Position statement on the definition, incidence, diagnosis and outcome of acute on chronic pancreatitis.

BACKGROUND: Acute on chronic pancreatitis (ACP) is a relatively common condition, but there are significant gaps in our knowledge on the definition, incidence, diagnosis, treatment and prognosis. METHODS: A systematic review that followed PICO (Population; Intervention; Comparator; Outcome) recommendation for quantitative questions and PICo (Population, Phenomenon of Interest, Context) for qualitative research was done to answer 10 of the most relevant questions about ACP. Quality of evidence was judged by the GRADE criteria (Grades of Recommendation, Assessment, Development and Evaluation). The manuscript was sent for review to 12 international experts from various disciplines and continents using a Delphi process. RESULTS: The quality of evidence, for most statements, was low to very low, which means that the recommendations in general are only conditional. Despite that, it was possible to reach strong levels of agreement by the expert panel for all 10 questions. A new consensus definition of ACP was reached. Although common, the real incidence of ACP is not known, with alcohol as a major risk factor. Although pain dominates, other non-specific symptoms and signs can be present. Serum levels of pancreatic enzymes may be less than 3 times the upper limit of normal and cross-sectional imaging is considered more accurate for the diagnosis in many cases. It appears that it is less severe and with a lower mortality risk than acute pancreatitis. CONCLUSIONS: Although the evidence base is poor, this position statement provides a foundation from which to advance management of ACP.

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 interventional endoscopy 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/OBJECTIVES: This paper is part of the international consensus guidelines on chronic pancreatitis, presenting for interventional endoscopy. METHODS: An international working group with experts on interventional endoscopy evaluated 26 statements generated from evidence on 9 clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation approach was used to evaluate the level of evidence. To determine the level of agreement, a nine-point Likert scale was used for voting on the statements. RESULTS: Strong consensus was obtained for 15 statements relating to nine questions including the recommendation that endoscopic intervention should be offered to patients with persistent severe pain but not to those without pain. Endoscopic decompression of the pancreatic duct could be used for immediate pain relief, and then offered surgery if this fails or needs repeated endoscopy. Endoscopic drainage is preferred for portal-splenic vein thrombosis and pancreatic fistula. A plastic stent should be placed and replaced 2-3 months later after insertion. Endoscopic extraction is indicated for stone fragments remaining after ESWL. Interventional treatment should be performed for symptomatic/complicated pancreatic pseudocysts. Endoscopic treatment is recommended for bile duct obstruction and afterwards surgery if this fails or needs repeated endoscopy. Surgery may be offered if there is significant calcification and/or mass of the pancreatic head. Percutaneous endovascular treatment is preferred for hemosuccus pancreaticus. Surgical treatment is recommended for duodenal stenosis due to chronic pancreatitis. CONCLUSIONS: This international expert consensus guideline provides evidenced-based statements concerning indications and key aspects for interventional endoscopy in the management of patients with chronic pancreatitis.

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.

International consensus guidelines on the role of diagnostic endoscopic ultrasound in the management of 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: Chronic pancreatitis (CP) is a complex inflammatory disease with variable presentations and outcomes. This statement is part of the international consensus guidelines on CP, specifically on the diagnostic role of endoscopic ultrasound (EUS). METHODS: An international working group with experts on the role of diagnostic EUS in the management of CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated two key statements generated from evidence on two questions deemed to be the most clinically relevant. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, 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: Strong consensus was obtained for both of the following statements [1]. The ideal threshold number of EUS criteria necessary to diagnose CP has not been firmly established, but the presence of 5 or more and 2 or less strongly suggests or refutes the diagnosis, respectively. The Rosemont scoring system standardizes the reporting of EUS signs indicative of chronic pancreatitis, but further studies are needed to demonstrate an overall improvement of its diagnostic accuracy over conventional scoring [2]. Specificity, inter- and intra-observer variability and pre-test probability limit the reliability and utility of EUS to help diagnose CP especially early stages of the disease. CONCLUSIONS: The presence of 5 or more and 2 or less EUS criteria strongly suggests or refutes the diagnosis of CP, respectively. Intra-observer variability still limits the role of EUS in diagnosing CP especially early stage disease.

International Consensus Guidelines for Risk Factors 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

Chronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP. An international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. Strong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers. Both genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.

International Consensus Guidelines for Risk Factors 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: Chronic pancreatitis (CP) is a complex inflammatory disease with remarkably impaired quality of life and permanent damage of the pancreas. This paper is part of the international consensus guidelines on CP and presents the consensus on factors elevating the risk for CP. METHODS: An international working group with 20 experts on CP from the major pancreas societies (IAP, APA, JPS, and EPC) evaluated 14 statements generated from evidence on four questions deemed to be the most clinically relevant in CP. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available per statement. To determine the level of agreement, the working group voted on the 14 statements for strength of agreement, using a nine-point Likert scale in order to calculate Cronbach's alpha reliability coefficient. RESULTS: Strong consensus and agreement were obtained for the following statements: Alcohol, smoking, and certain genetic alterations are risk factors for CP. Past history, family history, onset of symptoms, and life-style factors including alcohol intake and smoking history should be determined. Alcohol consumption dose-dependently elevates the risk of CP up to 4-fold. Ever smokers, even smoking less than a pack of cigarettes per day, have an increased risk for CP, as compared to never smokers. CONCLUSIONS: Both genetic and environmental factors can markedly elevate the risk for CP. Therefore, health-promoting lifestyle education and in certain cases genetic counselling should be employed to reduce the incidence of CP.

Guidelines on the histopathology of 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 the European Pancreatic Club.

BACKGROUND: Chronic pancreatitis is a complex multifactorial fibro-inflammatory disease. Consensus guidelines are needed for the histopathological evaluation of non-autoimmune chronic pancreatitis (CP). METHODS: An international working group with experts on the histopathology of CP evaluated 15 statements generated from evidence on seven key clinically relevant questions. The Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach was used to evaluate the level of evidence available for each statement. To determine the level of agreement, the working group voted on the statements for strength of agreement, using a nine-point Likert scale, and Cronbach's alpha reliability coefficients were calculated. RESULTS: Strong consensus was obtained for 12 statements relating to all seven key questions including that: the cardinal features of CP are the triad of fibrosis, loss of acinar tissue and duct changes; there are no unique histopathological features that distinguish the different aetiologies of CP; clinical history and laboratory investigations, including genetic testing, are important in establishing the aetiology of CP; there is no reproducible and universally accepted histological grading system for assessing severity of CP, although classification as "mild", "moderate" and "severe" is usually applied; scoring systems for fibrosis are not validated for clinical use; asymptomatic fibrosis is a common finding associated with ageing, and not necessarily evidence of CP; there are no obvious diagnostic macroscopic features of early CP; histopathology is not the gold standard for the diagnosis of CP; and cytology alone is not a reliable method for the diagnosis of CP. CONCLUSIONS: Cardinal histopathological features of CP are well-defined and internationally accepted and pathological assessment is relevant for the purpose of differential diagnosis with other pancreatic diseases, especially cancer. However, a reliable diagnosis of CP requires integration of clinical, laboratory and imaging features and cannot be made by histology alone.

The role of total pancreatectomy with islet autotransplantation in the treatment of chronic pancreatitis: A report from the International Consensus Guidelines in chronic pancreatitis.

BACKGROUND: Advances in our understanding of total pancreatectomy with islet autotransplantation (TPIAT) have been made. We aimed to define indications and outcomes of TPIAT. METHODS: Expert physician-scientists from North America, Asia, and Europe reviewed the literature to address six questions selected by the writing group as high priority topics. A consensus was reached by voting on statements generated from the review. RESULTS: Consensus statements were voted upon with strong agreement reached that (Q1) TPIAT may improve quality of life, reduce pain and opioid use, and potentially reduce medical utilization; that (Q3) TPIAT offers glycemic benefit over TP alone; that (Q4) the main indication for TPIAT is disabling pain, in the absence of certain medical and psychological contraindications; and that (Q6) islet mass transplanted and other disease features may impact diabetes mellitus outcomes. Conditional agreement was reached that (Q2) the role of TPIAT for all forms of CP is not yet identified and that head-to-head comparative studies are lacking, and that (Q5) early surgery is likely to improve outcomes as compared to late surgery. CONCLUSIONS: Agreement on TPIAT indications and outcomes has been reached through this working group. Further studies are needed to answer the long-term outcomes and maximize efforts to optimize patient selection.

Pancreas-specific plasma amylase for assessment and diagnosis of chronic pancreatitis: New insights on an old topic.

Background: Pancreatic function testing and imaging are used to inform the diagnosis of chronic pancreatitis, but most of these methods are time- and cost-consuming or lack diagnostic accuracy. Objective: We investigated the utility of pancreas-specific plasma amylase for assessment and diagnosis of chronic pancreatitis. Design: This was a prospective study of 121 consecutive patients with chronic pancreatitis and a reference population of 94 healthy controls. Pancreas-specific plasma amylase level was determined and analysed for its association with exocrine pancreatic insufficiency, diabetes and other clinical variables. Receiver operating characteristic curve analyses were performed to determine the diagnostic utility of plasma amylase for diagnosing chronic pancreatitis and to study associations with disease severity. The findings were validated in a further cohort of 57 patients with chronic pancreatitis. Results: Significant and independent associations between plasma amylase level and duration of chronic pancreatitis as well as the presence of exocrine pancreatic insufficiency and diabetes were observed (all p < 0.001). An amylase level below 17.3 U/l had a high specificity (94%) and moderate sensitivity (59%) for the diagnosis of chronic pancreatitis. Diagnostic performance was influenced by disease stage with the best performance observed for advanced disease. The findings were replicated in the validation cohort. Conclusion: Pancreas-specific plasma amylase may provide a clinically useful mean for assessment and diagnosis of chronic pancreatitis.

Guidelines for the Diagnostic Cross Sectional Imaging and Severity Scoring of Chronic Pancreatitis.

The paper presents the international guidelines for imaging evaluation of chronic pancreatitis. The following consensus was obtained: Computed tomography (CT) is often the most appropriate initial imaging modality for evaluation of patients with suspected chronic pancreatitis (CP) depicting most changes in pancreatic morphology. CT is also indicated to exclude other potential intraabdominal pathologies presenting with symptoms similar to CP. However, CT cannot exclude a diagnosis of CP nor can it be used to exclusively diagnose early or mild disease. Here magnetic resonance imaging (MRI) and MR cholangiopancreatography (MRCP) is superior and is indicated especially in patients where no specific pathological changes are seen on CT. Secretin-stimulated MRCP is more accurate than standard MRCP in the depiction of subtle ductal changes. It should be performed after a negative MRCP, when there is still clinical suspicion of CP. Endoscopic ultrasound (EUS) can also be used to diagnose parenchymal and ductal changes mainly during the early stage of the disease. No validated radiological severity scoring systems for CP are available, although a modified Cambridge Classification has been used for MRCP. There is an unmet need for development of a new and validated radiological CP severity scoring system based on imaging criteria including glandular volume loss, ductal changes, parenchymal calcifications and parenchymal fibrosis based on CT and/or MRI. Secretin-stimulated MRCP in addition, can provide assessment of exocrine function and ductal compliance. An algorithm is presented, where these imaging parameters can be incorporated together with clinical findings in the classification and severity grading of CP.

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.

International consensus statements on early chronic Pancreatitis. Recommendations from the working group for the international consensus guidelines for chronic pancreatitis in collaboration with The International Association of Pancreatology, American Pancreatic Association, Japan Pancreas Society, PancreasFest Working Group and European Pancreatic Club.

BACKGROUND: Chronic pancreatitis (CP) is a progressive inflammatory disorder currently diagnosed by morphologic features. In contrast, an accurate diagnosis of Early CP is not possible using imaging criteria alone. If this were possible and early treatment instituted, the later, irreversible features and complications of CP could possibly be prevented. METHOD: An international working group supported by four major pancreas societies (IAP, APA, JPS, and EPC) and a PancreasFest working group sought to develop a consensus definition and diagnostic criteria for Early CP. Ten statements (S1-10) concerning Early CP were used to gauge consensus on the Early CP concept using anonymous voting with a 9 point Likert scale. Consensus required an alpha ≥0.80. RESULTS: No consensus statement could be developed for a definition of Early-CP or diagnostic criteria. There was consensus on 5 statements: (S2) The word "Early" in early chronic pancreatitis is used to describe disease state, not disease duration. (S4) Early CP defines a stage of CP with preserved pancreatic function and potentially reversible features. (S8) Genetic variants are important risk factors for Early CP and can add specificity to the likely etiology, but they are neither necessary nor sufficient to make a diagnosis. (S9) Environmental risk factors can provide evidence to support the diagnosis of Early CP, but are neither necessary nor sufficient to make a diagnosis. (S10) The differential diagnosis for Early CP includes other disorders with morphological and functional features that overlap with CP. CONCLUSIONS: Morphology based diagnosis of Early CP is not possible without additional information. New approaches to the accurate diagnosis of Early CP will require a mechanistic definition that considers risk factors, biomarkers, clinical context and new models of disease. Such a definition will require prospective validation.

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.

Survival of patients with or without symptoms undergoing potentially curative resections for primary lung cancer.

BACKGROUND: Numerous historical screening programs to detect lung cancer have been undertaken. With technologic advances, complimentary diagnostic tests have been developed; however, only the National Lung Cancer Trial has demonstrated increased survival. Following the success of this study, screening programs are being trialled in several countries. Screening should, in theory, reduce lung cancer deaths by identifying asymptomatic patients with earlier tumors. This study asked whether lung cancer patients who are asymptomatic at presentation have a better survival than those who present with symptoms. METHODS: This was a retrospective analysis of a validated prospective thoracic surgery database from a tertiary center in the Northwest of England. Included were 1,546 consecutive patients (826 men, 720 women) who received operative intervention for non-small cell lung cancer. The main outcome measures included 5-year survival and univariate and multivariate Cox regression analysis. RESULTS: Cancer stage, age, and operation type were confirmed as being of prognostic importance, validating previous studies. Survival between asymptomatic or symptomatic patients did not differ significantly (p = 0.489), regardless of stage. The hazard ratios (with 95% confidence intervals) for variables associated with poorer outcome identified by Cox's regression analysis were male sex, 1.34 (1.15 to 1.56); advancing age, 1.03 (1.02 to 1.04); advancing stage, 3.30 (2.69 to 4.04); and pneumonectomy, 1.24 (1.01 to 1.52). Symptoms were not a significant variable affecting survival on multivariate analysis. CONCLUSIONS: This retrospective study from the Northwest of England showed that in our subset of lung cancer patients undergoing resection, asymptomatic patients with non-small cell lung cancer do not have improved survival, implying it is a systemic disease in many at diagnosis. Care should be taken when generalizing the results of the National Lung Screening Trial to all populations until further validation has been performed.