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.

Risk factors for failure to rescue after hepatectomy in a high-volume UK tertiary referral center.

BACKGROUND: Mortality after severe complications after hepatectomy (failure to rescue) is strongly linked to center volume. The aim of this study was to evaluate the risk factors for failure to rescue after hepatectomy in a high-volume center. METHODS: Retrospective study of 1,826 consecutive patients who underwent hepatectomy from 2011 to 2018. The primary outcome was a 90-day failure to rescue, defined as death within 90 days posthepatectomy after a severe (Clavien-Dindo grade 3+) complication. Risk factors for 90-day failure to rescue were evaluated using a multivariable binary logistic regression model. RESULTS: The cohort had a median age of 65.3 years, and 56.6% of patients were male. The commonest indication for hepatectomy was colorectal metastasis (58.9%), and 46.9% of patients underwent major or extra-major hepatectomy. Severe complications developed in 209 patients (11.4%), for whom the 30- and 90-day failure to rescue rates were 17.0% and 35.4%, respectively. On multivariable analysis, increasing age (P = .006) and modified Frailty Index (P = .044), complication type (medical or combined medical/surgical versus surgical; P < .001), and body mass index (P = .018) were found to be significant independent predictors of 90-day failure to rescue. CONCLUSION: Older and frail patients who experience medical complications are particularly at risk of failure to rescue after hepatectomy. These results may inform preoperative counseling and may help to identify candidates for prehabilitation. Further study is needed to assess whether failure to rescue rates could be reduced by perioperative interventions.

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.

Pancreatic exocrine insufficiency after non-pancreatic upper gastrointestinal surgery: meta-analysis.

BACKGROUND: Untreated pancreatic exocrine insufficiency (PEI) results in substantial patient harm. Upper gastrointestinal surgery (bariatric metabolic surgery and oesophagogastric resection) affects the delicate physiology of pancreatic exocrine function and may result in PEI. The aim of this study was to assimilate the literature on incidence, diagnosis, and management of PEI after bariatric metabolic surgery and oesophagogastric resection. METHODS: A systematic review of PubMed, MEDLINE, and Embase databases identified studies investigating PEI after non-pancreatic upper gastrointestinal surgery. Meta-analyses were undertaken for incidence of PEI and benefit of pancreatic enzyme replacement therapy. RESULTS: Among 1620 patients from 24 studies included in quantitative synthesis, 36.0% developed PEI. The incidence of PEI was 23.0 and 50.4% after bariatric metabolic surgery and oesophagogastric resection respectively. Notably, the incidence of PEI was 44% after biliopancreatic diversion with duodenal switch and 66.2% after total gastrectomy. The most common diagnostic test used was faecal elastase 1 (15 of 31 studies), with less than 200 µg/g being diagnostic of PEI. A total of 11 studies considered the management of pancreatic exocrine insufficiency, with 78.6% of patients responding positively to pancreatic enzyme replacement when it was prescribed. CONCLUSION: PEI is common after non-pancreatic upper gastrointestinal surgery and patients may benefit from enzyme replacement therapy.

Pancreatic exocrine insufficiency occurs when enzymes from the pancreas are unable to help digest food. Pancreatic exocrine insufficiency is known to cause disruptive symptoms after gastrointestinal surgery. Although such symptoms are well known after pancreatic surgery, after other gastrointestinal operations, including bariatric metabolic surgery and oesophagogastric cancer resection, pancreatic exocrine insufficiency is often overlooked as a cause of both symptoms and poor nutrition. This study looked at, and combined, all the current evidence on the rate of pancreatic exocrine insufficiency after these operations, the way it is diagnosed, and how it is treated. Pancreatic exocrine insufficiency may be more common than previously thought after bariatric metabolic surgery or oesophagogastric surgery, and clinicians working with these patients should have a low threshold for starting treatment.

A standardised nutritional drink as a test meal for the 13 C mixed triglyceride breath test for pancreatic exocrine insufficiency: A randomised, two-arm crossover comparative study.

BACKGROUND: The 13 C mixed triglyceride breath test (13 C MTGT) is a diagnostic test for pancreatic exocrine insufficiency (PEI). It is poorly standardised with much heterogeneity of the test meal, the commonest being toast and butter. A standardised oral nutritional supplement that could be easily transported, stored and made up would be valuable for making this test accessible outside of specialist centres. METHODS: A prospective, randomised, two-arm crossover study of different test meals was carried out in 14 healthy controls. The 13 C MTGT was performed in identical conditions on two separate days. Two test meals were given in random order, either standard (toast and butter) or novel (oral nutritional supplement), with 250 mg of 13 C-labelled mixed triglyceride incorporated. Breath samples were taken postprandially to calculate cumulative percentage dose recovery (cPDR) of 13 C at 6 h. RESULTS: All 14 participants completed both arms of the study with no protocol deviations. The mean cPDR was 39.39% (standard deviation [SD] 5.19) for the standard test meal and 39.93% (SD 5.20) for the novel test meal. A one-way repeated measures analysis of variance (ANOVA) found no significant difference in cPDR between the two meals, F(1, 13) = 0.18, p = 0.68 (minimum detectable difference of 0.81 at 80% power). CONCLUSION: This study demonstrates that a standardised oral nutritional supplement can be used without compromising 13 C recovery. Using this test meal provides a standardised dietary stimulus to the pancreas, avoiding possible variation in quantity of dietary components with other test meals. Further, the ease of use of this method would help establish the 13 C MTGT test more widely.

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.

Assessment of jejunal interposition perfusion using indocyanine green.

INTRODUCTION: Jejunal interposition (JI) is an option for oesophageal replacement in children; ensuring good graft perfusion is essential. We report three cases where Indocyanine Green (ICG) with Near-Infrared Fluorescence (NIRF) was used to assess perfusion during graft selection, passage into the chest and anastomotic assessment. This extra assessment may reduce risk of anastomotic leak and/or stricture. METHODS: We describe the technique and salient features of all patients who have undergone ICG/NIRF-assisted JI in our centre. Patient demographics, indications for surgery, intra-operative plan, video of NIR perfusion assessment, complications and outcomes were reviewed. RESULTS: ICG/NIRF was used in three patients (2M:1F) at a dose of 0.2 mg/kg. ICG/NIRF imaging helped select the jejunal graft and confirmed perfusion after division of segmental arteries. Perfusion was assessed before and after passing the graft through the diaphragmatic hiatus and before and after making the oesophago-jejunal anastomosis. Intrathoracic assessment at the end of the procedure confirmed good perfusion of mesentery and intrathoracic bowel. In two patients, the reassurance contributed to successful procedures. In the third patient, graft selection was satisfactory, but borderline perfusion on clinical assessment after passing the graft to the chest, confirmed by ICG/NIRF meant the graft was abandoned. CONCLUSIONS: ICG/NIRF imaging was feasible and augmented our subjective assessment of graft perfusion, giving greater confidence during graft preparation, movement, and anastomosis. In addition, the imaging helped us abandon one graft. This series demonstrates the feasibility and benefit of ICG/NIR use in JI surgery. Further studies are required to optimise ICG use in this setting.

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.

Casting a Wider NET: Pancreatic Exocrine Insufficiency Induced by Somatostatin Analogues among Patients with Neuroendocrine Tumours?

Somatostatin-analogues (SSAs) are a first-line treatment of unresectable neuroendocrine tumours (NETs). However, SSAs inhibit pancreatic secretions, which could lead to pancreatic exocrine insufficiency (PEI). PEI is known to be detrimental to patient quality of life and nutritional status. This study aimed to evaluate the effect of SSAs on pancreatic exocrine function in patients with NETs, using the 13C-mixed triglyceride breath test (13C-MTGT). Exocrine function was assessed using the 13C-MTGT at baseline and after a third SSA injection (two months). A quotient of 13CO2/12CO2 was measured by mass spectrometry, and the cumulative percent dose recovered at 6 h (cPDR) is reported. The secondary endpoints investigated were change in weight, HbA1C, and vitamin D levels. Ten patients completed the study. Exocrine function reduced in all patients (n = 10) following SSA therapy (median reduction from baseline: -23.4% (range: -42.1-0.5%, p = 0.005)). vitamin D levels decreased in all but one patient (median decrease from baseline: -26.5%, (-44.7-10%; p = 0.038)), and median HbA1C levels increased by 8.0% (0-59.3%; p = 0.008). Change in weight was not significant (median decrease from baseline: -0.21% (-4.5-3.5%, p = 1.000)). SSA therapy has a consistent impact on exocrine function from early in the treatment course, but the long-term clinical effects of this remain to be defined. Further studies are required to determine the clinical relevance of this observation and optimise the management of PEI in this cohort.

The impact of the COVID-19 pandemic upon pancreatic cancer treatment (CONTACT Study): a UK national observational cohort study.

INTRODUCTION: CONTACT is a national multidisciplinary study assessing the impact of the COVID-19 pandemic upon diagnostic and treatment pathways among patients with pancreatic ductal adenocarcinoma (PDAC). METHODS: The treatment of consecutive patients with newly diagnosed PDAC from a pre-COVID-19 pandemic cohort (07/01/2019-03/03/2019) were compared to a cohort diagnosed during the first wave of the UK pandemic ('COVID' cohort, 16/03/2020-10/05/2020), with 12-month follow-up. RESULTS: Among 984 patients (pre-COVID: n = 483, COVID: n = 501), the COVID cohort was less likely to receive staging investigations other than CT scanning (29.5% vs. 37.2%, p = 0.010). Among patients treated with curative intent, there was a reduction in the proportion of patients recommended surgery (54.5% vs. 76.6%, p = 0.001) and increase in the proportion recommended upfront chemotherapy (45.5% vs. 23.4%, p = 0.002). Among patients on a non-curative pathway, fewer patients were recommended (47.4% vs. 57.3%, p = 0.004) or received palliative anti-cancer therapy (20.5% vs. 26.5%, p = 0.045). Ultimately, fewer patients in the COVID cohort underwent surgical resection (6.4% vs. 9.3%, p = 0.036), whilst more patients received no anti-cancer treatment (69.3% vs. 59.2% p = 0.009). Despite these differences, there was no difference in median overall survival between the COVID and pre-COVID cohorts, (3.5 (IQR 2.8-4.1) vs. 4.4 (IQR 3.6-5.2) months, p = 0.093). CONCLUSION: Pathways for patients with PDAC were significantly disrupted during the first wave of the COVID-19 pandemic, with fewer patients receiving standard treatments. However, no significant impact on survival was discerned.

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.

The challenge of offering potentially curative treatment to patients with esophageal cancer and a history of liver transplantation: A literature review and case report.

BACKGROUND: With survival after liver transplantation continuing to improve, effective and evidence-based treatment of malignancies in this patient group is needed as a matter of urgency. Treatment outcomes for esophageal cancer, a challenging malignancy to treat in otherwise fit and well patients, after liver transplant are rarely reported. METHODS: A systematic literature review was performed according to the PRISMA guidance to identify studies reporting outcomes of radical esophageal cancer treatment in patients with liver transplant. Management strategies and oncological outcomes were compared with a case managed at our institution. RESULTS: Six studies were identified for review, and the outcomes of 13 patients were collated. The most common indication for liver transplant was alcohol-related liver disease (62%), and the most common tumor type was adenocarcinoma (54%). Neoadjuvant chemotherapy was delivered safely in 23% of cases in the literature and in the case managed at our institution. The median time from liver transplant to esophagectomy was 46 months, and the majority of patients underwent an Ivor-Lewis esophagectomy. The median follow-up from esophagectomy was 17 months, with a pooled 1-year survival of 77% and recurrence rate of 38%. This was comparable with corresponding rates reported for nontransplanted patients. CONCLUSION: This case report and systematic review demonstrates that radical treatment of esophageal cancer after liver transplantation is not only technically feasible when managed by expert multidisciplinary teams but that it also improves survival. Routine surveillance of liver transplant patients with evidence of Barrett's preoperatively should be considered and close involvement of appropriate specialists in individual treatment planning is vital to acceptable outcomes.