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.

Expansion of Liver Transplantation Criteria for Hepatocellular Carcinoma from Milan to UCSF in Australia and New Zealand and Justification for Metroticket 2.0.

Background: Expansion in liver transplantation (LT) criteria for HCC from Milan to UCSF has not adversely impacted overall survival, prompting further expansion towards Metroticket 2.0 (MT2). In this study, we compared patient survival post-transplant before and after 2007 and long-term outcomes for LT within Milan versus UCSF criteria (to determine the true benefit of the expansion of criteria) and retrospectively validated the MT2 criteria. Methods: Retrospective analysis of ANZLITR (including all patients transplanted for HCC since July 1997). The entire cohort was divided based on criteria used at the time of listing, namely, Milan era (1997−2006) and the UCSF era (2007−July 2015). Results: The overall 5- and 10-year cumulative survival rates for the entire cohort of 691 patients were 78% and 69%, respectively. Patients transplanted in UCSF era had significantly higher 5- and 10-year survival rates than in the Milan era (80% vs. 73% and 72% vs. 65%, respectively; p = 0.016). In the UCSF era, the 5-year survival rate for patients transplanted within Milan criteria was significantly better than those transplanted outside Milan but within UCSF criteria (83% vs. 73%; p < 0.024). Patients transplanted within the MT2 criteria had a significantly better 5- and 10-year survival rate as compared to those outside the criteria (81% vs. 64% and 73% vs. 50%, respectively; p = 0.001). Conclusion: Overall survival following LT for HCC has significantly improved over time despite expanding criteria from Milan to UCSF. Patients fulfilling the MT2 criteria have a survival comparable to the UCSF cohort. Thus, expansion of criteria to MT2 is justifiable.

Gastrointestinal Adenocarcinoma Incidence and Survival Trends in South Australia, 1990-2017.

BACKGROUND & AIMS: Globally, there has been a concerning rise in the incidence of young-onset cancers. The aim of this study was to provide trends in the incidence and survival of gastrointestinal adenocarcinomas (oesophagus, stomach, pancreas, and colorectal) in South Australia over a 27-year period. METHODS: This is a cross-sectional analysis of a prospective longitudinal database including all cases of gastrointestinal adenocarcinomas prospectively reported to the South Australian (State) Cancer Registry from 1990 to 2017. RESULTS: A total of 28,566 patients diagnosed with oesophageal, stomach, pancreatic, or colorectal adenocarcinoma between 1990 and 2017 were included in the study. While the overall incidence for gastrointestinal adenocarcinomas in individuals >50 years has decreased since 2000 (IRR of 0.97 (95% CI 0.94-1.00; p = 0.06)) compared to 1990-1999, the rate amongst individuals aged 18-50 has significantly increased (IRR 1.41 (95% CI 1.27-1.57; p < 0.001)) during the same reference time period. Although noted in both sexes, the rate of increase in incidence was significantly greater in males (11.5 to 19.7/100,000; p < 0.001). The overall survival from adenocarcinomas across all subsites improved in the >50-year cohort in the last decade (HR 0.89 (95% CI 0.86-0.93; p < 0.001)) compared to 1990-1999. In individuals aged 18-50 years, there has only been a significant improvement in survival for colorectal cancer (HR 0.82 (95% CI 0.68-0.99; p < 0.04)), but not the other subsites. A lower overall survival was noted for males in both age cohorts (18-50 years-HR 1.24 (95% CI 1.09-1.13; p < 0.01) and >50 years-HR 1.13 (95% CI 1.10-1.16; p < 0.001), respectively) compared to females. CONCLUSIONS: This study from South Australia demonstrates a significant increase in young-onset gastrointestinal adenocarcinomas over the last 28 years, with a greater increase in the male sex. The only significant improvement in survival in this cohort has been noted in colorectal cancer patients.

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.

Birth of a solid organ cancer-the cell fusion hypothesis presented with pancreatic cancer as a model: a narrative review.

OBJECTIVE: This hypothesis-driven narrative review aims to explore the evidence for the fundamental process of cell fusion between normal, but different, cell types in the genesis of a cancer cell. BACKGROUND: Finding out how a cancer is born must remain a top priority as this will allow us the opportunity to understand the disease before it acquires its largely 'untameable' heterogeneous form. The search for the cell of origin in solid organ cancers has remained elusive despite concerted attempts over many decades. There is always more than one cell type implicated in the causation of solid organ cancers. METHODS: Based on preliminary data from our laboratory and a review of the evidence in literature, we present a novel hypothesis to explain the origin of solid organ cancers using pancreatic cancer as an example. CONCLUSIONS: We hypothesize that, "Cancer is born from fusion and hybridization of normal cells from two different lineages located within the vicinity of each other that perceive a signal reminiscent of a threat to their extinction that leads to epigenetically-mediated transformations permitting them to achieve cell fusion." Addressing this hypothesis to prove, or disprove it, presents an opportunity to unravel the basis of carcinogenesis and potential re-think our strategies for treatment in terms of choice of chemotherapeutic agents, dosage of chemo- and radiation-therapy, and timing of interventions (surgery, chemotherapy and radiation therapy).

Down-regulation of metabolic pathways could offset the poor prognosis conferred by co-existent diabetes mellitus in pancreatic (head) adenocarcinoma.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) patients with diabetes mellitus (DM) have poor overall survival. Underlying mechanisms have not been fully clarified. This presents an opportunity for precision-oncology for which we systematically analysed publicly-available PDAC transcriptome data. METHODS: PDAC TCGA RNASeq data were used. Analyses were restricted to only 'high purity' and 'head' as anatomical site. Patients were characterised by: (1) Gene expression classification, and (2) Weighted gene correlation network analysis (WGCNA) to identify co-expression patterns of genes. Newly identified gene signature subclasses of pancreatic head PDAC were associated with clinical and functional characteristics of patients. RESULTS: Consensus clustering identified two patient subclasses within PDAC involving pancreatic head. WGCNA identified 11 distinct networks of gene expression patterns across two sub-classes. Class 1 patients demonstrated a significant upregulation of Module 5 and Module 6 gene expression compared to Class 2. Class 1 predominantly expressed the acinar, ductal and islet cell gene signatures. There were significantly less patients with DM in Class 1 subclass compared to Class 2 (p < 0.037). Patients with DM had significant downregulation of pathways involved in cellular metabolism, hormone secretion and paucity of islet cell markers with no reduced survival compared with non-diabetics. CONCLUSIONS: A significant proportion of patients with PDAC of pancreatic head and DM exhibit downregulation of pathways involved in cellular metabolism, hormone secretion and signalling accompanied by a paucity of islet expression. Investigating the relationship between DM and gene expression profiles in patients with PDAC presents opportunities to improve overall survival in diabetics with PDAC.

Evidence Map of Pancreatic Surgery-A living systematic review with meta-analyses by the International Study Group of Pancreatic Surgery (ISGPS).

BACKGROUND: Pancreatic surgery is associated with considerable morbidity and, consequently, offers a large and complex field for research. To prioritize relevant future scientific projects, it is of utmost importance to identify existing evidence and uncover research gaps. Thus, the aim of this project was to create a systematic and living Evidence Map of Pancreatic Surgery. METHODS: PubMed, the Cochrane Central Register of Controlled Trials, and Web of Science were systematically searched for all randomized controlled trials and systematic reviews on pancreatic surgery. Outcomes from every existing randomized controlled trial were extracted, and trial quality was assessed. Systematic reviews were used to identify an absence of randomized controlled trials. Randomized controlled trials and systematic reviews on identical subjects were grouped according to research topics. A web-based evidence map modeled after a mind map was created to visualize existing evidence. Meta-analyses of specific outcomes of pancreatic surgery were performed for all research topics with more than 3 randomized controlled trials. For partial pancreatoduodenectomy and distal pancreatectomy, pooled benchmarks for outcomes were calculated with a 99% confidence interval. The evidence map undergoes regular updates. RESULTS: Out of 30,860 articles reviewed, 328 randomized controlled trials on 35,600 patients and 332 systematic reviews were included and grouped into 76 research topics. Most randomized controlled trials were from Europe (46%) and most systematic reviews were from Asia (51%). A living meta-analysis of 21 out of 76 research topics (28%) was performed and included in the web-based evidence map. Evidence gaps were identified in 11 out of 76 research topics (14%). The benchmark for mortality was 2% (99% confidence interval: 1%-2%) for partial pancreatoduodenectomy and <1% (99% confidence interval: 0%-1%) for distal pancreatectomy. The benchmark for overall complications was 53% (99%confidence interval: 46%-61%) for partial pancreatoduodenectomy and 59% (99% confidence interval: 44%-80%) for distal pancreatectomy. CONCLUSION: The International Study Group of Pancreatic Surgery Evidence Map of Pancreatic Surgery, which is freely accessible via www.evidencemap.surgery and as a mobile phone app, provides a regularly updated overview of the available literature displayed in an intuitive fashion. Clinical decision making and evidence-based patient information are supported by the primary data provided, as well as by living meta-analyses. Researchers can use the systematic literature search and processed data for their own projects, and funding bodies can base their research priorities on evidence gaps that the map uncovers.

Pancreatic ductal adenocarcinoma survival in South Australia: time trends and impact of tumour location.

BACKGROUND: It is unclear how global developments in management of pancreatic ductal adenocarcinoma (PDAC) have affected survival of Australian patients. This study aimed to determine trends in survival of PDAC over the last three decades in South Australia and to compare survival based on cancer location (head and uncinate process versus body and tail). METHODS: A retrospective observational cohort study to include all cases of PDAC reported to the South Australian (state) Cancer Registry from 1990 to 2017. RESULTS: A total of 1051 patients diagnosed with PDAC between 1990 and 2017 were included. An overall increase in number of reported PDAC cases over time with more than a doubling in the crude rate from 1.73 to 3.50 per 100 000 persons between the decades 1990-1999 and 2010-2017 (P < 0.001) was noted. Overall median survival for PDAC was 7.4 months (95% confidence interval 6.8-8.0 months) and this has improved in recent decades. Overall median survival for PDAC affecting head and uncinate process of pancreas was significantly higher compared to body and tail (7.6 months versus 4.1 months; P < 0.001). CONCLUSIONS: This study from South Australia demonstrates an increased reporting of PDAC over the last three decades. Although overall survival for patients with PDAC remains low, there has been a modest improvement in recent decades. The overall survival is significantly lower for patients with PDAC involving the body and tail compared to the head and uncinate process of pancreas. Risk factors for poor survival include the male gender and advancing age (>70 years).

Eroded Gastric Band: Where to Next? An Analysis of the Largest Contemporary Series.

PURPOSE: Erosion of a laparoscopic adjustable gastric band (LAGB) is a devastating problem. There is no clear evidence in literature to guide the choice of revisional procedure following an eroded LAGB. The purpose of this study is to analyse the largest series of erosions following LAGB published to-date with an aim to share our experience with this rare complication and how we managed this cohort of patients following explantation of their LAGB. MATERIALS AND METHODS: This is a retrospective cohort study. Patient data is maintained prospectively in a surgical database. The study period was from January 1996 to January 2019. The outcomes of patients who underwent an erosion of LAGB were studied. RESULTS: Gastric band erosion was encountered in 4.7% of patients. Sixty patients opted for a revisional procedure which included 37 repeat LAGBs, 6 laparoscopic sleeve gastrectomies (LSG), 7 Roux-en-Y gastric bypasses (RYGB), 1 intragastric balloon, and 9 failed revisional procedures. Re-erosions were noted in 27% of patients who underwent a repeat gastric banding. Median %TWL at a 1-year follow-up was significantly higher in LSG and RYGB groups compared with that in LAGB (P < 0.008 and P < 0.000, respectively). There was no significant difference between the LSG and RYGB groups. CONCLUSION: The risk of re-erosion is increased in patients who undergo repeat AGB following a previous episode of erosion. Repeat LAGB should not be offered after a previous erosion. LSG and RYGB should be considered as appropriate revisional procedures in a patient who experience weight regain following explantation of an eroded LAGB.

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.

Detecting tumour response and predicting resectability after neoadjuvant therapy for borderline resectable and locally advanced pancreatic cancer.

BACKGROUND: This systematic review aimed to determine the accuracy of imaging modalities to predict resectability and R0 resection for borderline resectable (BRPC) or locally advanced pancreatic cancer (LAPC) after neoadjuvant therapy (NAT). METHODS: A systematic search of major databases was performed in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. RESULTS: Fifteen studies identified 995 patients of which 683 had BRPC and 312 LAPC. Computed tomography (CT) scan was the most common modality for re-staging (n = 14), followed by positron emission tomography (PET)-CT (n = 3) and endosonography (EUS) (n = 2). Stable disease on RECIST criteria was found in 67% of patients (range 53-80%) with 20% demonstrating reduction in tumour size. A total of 60% of patients underwent surgery post-NAT (range 31-85%) with a R0 rate of 88% (range 57-100%). Accuracy for predicting R0 resectability and T-stage on CT scan was 71 and 49%. A reduction in SUVmax on PET-CT and reduction of tumour stiffness on EUS elastography positively correlated with resectability. CONCLUSIONS: More than half the patients undergo resection post-NAT for LAPC and BRPC. Stable, or reduction of, tumour disease may predict resectability. Reduction in tumour SUVmax on PET-CT and decreased tumour stiffness on EUS elastography may be potential markers of NAT response and resectability.

Predicting post-operative pancreatic fistulae using preoperative pancreatic imaging: a systematic review.

BACKGROUND: Post-operative pancreatic fistulae (POPF) remain a major contributor to morbidity and mortality following pancreatic resection. Evidence for preoperative prediction of POPF based on cross-sectional imaging has not been systemically reviewed. This review aimed to determine whether preoperative imaging modalities can accurately predict the development of POPF. METHODS: A systematic review of major reference databases was undertaken, according to PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) guidelines, up to May 2018. RESULTS: There were 18 studies (2150 patients), seven used magnetic resonance imaging (MRI), five used computed tomography (CT) scans, four used transabdominal ultrasonography and one study each used MRI and CT and endoscopic ultrasonography elastography. All were retrospective, single-centre studies. Intensity of the pancreas signal relative to the spleen, liver or muscle was commonly used. Other studies compared signal intensity between unenhanced and post-contrast-enhanced pancreas, apparent diffusion coefficient values comparing normal parenchyma to fibrosis, perfusion fraction (f) of intravoxel incoherent motion diffusion-weighted imaging, or utilized a muscle-normalized signal intensity curve with signal intensity ratio or directly assessed pancreatic volume and duct width. Shear wave velocity measurement on transabdominal ultrasonography may reflect pancreas tissue fibrosis or stiffness and predict POPF. Most parameters used to predict the development of POPF were based on identifying imaging features of a fatty or fibrotic pancreas and main pancreatic duct diameter. CONCLUSION: A number of different and highly promising parameters have been used for preoperative prediction of POPF using ultrasound, MRI, CT or both. Large multicentre prospective studies are needed to determine which parameters most accurately predict POPF, using standardized definitions and methodology.