Clinical and Financial Validation of the International Study Group for Pancreatic Surgery (ISGPS) Definition of Post-Pancreatectomy Acute Pancreatitis (PPAP): International Multicenter Prospective Study.

OBJECTIVE: To validate the ISGPS definition and grading system of PPAP after pancreatoduodenectomy (PD). SUMMARY BACKGROUND DATA: In 2022, the International Study Group for Pancreatic Surgery (ISGPS) defined post-pancreatectomy acute pancreatitis (PPAP) and recommended a prospective validation of its diagnostic criteria and grading system. METHODS: This was a prospective, international, multicenter study including patients undergoing PD at 17 referral pancreatic centers across Europe, Asia, Oceania, and the United States. PPAP diagnosis required the following three parameters: (1) postoperative serum hyperamylasemia /hyperlipasemia (POH) persisting on postoperative days 1 and 2, (2) radiologic alterations consistent with PPAP, and (3) a clinically relevant deterioration in the patient's condition. To validate the grading system, clinical and economic parameters were analyzed across all grades. RESULTS: Among 2902 patients undergoing PD, 7.5% (n=218) developed PPAP (6.3% grade B and 1.2% grade C). POH occurred in 24.1% of patients. Hospital stay was associated with PPAP grades (No POH/PPAP 10 days (IQR 7-17) days, grade B 22 days (IQR 15-34) days, and grade C 43 days (IQR 27-54) days; P<0.001), as well as intensive care unit admission (No POH/PPAP 5.4%, grade B 12.6%, grade C 82.9%; P<0.010), and hospital readmission rates (No POH/PPAP 7.3%, grade B 16.1%, grade C 18.5%; P<0.05). Costs of grade B and C PPAP were 2 and 11 times greater than uncomplicated clinical course, resp. (P<0.001). CONCLUSIONS: This first prospective, international validation study of the ISGPS definition and grading system for PPAP highlighted the relevant clinical and financial implications of this condition. These results stress the importance of routine screening for PPAP in patients undergoing PD.

The burden of young-onset pancreatic cancer and its risk factors from 1990 to 2019: A systematic analysis of the global burden of disease study 2019.

OBJECTIVE: To investigate worldwide incidence, deaths, disability-adjusted life years (DALYs) and risk factors for young-onset pancreatic cancer (YOPC) using the Global Burden of Disease Study 2019-20 data. METHODS: We queried the Global Health Data Exchange tool for "pancreatic cancer" and "incidence", "deaths" as the "measure", and "DALYs" as the "cause" for the age group of 15-49 years to determine global, regional, and national trends in the incidence, deaths, and DALYs of YOPC. Sociodemographic index (SDI) was used to evaluate the associations between socioeconomic development and YOPC. Risk factors including smoking, tobacco use, hi2gh body mass index (BMI), and high fasting plasma glucose (FPG) were evaluated, and their attributable burden was estimated. RESULTS: Global incidence, death, and DALY rates of YOPC significantly increased from 1990 to 2019 ((0.30 (p = 0.001), 0.25 (p = 0.001), and 11.18 (p = 0.002), respectively). Regions with the highest and lowest incidence, death, and DALY rates of YOPC were Eastern Europe and Central Sub-Saharan Africa, respectively. Incidence, death, and DALY rates increased with increasing age and SDI. Leading risk factors for YOPC in 2019 were smoking and tobacco use. DALYs attributable to smoking and tobacco use decreased from 1990 to 2019, especially in females, while those attributable to high BMI and FPG increased during the same period. CONCLUSIONS: The global incidence, death and DALY rates of YOPC have significantly increased over 3 decades. Certain regions and nations are witnessing a higher increase in this trend. There is an urgent need for global efforts targeting preventable causes of YOPC.

'IHPBA-APHPBA clinical practice guidelines': international Delphi consensus recommendations for gallbladder cancer.

BACKGROUND: The Delphi consensus study was carried out under the auspices of the International and Asia-Pacific Hepato-Pancreato-Biliary Associations (IHPBA-APHPBA) to develop practice guidelines for management of gallbladder cancer (GBC) globally. METHOD: GBC experts from 17 countries, spanning 6 continents, participated in a hybrid four-round Delphi consensus development process. The methodology involved email, online consultations, and in-person discussions. Sixty eight clinical questions (CQs) covering various domains related to GBC, were administered to the experts. A consensus recommendation was accepted only when endorsed by more than 75% of the participating experts. RESULTS: Out of the sixty experts invited initially to participate in the consensus process 45 (75%) responded to the invitation. The consensus was achieved in 92.6% (63/68) of the CQs. Consensus covers epidemiological aspects of GBC, early, incidental and advanced GBC management, definitions for radical GBC resections, the extent of liver resection, lymph node dissection, and definitions of borderline resectable and locally advanced GBC. CONCLUSIONS: This is the first international Delphi consensus on GBC. These recommendations provide uniform terminology and practical clinical guidelines on the current management of GBC. Unresolved contentious issues like borderline resectable/locally advanced GBC need to be addressed by future clinical studies.

Mortality and costs related to severe acute pancreatitis in the intensive care units of Australia and New Zealand (ANZ), 2003-2020.

BACKGROUND AND OBJECTIVE: Comprehensive data on the burden of severe acute pancreatitis (SAP) in global intensive care units (ICUs) and trends over time are lacking. Our objective was to compare trends in hospital and ICU mortality, in-hospital and ICU length of stay, and costs related to ICU admission in Australia and New Zealand (ANZ) for SAP. METHODS: We performed a retrospective, observational, cohort study of ICU admissions reported to the ANZ Intensive Care Society Adult Patient Database over three consecutive six-year time periods from 2003 to 2020. RESULTS: 12,635 patients with SAP from 189 ICUs in ANZ were analysed. No difference in adjusted hospital mortality (11.4% vs 11.5% vs 11.0%, p = 0.85) and ICU mortality rates (7.5% vs 8.0% vs 8.1%, p = 0.73) were noted over the study period. Median length of hospital admission reduced over time (13.9 days in 2003-08, 13.1 days in 2009-14 and 12.5 days in 2015-20; p < 0.01). No difference in length of ICU stay was noted over the study period (p = 0.13). The cost of managing SAP in ANZ ICUs remained constant over the three time periods. CONCLUSIONS: In critically-ill SAP patients in ANZ, no change in mortality has been noted over nearly two decades. There was a slight reduction in hospital stay (1 day), while the length of ICU stay remained unchanged. Given the significant costs related to care of patients with SAP in ICU, these findings highlight the need to prioritise resource allocation for healthcare delivery and targeted clinical research to identify treatments aimed at reducing mortality.

Extended distal pancreatectomy in pancreatic cancer: is it justified? A systematic review of literature.

Background: Extended distal pancreatectomy (EDP) is being increasingly performed for pancreatic cancers with suspected invasion into the adjacent organs. However, the perioperative safety and oncological efficacy of this procedure merit further elucidation. Methods: Major databases were searched for studies evaluating EDP, and a meta-analysis was performed using fixed- or random-effects models. Results: Fifteen studies were included in the analysis. EDP was found to be associated with significantly greater incidence of postoperative pancreatic fistula overall and with major complications, re-explorations, mortality and readmissions. However, on pooled analysis of 3- and 5-year survival, EDP was found to be noninferior to standard distal pancreatectomy. Conclusion: EDP is feasible and may offer equivalent survival in highly selected patients but carries a higher risk of perioperative morbidity and mortality.

Impact of Unplanned Intra-Operative Conversions on Outcomes in Minimally Invasive Pancreatoduodenectomy.

BACKGROUND: Minimally-invasive pancreatoduodenectomy (MIPD) is fraught with the risk of complication-related deaths (LEOPARD-2), a significant volume-outcome relationship and a long learning curve. With rates of conversion for MIPD approaching 40%, the impact of these on overall patient outcomes, especially, when unplanned, are yet to be fully elucidated. This study aimed to compare peri-operative outcomes of (unplanned) converted MIPD against both successfully completed MIPD and upfront open PD. METHODS: A systematic review of major reference databases was undertaken. The primary outcome of interest was 30-day mortality. Newcastle-Ottawa scale was used to judge the quality of the studies. Meta-analysis was performed using pooled estimates, derived using random effects model. RESULTS: Six studies involving 20,267 patients were included in the review. Pooled analysis demonstrated (unplanned) converted MIPD were associated with an increased 30-day (RR 2.83, CI 1.62- 4.93, p = 0.0002, I2 = 0%) and 90-day (RR 1.81, CI 1.16- 2.82, p = 0.009, I2 = 28%) mortality and overall morbidity (RR 1.41, CI 1.09; 1.82, p = 0.0087, I2 = 82%) compared to successfully completed MIPD. Patients undergoing (unplanned) converted MIPD experienced significantly higher 30-day mortality (RR 3.97, CI 2.07; 7.65, p < 0.0001, I2 = 0%), pancreatic fistula (RR 1.65, CI 1.22- 2.23, p = 0.001, I2 = 0%) and re-exploration rates (RR 1.96, CI 1.17- 3.28, p = 0.01, I2 = 37%) compared upfront open PD. CONCLUSIONS: Patient outcomes are significantly compromised following unplanned intraoperative conversions of MIPD when compared to successfully completed MIPD and upfront open PD. These findings stress the need for objective evidence-based guidelines for patient selection for MIPD.

Global Perceptions on ERAS® in Pancreatoduodenectomy.

BACKGROUND: Uptake of ERAS® pathways for pancreatic surgery have been slow and impacted by low compliance. OBJECTIVE: To explore global awareness, perceptions and practice of ERAS® peri-pancreatoduodenectomy (PD). METHODS: A structured, web-based survey (EPSILON) was administered through the ERAS® society and IHPBA membership. RESULTS: The 140 respondents included predominantly males (86.4%), from Europe (45%), practicing surgery (95%) at academic/teaching hospitals (63.6%) over a period of 10-20 years (38.6%). Most respondents identified themselves as general surgeons (68.6%) with 40.7% reporting an annual PD volume of 20-50 cases, practicing post-PD clinical pathways (37.9%), with 31.4% of respondents auditing their outcomes annually. Reduced medical complications, cost and hospital length of stay, and improved patient satisfaction were perceived benefits of compliance to enhancing-recovery. Multidisciplinary co-ordination was considered the most important factor in the implementation and sustainability of peri-PD ERAS® pathways, while reluctance to change among health care practitioners, difficulties in data collection and audit, lack of administrative support, and recruitment of an ERAS® dedicated nurse were reported to be important barriers. CONCLUSIONS: The EPSILON survey highlighted global clinician perceptions regarding the benefits of compliance to peri-PD ERAS®, the importance of individual components, perceived facilitators and barriers, to the implementation and sustainability of these pathways.

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

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

Can we predict the need for nutritional support following pancreatoduodenectomy?

BACKGROUND: The practice of routine placement of a tube jejunostomy at the time of pancreatoduodenectomy has given way to a more selective approach. However, the indications of establishing enteral access at the time of surgery remain poorly defined. This study aimed to assess the preoperative and intraoperative factors associated with the need for nutritional support after pancreatoduodenectomy, to guide decision-making for the establishment of intraoperative feeding access. METHODS: Retrospective study, analyzing the data of 562 consecutive patients, who underwent pancreatoduodenectomy between March 2013 to December 2020. Univariate and multiple logistic regression analysis was carried out to ascertain the factors associated with the initiation of and need for nutritional support for more than 7 days postop. The utility of tube jejunostomy was studied in patients in whom it was performed. RESULTS: Of 562 patients, 105 (18.7%) needed nutritional support. A tube jejunostomy was performed in 46 (8.2%) patients, parenteral nutrition was used in 83 (14.8%), and nasojejunal tube placed in 28 (4.9%) patients. On logistic regression analysis, age, serum albumin <3.0 gm/dl and operative blood loss were independently associated with the initiation of supportive nutrition, while preoperative gastric outlet obstruction (OR 3.105, 95% CI1.201-8.032, p = 0.019) and serum albumin <3.0 gm/dl (OR 2.669, 95% CI 1.131-6.300, p = 0.025) were associated with the need for prolonged nutritional support. The maximal benefit of tube jejunostomy was in patients with mental health disorders (83.3%). CONCLUSION: Tube jejunostomy for nutritional support after pancreatoduodenectomy can be considered in patients with preoperative gastric outlet obstruction, serum albumin <3.0 gm/dl and mental health disorders.

Post-hepatectomy venous thromboembolism: a systematic review with meta-analysis exploring the role of pharmacological thromboprophylaxis.

PURPOSE: Patients undergoing hepatectomy are at moderate-to-high risk of venous thromboembolism (VTE). This study critically examines the efficacy of combining pharmacological (PTP) and mechanical thromboprophylaxis (MTP) versus only MTP in reducing VTE events against the risk of hemorrhagic complications. METHODS: A systematic review of major reference databases was undertaken, and a meta-analysis was performed using common-effects model. Risk of bias assessment was performed using Newcastle-Ottawa scale. Trial sequential analysis (TSA) was used to assess the precision and conclusiveness of the results. RESULTS: 8 studies (n = 4238 patients) meeting inclusion criteria were included in the analysis. Use of PTP + MTP was found to be associated with significantly lower VTE rates compared to only MTP (2.5% vs 5.3%; pooled RR 0.50, p = 0.03, I2 = 46%) with minimal type I error. PTP + MTP was not associated with an increased risk of hemorrhagic complications (3.04% vs 1.9%; pooled RR 1.54, p = 0.11, I2 = 0%) and had no significant impact on post-operative length of stay (12.1 vs 10.8 days; pooled MD - 0.66, p = 0.98, I2 = 0%) and mortality (2.9% vs 3.7%; pooled RR 0.73, p = 0.33, I2 = 0%). CONCLUSION: Despite differences in the baseline patient characteristics, extent of hepatectomy, PTP regimens, and heterogeneity in the pooled analysis, the current study supports the use of PTP in post-hepatectomy patients (grade of recommendation: strong) as the combination of PTP + MTP is associated with a significantly lower incidence of VTE (level of evidence, moderate), without an increased risk of post-hepatectomy hemorrhage (level of evidence, low).

Critical thresholds: key to unlocking the door to the prevention and specific treatments for acute pancreatitis.

Acute pancreatitis (AP), an acute inflammatory disorder of the exocrine pancreas, is one of the most common gastrointestinal diseases encountered in emergency departments with no specific treatments. Laboratory-based research has formed the cornerstone of endeavours to decipher the pathophysiology of AP, because of the limitations of such study in human beings. While this has provided us with substantial understanding, we cannot answer several pressing questions. These are: (a) Why is it that only a minority of individuals with gallstones, or who drink alcohol excessively, or are exposed to other causative factors develop AP? (b) Why do only some develop more severe manifestations of AP with necrosis and/or organ failure? (c) Why have we been unable to find an effective therapeutic for AP? This manuscript provides a state-of-the-art review of our current understanding of the pathophysiology of AP providing insights into the unanswered clinical questions. We describe multiple protective factors operating in most people, and multiple stressors that in a minority induce AP, independently or together, via amplification loops. We present testable hypotheses aimed at halting progression of severity for the development of effective treatments for this common unpredictable disease.

Forecasting surgical costs: Towards informed financial consent and financial risk reduction.

BACKGROUND: Health care expenditure is increasing around the world and surgery is a major cause of financial hardship to patients and their families. Using pancreatoduodenectomy (PD), one of the most complex, morbid and costly operation as an example, this study aimed to identify the cost drivers of surgery, estimate relative contribution of these drivers, and derive and validate a cohort-specific cost forecasting tool. METHODS: Data on the costs of 1406 patients undergoing PD in three tertiary hospitals in India, Italy and the United States were analysed. Cost drivers were identified and cost models developed using a 4-stage process. RESULTS: There was a significant difference in overall cost of PD between the 3 cohorts. The cost drivers common to the 3 cohorts included duration of hospital stay and the outcome of death (Clavien-Dindo 5). Significant cohort-specific cost drivers included co-morbidities, operating theatre utilisation times and operative blood loss, development of pancreatectomy-specific complications (POPF, DGE, PPH), and need for interventional radiology to manage complications. Based on this, a cost forecasting tool was developed. CONCLUSIONS: Drivers of costs for a surgical procedure (e.g. PD) are different between hospitals. Developing cost models/nomograms to predict the expected cost of surgery and perioperative care will not be applicable between hospitals. However, the approach could be used to develop context-specific data that will provide patients (at the time of the informed financial consent) and funding agencies with a more realistic cost estimate for a given operation. The developed cost forecasting tool warrants future validation.

Surgery for pancreatic cancer: current controversies and challenges.

Two areas that remain the focus of improvement in pancreatic cancer include high post-operative morbidity and inability to uniformly translate surgical success into long-term survival. This narrative review addresses specific aspects of pancreatic cancer surgery, including neoadjuvant therapy, vascular resections, extended pancreatectomy, extent of lymphadenectomy and current status of minimally invasive surgery. R0 resection confers longer disease-free survival and overall survival. Vascular and adjacent organ resections should be undertaken after neoadjuvant therapy, only if R0 resection can be ensured based on high-quality preoperative imaging, and that too, with acceptable post-operative morbidity. Extended lymphadenectomy does not offer any advantage over standard lymphadenectomy. Although minimally invasive distal pancreatectomies offers some short-term benefits over open distal pancreatectomy, safety remains a concern with minimally invasive pancreatoduodenectomy. Strict adherence to principles and judicious utilization of surgery within a multimodality framework is the way forward.

Lay abstract Two main areas of focus in pancreatic cancer research are the high rates of post-surgery complications and poor survival despite completely removing the tumor. Complete, margin-negative resection (where some healthy tissue is removed to ensure the whole tumor is cut out) is the only way to ensure long-term survival. However, such extensive resections, especially when they involve nearby blood vessels and/or organs, should only be undertaken if the imaging done pre-surgery indicates the possibility that a complete, margin-negative resection can be achieved. It should be noted that the removal of lymph nodes, in addition to the ones normally removed during a pancreatic resection, does not confer a survival benefit. Distal pancreatectomy (performed for tumors involving the body or tail of the pancreas) is safe and feasible using minimal access methods; however, the safety of minimally-invasive pancreatoduodenectomy (performed for tumors of the head of the pancreas) remains to be proven. The oncological benefit of minimally-invasive distal pancreatectomy over open surgery has not been established.

Pancreatic cancer in Australia: is not it time we address the inequitable resource problem?

The present study reviewed the geographical variations in the delivery of pancreatic cancer therapy and whether this impacts overall survival. The evidence suggests a difference in the accessibility of pancreatic cancer care to patients in rural as compared with urban Australia. While centralization of pancreatic surgery is essential to deliver high quality care to patients, it may be interfering with the ease of access of this form of care to patients in regional areas. Access to chemotherapy in regional Australia is also limited. There is need for a concerted effort to improve the overall care and uptake of medical services to patients in metropolitan and remote Australia with the overarching aim of improving survival and meaningful quality of life.

Deviations from a clinical pathway post pancreatoduodenectomy predict 90-day unplanned re-admission.

Aim: To determine the frequency and relevance of deviations from a post pancreatoduodenectomy (PD) clinical care pathway. Materials & methods: A retrospective analysis using a prospectively maintained database of a post-PD clinical care pathway was carried out between May 2016 and March 2018. Patients were divided based on the number of factors deviating from the clinical care pathway (Group I: no deviation; Group II: deviation in 1-4 factors; Group III: deviation in 5-8 factors). The analysis included profiling of patients on different demographic and clinical as well as medical and surgical outcome parameters (discharge by postoperative day 8 and 90-day unplanned re-admission rate). Results: Post-PD clinical care pathways are feasible but deviations from the pathway are frequent (91%). An increase in frequency of deviations from the pathway was significantly associated with increased risk of POPF and delayed gastric emptying, delayed discharge, risk of mortality and 90-day unplanned re-admission rate. Conclusion: Deviations from a post-PD clinical care pathway are common. Poor nutrition and cardiac co-morbidities are associated with an increased likelihood of deviation. As the number of deviations increase, so does the risk of significant complications and interventions, delayed discharge and 90-day re-admission rate.

ERBB2 and KRAS alterations mediate response to EGFR inhibitors in early stage gallbladder cancer.

The uncommonness of gallbladder cancer in the developed world has contributed to the generally poor understanding of the disease. Our integrated analysis of whole exome sequencing, copy number alterations, immunohistochemical, and phospho-proteome array profiling indicates ERBB2 alterations in 40% early-stage rare gallbladder tumors, among an ethnically distinct population not studied before, that occurs through overexpression in 24% (n = 25) and recurrent mutations in 14% tumors (n = 44); along with co-occurring KRAS mutation in 7% tumors (n = 44). We demonstrate that ERBB2 heterodimerizes with EGFR to constitutively activate the ErbB signaling pathway in gallbladder cells. Consistent with this, treatment with ERBB2-specific, EGFR-specific shRNA or with a covalent EGFR family inhibitor Afatinib inhibits tumor-associated characteristics of the gallbladder cancer cells. Furthermore, we observe an in vivo reduction in tumor size of gallbladder xenografts in response to Afatinib is paralleled by a reduction in the amounts of phospho-ERK, in tumors harboring KRAS (G13D) mutation but not in KRAS (G12V) mutation, supporting an essential role of the ErbB pathway. In overall, besides implicating ERBB2 as an important therapeutic target under neo-adjuvant or adjuvant settings, we present the first evidence that the presence of KRAS mutations may preclude gallbladder cancer patients to respond to anti-EGFR treatment, similar to a clinical algorithm commonly practiced to opt for anti-EGFR treatment in colorectal cancer.