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.

Enhanced Recovery After Surgery Program in Patients Undergoing Pancreaticoduodenectomy: A PRISMA-Compliant Systematic Review and Meta-Analysis.

Enhanced recovery after surgery (ERAS) pathways are multimodal, evidence-based approaches to optimize patient outcome after surgery. However, the use of ERAS protocols to improve morbidity and recovery time without compromising safety following pancreaticoduodenectomy (PD) remains to be elucidated.We conducted a systemic review and meta-analysis to assess the safety and efficacy of ERAS protocols compared with conventional perioperative care (CPC) in patients following PD.PubMed, Medline, Embase, and Science Citation Index Expanded and Cochrane Central Register of Controlled Trials (CENTRAL) in The Cochrane Library were searched between January 2000 and June 2015.The patients who underwent PD with ERAS protocols or CPC were eligible. The studies that compared postoperative length of hospital stay (PLOS), postoperative complications, or in-hospital costs in the 2 groups were included.A meta-analysis, meta-regression, sensitivity analysis, and subgroup analysis were performed to estimate the postoperative outcomes between the 2 groups and identified the potential confounders. We used the methodological index for nonrandomized studies checklist to assess methodological qualities. Weighted mean differences (WMD) or odds ratios (OR) were calculated with their corresponding 95% confidence intervals (CI). The publication bias tests were also performed through the funnel plots.In total, 14 nonrandomized comparative studies with 1409 ERAS cases and 1310 controls were analyzed. Implementation of an ERAS protocol significantly reduced PLOS (WMD: -4.17 days; 95%CI: -5.72 to -2.61), delayed gastric emptying (OR: 0.56; 95%CI: 0.44-0.71), overall morbidity (OR: 0.63; 95% CI: 0.54-0.74), and in-hospital costs compared to CPC (all P < 0.001). There were no statistically significant differences in other postoperative outcomes. Age, gender, and ERAS component implementation did not significantly contribute to heterogeneity for PLOS as shown by meta-regression analysis.Our study suggested that ERAS was as safe as CPC and improved recovery of patients undergoing PD, thus reducing in-hospital costs. General adoption of ERAS protocols during PD should be recommended.

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.

What Is the Best Way to Identify Malignant Transformation Within Pancreatic IPMN: A Systematic Review and Meta-Analyses.

OBJECTIVES: Pancreatic intraductal papillary mucinous neoplasias (IPMNs) represent 25% of all cystic neoplasms and are precursor lesions for pancreatic ductal adenocarcinoma. This study aims to identify the best imaging modality for detecting malignant transformation in IPMN, the sensitivity and specificity of risk features on imaging, and the usefulness of tumor markers in serum and cyst fluid to predict malignancy in IPMN. METHODS: Databases were searched from November 2006 to March 2014. Pooled sensitivity and specificity of diagnostic techniques/imaging features of suspected malignancy in IPMN using a hierarchical summary receiver operator characteristic (HSROC) approach were performed. RESULTS: A total of 467 eligible studies were identified, of which 51 studies met the inclusion criteria and 37 of these were incorporated into meta-analyses. The pooled sensitivity and specificity for risk features predictive of malignancy on computed tomography/magnetic resonance imaging were 0.809 and 0.762 respectively, and on positron emission tomography were 0.968 and 0.911. Mural nodule, cyst size, and main pancreatic duct dilation found on imaging had pooled sensitivity for prediction of malignancy of 0.690, 0.682, and 0.614, respectively, and specificity of 0.798, 0.574, and 0.687. Raised serum carbohydrate antigen 19-9 (CA19-9) levels yielded sensitivity of 0.380 and specificity of 0903. Combining parameters yielded a sensitivity of 0.743 and specificity of 0.906. CONCLUSIONS: PET holds the most promise in identifying malignant transformation within an IPMN. Combining parameters increases sensitivity and specificity; the presence of mural nodule on imaging was the most sensitive whereas raised serum CA19-9 (>37 KU/l) was the most specific feature predictive of malignancy in IPMNs.

Incidence of post-ERCP pancreatitis from direct pancreatic juice collection in hereditary pancreatitis and familial pancreatic cancer before and after the introduction of prophylactic pancreatic stents and rectal diclofenac.

OBJECTIVES: Individuals from hereditary pancreatitis (HP) and familial pancreatic cancer (FPC) kindreds are at increased risk of developing pancreatic cancer. Premalignant molecular changes may be detected in pancreatic juice collected by endoscopic retrograde cholangiopancreatography (ERCP). The objective was to determine the risk of post-ERCP pancreatitis (PEP). METHODS: A prospective study (1999-2013) was undertaken of 80 ERCPs (24 in HP and 56 in FPC) from 60 individuals and the impact of PEP prophylaxis using a self-expelling pancreatic stent and 50 mg diclofenac per rectum from 2008. RESULTS: There was no PEP in the HP cohort and 13 (23.2%) PEP from 56 procedures in the FPC cohort (P = 0.0077). Up to 2008 PEP had occurred in 7 (43.8%) of 16 procedures in FPC individuals versus none of 18 procedures in HP individuals (P = 0.0021). After the introduction of prophylaxis, the incidence of PEP fell to 6 (15.0%) of 40 procedures in FPC individuals (P = 0.0347).The odds ratio (95% confidence interval) was 0.23 (0.06-0.84) in favor of prophylaxis (0.035). CONCLUSIONS: Individuals with HP are at minimal risk for PEP. Although the risk of PEP in individuals with FPC can be reduced by using prophylactic self-expelling stents and diclofenac, it remains too high for routine screening.

Endoscopic ultrasound-guided choledoco-duodenostomy as an alternative to percutaneous trans-hepatic cholangiography.

BACKGROUND: Endoscopic ultrasonography (EUS)-guided choledochoduodenostomy (CDS) is an alternative to percutaneous transhepatic cholangiography (PTC) drainage in patients with an obstructed biliary system where conventional endoscopic retrograde biliary drainage (ERBD) has been unsuccessful. METHODS: Five EUS-CDS procedures were reviewed to assess whether successful decompression was achieved and maintained. RESULTS: There was technical success in each instance with no immediate complications. There was a significant fall in the median bilirubin of 164 mmol/l. The median follow-up was 44 days. In one patient the stent migrated with no adverse outcome. CONCLUSION: EUS-CDS is a viable alternative to PTC with fewer complications and comparable success rates. EUS-CDS may offer a future route for novel therapeutic advances.

Partial pancreatic resection for pancreatic malignancy is associated with sustained pancreatic exocrine failure and reduced quality of life: a prospective study.

OBJECTIVES: Pancreatic resection for cancer may produce pancreatic exocrine insufficiency (PEI), which is poorly understood. This study examined the coefficient of fat absorption (CFA), symptoms, quality of life (QoL) and the accuracy of faecal elastase-1 (FE-1) measurement to predict PEI. METHODS: Forty patients were analysed following resection for pancreatic malignancy. The primary endpoint was PEI diagnosis defined by CFA <93%; secondary endpoints were PEI diagnosis using FE-1 <200 µg/g, body mass index (BMI), and symptom and QoL analysis. Interventions were 3-day stool collection, EORTC QLQ-C30 (version 1) questionnaire and patient's diary, at 6 weeks and 3, 6 and 12 months after surgery. RESULTS: CFA <93% was present in 67% of patients at 6 weeks and in 55% at 12 months. PEI using FE-1 was present in 77 and 83% of patients, respectively. No significant changes between time-points were observed. Sensitivity, specificity, PPV, NPV and accuracy for FE-1 in detecting CFA <93% were 91, 35, 70, 71 and 70%, respectively. CFA and FE-1 levels were uncorrelated. Overall, QoL increased at 6 (p = 0.0212) and 12 (p < 0.0001) months after surgery, mainly driven by physical, role and social functioning, and by appetite. Importantly, however, BMI and symptoms were unaffected by PEI, which suggests a subclinical presentation; such patients had attributes indicating poorer QoL (notably insomnia, p = 0.0012). CONCLUSIONS: PEI was common and sustained following resection and not associated with significant symptoms. These patients had a tendency toward poorer QoL. FE-1 is a poor surrogate for diagnosing impaired fat absorption. Postoperative pancreatic enzyme replacement should be considered more routinely. and IAP.

Minimal access retroperitoneal pancreatic necrosectomy: improvement in morbidity and mortality with a less invasive approach.

OBJECTIVE: Comparison of minimal access retroperitoneal pancreatic necrosectomy (MARPN) versus open necrosectomy in the treatment of infected or nonresolving pancreatic necrosis. SUMMARY OF BACKGROUND DATA: Infected pancreatic necrosis may lead to progressive organ failure and death. Minimal access techniques have been developed in an attempt to reduce the high mortality of open necrosectomy. METHODS: This was a retrospective analysis on a prospective data base comprising 189 consecutive patients undergoing MARPN or open necrosectomy (August 1997 to September 2008). Outcome measures included total and postoperative ICU and hospital stays, organ dysfunction, complications and mortality using an intention to treat analysis. RESULTS: Overall 137 patients underwent MARPN versus open necrosectomy in 52. Median (range) age of the patients was 57.5 (18-85) years; 118 (62%) were male. A total of 131 (69%) patients were tertiary referrals, with a median time to transfer from index hospital of 19 (2-76) days. Etiology was gallstones or alcohol in 129 cases (68%); 98 of 168 (58%) patients had a positive culture at the first procedure. Of the 137 patients, 34 (31%) had postoperative organ failure in the MARPN group, and 39 of 52 (56%) in the open group (P<0.0001); 59/137 (43%) versus 40/52 (77%), respectively, required postoperative ICU support (P<0.0001). Of the 137 patients 75 (55%) had complications in the MARPN group and 42 of 52 (81%) in the open group (P=0.001). There were 26 (19%) deaths in the MARPN group and 20 (38%) following open procedure (P=0.009). Age (P<0.0001), preoperative multiorgan failure (P<0.0001), and surgical procedure (MARPN, P=0.016) were independent predictors of mortality. CONCLUSION: This study has shown significant benefits for a minimal access approach including fewer complications and deaths compared with open necrosectomy.

The variable phenotype of the p.A16V mutation of cationic trypsinogen (PRSS1) in pancreatitis families.

OBJECTIVE: To characterise the phenotypes associated with the p.A16V mutation of PRSS1. DESIGN: Clinical and epidemiological data were collected for any family in which a p.A16V mutation was identified, either referred directly to the European Registry of Hereditary Pancreatitis and Familial Pancreatic Cancer or via a collaborator. DNA samples were tested for mutations in PRSS1, SPINK1, CFTR and CTRC. PATIENTS: Participants were recruited on the basis of either family history of pancreatitis (acute or chronic) or the results of genetic testing. Families were categorised as having hereditary pancreatitis (HP), idiopathic disease or pancreatitis in a single generation. HP was defined as >or=2 cases in >or=2 generations. Main outcome measures Onset of painful episodes of pancreatitis, death from pancreatic cancer, diagnosis of diabetes mellitus and exocrine pancreatic failure. RESULTS: Ten families with p.A16V mutations were identified (22 affected individuals): six HP families, three with idiopathic disease and one with only a single generation affected. The median age of onset, ignoring non-penetrants, was 10 years (95% CI 5 to 25). There were eight confirmed cases of exocrine failure, four of whom also had diabetes mellitus. There were three pancreatic cancer cases. Two of these were confirmed as p.A16V carriers, only one of whom was affected by pancreatitis. Those with p.A16V pancreatitis were compared to affected individuals with p.R122H, p.N29I and no PRSS1 mutation. No significant differences were proven using logrank or Mann-Whitney U tests. CONCLUSIONS: Penetrance of p.A16V is highly variable and family dependent, suggesting it contributes to multigenic inheritance of a predisposition to pancreatitis.

Direct activation of cytosolic Ca2+ signaling and enzyme secretion by cholecystokinin in human pancreatic acinar cells.

BACKGROUND & AIMS: Cholecystokinin (CCK) has been thought to act only indirectly on human pancreatic acinar cells via vagal nerve stimulation, rather than by direct CCK receptor activation as on rodent pancreatic acinar cells. We tested whether CCK (CCK-8 and human CCK-58) can act directly on human pancreatic acinar cells. METHODS: Human acinar cells were freshly isolated from pancreatic transection line samples, loaded with Fluo4-AM or quinacrine, and examined for Ca(2+), metabolic and secretory responses to CCK-8, human CCK-58, or acetylcholine with confocal microscopy. RESULTS: CCK-8 and human CCK-58 at physiologic concentrations (1-20 pmol/L) elicited rapid, robust, oscillatory increases of the cytosolic Ca(2+) ion concentration, showing apical to basal progression, in acinar cells from 14 patients with unobstructed pancreata. The cytosolic Ca(2+) ion concentration increases were followed by increases in mitochondrial adenosine triphosphate production and secretion. CCK-elicited Ca(2+) signals and exocytosis were not inhibited by atropine (1 mumol/L) or tetrodotoxin (100 nmol/L), showing that CCK was unlikely to have acted via neurotransmitter release. CCK-elicited Ca(2+) signals were inhibited reversibly by caffeine (5-20 mmol/L), indicating involvement of intracellular inositol trisphosphate receptor Ca(2+) release channels. Acetylcholine (50 nmol/L) elicited similar Ca(2+) signals. CONCLUSIONS: CCK at physiologic concentrations in the presence of atropine and tetrodotoxin elicits cytosolic Ca(2+) signaling, activates mitochondrial function, and stimulates enzyme secretion in isolated human pancreatic acinar cells. We conclude that CCK acts directly on acinar cells in the human pancreas.

Trypsinogen mutations in pancreatic disorders.

There are multiple PRSS1 mutations described in hereditary pancreatitis but only a minority of these are clinically relevant. The two most frequent point mutations are in exon 2 (N29I) and exon3 (R122H), found in diverse racial populations. Both mutations result in early onset pancreatitis but the mechanism underlying this phenotype is unclear. The frequency of these mutations in such diverse populations suggests they have spontaneously occurred many times. The origin of the major mutations may be explained by gene conversions, accounting for multiple founders. The implications are discussed in terms of mechanism of action of the mutations and clinical presentation.

Cancer in the elderly: pancreatic cancer.

Pancreatic cancer remains a devastating and difficult disease to diagnose and successfully treat. Its incidence increases with age, with 60% of patients being over the age of 65 at presentation. Due to the insidious nature and asymptomatic onset of pancreatic cancer approximately 85% of patients present with disseminated or locally advanced disease resulting in a very poor prognosis. In the past the elderly patient, who may be felt to be too frail for operative procedures or further therapy, may have missed out on optimal treatment. In this article we review the investigation and treatment of pancreatic cancer and examine current evidence with regard to pancreatic cancer in the elderly. The evidence suggests that surgical resection can be performed safely in patients who are fit for surgery in specialist centres but may require more intensive post-operative rehabilitation.

Ethanol toxicity in pancreatic acinar cells: mediation by nonoxidative fatty acid metabolites.

Ethanol causes pancreatic damage by an unknown mechanism. Previously, we demonstrated that a sustained rise of the cytosolic Ca(2+) concentration ([Ca(2+)](i)) causes pancreatic acinar cell injury. Here we have investigated the effects of ethanol and its metabolites on Ca(2+) signaling in pancreatic acinar cells. Most cells exposed to ethanol (up to 850 mM) showed little or no increase in [Ca(2+)](i) (and never at concentrations <50 mM). During sustained exposure to 850 mM ethanol, acetylcholine (ACh) evoked a normal [Ca(2+)](i) elevation and following ACh removal there was a normal and rapid recovery to a low resting level. The oxidative metabolite acetaldehyde (up to 5 mM) had no effect, whereas the nonoxidative unsaturated metabolite palmitoleic acid ethyl ester (10-100 microM, added on top of 850 mM ethanol) induced sustained, concentration-dependent increases in [Ca(2+)](i) that were acutely dependent on external Ca(2+) and caused cell death. These actions were shared by the unsaturated metabolite arachidonic acid ethyl ester, the saturated equivalents palmitic and arachidic acid ethyl esters, and the fatty acid palmitoleic acid. In the absence of external Ca(2+), releasing all Ca(2+) from the endoplasmic reticulum by ACh (10 microM) or the specific Ca(2+) pump inhibitor thapsigargin (2 microM) prevented such Ca(2+) signal generation. We conclude that nonoxidative fatty acid metabolites, rather than ethanol itself, are responsible for the marked elevations of [Ca(2+)](i) that mediate toxicity in the pancreatic acinar cell and that these compounds act primarily by releasing Ca(2+) from the endoplasmic reticulum.

Acute pancreatitis and organ failure: pathophysiology, natural history, and management strategies.

Acute pancreatitis is a common condition that carries a significant risk of morbidity and mortality. It is characterized by intra-acinar cell activation of digestive enzymes and a subsequent systemic inflammatory response governed by the release of proinflammatory cytokines. In 80% of patients the disease runs a self-limiting course, but in the rest, pancreatic necrosis and systemic organ failure carry a mortality rate of up to 40%. The key to management is early identification of the patients liable to have a severe attack and require treatment in a high-dependency or critical-care setting by a specialist team. In gallstone-induced pancreatitis, early removal of ductal calculi by endoscopic sphincterotomy is indicated. The use of prophylactic antibiotics to prevent the infection of pancreatic necrosis remains controversial, but once established, infected necrosis must be removed. Although a number of techniques to accomplish this end have been described, minimally invasive techniques are gaining in popularity.

Signal transduction, calcium and acute pancreatitis.

Evidence consistently suggests that the earliest changes of acute pancreatitis are intracellular, the hallmark of which is premature intracellular activation of digestive zymogens, accompanied by disruption of normal signal transduction and secretion. Principal components of physiological signal transduction include secretagogue-induced activation of G-protein-linked receptors, followed by generation of inositol 1,4,5-trisphosphate, nicotinic acid adenine dinucleotide phosphate and cyclic ADP-ribose. In response, calcium is released from endoplasmic reticulum terminals within the apical, granular pole of the cell, where calcium signals are usually contained by perigranular mitochondria, in turn responding by increased metabolism. When all three intracellular messengers are administered together, even at threshold concentrations, dramatic potentiation results in sustained, global, cytosolic calcium elevation. Prolonged, global elevation of cytosolic calcium is also induced by hyperstimulation, bile salts, alcohol and fatty acid ethyl esters, and depends on continued calcium entry into the cell. Such abnormal calcium signals induce intracellular activation of digestive enzymes, and of nuclear factor kappaB, as well as the morphological changes of acute pancreatitis. Depletion of endoplasmic reticulum calcium and mitochondrial membrane potential may contribute to further cell injury. This review outlines current understanding of signal transduction in the pancreas, and its application to the pathophysiology of acute pancreatitis.

New Techniques and Agents in the Adjuvant Therapy of Pancreatic Cancer.

Pancreatic ductal adenocarcinoma represents a major oncological challenge. Despite improvements in surgical techniques, long-term survival after resection is poor, with few patients surviving after 5 years. Until recently, there have been no large randomized trials of adjuvant therapy in pancreatic ductal adenocarcinoma. However, major trials such as the European Study Group for Pancreatic Cancer (ESPAC-1) and ESPAC-3 trials have set new standards for patient recruitment and development in this field. Adjuvant therapy has the potential to improve both patient survival and quality of life after curative resection. Currently, the best treatment is with 5-fluorouracil with folinic acid, but in the light of ongoing clinical trials, this may be supplanted by gemcitabine as the treatment of choice. Chemoradiotherapy does not appear to be beneficial in the adjuvant setting, but trials of a wide variety of other techniques and agents in the treatment of advanced disease are being undertaken and some of these will almost certainly be extended into the adjuvant setting in time. Great progress has been made in the adjuvant treatment of pancreatic cancer in the past 10 years and similar advances are likely over the next decade.

New techniques and agents in the adjuvant therapy of pancreatic cancer.

Pancreatic ductal adenocarcinoma represents a major oncological challenge. Despite improvements in surgical techniques, long-term survival after resection is poor, with few patients surviving after 5 years. Until recently, there have been no large randomized trials of adjuvant therapy in pancreatic ductal adenocarcinoma. However, major trials such as the European Study Group for Pancreatic Cancer (ESPAC-1) and ESPAC-3 trials have set new standards for patient recruitment and development in this field. Adjuvant therapy has the potential to improve both patient survival and quality of life after curative resection. Currently, the best treatment is with 5-fluorouracil with folinic acid, but in the light of ongoing clinical trials, this may be supplanted by gemcitabine as the treatment of choice. Chemoradiotherapy does not appear to be beneficial in the adjuvant setting, but trials of a wide variety of other techniques and agents in the treatment of advanced disease are being undertaken and some of these will almost certainly be extended into the adjuvant setting in time. Great progress has been made in the adjuvant treatment of pancreatic cancer in the past 10 years and similar advances are likely over the next decade.