due to inherited PRSS1 mutations is high enough to justify surveillance; (2) the risk of pancreatic cancer in patients with CP associated with SPINK1 p. N34S is not high enough to justify surveillance; (3) surveillance should be undertaken in pancreatic specialist centers; (4) surveillance should only be introduced after the age of 40 years and stopped when the patient would no longer be suitable for surgical intervention. All patients with CP should be advised to lead a healthy lifestyle aimed at avoiding risk factors for progression of CP and pancreatic cancer. There was only moderate or weak agreement on the best methods of screening and surveillance in other types of environmental, familial and genetic forms of CP. CONCLUSIONS: Patients with inherited PRSS1 mutations should undergo surveillance for pancreatic cancer, but the best methods for cancer detection need further investigation.

The Impact of Positive Resection Margins on Survival and Recurrence Following Resection and Adjuvant Chemotherapy for Pancreatic Ductal Adenocarcinoma.

OBJECTIVE AND BACKGROUND: Local and distant disease recurrence are frequently observed following pancreatic cancer resection, but an improved understanding of resection margin assessment is required to aid tailored therapies. METHODS: Analyses were carried out to assess the association between clinical characteristics and margin involvement as well as the effects of individual margin involvement on site of recurrence and overall and recurrence-free survival using individual patient data from the European Study Group for Pancreatic Cancer (ESPAC)-3 randomized controlled trial. RESULTS: There were 1151 patients, of whom 505 (43.9%) had an R1 resection. The median and 95% confidence interval (CI) overall survival was 24.9 (22.9-27.2) months for 646 (56.1%) patients with resection margin negative (R0 >1 mm) tumors, 25.4 (21.6-30.4) months for 146 (12.7%) patients with R1<1 mm positive resection margins, and 18.7 (17.2-21.1) months for 359 (31.2%) patients with R1-direct positive margins (P < 0.001). In multivariable analysis, overall R1-direct tumor margins, poor tumor differentiation, positive lymph node status, WHO performance status ≥1, maximum tumor size, and R1-direct posterior resection margin were all independently significantly associated with reduced overall and recurrence-free survival. Competing risks analysis showed that overall R1-direct positive resection margin status, positive lymph node status, WHO performance status 1, and R1-direct positive superior mesenteric/medial margin resection status were all significantly associated with local recurrence. CONCLUSIONS: R1-direct resections were associated with significantly reduced overall and recurrence-free survival following pancreatic cancer resection. Resection margin involvement was also associated with an increased risk for local recurrence.

Immune Cell and Stromal Signature Associated With Progression-Free Survival of Patients With Resected Pancreatic Ductal Adenocarcinoma.

BACKGROUND & AIMS: Changes to the microenvironment of pancreatic ductal adenocarcinomas (PDACs) have been associated with poor outcomes of patients. We studied the associations between composition of the pancreatic stroma (fibrogenic, inert, dormant, or fibrolytic stroma) and infiltration by inflammatory cells and times of progression-free survival (PFS) of patients with PDACs after resection. METHODS: We obtained 1824 tissue microarray specimens from 385 patients included in the European Study Group for Pancreatic Cancer trial 1 and 3 and performed immunohistochemistry to detect alpha smooth muscle actin, type 1 collagen, CD3, CD4, CD8, CD68, CD206, and neutrophils. Tumors that expressed high and low levels of these markers were compared with patient outcomes using Kaplan-Meier curves and multivariable recursive partitioning for discrete-time survival tree analysis. Prognostic index was delineated by a multivariable Cox proportional hazards model of immune cell and stromal markers and PFS. Findings were validated using 279 tissue microarray specimens from 93 patients in a separate cohort. RESULTS: Levels of CD3, CD4, CD8, CD68, and CD206 were independently associated with tumor recurrence. Recursive partitioning for discrete-time survival tree analysis identified a high level of CD3 as the strongest independent predictor for longer PFS. Tumors with levels of CD3 and high levels of CD206 associated with a median PFS time of 16.6 months and a median prognostic index of -0.32 (95% confidence interval [CI] -0.35 to -0.31), whereas tumors with low level of CD3 cell and low level of CD8 and high level of CD68 associated with a median PFS time of 7.9 months and a prognostic index of 0.32 (95% CI 0.050-0.32); we called these patterns histologic signatures. Stroma composition, when unassociated with inflammatory cell markers, did not associate significantly with PFS. In the validation cohort, the histologic signature resulted in an error matrix accuracy of predicted response of 0.75 (95% CI 0.64-0.83; accuracy P < .001). CONCLUSIONS: In an analysis of PDAC tissue microarray specimens, we identified and validated a histologic signature, based on leukocyte and stromal factors, that associates with PFS times of patients with resected PDACs. Immune cells might affect the composition of the pancreatic stroma to affect progression of PDAC. These findings provide new insights into the immune response to PDAC.

A systematic review and meta-analysis of metal versus plastic stents for drainage of pancreatic fluid collections: metal stents are advantageous.

BACKGROUND: The use of fully covered metal stents (FCSEMS) and specifically designed lumen apposing metal stents for transmural drainage of pancreatic fluid collections has become widespread. A systematic review published in 2015 did not support the routine use of metal stents for drainage of pancreatic fluid collections. However, recent studies have shown conflicting data; therefore a systematic review and meta-analysis was performed. METHOD: We conducted a database search for original comparative studies between plastic and metal stents. The random effects model was used to calculate pooled risk ratios (RR) with 95% confidence intervals (CI). Outcomes analysed were clinical success, adverse events and requirement of further intervention. RESULTS: The search identified 936 studies, 7 studies with 681 (340 metal, 341 plastic) patients met inclusion criteria and were included in the meta-analysis. Clinical success was achieved in 93.8% versus 86.2% in the metal and plastic groups, respectively, RR 1.08 [95% CI 1.02-1.14]; p = 0.009. Adverse events were reduced for metal stents when compared with plastic (10.2% vs. 25.0%), RR 0.42 [95% CI 0.22-0.81]; p = 0.010. Metal stent usage reduced bleeding (2.8% vs. 7.9%), RR 0.37; [95% CI 0.18-0.75]; p = 0.006. Further intervention was required in 12.4% of patients in the metal stent group versus 26.7% for plastic stents, RR 0.54; [95% CI 0.22-1.29]; p = 0.165. CONCLUSIONS: The use of metal stents for drainage of pancreatic fluid collections is associated with improved clinical success, fewer adverse events and reduced bleeding compared to plastic stents.

Cytoplasmic HuR Status Predicts Disease-free Survival in Resected Pancreatic Cancer: A Post-hoc Analysis From the International Phase III ESPAC-3 Clinical Trial.

OBJECTIVES: We tested cytoplasmic HuR (cHuR) as a predictive marker for response to chemotherapy by examining tumor samples from the international European Study Group of Pancreatic Cancer-3 trial, in which patients with resected pancreatic ductal adenocarcinoma (PDA) received either gemcitabine (GEM) or 5-fluorouracil (5-FU) adjuvant monotherapy. BACKGROUND: Previous studies have implicated the mRNA-binding protein, HuR (ELAVL1), as a predictive marker for PDA treatment response in the adjuvant setting. These studies were, however, based on small cohorts of patients outside of a clinical trial, or a clinical trial in which patients received multimodality therapy with concomitant radiation. METHODS: Tissue samples from 379 patients with PDA enrolled in the European Study Group of Pancreatic Cancer-3 trial were immunolabeled with an anti-HuR antibody and scored for cHuR expression. Patients were dichotomized into groups of high versus low cHuR expression. RESULTS: There was no association between cHuR expression and prognosis in the overall cohort [disease-free survival (DFS), P = 0.44; overall survival, P = 0.41). Median DFS for patients with high cHuR was significantly greater for patients treated with 5-FU compared to GEM [20.1 months, confidence interval (CI): 8.3-36.4 vs 10.9 months, CI: 7.5-14.2; P = 0.04]. Median DFS was similar between the treatment arms in patients with low cHuR (5-FU, 12.8 months, CI: 10.6-14.6 vs GEM, 12.9 months, CI: 11.2-15.4). CONCLUSIONS: Patients with high cHuR-expressing tumors may benefit from 5-FU-based adjuvant therapy as compared to GEM, whereas those patients with low cHuR appear to have no survival advantage with GEM compared with 5-FU. Further studies are needed to validate HuR as a biomarker in both future monotherapy and multiagent regimens.

Partial pancreatoduodenectomy versus duodenum-preserving pancreatic head resection in chronic pancreatitis: the multicentre, randomised, controlled, double-blind ChroPac trial.

BACKGROUND: There is substantial uncertainty regarding the optimal surgical treatment for chronic pancreatitis. Short-term outcomes have been found to be better after duodenum-preserving pancreatic head resection (DPPHR) than after partial pancreatoduodenectomy. Therefore, we designed the multicentre ChroPac trial to investigate the long-term outcomes of patients with chronic pancreatitis within 24 months after surgery. METHODS: This randomised, controlled, double-blind, parallel-group, superiority trial was done in 18 hospitals across Europe. Patients with chronic pancreatitis who were planned for elective surgical treatment were randomly assigned to DPPHR or partial pancreatoduodenectomy with a central web-based randomisation tool. The primary endpoint was mean quality of life within 24 months after surgery, measured with the physical functioning scale of the European Organisation for Research and Treatment of Cancer QLQ-C30 questionnaire. Primary analysis included all patients who underwent one of the assigned procedures; safety analysis included all patients who underwent surgical intervention (categorised into groups as treated). Patients and outcome assessors were masked to group assignment. The trial was registered, ISRCTN38973832. Recruitment was completed on Sept 3, 2013. FINDINGS: Between Sept 10, 2009, and Sept 3, 2013, 250 patients were randomly assigned to DPPHR (n=125) or partial pancreatoduodenectomy (n=125), of whom 226 patients (115 in the DPPHR group and 111 in the partial pancreatoduodenectomy group) were analysed. No difference in quality of life was seen between the groups within 24 months after surgery (75·3 [SD 16·4] for partial pancreatoduodenectomy vs 73·0 [16·4] for DPPHR; mean difference -2·3, 95% CI -6·6 to 2·0; p=0·284). The incidence and severity of serious adverse events did not differ between the groups. 70 (64%) of 109 patients in the DPPHR group and 61 (52%) of 117 patients in the partial pancreatoduodenectomy group had at least one serious adverse event, with the most common being reoperations (for reasons other than chronic pancreatitis), gastrointestinal problems, and other surgical morbidity. INTERPRETATION: No differences in quality of life after surgery for chronic pancreatitis were seen between the interventions. Results from single-centre trials showing superiority for DPPHR were not confirmed in the multicentre setting. FUNDING: German Research Foundation (DFG).

Comparison of adjuvant gemcitabine and capecitabine with gemcitabine monotherapy in patients with resected pancreatic cancer (ESPAC-4): a multicentre, open-label, randomised, phase 3 trial.

BACKGROUND: The ESPAC-3 trial showed that adjuvant gemcitabine is the standard of care based on similar survival to and less toxicity than adjuvant 5-fluorouracil/folinic acid in patients with resected pancreatic cancer. Other clinical trials have shown better survival and tumour response with gemcitabine and capecitabine than with gemcitabine alone in advanced or metastatic pancreatic cancer. We aimed to determine the efficacy and safety of gemcitabine and capecitabine compared with gemcitabine monotherapy for resected pancreatic cancer. METHODS: We did a phase 3, two-group, open-label, multicentre, randomised clinical trial at 92 hospitals in England, Scotland, Wales, Germany, France, and Sweden. Eligible patients were aged 18 years or older and had undergone complete macroscopic resection for ductal adenocarcinoma of the pancreas (R0 or R1 resection). We randomly assigned patients (1:1) within 12 weeks of surgery to receive six cycles of either 1000 mg/m2 gemcitabine alone administered once a week for three of every 4 weeks (one cycle) or with 1660 mg/m2 oral capecitabine administered for 21 days followed by 7 days' rest (one cycle). Randomisation was based on a minimisation routine, and country was used as a stratification factor. The primary endpoint was overall survival, measured as the time from randomisation until death from any cause, and assessed in the intention-to-treat population. Toxicity was analysed in all patients who received trial treatment. This trial was registered with the EudraCT, number 2007-004299-38, and ISRCTN, number ISRCTN96397434. FINDINGS: Of 732 patients enrolled, 730 were included in the final analysis. Of these, 366 were randomly assigned to receive gemcitabine and 364 to gemcitabine plus capecitabine. The Independent Data and Safety Monitoring Committee requested reporting of the results after there were 458 (95%) of a target of 480 deaths. The median overall survival for patients in the gemcitabine plus capecitabine group was 28·0 months (95% CI 23·5-31·5) compared with 25·5 months (22·7-27·9) in the gemcitabine group (hazard ratio 0·82 [95% CI 0·68-0·98], p=0·032). 608 grade 3-4 adverse events were reported by 226 of 359 patients in the gemcitabine plus capecitabine group compared with 481 grade 3-4 adverse events in 196 of 366 patients in the gemcitabine group. INTERPRETATION: The adjuvant combination of gemcitabine and capecitabine should be the new standard of care following resection for pancreatic ductal adenocarcinoma. FUNDING: Cancer Research UK.

The diagnostic value of Rosemont and Japanese diagnostic criteria for 'indeterminate', 'suggestive', 'possible' and 'early' chronic pancreatitis.

BACKGROUND: Longitudinal data are lacking to support consensus criteria for diagnosing early chronic pancreatitis. METHODS: Retrospective single centre study of the initial evidence for chronic pancreatitis (CP), with reassessment after follow-up (January 2003-November 2016). RESULTS: 807 patients were previously diagnosed with chronic pancreatitis. This diagnosis was rejected in 118 patients: 52 had another pathology altogether, the remaining 66 patients formed the study population. 38 patients with 'normal' imaging were reclassified as chronic abdominal pain syndrome (CAPS), and 28 patients had minimal change features of CP on EUS (MCEUS) but never progressed. Strict application of the Japanese diagnostic criteria would diagnose only two patients with early CP and eleven as possible CP. Patients were more likely to have MCEUS if the EUS was performed within 12 months of an attack of acute pancreatitis. 40 patients with MCEUS were identified, including an additional 12 who progressed to definite CP after a median of 30 (18.75-36.5) months. Those continuing to consume excess alcohol and/or continued smoking were significantly more likely to progress. Those who progressed were more likely to develop pancreatic exocrine insufficiency, require pancreatic surgery and had higher mortality. CONCLUSION: There needs to be more stringent application of the systems used for diagnosing chronic pancreatitis with revision of the current terminology 'indeterminate', 'suggestive', 'possible', and 'early' chronic pancreatitis. All patients with MCEUS features of CP require ongoing clinical follow up of at least 30 months and all patients with these features should be strongly counselled regarding smoking cessation and abstinence from alcohol.

Guidelines for the understanding and management of pain in chronic pancreatitis.

Abdominal pain is the foremost complication of chronic pancreatitis (CP). Pain can be related to recurrent or chronic inflammation, local complications or neurogenic mechanisms with corresponding changes in the nervous systems. Both pain intensity and the frequency of pain attacks have been shown to reduce quality of life in patients with CP. Assessment of pain follows the guidelines for other types of chronic pain, where the multidimensional nature of symptom presentation is taken into consideration. Quantitative sensory testing may be used to characterize pain, but is currently used in a research setting in advanced laboratories. For pain relief, current guidelines recommend a simple stepwise escalation of analgesic drugs with increasing potency until pain relief is obtained. Abstinence from alcohol and smoking should be strongly advised. Pancreatic enzyme therapy and antioxidants may be helpful as initial treatment. Endoscopic treatment can be used in patients with evidence of ductal obstruction and may be combined with extracorporeal shock wave lithothripsy. The best candidates are those with distal obstruction of the main pancreatic duct and in early stage of disease. Behavioral interventions should be part of the multidisciplinary approach to chronic pain management particularly when psychological impact is experienced. Surgery should be considered early and after a maximum of five endoscopic interventions. The type of surgery depends on morphological changes of the pancreas. Long-term effects are variable, but high success rates have been reported in open studies and when compared with endoscopic treatment. Finally, neurolytical interventions and neuromodulation can be considered in difficult patients.

Association of genetic polymorphisms with survival of pancreatic ductal adenocarcinoma patients.

Germline genetic variability might contribute, at least partially, to the survival of pancreatic ductal adenocarcinoma (PDAC) patients. Two recently performed genome-wide association studies (GWAS) on PDAC overall survival (OS) suggested (P < 10(-5)) the association between 30 genomic regions and PDAC OS. With the aim to highlight the true associations within these regions, we analyzed 44 single-nucleotide polymorphisms (SNPs) in the 30 candidate regions in 1722 PDAC patients within the PANcreatic Disease ReseArch (PANDoRA) consortium. We observed statistically significant associations for five of the selected regions. One association in the CTNNA2 gene on chromosome 2p12 [rs1567532, hazard ratio (HR) = 1.75, 95% confidence interval (CI) 1.19-2.58, P = 0.005 for homozygotes for the minor allele] and one in the last intron of the RUNX2 gene on chromosome 6p21 (rs12209785, HR = 0.88, 95% CI 0.80-0.98, P = 0.014 for heterozygotes) are of particular relevance. These loci do not coincide with those that showed the strongest associations in the previous GWAS. In silico analysis strongly suggested a possible mechanistic link between these two SNPs and pancreatic cancer survival. Functional studies are warranted to confirm the link between these genes (or other genes mapping in those regions) and PDAC prognosis in order to understand whether these variants may have the potential to impact treatment decisions and design of clinical trials.

Outcomes From Minimal Access Retroperitoneal and Open Pancreatic Necrosectomy in 394 Patients With Necrotizing Pancreatitis.

OBJECTIVE: To examine the outcomes from minimal access retroperitoneal pancreatic necrosectomy (MARPN) and open pancreatic necrosectomy (OPN) for severe necrotizing pancreatitis in a single center. BACKGROUND: The optimal management of severe pancreatic necrosis is evolving with a few large center single series. METHODS: Between 1997 and 2013, patients with necrotizing pancreatitis at the Liverpool Pancreas Center were reviewed. Outcome measures were retrospectively analyzed by intention to treat. RESULTS: There were 394 patients who had either MARPN (274, 69.5%) or OPN (120, 30.5%). Complications occurred in 174 MARPN patients (63.5%) and 98 (81.7%) OPN patients (P < 0.001). OPN was associated with increased postoperative multiorgan failure [42 (35%) vs 56 (20.4%), P = 0.001] and median (inter-quartile range) Acute Physiology and Chronic Health Evaluation II score 9 (6-11.5) vs 8 (5-11), P < 0.001] with intensive care required less frequently in MARPN patients [40.9% (112) vs 75% (90), P < 0.001]. The mortality rate was 42 (15.3%) in MARPNs and 28 (23.3%) in OPNs (P = 0.064). Both the mortality and the overall complication rates decreased between 1997-2008 and 2008-2013 [49 (23.8%) vs 21 (11.2%) P = 0.001, respectively; and 151 (73.3%) vs 121 (64.4%), P = 0.080, respectively). Increased mortality was independently associated with age (P < 0.001), preoperative intensive care stay (P = 0.014), and multiple organ failure (P < 0.001); operation before 2008 (P < 0.001) and conversion to OPN (P = 0.035). MARPN independently reduced mortality odds risk (odds ratio = 0.27; 95% confidence interval = 0.12-0.57; P < 0.001). CONCLUSIONS: Increasing experience and advances in perioperative care have led to improvement in outcomes. The role of MARPN in reducing complications and deaths within a multimodality approach remains substantial and should be used initially if feasible.