Involvement of the Gut Microbiome in the Local and Systemic Immune Response to Pancreatic Ductal Adenocarcinoma.

The systemic and local immunosuppression exhibited by pancreatic ductal adenocarcinoma (PDAC) contributes significantly to its aggressive nature. There is a need for a greater understanding of the mechanisms behind this profound immune evasion, which makes it one of the most challenging malignancies to treat and thus one of the leading causes of cancer death worldwide. The gut microbiome is now thought to be the largest immune organ in the body and has been shown to play an important role in multiple immune-mediated diseases. By summarizing the current literature, this review examines the mechanisms by which the gut microbiome may modulate the immune response to PDAC. Evidence suggests that the gut microbiome can alter immune cell populations both in the peripheral blood and within the tumour itself in PDAC patients. In addition, evidence suggests that the gut microbiome influences the composition of the PDAC tumour microbiome, which exerts a local effect on PDAC tumour immune infiltration. Put together, this promotes the gut microbiome as a promising route for future therapies to improve immune responses in PDAC patients.

Comprehensive, long-term evaluation of pancreatic exocrine insufficiency after pancreatoduodenectomy.

AIMS: Treatment of pancreatic exocrine insufficiency (PEI) following pancreatoduodenectomy (PD) improves quality of life, clinical outcomes, and survival. However, diagnosing PEI following PD is challenging owing to the difficulties with current tests and often non-specific symptoms. This work aims to quantify the true rate of long-term PEI in patients following a PD. METHODS: Patients underwent a PEI screen approximately one to two years following PD for oncologic indication, including the 13C Mixed triglyceride breath test (13CMTGT), faecal elastase 1 (FE-1) and the PEI Questionnaire (PEI-Q). Four reviewers with expertise in PEI reviewed the results blinded to other decisions to classify PEI status; disagreements were resolved on consensus. RESULTS: 26 patients were recruited. Of those with valid test results, these were indicative of PEI based on pre-specified thresholds for 60 % (15/25) for the 13CMTGT, 82 % (18/22) for FE-1, and 88 % (22/25) for the PEI-Q. After discussion between reviewers, the consensus PEI prevalence was 81 % (95 % CI: 61-93 %; 21/26), with 50 % (N = 13) classified as having severe, 23 % (N = 6) moderate, and 8 % (N = 2) mild PEI. DISCUSSION: Since no ideal test exists for PEI, this collation of diagnostic modalities and blinded expert review was designed to ascertain the true rate of long-term PEI following PD. This required our cohort to survive a year, travel to hospital, and undergo a period of starvation and PERT hold, and therefore there is likely to be recruitment bias towards fitter, younger patients with less aggressive pathology. Despite this, over 80 % were deemed to have PEI, with over 90 % of these being considered moderate or severe.

Investigating misdiagnosis of suspected cancer among patients undergoing pancreatoduodenectomy: three decades of experience.

BACKGROUND: Diagnostic error can result in pancreatoduodenectomy (PD) being mistakenly performed for benign disease. The aims of this study were to observe the error rate in PD over three decades and identify characteristics of benign disease that can mimic malignancy. METHODS: Patients with a benign histological diagnosis after having PD performed for suspected malignancy between 1988 and 2019 were selected for review. Preoperative clinical features, imaging and pathological samples were reviewed alongside resection specimens to identify features that may have led to misdiagnosis. RESULTS: Over the study period, 1812 patients underwent PD for suspected malignancy and 97 (5.2 %) of these had a final benign diagnosis. The rate of benign cases reduced across the study period. Some 62 patients proceeded to surgery without a preoperative tissue diagnosis; the decision to operate was made upon clinical and radiologic features alone. There were six patients who had a preoperative pathological sample suspicious for malignancy, of which two had autoimmune pancreatitis in the postoperative histology specimen. DISCUSSION: Benign conditions, notably autoimmune and chronic pancreatitis, can mimic malignancy even with the use of EUS-FNA. The results of all available diagnostic modalities should be interpreted by a multidisciplinary team and honest discussions with the patient should follow.

Pancreatic Exocrine Insufficiency and the Gut Microbiome in Pancreatic Cancer: A Target for Future Diagnostic Tests and Therapies?

Pancreatic exocrine insufficiency (PEI) is common amongst pancreatic cancer patients and is associated with poorer treatment outcomes. Pancreatic enzyme replacement therapy (PERT) is known to improve outcomes in pancreatic cancer, but the mechanisms are not fully understood. The aim of this narrative literature review is to summarise the current evidence linking PEI with microbiome dysbiosis, assess how microbiome composition may be impacted by PERT treatment, and look towards possible future diagnostic and therapeutic targets in this area. Early evidence in the literature reveals that there are complex mechanisms by which pancreatic secretions modulate the gut microbiome, so when these are disturbed, as in PEI, gut microbiome dysbiosis occurs. PERT has been shown to return the gut microbiome towards normal, so called rebiosis, in animal studies. Gut microbiome dysbiosis has multiple downstream effects in pancreatic cancer such as modulation of the immune response and the response to chemotherapeutic agents. It therefore represents a possible future target for future therapies. In conclusion, it is likely that the gut microbiome of pancreatic cancer patients with PEI exhibits dysbiosis and that this may potentially be reversible with PERT. However, further human studies are required to determine if this is indeed the case.

Resection of isolated liver oligometastatic disease in pancreatic ductal adenocarcinoma: Is there a survival benefit? A systematic review.

BACKGROUND: Presence of liver metastatic disease in pancreatic ductal adenocarcinoma (PDAC), either synchronous or metachronous after pancreatic resection, is a terminal diagnosis that warrants management with palliative intent as per all international practice guidelines. However, there is an increasing interest on any potential value of surgical treatment of isolated oligometastatic disease in selected cases. AIM: To present the published evidence on surgical management of PDAC liver metastases, synchronous and metachronous, and compare the outcomes of these treatments to the current standard of care. METHODS: A systematic review was performed in line with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines to compare the outcomes of both synchronous and metachronous liver metastases resection to standard care. RESULTS: 356 studies were identified, 31 studies underwent full-text review and of these 10 were suitable for inclusion. When synchronous resection of liver metastases was compared to standard care, most studies did not demonstrate a survival benefit with the exception of one study that utilised neoadjuvant treatment. However, resection of metachronous disease appeared to confer a survival advantage when compared to treatment with chemotherapy alone. CONCLUSION: A survival benefit may exist in resection of selected cases of metachronous liver oligometastatic PDAC disease, after disease biology has been tested with time and systemic treatment. Any survival benefit is less clear in synchronous cases; however an approach with neoadjuvant treatment and consideration of resection in some selected cases may confer some benefit. Future studies should focus on pathways for selection of cases that may benefit from an aggressive approach.

Low C-reactive Protein and Urea Distinguish Primary Nonfunction From Early Allograft Dysfunction Within 48 Hours of Liver Transplantation.

Primary nonfunction (PNF) is a life-threatening complication of liver transplantation (LT), but in the early postoperative period, it can be difficult to differentiate from early allograft dysfunction (EAD). The aim of this study was to determine if serum biomarkers can distinguish PNF from EAD in the initial 48 h following LT. Materials and Methods: A retrospective study of adult patients that underwent LT between January 2010 and April 2020 was performed. Clinical parameters, absolute values and trends of C-reactive protein (CRP), blood urea, creatinine, liver function tests, platelets, and international normalized ratio in the initial 48 h after LT were compared between the EAD and PNF groups. Results: There were 1937 eligible LTs, with PNF and EAD occurring in 38 (2%) and 503 (26%) patients, respectively. A low serum CRP and urea were associated with PNF. CRP was able to differentiate between the PNF and EAD on postoperative day (POD)1 (20 versus 43 mg/L; P < 0.001) and POD2 (24 versus 77; P < 0.001). The area under the receiver operating characteristic curve (AUROC) of POD2 CRP was 0.770 (95% confidence interval [CI] 0.645-0.895). The urea value on POD2 (5.05 versus 9.0 mmol/L; P = 0.002) and trend of POD2:1 ratio (0.71 versus 1.32 mmol/L; P < 0.001) were significantly different between the groups. The AUROC of the change in urea from POD1 to 2 was 0.765 (95% CI 0.645-0.885). Aspartate transaminase was significantly different between the groups, with an AUROC of 0.884 (95% CI 0.753-1.00) on POD2. Discussion: The biochemical profile immediately following LT can distinguish PNF from EAD; CRP, urea, and aspartate transaminase are more effective than ALT and bilirubin in distinguishing PNF from EAD in the initial postoperative 48 h. Clinicians should consider the values of these markers when making treatment decisions.

Recent Advances in Pancreatic Ductal Adenocarcinoma: Strategies to Optimise the Perioperative Nutritional Status in Pancreatoduodenectomy Patients.

Pancreatic ductal adenocarcinoma (PDAC) is an aggressive malignancy for which the mainstay of treatment is surgical resection, followed by adjuvant chemotherapy. Patients with PDAC are disproportionately affected by malnutrition, which increases the rate of perioperative morbidity and mortality, as well as reducing the chance of completing adjuvant chemotherapy. This review presents the current evidence for pre-, intra-, and post-operative strategies to improve the nutritional status of PDAC patients. Such preoperative strategies include accurate assessment of nutritional status, diagnosis and appropriate treatment of pancreatic exocrine insufficiency, and prehabilitation. Postoperative interventions include accurate monitoring of nutritional intake and proactive use of supplementary feeding methods, as required. There is early evidence to suggest that perioperative supplementation with immunonutrition and probiotics may be beneficial, but further study and understanding of the underlying mechanism of action are required.

Relieving Pressure on the Emergency Department with a New Treatment Pathway for Hand Trauma Patients - A Three-Year Experience with 15,539 Patients.

Background: Hand injuries are a significant and rising burden on the Emergency Department (ED), often leading to protracted waiting times for patients awaiting specialist input. To combat this, a new treatment pathway for hand trauma was introduced at our institution to reduce waiting times and pressure on the ED. Methods: The treatment pathway performance using waiting times, length of stay and cost metrics was measured prior to and following the introduction of a new treatment pathway. Results: There were 15,539 patients reviewed in total. After the new pathway had been introduced, the number of assessments in ED significantly reduced (Year 1: 907 [19.9%] vs. Year 2: 422 [7.9%]; p < 0.001), and the proportion of patients who had an operation on the same day that they were assessed significantly increased (69 [1.5%] vs. 403 [7.5%] patients; p < 0.001). The median waiting time from assessment to operation and length of stay also significantly reduced following the introduction of the treatment pathway (Year 1: 53 hours and Year 2: 45 hours; p < 0.001). Conclusions: Our data over 3 years shows that these changes have been maintained and, in some cases, have continued to improve since the introduction of the new treatment pathway. We advocate the use of such an approach for all hand trauma centres worldwide to replicate these improvements in patient care. Level of Evidence: Level III.

Perioperative interventions to reduce pancreatic fistula following pancreatoduodenectomy: meta-analysis.

BACKGROUND: Data on interventions to reduce postoperative pancreatic fistula (POPF) following pancreatoduodenectomy (PD) are conflicting. The aim of this study was to assimilate data from RCTs. METHODS: MEDLINE and Embase databases were searched systematically for RCTs evaluating interventions to reduce all grades of POPF or clinically relevant (CR) POPF after PD. Meta-analysis was undertaken for interventions investigated in multiple studies. A post hoc analysis of negative RCTs assessed whether these had appropriate statistical power. RESULTS: Among 22 interventions (7512 patients, 55 studies), 12 were assessed by multiple studies, and subjected to meta-analysis. Of these, external pancreatic duct drainage was the only intervention associated with reduced rates of both CR-POPF (odds ratio (OR) 0.40, 95 per cent c.i. 0.20 to 0.80) and all-POPF (OR 0.42, 0.25 to 0.70). Ulinastatin was associated with reduced rates of CR-POPF (OR 0.24, 0.06 to 0.93). Invagination (versus duct-to-mucosa) pancreatojejunostomy was associated with reduced rates of all-POPF (OR 0.60, 0.40 to 0.90). Most negative RCTs were found to be underpowered, with post hoc power calculations indicating that interventions would need to reduce the POPF rate to 1 per cent or less in order to achieve 80 per cent power in 16 of 34 (all-POPF) and 19 of 25 (CR-POPF) studies respectively. CONCLUSION: This meta-analysis supports a role for several interventions to reduce POPF after PD. RCTs in this field were often relatively small and underpowered, especially those evaluating CR-POPF.

Influence of body composition measures on chyle leak after oesophagectomy.

Background: Chyle leak (CL) is an infrequent but potentially serious complication of oesophagectomy. Sarcopenia is an increasingly recognised prognostic factor in oesophageal cancer surgery. The aim of this study was to identify the influence of body composition measures on CL following oesophagectomy. Methods: Patients who developed CL after oesophagectomy between January 2006-December 2020 were identified retrospectively from a prospectively maintained dataset. A control group of patients undergoing oesophagectomy, who did not experience chyle leak during the same time period, was also collected. Relationships between CL and demographics, operative factors and body composition measures were investigated as primary outcomes. Risk factors for severe CL were evaluated as a secondary outcome. Results: There were 26 patients who developed a CL following an oesophagectomy. On univariate analysis, preoperative body mass index (BMI) (P=0.001), subcutaneous fat index (P=0.001) and total fat index (P=0.004) were significantly associated with CL. On multivariate analysis, a lower preoperative subcutaneous fat index was a significant independent predictor of CL (P=0.003). Sarcopenia, as an overall measure, was not found to be a significant predictor of developing CLs. No significant predictors of severe CL were identified. Conclusions: A reduced preoperative BMI and body fat composition are risk factors for CL after oesophagectomy. Sarcopenia does not predict either the occurrence or severity of CL. This presents potentially modifiable risk factors for CL after oesophagectomy and emphasises the importance of physiological and nutritional optimisation before oesophagectomy.

Early oral feeding after pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: The effect of early oral feeding (EOF) after pancreatoduodenectomy (PD) upon perioperative complications and outcomes is unknown, therefore the aim of this systematic review and meta-analysis was to investigate the effect of EOF on clinical outcomes after PD, such as postoperative pancreatic fistula (POPF), delayed gastric emptying (DGE) and length of stay (LOS). METHODS: A systematic review and meta-analysis was performed in line with the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidance and assimilated evidence from studies reporting outcomes for patients who received EOF after PD compared to enteral tube feeding (EN) or parenteral nutrition (PN). RESULTS: Four studies reported outcomes after EOF compared to EN/PN after PD and included 553 patients. Meta-analyses showed no difference in rates of CR-POPF (OR 0.74; 95%CI 0.44-1.24; p = 0.25) or DGE (Grade B/C) (OR 0.83; 95%CI 0.31-2.21; p = 0.70). LOS was significantly shorter in the EOF group compared to the EN/PN group (Mean Difference -3.40 days; 95% -6.11-0.70 days; p = 0.01). CONCLUSION: Current available evidence suggests that EOF after PD is not associated with increased risk of DGE, does not exacerbate POPF and appears to reduce length of stay.

Can trainees safely perform pancreatoenteric anastomosis? A systematic review, meta-analysis, and risk-adjusted analysis of postoperative pancreatic fistula.

BACKGROUND: The complexity of pancreaticoduodenectomy and fear of morbidity, particularly postoperative pancreatic fistula, can be a barrier to surgical trainees gaining operative experience. This meta-analysis sought to compare the postoperative pancreatic fistula rate after pancreatoenteric anastomosis by trainees or established surgeons. METHODS: A systematic review of the literature was performed using Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines, with differences in postoperative pancreatic fistula rates after pancreatoenteric anastomosis between trainee-led versus consultant/attending surgeons pooled using meta-analysis. Variation in rates of postoperative pancreatic fistula was further explored using risk-adjusted outcomes using published risk scores and cumulative sum control chart analysis in a retrospective cohort. RESULTS: Across 14 cohorts included in the meta-analysis, trainees tended toward a lower but nonsignificant rate of all postoperative pancreatic fistula (odds ratio: 0.77, P = .45) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.69, P = .37). However, there was evidence of case selection, with trainees being less likely to operate on patients with a pancreatic duct width <3 mm (odds ratio: 0.45, P = .05). Similarly, analysis of a retrospective cohort (N = 756 cases) found patients operated by trainees to have significantly lower predicted all postoperative pancreatic fistula (median: 20 vs 26%, P < .001) and clinically relevant postoperative pancreatic fistula (7 vs 9%, P = .020) rates than consultant/attending surgeons, based on preoperative risk scores. After adjusting for this on multivariable analysis, the risks of all postoperative pancreatic fistula (odds ratio: 1.18, P = .604) and clinically relevant postoperative pancreatic fistula (odds ratio: 0.85, P = .693) remained similar after pancreatoenteric anastomosis by trainees or consultant/attending surgeons. CONCLUSION: Pancreatoenteric anastomosis, when performed by trainees, is associated with acceptable outcomes. There is evidence of case selection among patients undergoing surgery by trainees; hence, risk adjustment provides a critical tool for the objective evaluation of performance.

External validation of postoperative pancreatic fistula prediction scores in pancreatoduodenectomy: a systematic review and meta-analysis.

BACKGROUND: Multiple risk scores claim to predict the probability of postoperative pancreatic fistula (POPF) after pancreatoduodenectomy. It is unclear which scores have undergone external validation and are the most accurate. The aim of this study was to identify risk scores for POPF, and assess the clinical validity of these scores. METHODS: Areas under receiving operator characteristic curve (AUROCs) were extracted from studies that performed external validation of POPF risk scores. These were pooled for each risk score, using intercept-only random-effects meta-regression models. RESULTS: Systematic review identified 34 risk scores, of which six had been subjected to external validation, and so included in the meta-analysis, (Tokyo (N=2 validation studies), Birmingham (N=5), FRS (N=19), a-FRS (N=12), m-FRS (N=3) and ua-FRS (N=3) scores). Overall predictive accuracies were similar for all six scores, with pooled AUROCs of 0.61, 0.70, 0.71, 0.70, 0.70 and 0.72, respectively. Considerably heterogeneity was observed, with I2 statistics ranging from 52.1-88.6%. CONCLUSION: Most risk scores lack external validation; where this was performed, risk scores were found to have limited predictive accuracy. . Consensus is needed for which score to use in clinical practice. Due to the limited predictive accuracy, future studies to derive a more accurate risk score are warranted.

Long-term outcomes of delayed biliary strictures following cholecystectomy.

BACKGROUND: Delayed biliary strictures (DBS) after cholecystectomy are uncommon and little is known of their aetiology or long-term consequences. The aims of this study were to investigate the clinical and economic impact of DBS after cholecystectomy. METHODS: Patients who developed DBS after cholecystectomy were identified from a prospectively collected and maintained database. Risk factors for stricture development, quality of life (QoL) and long-term biliary complication rates were explored. Costs of treatment and follow up were determined. The same outcomes among patients with minor or major bile duct injury (BDI) were used as a comparison. RESULTS: Among 44 patients, a laparoscopic converted to open procedure or post cholecystectomy bile leak affected some 18 and 12 patients respectively. Most DBS required surgical treatment (40). Over a median follow-up of 8.9 years after DBS treatment, 16 (36%) patients developed biliary complications (similar to minor, 26%, and major BDI, 40%) and 1 patient died of causes related to the biliary stricture. Costs of treating DBS and its follow up (£14,309.26 per patient), were similar to previously reported costs for major BDI (£15,784). CONCLUSION: DBS typically occur after a technically and/or complicated cholecystectomy. Clinical, economic and QoL outcomes are similar to patients with major BDI.

Seventh Day Syndrome Revisited: Early Recognition of the Clinical Syndrome and an Evolving Understanding of Its Etiology.

Background: Unexplained acute failure of an initially functioning liver graft early post-transplant has been described as Seventh-Day Syndrome (7DS). The aims of this study were to describe the clinical syndrome in detail based on an institutional case series and literature review. Methods: A retrospective review of adult patients that underwent deceased donor liver transplantation at our institution between January 2010 and 2020 was performed to identify patients that developed 7DS. Relevant clinical variables were obtained from medical records. Existing cases in the literature were identified by a systematic literature search according to PRISMA guidelines. Pooled analysis was used to describe the incidence, retransplantation, and mortality rate. Histological findings from institutional and published literature cases were collected and appraised. Results: Six of 1,907 liver transplantations at our institution (0.3%) developed 7DS. Seven case series, describing 42 patients with 7DS, and two single case reports were identified from literature review. Pooled incidence of 7DS was low (2.1%, 95%CI: 0.7-3.9%) and associated with high mortality (74.8%, 95%CI: 49.2-94.6%). Retransplantation was performed in 23/42 (55%) patients and 4/23 (17%) survived. Review of histology showed frequent intrahepatic thrombi and arteritis. Rejection, with features of potential antibody mediated rejection, often preceded or accompanied progressive zonal coagulative necrosis and hemorrhage. Conclusions: 7DS is a rare clinical syndrome after liver transplantation and associated with high mortality. Antibody-mediated rejection, as suggested in early reports, is likely to be involved in the pathogenesis. Early recognition would allow rapid clinical diagnostics and expedited decisions, such as treatment of AMR if diagnosed or early retransplantation.

Risk factors for anastomotic stricture after hepaticojejunostomy for bile duct injury-A systematic review and meta-analysis.

BACKGROUND: After major bile duct injury, hepaticojejunostomy can result in good long-term patency, but anastomotic stricture is a common cause of long-term morbidity. There is a need to assimilate high-level evidence to establish risk factors for development of anastomotic stricture after hepaticojejunostomy for bile duct injury. METHODS: A systematic review of studies reporting the rate of anastomotic stricture after hepaticojejunostomy for bile duct injury was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Meta-analyses of proposed risk factors were then performed. RESULTS: Meta-analysis included 5 factors (n = 2,155 patients, 17 studies). Concomitant vascular injury (odds ratio 4.96; 95% confidence interval 1.92-12.86; P = .001), postrepair bile leak (odds ratio: 8.03; 95% confidence interval 2.04-31.71; P = .003), and repair by nonspecialist surgeon (odds ratio 11.29; 95% confidence interval 5.21-24.47; P < .0001) increased the rate of anastomotic stricture of hepaticojejunostomy after bile duct injury. Level of injury according to the Strasberg Grade did not significantly affect the rate of anastomotic stricture (odds ratio: 0.97; 95% confidence interval 0.45-2.10; P = .93). Owing to heterogeneity of reporting, it was not possible to perform a meta-analysis for the impact of timing of repair on anastomotic stricture rate. CONCLUSION: The only modifiable risk factor, repair by a nonspecialist surgeon, demonstrates the importance of broad awareness of these data. Knowledge of these risk factors may permit risk stratification of follow-up, better informed consent, and understanding of prognosis.