The epidemiology of acute pancreatitis in Tasmania over a 12-year period: Is this a disease of disadvantage?

BACKGROUND: The global incidence of acute pancreatitis (AP) is increasing, but little information exists about trends in Australia. This study aimed to describe incidence trends, along with clinical and socio-demographic associations, in the state of Tasmania over a recent 12-year period. METHODS: The study cohort was obtained by linking clinical and administrative datasets encompassing the whole Tasmanian population between 2007 and 2018, inclusive. Pancreatitis case definition was based on relevant ICD-10 hospitalization codes, or elevated serum lipase or amylase in pathology data. Age-standardised incidence rates were estimated, overall and stratified by sex, aetiology, and Index of Relative Socio-economic Disadvantage (IRSD). RESULTS: In the study period, 4905 public hospital AP episodes were identified in 3503 people. The age-standardised person-based incidence rate across the entire period was 54 per 100,000 per year. Incidence was inversely related to IRSD score; 71 per 100,000 per year in the most disadvantaged quartile compared to 32 in the least disadvantaged. Biliary AP incidence was higher than that of alcohol-related AP, although the greatest incidence was in "unspecified" cases. There was an increase in incidence for the whole cohort (average annual percent change 3.23 %), largely driven by the two most disadvantaged IRSD quartiles; the least disadvantaged quartile saw a slight overall decrease. CONCLUSION: This is the first Australian study providing robust evidence that AP incidence is increasing and is at the upper limit of population-based studies worldwide. This increased incidence is greatest in socio-economically disadvantaged areas, meriting further research to develop targeted, holistic management strategies.

Fluid resuscitation in the early management of acute pancreatitis - evidence from a systematic review and meta-analysis.

BACKGROUND: Third space fluid loss is one of the hallmarks of the pathophysiology of acute pancreatitis (AP) contributing to complications, including organ failure and death. We conducted a systematic review of literature to determine the ideal fluid resuscitation in the early management of AP, primarily comparing aggressive versus moderate intravenous fluid resuscitation (AIR vs MIR). METHODS: A systematic review of major reference databases was undertaken. Meta-analysis was performed using random-effects model. Bias was assessed using Cochrane risk of bias and ROBINS-I tools for randomized and non-randomised studies, respectively. RESULTS: Twenty studies were included in the analysis. Though there was no significant difference in mortality between AIR and MIR groups (8.3% versus 6.0%; p = 0.3), AIR cohort had significantly higher rates of organ failure (p = 0.009), including pulmonary (p = 0.02) and renal (p = 0.01) complications. Similarly, there was no difference in mortality between normal saline (NS) and Ringer's lactate (RL) (3.17% versus 3.01%; p = 0.23), though patients treated with NS had a significantly longer length of hospital stay (LOS) (p = 0.009). CONCLUSIONS: Current evidence appears to support moderate intravenous resuscitation (level of evidence, low) with RL (level of evidence, moderate) in the early management of AP.

A core set of quality performance indicators for HPB procedures: a global consensus for hepatectomy, pancreatectomy, and complex biliary surgery.

BACKGROUND: Surgery for hepatopancreaticobiliary (HPB) conditions is performed worldwide. This investigation aimed to develop a set of globally accepted procedural quality performance indicators (QPI) for HPB surgical procedures. METHODS: A systematic literature review generated a dataset of published QPI for hepatectomy, pancreatectomy, complex biliary surgery and cholecystectomy. Using a modified Delphi process, three rounds were conducted with working groups composed of self-nominating members of the International Hepatopancreaticobiliary Association (IHPBA). The final set of QPI was circulated to the full membership of the IHPBA for review. RESULTS: Seven "core" indicators were agreed for hepatectomy, pancreatectomy, and complex biliary surgery (availability of specific services on site, a specialised surgical team with at least two certified HPB surgeons, a satisfactory institutional case volume, synoptic pathology reporting, undertaking of unplanned reintervention procedures within 90 days, the incidence of post-procedure bile leak and Clavien-Dindo grade ≥III complications and 90-day post-procedural mortality). Three further procedure specific QPI were proposed for pancreatectomy, six for hepatectomy and complex biliary surgery. Nine procedure-specific QPIs were proposed for cholecystectomy. The final set of proposed indicators were reviewed and approved by 102 IHPBA members from 34 countries. CONCLUSIONS: This work presents a core set of internationally agreed QPI for HPB surgery.

Enhancing the cost-effectiveness of surgical care in pancreatic cancer: a systematic review and cost meta-analysis with trial sequential analysis.

BACKGROUND: Clinical pathways (CP) based on Enhanced recovery after surgery (ERAS®) are increasingly utilised in patients undergoing pancreatoduodenectomy (PD). This systematic review aimed to compare the impact of CPs versus conventional care (CC) on peri-PD costs. METHODS: A systematic review of major reference databases was undertaken. Quality assessment was performed using the CHEERS checklist. Incremental cost-effectiveness ratios were calculated as part of the cost-effectiveness analysis. A meta-analysis was performed using random-effects models and Trial sequential analysis (TSA) was used to assess the precision and conclusiveness of the results. RESULTS: 14 studies meeting inclusion criteria were included for full qualitative synthesis. All studies reported a reduction in overall costs, length of stay and overall complication rates for CPs when compared to CC. Meta-analysis performed on nine studies demonstrated significantly reduced costs in the CP group, with considerable heterogeneity (Pooled mean difference of $ 4.28 × 103, p < 0.01, I2 = 95%). Cost-effectiveness analysis in relation to complications demonstrated dominance of CPs over CC in being cheaper as well as more effective. TSA supported the cost benefit of enhanced-recovery CPs, displaying minimal type 1 error. CONCLUSION: Peri-PD CPs result in significant cost-reduction in comparison to CC.

Islets and pancreatic ductal adenocarcinoma - An opportunity for translational research from the 'Bench to the Bedside'.

The islet-acinar axis is of prime importance to the optimal functioning of the human pancreas. Not only is this inter-relationship important for normal physiological processes, it is also relevant in diseased states, including chronic pancreatitis and pancreatic ductal adenocarcinoma (PDAC). Early experiments, nearly 4 decades ago, explored the role of islets in the development and progression of PDAC. These led to further studies that provided compelling evidence to support the role of islets and their hormones in PDAC. This association presents oncologists with therapeutic options not only for managing, but potentially preventing PDAC, a cancer that is well known for its poor patient outcomes. This review will discuss the accumulated evidence regarding the role of islets and their hormones in PDAC and highlight areas for future research.

Exploring pre-surgery donor-specific antibodies in the context of organ shortage in liver transplant.

BACKGROUND: There is a growing disparity between the number of liver transplant (LT) candidates and availability of suitable liver allografts. Antibody-mediated rejection (AMR), secondary to positive donor-specific antibodies (DSA), remains a concern in liver transplantation. This study aimed to correlate expression of DSA on pre-transplant screening and outcomes of LT, specifically development of AMR in liver allografts and liver function profile in the post-operative period. METHODS: Data of consecutive patients undergoing orthotopic LT (OLT) at the South Australian Liver Transplant Unit was analysed. All patients underwent DSA testing pre-transplant. RESULTS: Within a cohort of 96 patients, over a post-OLT median follow-up of 849 days, only 2 patients (2%) developed AMR. While both patients had a positive DSA test preoperatively, overall DSA positivity was noted in 31% patients, with a specificity for prediction of AMR of 0.708. No significant association was noted between AMR (p = 0.092), T cell-mediated rejection/TCMR (p = 0.797) or late hepatic artery thrombosis/LHAT (p = 0.521). There was no significant interaction effect between DSA positivity and serum bilirubin or transaminases over a period of 100 days. CONCLUSION: AMR following LT is uncommon. A positive DSA pre-transplant does not imply a definite risk of AMR. Also, there does not exist a significant interaction in time between DSA expression and serum bilirubin or transaminase levels. Until there emerges evidence to the contrary, it appears reasonable to consider DSA-positive donors within the broad context of marginal donors in the context of a worldwide shortage of LT donor allografts.

Gallbladder cancer: a journey of a thousand steps.

This article traces the journey of one of the teams from India that has been actively managing and researching gallbladder cancer for more than a decade, providing insights into the work carried out and highlighting areas that warrant future research in this cancer traditionally known for its dismal outcomes.

Maximum surgical blood order schedule for pancreatoduodenectomy: a long way from uniform applicability!

BACKGROUND: Unnecessary preoperative ordering of blood and blood products results in wastage of a valuable life-saving resource and poses a significant financial burden on healthcare systems. AIM: To determine patient-specific factors associated with intra-operative transfusions, and if intra-operative blood transfusions impact postoperative morbidity. PATIENTS & METHODS: Analysis of consecutive patients undergoing pancreatoduodenectomy (PD) for pancreatic tumors. RESULTS: A total of 384 patients underwent a classical PD with an estimated median blood loss of 200 cc and percentage transfused being 9.6%. Pre-existing hypertension, synchronous vascular resection, end-to-side pancreaticojejunostomy and nodal disease burden significantly associated with the need for intra-operative transfusions. Intra-operative blood transfusion not associated with postoperative morbidity. CONCLUSION: Optimization of MSBOS protocols for PD is required for more judicious use of blood products.

Does the Ileal Brake Contribute to Delayed Gastric Emptying After Pancreatoduodenectomy?

Delayed gastric emptying (DGE) represents a significant cause for morbidity following pancreatoduodenectomy (PD). At a time when no specific and universally effective therapy exists to treat these patients, elucidating other potential (preventable or treatable) mechanisms for DGE is important. The aim of the manuscript was to test the hypothesis that ileal brake contributes to DGE in PD patients receiving jejunal tube feeding by systematically reviewing experimental and clinical literature. A series of clinically relevant questions were framed related to the potential role of the ileal brake in development of DGE post-PD and formed the basis of targeted literature searches. A comprehensive search of major reference databases from January 1980 to June 2015 was carried out which included human and animal studies. The ileal brake is a feedback loop neurally mediated by the vagus and sympatho-adrenergic pathways and hormonally by gut peptides including glucagon-like peptide-1, peptide YY (PYY), and neurotensin. The most potent stimulus for this inhibitory reflex is intra-ileal fat. There is evidence to indicate the role of an inhibitory reflex (on gastric emptying) mediated by PYY and CCK which, in turn, are stimulated by nutrient delivery into the distal small intestine providing indirect support to the role of ileal brake in post-PD DGE. The ileal brake is a likely factor contributing to DGE post-PD. While there has been no study to directly test this hypothesis, there is compelling indirect evidence to support it. Designing a trial that would answer such a question appears to be the most appropriate way forward.

Does revision of resection margins based on frozen section improve overall survival following pancreatoduodenectomy for pancreatic ductal adenocarcinoma? A meta-analysis.

BACKGROUND: Margin status is the main surgical determinant of long-term outcome in pancreatic cancer. Intraoperative frozen section (IOFS) detects microscopic positive margins at a stage when margin revision is possible. The aim of this study was to determine if IOFS driven-revision of pancreatic resection margin(s) improves overall survival (OS) in pancreatic cancer. METHODS: A systematic review of major reference databases was undertaken. Patients were divided into 3 groups based on initial FS (FSR0 for negative margin and FSR1 for positive microscopic margin) and final Permanent Section report (PSR0 for negative margin and PSR1 for positive microscopic margin): Group 1 (FSR0 â†’ PSR0), Group 2 (FSR1 â†’ PSR0), and Group 3 (FSR1 â†’ PSR1). Patients in Groups 2 and 3 had surgical revision of the FSR1 margin. Data was meta-analysed. RESULTS: 4 studies included in the final analysis. No difference in OS and incidence of lymph node metastases between Groups 2 and 3 (P = 0.590 and P = 0.410). CONCLUSIONS: IOFS-based revision of R1 pancreatic resection margin does not improve OS, even when it results in an R0 margin. This suggests that any benefit of margin revision based on FS is over-ridden by markers of more advanced or aggressive disease.

Justifying vein resection with pancreatoduodenectomy.

Interest in radical surgery to achieve complete resection and improve long-term survival in patients undergoing pancreatoduodenectomy for ductal adenocarcinoma has been renewed. This surgery includes extended lymphadenectomy, multivisceral resections, and synchronous arterial and venous resections. The evidence that these surgeries improve long-term survival is poor, except perhaps for synchronous venous resection, which can be justified if a margin negative (R0) resection is achieved without increased morbidity and mortality, and if there is no invasion of the vein wall. The recognition of patients with borderline resectable pancreatic cancer and the increasing use of neoadjuvant treatment makes it more difficult to know if the vein is invaded, increases reliance on trial dissection to establish resectability, and might increase the number of synchronous venous resections done. This Personal View seeks to review the justification for pancreatoduodenectomy with synchronous venous resection to promote debate and draw attention to the gaps in knowledge for further research.

How does cigarette smoking cause acute pancreatitis?

INTRODUCTION: Acute Pancreatitis (AP) is an emerging health problem world-wide and it is a major cause of admissions for gastrointestinal disease in many countries. Amongst the more common causes (alcohol and gallstones), recent evidence has emerged indicating that smoking is an independent risk factor for AP. However, the mechanisms involved in smoking-induced AP have not been completely elucidated. This review puts together all the published evidence in literature to present the clinical and laboratory evidence relating smoking to the causation of AP. DISCUSSION: The two main metabolites from cigarette smoke, namely nicotine and NNK are able to induce functional and histological changes within the pancreas consistent with AP. The major mechanisms involved include their action on acinar cells and zymogen secretion through pathways involving CCK and the nicotinic preganglionic receptors. Effects on the pancreatic microvasculature may be mediated through the nitric oxide pathway. There is indirect evidence to suggest that nicotine and acrolein may lead to CFTR dysfunction thereby influencing ductal secretion. However, direct evidence for this effect is needed. The effect of cigarette smoke metabolites on stellate cells and the islets warrants further investigation in the context of pathogenesis of AP. CONCLUSION: Using a step-wise approach, the review revisits the effects of the various metabolites of cigarette smoke on the constituents of the pancreas (exocrine, endocrine, neurohormonal, stellate cells, ductal system) and highlights their proven, and potential, mechanisms in triggering off an attack of AP.

Redefining early gastric cancer.

BACKGROUND: The problem is that current definitions of early gastric cancer allow the inclusion of regional lymph node metastases. The increasing use of endoscopic submucosal dissection to treat early gastric cancer is a concern because regional lymph nodes are not addressed. The aim of the study was thus to critically evaluate current evidence with regard to tumour-specific factors associated with lymph node metastases in "early gastric cancer" to develop a more precise definition and improve clinical management. METHODS: A systematic and comprehensive search of major reference databases (MEDLINE, EMBASE, PubMed and the Cochrane Library) was undertaken using a combination of text words "early gastric cancer", "lymph node metastasis", "factors", "endoscopy", "surgery", "lymphadenectomy" "mucosa", "submucosa", "lymphovascular invasion", "differentiated", "undifferentiated" and "ulcer". All available publications that described tumour-related factors associated with lymph node metastases in early gastric cancer were included. RESULTS: The initial search yielded 1494 studies, of which 42 studies were included in the final analysis. Over time, the definition of early gastric cancer has broadened and the indications for endoscopic treatment have widened. The mean frequency of lymph node metastases increased on the basis of depth of infiltration (mucosa 6% vs. submucosa 28%), presence of lymphovascular invasion (absence 9% vs. presence 53%), tumour differentiation (differentiated 13% vs. undifferentiated 34%) and macroscopic type (elevated 13% vs. flat 26%) and tumour diameter (≤2 cm 8% vs. >2 cm 25%). CONCLUSION: There is a need to re-examine the diagnosis and staging of early gastric cancer to ensure that patients with one or more identifiable risk factor for lymph node metastases are not denied appropriate chemotherapy and surgical resection.

D2 lymphadenectomy is not only safe but necessary in the era of neoadjuvant chemotherapy.

BACKGROUND: Patients with locally advanced resectable gastric cancers are increasingly offered neoadjuvant chemotherapy (NACT) following the MAGIC and REAL-2 trials. However, information on the toxicity of NACT, its effects on perioperative surgical outcomes and tumor response is not widely reported in literature. METHODS: Analysis of a prospective database of gastric cancer patients undergoing radical D2 gastrectomy over 2 years was performed. Chemotherapy-related toxicity, perioperative outcomes and histopathological responses to NACT were analyzed. The data is presented and compared to a cohort of patients undergoing upfront surgery in the same time period. RESULTS: In this study, 139 patients (42 female and 97 male patients, median age 53 years) with gastric adenocarcinoma received NACT. Chemotherapy-related toxicity was noted in 32% of patients. Of the 139 patients, 129 underwent gastrectomy with D2 lymphadenectomy, with 12% morbidity and no mortality. Major pathological response of primary tumor was noted in 22 patients (17%). Of these 22 patients, lymph node metastases were noted in 12 patients. The median blood loss and lymph node yield was not significantly different to the 62 patients who underwent upfront surgery. Patients who underwent upfront surgery were older (58 vs. 52 years, P <0.02), had a higher number of distal cancers (63% vs. 82%, P <0.015) and a longer hospital stay (11 vs. 9 days, P <0.001). CONCLUSIONS: Perioperative outcomes of gastrectomy with D2 lymphadenectomy for locally advanced, resectable gastric cancer were not influenced by NACT. The number of lymph nodes harvested was unaltered by NACT but, more pertinently, metastases to lymph nodes were noted even in patients with a major pathological response of the primary tumor. D2 lymphadenectomy should be performed in all patients irrespective of the degree of response to NACT.

Pancreatic nociception--revisiting the physiology and pathophysiology.

BACKGROUND: Pain management of many pancreatic diseases remains a major clinical concern. This problem reflects our poor understanding of pain signaling from the pancreas. OBJECTIVES: This review provides an overview of our current knowledge, with emphasis on current pain management strategies and recent experimental findings. METHODS: A systematic search of the scientific literature was carried out using EMBASE, PubMed/MEDLINE, and the Cochrane Central Register of Controlled Trials for the years 1965-2011 to obtain access to all publications, especially randomized controlled trials, systematic reviews, and meta-analyses exploring pain and its management in disease states such as acute pancreatitis (AP), chronic pancreatitis (CP) and pancreatic cancer (PC). RESULTS: Over the last decade, numerous molecular mediators such as nerve growth factor and the transient receptor potential (TRP) cation channel family have been implicated in afferent nerve signaling. More recent animal studies have indicated the location of the receptive fields for the afferent nerves in the pancreas and shown that these are activated by agents including cholecystokinin octapeptide, 5-hydroxytryptamine and bradykinin. Studies with PC specimens have shown that neuro-immune interactions occur and numerous agents including TRP cation channel V1, artemin and fractalkine have been implicated. Experimental studies in the clinical setting have demonstrated impairment of inhibitory pain modulation from supraspinal structures and implicated neuropathic pain mechanisms. CONCLUSIONS: Our knowledge in this area remains incomplete. Characterization of the mediators and receptors/ion channels on the sensory nerve terminals are required in order to facilitate the development of new pharmaceutical treatments for AP and CP.