Lipase-to-Amylase Ratio for the Prediction of Clinically Relevant Postoperative Pancreatic Fistula following Pancreaticoduodenectomy.

AIM: Postoperative pancreatic fistula(POPF) represents a leading cause of morbidity and mortality following major pancreatic resections. This study aimed to evaluate the use of post-operative drain fluid lipase-to-amylase ratio(LAR) for the prediction of clinically relevant fistulae(CR-POPF). METHODS: Consecutive patients undergoing pancreaticoduodenectomy between 2017-2021 at a tertiary centre were retrospectively reviewed. Univariable and multivariable analyses were performed to identify predictors for CR-POPF(ISGPS Grades B/C). Receiver operator characteristic(ROC) curve analyses were conducted to evaluate the performance of LAR and determine optimum prediction thresholds. RESULTS: Among 130 patients, 28(21.5%) developed CR-POPF. Variables positively associated with CR-POPF included soft gland texture, acinar cell density, diagnosis other than PDAC or chronic pancreatitis, resection without neoadjuvant therapy, and postoperative drain fluid lipase, amylase, and LAR(all p < 0.05). Multivariable regression analysis identified LAR as an independent predictor of CR-POPF(p < 0.05). ROC curve analysis showed that LAR had moderate ability to predict CR-POPF on POD1(AUC = 0.64,95%CI = 0.54-0.74) and excellent ability on POD3(AUC = 0.85,95%CI = 0.78-0.92) and POD5(AUC = 0.86,95%CI = 0.79-0.92). Optimum thresholds were consistent over POD1-5 (ratio > 2.6) and associated with 92% sensitivity and 46-71% specificity. CONCLUSION: Postoperative drain fluid LAR represents a reliable predictor for the development of CR-POPF. With early prognostication, the postoperative care of patients deemed at risk of developing high-grade fistulas may be optimised.

Kidney Transplantation Outcomes From Uncontrolled Donation After Circulatory Death: A Systematic Review and Meta-analysis.

BACKGROUND: Uncontrolled donation after circulatory death (uDCD) is a potential additional source of donor kidneys. This study reviewed uDCD kidney transplant outcomes to determine if these are comparable to controlled donation after circulatory death (cDCD). METHODS: MEDLINE, Cochrane, and Embase databases were searched. Data on demographic information and transplant outcomes were extracted from included studies. Meta-analyses were performed, and risk ratios (RR) were estimated to compare transplant outcomes from uDCD to cDCD. RESULTS: Nine cohort studies were included, from 2178 uDCD kidney transplants. There was a moderate degree of bias, as 4 studies did not account for potential confounding factors. The median incidence of primary nonfunction in uDCD was 12.3% versus 5.7% for cDCD (RR, 1.85; 95% confidence intervals, 1.06-3.23; P = 0.03, I 2 = 75). The median rate of delayed graft function was 65.1% for uDCD and 52.0% for cDCD. The median 1-y graft survival for uDCD was 82.7% compared with 87.5% for cDCD (RR, 1.43; 95% confidence intervals, 1.02-2.01; P = 0.04; I 2 = 71%). The median 5-y graft survival for uDCD and cDCD was 70% each. Notably, the use of normothermic regional perfusion improved primary nonfunction rates in uDCD grafts. CONCLUSIONS: Although uDCD outcomes may be inferior in the short-term, the long-term outcomes are comparable to cDCD.

Systematic Review of Preoperative Prognostic Biomarkers in Perihilar Cholangiocarcinoma.

Perihilar cholangiocarcinoma (pCCA) is an uncommon malignancy with generally poor prognosis. Surgery is the primary curative treatment; however, the perioperative mortality and morbidity rates are high, with a low 5-year survival rate. Use of preoperative prognostic biomarkers to predict survival outcomes after surgery for pCCA are not well-established currently. This systematic review aimed to identify and summarise preoperative biomarkers associated with survival in pCCA, thereby potentially improving treatment decision-making. The Embase, Medline, and Cochrane databases were searched, and a systematic review was performed using the PRISMA guidelines. English-language studies examining the association between serum and/or tissue-derived biomarkers in pCCA and overall and/or disease-free survival were included. Our systematic review identified 64 biomarkers across 48 relevant studies. Raised serum CA19-9, bilirubin, CEA, neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and tumour MMP9, and low serum albumin were most associated with poorer survival; however, the cutoff values used widely varied. Several promising molecular markers with prognostic significance were also identified, including tumour HMGA2, MUC5AC/6, IDH1, PIWIL2, and DNA index. In conclusion, several biomarkers have been identified in serum and tumour specimens that prognosticate overall and disease-free survival after pCCA resection. These, however, require external validation in large cohort studies and/or in preoperatively obtained specimens, especially tissue biopsy, to recommend their use.

Evolution of laparoscopic pancreaticoduodenectomy at Westmead Hospital.

BACKGROUND: Despite its proposed benefits, laparoscopic pancreaticoduodenectomy (LPD) has not been widely adopted due to its technical complexity and steep learning curve. The aim of this study was to report a single surgeon's experience in the stepwise implementation of LPD and evolution of technique over a nine-year period in a moderate-high volume unit. METHODS: Carefully selected patients underwent LPD initially by hybrid approach (laparoscopic resection and open reconstruction), which evolved into a total LPD (laparoscopic resection and reconstruction). Data was prospectively collected to include patient characteristics, intraoperative data, evolution of technique and postoperative outcomes. RESULTS: A total of 25 patients underwent hybrid LPD (HLPD) and 20 patients underwent total LPD (TLPD). There was no 90-day mortality. Three patients developed a postoperative pancreatic fistula (POPF), all of which occurred in patients undergoing HLPD. There was no POPF in 20 consecutive TLPD. There was no evidence of anastomotic strictures in the hepaticojejunostomy in patients undergoing TLPD at long term follow up. CONCLUSION: A gradual and cautious progression from HLPD to TLPD is essential to ensure safe implementation into a unit. LPD should only be considered in carefully selected patients, with outcomes subjected to regular and rigorous independent audit.

Gene expression profiling of pancreatic ductal adenocarcinomas in response to neoadjuvant chemotherapy.

AIM: Pancreatic ductal adenocarcinoma (PDAC) has the lowest survival rate of all major cancers. Chemotherapy is the mainstay systemic therapy for PDAC, and chemoresistance is a major clinical problem leading to therapeutic failure. This study aimed to identify key differences in gene expression profile in tumors from chemoresponsive and chemoresistant patients. METHODS: Archived formalin-fixed paraffin-embedded tumor tissue samples from patients treated with neoadjuvant chemotherapy were obtained during surgical resection. Specimens were macrodissected and gene expression analysis was performed. Multi- and univariate statistical analysis was performed to identify differential gene expression profile of tumors from good (0%-30% residual viable tumor [RVT]) and poor (>30% RVT) chemotherapy-responders. RESULTS: Initially, unsupervised multivariate modeling was performed by principal component analysis, which demonstrated a distinct gene expression profile between good- and poor-chemotherapy responders. There were 396 genes that were significantly (p < 0.05) downregulated (200 genes) or upregulated (196 genes) in tumors from good responders compared to poor responders. Further supervised multivariate analysis of significant genes by partial least square (PLS) demonstrated a highly distinct gene expression profile between good- and poor responders. A gene biomarker of panel (IL18, SPA17, CD58, PTTG1, MTBP, ABL1, SFRP1, CHRDL1, IGF1, and CFD) was selected based on PLS model, and univariate regression analysis of individual genes was performed. The identified biomarker panel demonstrated a very high ability to diagnose good-responding PDAC patients (AUROC: 0.977, sensitivity: 82.4%; specificity: 87.0%). CONCLUSION: A distinct tumor biological profile between PDAC patients who either respond or not respond to chemotherapy was identified.

Clinical validation of the international study group of pancreatic surgery (ISGPS) definition for post-pancreatectomy acute pancreatitis.

BACKGROUND: The diagnosis of postoperative or post-pancreatectomy acute pancreatitis (PPAP) is controversial. In 2021, the International Study Group of Pancreatic Surgery (ISGPS) published the first unifying definition and grading system for PPAP. This study sought to validate recent consensus criteria, using a cohort of patients undergoing pancreaticoduodenectomy (PD) in a high-volume pancreaticobiliary specialty unit. METHODS: All consecutive patients undergoing PD at a tertiary referral centre between January 2016 and December 2021 were retrospectively reviewed. Patients with serum amylase recorded within 48h from surgery were included for analysis. Postoperative data were extracted and evaluated against the ISGPS criteria, including the presence of postoperative hyperamylasaemia, radiologic features consistent with acute pancreatitis, and clinical deterioration. RESULTS: A total of 82 patients were evaluated. The overall incidence of PPAP was 32% (26/82) in this cohort, of which 3/26 demonstrated postoperative hyperamylasaemia and 23/26 had clinically relevant PPAP (Grade B or C) when correlated radiologic and clinical criteria. CONCLUSIONS: This study is among the first to apply the recently published consensus criteria for PPAP diagnosis and grading to clinical data. While the results support their utility in establishing PPAP as a distinct post-pancreatectomy complication, there remains a need for future large-scale validation studies.

Reducing unplanned general surgical readmissions: a review of the Australian and New Zealand National Surgical Quality Improvement Program Database.

BACKGROUND: Unplanned surgical readmissions are an important indicator of quality care and are a key focus of improvement programs. The aims of this study were to evaluate the factors that lead to unplanned hospital readmissions in patients undergoing general surgical procedures and to identify preventable readmissions. METHODS: A retrospective review of the American College of Surgeons National Surgical Quality Improvement Program database from 2016 to 2020 at a tertiary hospital was conducted to identify patients undergoing a general surgical procedure. Various perioperative parameters were studied to identify risk factors and reasons for unplanned readmission. Preventable readmissions were identified. RESULTS: A total of 3069 patients underwent a general surgical procedure. Of these, the overall unplanned readmission rate was 8.8% (n = 247). The most common reason for readmission was associated with surgical site infections (n = 112, 44.3%) followed by pain (n = 50, 20.2%), with over 45% deemed as preventable readmissions. Factors associated with increased risk of readmission included older age, longer index length of stay, prolonged operative time, elective procedures, higher ASA score and contaminated procedures. CONCLUSION: Unplanned readmissions are more likely to occur in patients who develop postoperative complications. Understanding factors associated with readmissions may facilitate targeted quality improvement projects that reduce hospital readmission after surgery.

Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio use in detecting bowel ischaemia in adhesional small bowel obstruction.

BACKGROUND: Bowel ischaemia significantly increases morbidity and mortality from adhesional small bowel obstruction. Current biomarkers and clinical parameters have poor predictive value for ischaemia. Our study investigated whether neutrophil-lymphocyte ratio (NLR) and platelet-lymphocyte ratio (PLR) could be used to predict bowel ischaemia in adhesional small bowel obstruction. METHODS: This single-centre retrospective study collected clinical, biochemical and radiological data from patients with adhesional small bowel obstruction between 2017 and 2020 who underwent operative management. The presence or absence of bowel ischaemia/infarction was used to distinguish two populations. Biochemical markers on admission and immediately prior to operation were collected to give platelet-lymphocyte ratio (PLR0 and PLRPRE-OP , respectively) and neutrophil-lymphocyte ratio (NLR0 and NLRPRE-OP , respectively). SAS 9.4 (SAS Institute Inc., Cary, NC) software was used for data analysis with Mann-Whitney U testing for continuous variables and Pearson Chi-square test for categorical variables. Sensitivity and specificity for PLR and NLR were calculated by means of receiver operating characteristic (ROC) curve analysis. RESULTS: Twenty-seven patients had intra-operative bowel ischaemia whilst the remaining 73 had no evidence of bowel ischaemia. Both median PLRPRE-OP and NLRPRE-OP were significantly higher in patients with bowel ischaemia compared to those without (PLRPRE-OP 272 [IQR 224-433] and 231 [IQR 146-295] respectively, P = 0.027; NLRPRE-OP 12.5 [IQR 8.6-21.3] v. 5.5 [IQR 3.5-10.2] respectively, P ≤ 0.001). Area under the receiver operator characteristic curve (AUC) was 0.762 for NLRPRE-OP , with a sensitivity of 85.1% and specificity of 63% for NLR 7.4. CONCLUSION: Raised NLR is predictive of bowel ischaemia in patients with adhesional small bowel obstruction.

The role of staging laparoscopy in pancreatic adenocarcinoma and its effect on patients' survival.

BACKGROUND: Prompt and accurate staging of pancreatic cancer is essential to distinguish patients to benefit from resection with curative intent and those with unresectable disease. A staging laparoscopy is used preoperatively to identify macroscopic or occult metastases not identified on imaging. This single-institution study aims to evaluate the role of staging laparoscopy in patients with pancreatic adenocarcinoma and its effect on overall survival. METHOD: Clinicopathologic data were evaluated for all patients undergoing staging laparoscopy for pancreatic adenocarcinoma from July 2014 to December 2019. The study identified 155 patients eligible for analysis. All patients were followed for at least 2 years. Clinical backgrounds, survival curves and prognostic factors were investigated. RESULTS: Resectability status among the cohort was 62 (40%) upfront resectable, 53 (34%) borderline resectable and 40 (26%) locally advanced disease. The median age was 69, with 44% male patients. Median CA19-9 value was 125 kU/L, and median CA125 value was 22 kU/L. Staging laparoscopy resulted in upstaging nine (15%) upfront resectable patients, five (9%) borderline resectable patients and ten (25%) locally advanced patients. There was positive cytology in 19 (12%), peritoneal deposits in six (4%) and peritoneal liver deposits in seven (5%) patients. Overall, the number needed to treat (NNT) to avoid an unnecessary laparotomy was eight patients. CONCLUSION: Staging laparoscopy continues to be a valuable investigation of pancreatic adenocarcinoma. In this institution, one in every eight patients undergoing a staging laparoscopy was upstaged to metastatic disease, thus avoiding an unnecessary laparotomy or a non-curative resection.

The Right Treatment Strategy for the Right Patient: A Biomarker-Driven Approach to Neoadjuvant vs. Surgery-First Management of Resectable and Borderline Resectable Pancreatic Cancer.

The genomic heterogeneity of pancreatic ductal adenocarcinoma (PDAC) is becoming increasingly appreciated. We aimed to evaluate the ability of a triple biomarker panel (S100A4, Ca-125, and mesothelin) to predict: (i) genetic PDAC subtypes; (ii) clinical phenotypes; and (iii) the optimal treatment strategy (neoadjuvant vs. surgery-first) in resectable and borderline resectable PDAC. Patients who underwent resection for resectable and borderline resectable PDAC were included from one single-institutional cohort and one multi-institutional cohort from the Australian Pancreatic Genome Initiative (APGI). Tumors were immunohistochemically evaluated for S100A4, Ca-125, and mesothelin, and a subset from the APGI cohort underwent RNA sequencing. This study included 252 and 226 patients from the single institution and the APGI cohorts, respectively. Triple-negative biomarker status correlated with non-squamous PDAC genotypes (p = 0.020), lower rates of distant recurrence (p = 0.002), and longer median overall survival (mOS) with the surgery-first approach compared with neoadjuvant treatment (33.3 vs. 22.2 mths, p = 0.038) in resectable PDAC. In contrast, the triple-positive disease was associated with longer mOS with neoadjuvant treatment compared with the surgery-first approach (29.5 vs. 13.7 mths, p = 0.021) in resectable and borderline resectable PDAC. In conclusion, the triple biomarker panel predicts genetic PDAC subtypes, clinical phenotypes, and optimal treatment strategies in resectable and borderline resectable PDAC.

The Role of Targeted Versus Standard Antibiotic Prophylaxis in Pancreatoduodenectomy in Reducing Postoperative Infectious Complications: A Systematic Review and Meta-analysis.

INTRODUCTION: Infectious complications are common after pancreatoduodenectomy, which in turn are associated with preoperative biliary drainage. Current guidelines recommend a first-generation cephalosporin as perioperative antibiotic prophylaxis. However, some studies support the use of targeted antibiotics. The aim of this systematic review and meta-analysis is to evaluate the role of prophylactic targeted antibiotics compared to standard antibiotics in reducing postoperative infections after pancreatoduodenectomy. METHODS: A search from MEDLINE, EMBASE, and Cochrane library from 1946 to July 2020 was conducted. Studies were included if they compared targeted antibiotics with standard perioperative antibiotics while including outcome data on surgical site infections (SSI). Targeted therapy was defined as perioperative antibiotics targeting organisms prevalent in bile instrumentation or by culture data obtained from the patient or institution. Outcomes assessed were the rate of SSIs and their microbiology profile. Analyses included demographic data, perioperative antibiotics, postoperative outcomes including microbiology data, and meta-analysis was performed where applicable. RESULTS: Seven studies were included, with a total of 849 patients undergoing pancreatoduodenectomy. Targeted antibiotics were associated with a significantly lower rate of postoperative SSI compared to standard antibiotic therapy [21.1% vs 41.9%; risk ratios (RR) 0.55, 95% confidence interval 0.37-0.81]. Wound/incisional site infections and organ space infections were lower in patients receiving targeted antibiotic prophylaxis (RR 0.33, P = 0.0002 and RR 0.54, P = 0.0004, respectively). Enterococcus species were the most common bacteria reported. CONCLUSION: There was a significant reduction in overall SSI rates when targeted antibiotics was used. Current standard antibiotic prophylaxis is inadequate in covering microbes prevalent in postoperative infections developing after pancreatoduodenectomy.

A multi-center post-market clinical study to confirm safety and performance of PuraStat® in the management of bleeding during open liver resection.

BACKGROUND: PuraStat® is a non-bioactive haemostatic agent that has demonstrated efficacy in a number of different surgical procedures. We performed a prospective multi-centre post-market study to evaluate the efficacy and safety of PuraStat® in liver resections performed for metastatic tumors. METHODS: This was a prospective cohort study. Patients undergoing liver resection for metastatic tumor were screened for eligibility, and included if they were ≥18 years old, undergoing open liver resection, had normal liver function, and required application of PuraStat® for haemostasis where standard haemostatic techniques were either insufficient or impractical. The primary endpoint was "time to haemostasis" (TTH). Secondary endpoints included blood loss, total postoperative drainage volume, transfusion of blood products, and ease of use. RESULTS: Eighty patients were included for analysis in the intention to treat population. 207 bleeding sites were treated with PuraStat. Of these, 190 (91.7%) bleeding sites reached haemostasis after PuraStat® application. Mean TTH (mm:ss) was 1:01 (SD 1:06, range 0:09-6:55). Ease of use of the product was described as either "excellent" or "good" in 78 (98.8%) patients. No serious adverse events were identified. CONCLUSION: This study confirms the safety, efficacy and ease of use of PuraStat® in the management of bleeding in liver surgery.

Urinary metabolite prognostic biomarker panel for pancreatic ductal adenocarcinomas.

BACKGROUND: Patients with pancreatic ductal adenocarcinoma (PDAC) have a very low survival rate and surgical resection is the only curative intent treatment available. However, the majority of patients relapse after surgery and identification of biomarkers for accurate prognostication of PDAC patients is required. We have recently identified a six biomarker (i.e., trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone) urinary metabolite panel with very high potential to diagnose PDAC (Int J Cancer 2021;148:1508-18). This study aimed to assess the prognostic ability of these previously identified diagnostic metabolites in the urine of PDAC patients. METHODS: Metabolite data from 88 PDAC patients was statistically assessed for their prognostic ability. RESULTS: A panel of three metabolites (i.e., trigonelline, hippurate and myoinositol) was able to stratify patients with good- or poor-prognosis based on overall survival. The PDAC patients with abnormal levels of 2 or more metabolites in their urine demonstrated significantly lower survival compared to patients with abnormal levels of one or less metabolites. CONCLUSION: These results demonstrate that the selected three metabolite panel could be used to stratify patients based on their prognostic outcomes and if independently validated may lead to the development of a urinary prognostic biomarker test for PDAC. GENERAL SIGNIFICANCE: This study highlights the potential of using 1H-nuclear magnetic resonance spectroscopy for the identification of novel metabolites which can prognosticate cancer patients.

Survival in borderline resectable and locally advanced pancreatic cancer is determined by the duration and response of neoadjuvant therapy.

BACKGROUND: Pancreatic cancer is the 8th commonest cancer and the 5th commonest cause of cancer-related death in Australia, with a 9% average 5-year survival. This study aims to investigate the effects of neoadjuvant treatment on overall survival (OS) and recurrence-free survival (RFS) in borderline resectable (BRPC) and locally advanced (LAPC) pancreatic adenocarcinoma followed by curative resection. MATERIALS AND METHODS: Prospectively-collected demographic, medical, surgical and pathological data of patients with BRPC and LAPC treated with both neoadjuvant therapy (NAT) and surgery at a single tertiary referral centre in Australia were reviewed and analysed. RESULTS: Between 2012 and 2018, 60 patients, 34 with BRPC and 26 with LAPC, were treated with NAT followed by curative resection. The commonest neoadjuvant chemotherapy regimens were Gemcitabine + Abraxane (51.7%) and FOLFIRINOX (35.0%), with 48.3% of patients additionally receiving neoadjuvant radiotherapy. Median RFS was 30 months and median OS was 35 months. On multivariable analysis, inferior OS was predicted by enlarged loco-regional lymph nodes on initial computed tomography (p = 0.032), larger tumour size post-NAT (p = 0.006) and Common Terminology Criteria for Adverse Events post-NAT toxicity greater than grade 2 (p = 0.015). LAPC patients received more neoadjuvant chemotherapy (p = 0.008) and radiotherapy (p = 0.021) than BRPC and achieved a superior pathological response (p = 0.010). CONCLUSION: Patients who respond to NAT likely have a favourable disease biology and will progress well following resection. It is these patients who should be selected for more aggressive upfront management, and those with resistant disease should be spared from high-risk surgery.

Increased postoperative pancreatic fistula rate after distal pancreatectomy compared with pancreatoduodenectomy is attributable to a difference in acinar scores.

BACKGROUND: Postoperative pancreatic fistula (POPF) is a potentially lethal complication of pancreatic surgery. POPF rate is consistently higher after distal pancreatectomy (DP) compared with pancreatoduodenectomy (PD). The acinar score of the remnant pancreas is associated with postoperative pancreatitis and POPF. This study aimed to: (i) confirm the difference in POPF rate after DP vs PD; (ii) confirm the association between acinar score and POPF; and (iii) evaluate the difference in acinar scores between DP and PD. METHODS: Patients undergoing DP or PD at a single institution from 2011 to 2017 were included. Hematoxylin and eosin-stained slides of the pancreatic resection margin were evaluated for all patients and scored for acinar cell density. Clinicopathological data were retrieved from a prospectively maintained database. RESULTS: Two hundred and ninety-four patients were included in the analysis (206 PD, 88 DP). The POPF rate was significantly higher after DP than PD (20.4% vs 11.2%, P = .043). Acinar score >50 was independently associated with the development of POPF (OR 6.457, P = .003). DP was associated with a higher median acinar score than PD (65 vs 50, P < .001). CONCLUSION: The POPF rate is significantly higher after DP compared with PD and is attributable to a higher acinar score of the pancreatic resection margin.

A unique urinary metabolomic signature for the detection of pancreatic ductal adenocarcinoma.

Our study aimed to identify a urinary metabolite panel for the detection/diagnosis of pancreatic ductal adenocarcinoma (PDAC). PDAC continues to have poor survival outcomes. One of the major reasons for poor prognosis is the advanced stage of the disease at diagnosis. Hence, identification of a novel and cost-effective biomarker signature for early detection/diagnosis of PDAC could lead to better survival outcomes. Untargeted metabolomics was employed to identify a novel metabolite-based biomarker signature for PDAC diagnosis. Urinary metabolites from 92 PDAC patients (56 discovery cohort and 36 validation cohort) were compared with 56 healthy volunteers using 1 H nuclear magnetic resonance spectroscopy. Multivariate (partial-least squares discriminate analysis) and univariate (Mann-Whitney's U-test) analyses were performed to identify a metabolite panel which can be used to detect PDAC. The selected metabolites were further validated for their diagnostic potential using the area under the receiver operating characteristic (AUROC) curve. Statistical analysis identified a six-metabolite panel (trigonelline, glycolate, hippurate, creatine, myoinositol and hydroxyacetone), which demonstrated high potential to diagnose PDAC, with AUROC of 0.933 and 0.864 in the discovery and validation cohort, respectively. Notably, the identified panel also demonstrated very high potential to diagnose early-stage (I and II) PDAC patients with AUROC of 0.897. These results demonstrate that the selected metabolite signature could be used to detect PDAC and will pave the way for the development of a urinary test for detection/diagnosis of PDAC.