Donor Liver Blood Tests and Liver Transplant Outcomes: UK Registry Cohort Study.

BACKGROUND: Safely increasing organ utilization is a global priority. Donor serum transaminase levels are often used to decline livers, despite minimal evidence to support such decisions. This study aimed to investigate the impact of donor "liver blood tests" on transplant outcomes. METHODS: This retrospective cohort study used the National Health Service registry on adult liver transplantation (2016-2019); adjusted regressions models were used to assess the effect of donor "liver blood tests" on outcomes. RESULTS: A total of 3299 adult liver transplant recipients were included (2530 following brain stem death, 769 following circulatory death). Peak alanine transaminase (ALT) ranged from 6 to 5927 U/L (median = 45). Donor cause of death significantly predicted donor ALT; 4.2-fold increase in peak ALT with hypoxic brain injury versus intracranial hemorrhage (adjusted P < 0.001). On multivariable analysis, adjusting for a wide range of factors, transaminase level (ALT or aspartate aminotransferase) failed to predict graft survival, primary nonfunction, 90-d graft loss, or mortality. This held true in all examined subgroups, that is, steatotic grafts, donation following circulatory death, hypoxic brain injury donors, and donors, in which ALT was still rising at the time of retrieval. Even grafts from donors with extremely deranged ALT (>1000 U/L) displayed excellent posttransplant outcomes. In contrast, donor peak alkaline phosphatase was a significant predictor of graft loss (adjusted hazard ratio = 1.808; 1.016-3.216; P = 0.044). CONCLUSIONS: Donor transaminases do not predict posttransplant outcomes. When other factors are favorable, livers from donors with raised transaminases can be accepted and transplanted with confidence. Such knowledge should improve organ utilization decision-making and prevent future unnecessary organ discard. This provides a safe, simple, and immediate option to expand the donor pool.

Multi-Centre UK Analysis of Simultaneous Pancreas and Kidney (SPK) Transplant in Recipients With Type 2 Diabetes Mellitus.

90% of the UK diabetic population are classified as T2DM. This study aims to compare outcomes after SPK transplant between recipients with T1DM or T2DM. Data on all UK SPK transplants from 2003-2019 were obtained from the NHSBT Registry (n = 2,236). Current SPK transplant selection criteria for T2DM requires insulin treatment and recipient BMI < 30 kg/m2. After exclusions (re-transplants/ambiguous type of diabetes) we had a cohort of n = 2,154. Graft (GS) and patient (PS) survival analyses were conducted using Kaplan-Meier plots and Cox-regression models. Complications were compared using chi-squared analyses. 95.6% of SPK transplants were performed in recipients with T1DM (n = 2,060). Univariate analysis showed comparable outcomes for pancreas GS at 1 year (p = 0.120), 3 years (p = 0.237), and 10 years (p = 0.196) and kidney GS at 1 year (p = 0.438), 3 years (p = 0.548), and 10 years (p = 0.947). PS was comparable at 1 year (p = 0.886) and 3 years (p = 0.237) and at 10 years (p = 0.161). Multi-variate analysis showed comparable outcomes in pancreas GS (p = 0.564, HR 1.221, 95% CI 0.619, 2.406) and PS(p = 0.556, HR 1.280, 95% CI 0.563, 2.911). Comparable rates of common complications were demonstrated. This is the largest series outside of the US evaluating outcomes after SPK transplants and shows similar outcomes between T1DM and T2DM recipients. It is hoped dissemination of this data will lead to increased referral rates and assessment of T2DM patients who could benefit from SPK transplantation.

Systematic review and meta-analysis of survival outcomes in T2a and T2b gallbladder cancers.

BACKGROUND: The 8th edition of AJCC TNM staging of Gallbladder cancer subdivided T2 stage into T2a and T2b based on tumour location. This meta-analysis aimed to investigate the long-term outcomes in T2a and T2b gallbladder cancers. METHODS: Literature search of Medline, Web of science, Embase and Cochrane databases was performed. Study characteristics, survival and recurrence data were extracted for meta-analysis of effect estimates and of individual patient data. RESULTS: Fifteen retrospective studies (2531 patients, T2a = 1332, T2b = 199) were included in the meta-analysis. Overall survival (OS) was significantly worse in patients with T2b compared to T2a tumours (HR 2.18, 95% CI 1.67-2.86, p < 0.0001). Meta-analysis of individual patient data (n = 629) showed similar results (HR 1.92, 95% CI 1.43-2.58, p < 0.00001). Patients with T2b tumours had higher risk of recurrence compared to T2a (OR 3.19, 95% CI 1.40-7.28, p = 0.006) and were more likely to receive adjuvant chemotherapy (OR 1.76, 95% CI 1.12-2.84, p = 0.014). Liver resection improved OS in T2b tumours (HR 2.99, CI 1.73-5.16, p < 0.0001). CONCLUSION: T2b gallbladder tumours have worse overall survival and increase risk of recurrence compared to T2a. Liver resection appears to improve OS in patients with T2b tumours. However, high quality multicenter data is required to confirm these results.

Too Fat for Transplant? The Impact of Recipient BMI on Pancreas Transplant Outcomes.

BACKGROUND: In many transplant centers, a recipient body mass index (BMI) >30 kg/m2 would be considered a contraindication for pancreas transplantation. This study aims to investigate the impact of recipient BMI on graft outcomes after pancreas transplantation. METHODS: Retrospective data on all UK solid organ pancreas transplants from 1994 to 2016 were obtained from the National Health Service Blood and Transplant UK Transplant Registry, n = 2618. Cases missing BMI data were excluded, resulting in a final cohort of n = 1452. Graft and patient survival analysis were conducted using Kaplan-Meier plots and Cox regression models. RESULTS: The mean recipient BMI was 24.8 kg/m2 (±2.4). There were 507 overweight (BMI 25-29.9) and 146 obese (>30) recipients receiving pancreas transplants. Univariate analysis showed no statistically significant difference between overweight BMI categories compared with normal BMI (18.5-24.9 kg/m2). Multivariate analysis revealed increasing recipient BMI had a significant impact on graft survival (P = 0.03, hazard ratio 1.04, 95% confidence interval, 1.00-1.08). Receiver operating characteristic curve analyses revealed no value of BMI that provided both specific and sensitive discrimination between death and survival of both grafts or patients. Recipients on dialysis with a BMI >30 kg/m2 had a statistically significant decrease in both graft (P = 0.002) and patient survival (P = 0.015). CONCLUSIONS: Analysis of available UK Pancreas data has shown recipient BMI is an independent risk factor for patient survival after transplantation. However, we have been unable to define a specific cutoff value above which patients have poorer outcomes. Obese patients on hemodialysis had the poorest graft survival, and preemptive transplantation may be beneficial in this cohort.

Therapeutic Strategies Toward Lactate Dehydrogenase Within the Tumor Microenvironment of Pancreatic Cancer.

OBJECTIVES: Pancreatic stellate cells (PSCs) play a key metabolic role within the tumor microenvironment (stroma) of pancreatic ductal adenocarcinoma (PDAC), being glycolytic and associated with protumorigenic acidification from excess lactate. This study investigates the clinical significance of glycolytic enzyme lactate dehydrogenase (LDH) and determines efficacy of the novel pan-LDH inhibitor Galloflavin. METHODS: An in vitro Transwell system was adopted for coculture of PSCs and 3 PDAC cell lines (MIA PaCa-2, PANC-1, and BxPC-3). Cells were treated with Galloflavin, and outcomes were analyzed regarding proliferation, apoptosis, lactate production, and glycolytic enzyme protein expression. Immunohistochemical staining for lactate dehydrogenase B (LDHB) was performed on 59 resected PDAC tumors annotated for clinical outcome. RESULTS: Galloflavin reduced PDAC proliferation in monoculture (P < 0.01); however, in co-culture with PSCs, an antiproliferative effect was only evident in PANC-1 (P = 0.001). An apoptotic effect was observed in MIA PaCa-2 and BxPC-3 in coculture (P < 0.05). A reduction in media lactate was observed in coculture (P < 0.01) with PSCs. Immunohistochemistry revealed stromal and tumoral LDHB expression had no impact on survival. CONCLUSIONS: Galloflavin has the potential to neutralize the acidic PDAC microenvironment and thereby reduce tumor invasiveness and metastasis. Patients with lower LDHB expression are more likely to be beneficial responders.

Splenic preservation versus splenectomy in laparoscopic distal pancreatectomy: a propensity score-matched study.

BACKGROUND: The laparoscopic approach in distal pancreatectomy is associated with higher rates of splenic preservation compared to open surgery. Although favorable postoperative short-term outcomes have been reported in open spleen-preserving distal pancreatectomy when compared to distal pancreatectomy with splenectomy, it is unclear whether this observation applies to the laparoscopic approach. The aim of this study is to compare laparoscopic spleen-preserving distal pancreatectomy (LSPDP) with laparoscopic distal pancreatectomy with splenectomy (LDPS). STUDY DESIGN: This is a UK wide, propensity score-matched study, including patients who underwent LSPDP or LDPS between 2006 and 2016. Short-term outcomes were compared between LSPDP and LDPS according to intention to treat. Additionally, risk factors for unplanned splenectomy were explored. RESULTS: A total of 456 patients were included from eleven centers (229 LSPDP and 227 LDPS). We were able to match 173 LSPDP cases to 173 LDPS cases, according to intention to treat. No differences were seen in postoperative morbidity between the groups. The only identified risk factor for unplanned splenectomy was tumor size ≥ 30 mm. CONCLUSIONS: Preserving the spleen during laparoscopic distal pancreatectomy is not associated with a lower postoperative morbidity compared to sacrificing the spleen. Tumor size is a risk factor for unplanned splenectomy.

Preemptive Appendicectomy at the Time of Pancreas Transplantation: Is It Necessary?

OBJECTIVES: Pancreas transplant is a major intraabdominal operation, and in most cases the graft is placed in the rightiliac fossa. At our center, preemptive appendicectomy is performed at the time of pancreas transplant to prevent any future risk in a complex transplant patient. The aim of this study was to review all histology reports from the removed appendices. MATERIALS AND METHODS: The histology reports from all incidental appendicectomies performed at pancreas transplant were reviewed. RESULTS: Between January 2001 and June 2016, 107 pancreas transplants were performed (86 simultaneous pancreas and kidney transplants, 11 pancreas after kidney transplants, and 10 pancreas transplants alone), and 65 appendix histology reports were available from this patient group. All were preemptive appendicectomies as none of the patients had symptoms to suggest acute appendicitis. Of the 65 appendix histologies, 43 (66.2%) were reported as normal. Twenty specimens (30.8%) showed fibrosis consistent with previous inflammation of the appendix, and 12 specimens (18.5%) showed fecal material in the lumen (1 due to an obstructing fecalith and another 2 showing luminal distension with feces). Three specimens (4.6%) showed lymphoid hyperplasia. There were 5 (7.7 %) unexpected findings upon histology. In review of histology reports, 1 patient had a 1.1-mm carcinoid tumor in an otherwise normal appendix, 1 had an Enterobius species worm infestation, 1 had focal endometriosis, 1 had crypt abscesses suggestive of inflammatory bowel disease, 1 had a metaplastic polyp, and 1 had melanosis coli of unknown clinical significance. There were no cases of overt acute appendicitis. No patients experienced a complication as a direct result of their appendicectomy. CONCLUSIONS: A policy ofroutine appendicectomy atthe time of pancreas transplant appears to be justified and safe.

The association of pregnane X receptor activation with outcomes after liver transplantation-A retrospective study.

BACKGROUND: Many complications following liver transplantation are linked to ischemia-reperfusion injury. Activation of the pregnane X receptor (PXR) has been shown to alleviate this process in animal models. The aim of this retrospective study was to investigate the effect of early activation of human PXR (hPXR) on postoperative complications and survival following liver transplantation. METHODS: The study included deceased donor liver transplants at a single center over 6 years. Estimated hPXR activation value on day 7 (EPAV7 ) was calculated per patient based on potency/total dose of known hPXR-activating drugs administered in the first week post-transplantation. Patients were divided into low and high hPXR activation groups based on EPAV7 . RESULTS: Overall, 240 liver transplants were included. Average EPAV7 was significantly lower in patients who developed anastomotic biliary strictures (17.7 ± 5.5 vs 35.1 ± 5.7 in stricture-free patients; P = .03) and sepsis (16.4 ± 7.1 vs 34.9 ± 5.5; P = .04). Patient survival was significantly improved in the high hPXR group (5-year survival: 88.7% ± 3.8% versus 70.7% ± 5.8% [low hPXR]; P = .023). Regression analysis identified EPAV7 as a significant independent predictor of patient survival. CONCLUSION: hPXR activation within the first week of liver transplantation is a prognostic indicator of patient survival, possibly due to the associated lower biliary stricture and infection rates.

UK registry analysis of donor substance misuse and outcomes following pancreas transplantation.

Substance abuse is unfortunately common in organ donors. Often, these organs are declined for transplant, not only because of concerns around blood-borne virus transmission but also because of perceived poor outcomes. In kidney transplantation, previous studies have demonstrated donor smoking status significantly impacts transplant outcome, but intravenous drug use or alcohol dependence does not. This study aims to clarify these issues in pancreas transplantation. Retrospective data on all UK solid organ pancreas transplants from 1994 to 2015 were obtained from the NHSBT UK Transplant Registry. The impact of illicit drug misuse, alcohol abuse, and smoking on graft and patient survival were analyzed using Kaplan-Meier plots and a Cox regression model. A total of 1175 of the 2317 (49.5%) donors were categorized as substance misusers. Univariate survival analysis revealed no significant impact of substance misuse on 10-year graft or patient survival. Multivariate analysis confirmed substance misuse was not associated with impaired graft or patient survival. A history of donor substance misuse does not negatively impact 10-year graft or patient survival following pancreas transplantation. This is a large national registry analysis with long-term follow-up data and should therefore provide clinicians with reassurance when considering pancreas grafts from substance misuse donors.

The role of pancreatic stellate cells in pancreatic cancer.

BACKGROUND: The prognosis of pancreatic cancer remains desperately poor, with little progress made over the past 30 years despite the development of new combination chemotherapy regimens. Stromal activity is especially prominent in the tissue surrounding pancreatic tumours, and has a profound influence in dictating tumour development and dissemination. Pancreatic stellate cells (PaSCs) have a key role in this tumour microenvironment, and have been the subject of much research in the past decade. This review examines the relationship between PaSCs and cancer cells. METHODS: A comprehensive literature search was performed of multiple databases up to March 2014, including Medline, Pubmed and Google Scholar. RESULTS: A complex bidirectional interplay exists between PaSCs and cancer cells, resulting in a perpetuating loop of increased activity and an overriding pro-tumorigenic effect. This involves a number of signalling pathways that also impacts on other stromal components and vasculature, contributing to chemoresistance. The Reverse Warburg Effect is also introduced as a novel concept in tumour stroma. CONCLUSION: This review highlights the pancreatic tumour microenvironment, and in particular PaSCs, as an ideal target for therapeutics. There are a number of cellular processes involving PaSCs which could hold the key to more effectively treating pancreatic cancer. The feasibility of targeting these pathways warrant further in depth investigation, with the aim of reducing the aggressiveness of pancreatic cancer and improving chemodelivery.

Autoimmune pancreatitis - diagnosis, management and longterm follow-up.

BACKGROUND & AIMS: Autoimmune pancreatitis (AIP) is a fibroinflammatory condition affecting the pancreas and could present as a multisystem disorder. Diagnosis and management can pose a diagnostic challenge in certain groups of patients. We report our experience of managing this condition in a tertiary pancreaticobiliary centre in the North East of England. METHODS: Patients were identified from a prospectively maintained database of patients diagnosed with AIP between 2005 and 2013. Diagnosis of definite/probable AIP was based on the revised HISORt criteria. When indicated, patients were treated with steroids and relapses were treated with azathioprine. All patients have been followed up to date. RESULTS: Twenty-two patients were diagnosed with AIP during this period. All patients had pancreatic protocol CT performed while some patients had either MR or EUS as part of the work up. Fourteen out of 22 (64%) had an elevated IgG4 level (mean: 10.9 g/L; range 3.4 - 31 g/L). Four (18%) patients underwent surgery. Extrapancreatic involvement was seen in 15 (68%) patients, with biliary involvement being the commonest. Nineteen (86%) were treated with steroids and five (23%) required further immunosuppression for treatment of relapses. The mean follow up period was 36.94 months (range 7 - 94). CONCLUSION: Autoimmune pancreatitis is being increasingly recognized in the British population. Extrapancreatic involvement, particularly extrahepatic biliary involvement seems to be a frequent feature. Diagnosis should be based on accepted criteria as this significantly reduces the chances of overlooking malignancy. Awareness of this relatively rare condition and a multi-disciplinary team approach will help us to diagnose and treat this condition more effectively thereby reducing unnecessary interventions.

A cadaver lab training facility to facilitate laparoscopic liver resection.

INTRODUCTION: Laparoscopic liver surgery is becoming increasingly common; however, doubts still remain regarding its more widespread application and whether it improves patient outcome. The authors would like to present their experience of using a dedicated cadaver laparoscopic training laboratory to facilitate the introduction of a laparoscopic liver resection (LLR) program. METHODS: A course was designed by a faculty of experienced, advanced laparoscopic surgeons providing an intensive 2-day course of lectures, debate, exchange, and practical hands-on with a live link to clinical LLR operations. Participant evaluation and feedback for each course was analyzed. RESULTS: After 4 courses (2007 to 2009) and 32 participants, scores were graded from 1 (poor) to 6 (excellent no improvement). The course was graded for content, structure, delivery, resources, facility, and value for money. The overall rating for cadaver teaching sessions scored as follows: score 6 (43%), score 5 (32%), and score 4 (25%). CONCLUSIONS: A dedicated cadaver LLR facility is not only an excellent method to train individuals for safe introduction of clinical liver resection program but it also has the potential to provide certification within this growing technique.

Successful endovascular salvage of a pancreatic graft after a venous thrombosis: case report and literature review.

Simultaneous kidney and pancreatic transplant is the criterion standard for treatment of end-stage renal failure because of diabetic nephropathy. Venous thrombosis occurs in approximately 5% of pancreatic transplants, and it is notoriously difficult to treat, forming the most common nonimmunologic cause of graft loss. We report a case of early detection of pancreatic graft venous thrombosis by measuring urinary amylase, resulting in the successful endovascular salvage of the pancreatic graft.

Laparoscopic liver resection: is there a learning curve?

BACKGROUND: Laparoscopic liver resection (LLR) is becoming an accepted treatment option for resecting both benign and malignant tumours. However, it is critical that the laparoscopic approach does not compromise the technical quality of the liver resection. The aim of this paper was to review the learning curve of LLR in a specialist HPB unit. METHODS: A prospective database was searched to identify patients undergoing LLR over a 4-year period. To assess the effect of the learning curve on outcome, the series was evaluated during two eras--early versus late. RESULTS: Fifty-one (27 males, median age 68 years) patients were identified with 37 having LLR. The most common indication was for colorectal liver metastases, and the most common procedure was a non-anatomical metastectomy. Changes in management decisions (n = 14) occurred more frequently during the first era (9 vs. 5; p > 0.05). More patients underwent right hepatectomy in the late group (3 vs. 1; p < 0.05). There did not appear to be any difference in duration of surgery for laparoscopic left lateral resection between the eras (200 vs. 240 min; p > 0.05) which probably reflected trainees performing more operations during the late era. Left hepatectomy was most commonly performed in the early era compared to more right hepatectomies during the late era. CONCLUSION: LLR is associated with a learning curve, but once this has been overcome it can be safely utilised in the management of malignant liver lesions even for major resections, surgical training and simultaneous resections.

Endoscopic botulinum toxin injection for the treatment of diabetic gastropathy in pancreas and islet-cell transplant patients.

OBJECTIVES: Gastroparesis is a well-recognized, long-term complication of diabetes. Prokinetic drugs are often not effective, prompting the development of alternative therapies. We report our experience of using one such alternative, endoscopic botulinum toxin injection, to ameliorate diabetic gastropathy in association with pancreas and islet-cell transplant patients. MATERIALS AND METHODS: Three male diabetic patients aged 42 to 55 years had been treated with botulinum toxin in our center. Two patients were both after-simultaneous pancreas-kidney transplant and 1 was awaiting islet-cell transplant after pancreatectomy. Mechanical gastric outlet obstruction was first excluded by radiological and endoscopic studies. Between 100 and 200 IU of toxin were then injected in the prepyloric region using an endoscopic technique. A subjective scoring scale was used to assess symptoms before and after botulinum therapy. RESULTS: Improvement in subjective symptom severity scoring was seen in all patients, with a posttreatment improvement from 55% to 91%. Such improvement was temporary in 2 patients and long-lasting in 1 patient. CONCLUSIONS: The time for improvement of gastric autonomic function after pancreas or islet-cell transplantation remains unclear. Some patients may continue to be symptomatic, leading to increasing morbidity. However, endoscopic botulinum injections may provide short-term relief while waiting for improvement and spare patients the morbidity associated with more-invasive therapies.

Surgical adjuncts to laparoscopic distal pancreatectomy.

Abstract Laparoscopic distal pancreatectomy (LDP) has emerged as an alternative approach to traditional open surgery for managing isolated pathology in the body and tail of the pancreas. Experience with this technique to date is limited with only small series reported in the literature. Common difficulties with this operation are related to dissection of the pancreas from the portal vein and management of the pancreatic stump. In this paper we describe our single centre experience to date and describe strategies we have developed which we believe facilitate safe and effective laparoscopic distal pancreatectomy.

Successful management of necrotizing pancreatitis by percutaneous necrosectomy after orthotopic liver transplant for paracetamol induced acute liver failure: a case report.

OBJECTIVES: Acute pancreatitis, which can develop after any whole-organ transplant, is often associated with immunosuppression. Pancreatitis that complicates a liver transplant can be a significant problem that results in a high mortality rate. MATERIALS AND METHODS: We describe the successful use of minimally invasive techniques to treat severe acute pancreatitis. To our knowledge, this is the first reported case in which major laparotomy was precluded by the use of percutaneous necrosectomy to manage necrotizing pancreatitis in a liver transplant recipient. We also briefly review the published literature on severe acute pancreatitis in liver transplant recipients. RESULTS: Our patient, who had a Model for End- Stage Liver Disease score of 39 when transplanted and an Acute Physiology and Chronic Health Evaluation II score of 19 when infected necrosis in his pancreas was diagnosed, recovered completely after 92 days of hospitalization. He underwent 2 percutaneous drainage procedures and 3 percutaneous necrosectomies to treat his pancreatic complication. A review of the literature revealed that severe acute pancreatitis significantly increases morbidity and mortality in liver transplant recipients. Unlike necrotizing pancreatitis, which develops outside the context of liver transplant where there is a distinct shift towards minimally invasive procedures, infected necrosis associated with fulminant liver failure or a liver transplant is usually treated with open necrosectomy. CONCLUSIONS: Severe acute pancreatitis in liver transplant recipients should be managed exactly as it is in patients who have not received a liver transplant. Anatomically guided minimally invasive necrosectomy appears to be beneficial, especially when patients are critically unwell, as they are following a liver transplant.

Pancreas transplantation.

Since the introduction of pancreas transplantation more than 40 years ago, efforts to develop more minimally invasive techniques for endocrine replacement therapy have been in progress, yet this surgical procedure still remains the treatment of choice for diabetic patients with end-stage renal failure. Many improvements have been made in the surgical techniques and immunosuppressive regimens, both of which have contributed to an increasing number of indications for pancreas transplantation. This operation can be justified on the basis that patients replace daily injections of insulin with an improved quality of life but at the expense of a major surgical procedure and lifelong immunosuppression. The various indications, categories, and outcomes of patients having a pancreas transplant are discussed, particularly with reference to the effect on long-term diabetic complications.