Significance of steatosis in pancreatic transplantation.

The on-going success of whole organ pancreatic transplantation is dependent on overcoming the imbalance between demand and supply of optimal organs as well as tackling the vast comorbidity associated with the procedure. Pancreas steatosis is a common contributing factor to the problem and with obesity pandemics affecting the global population; the size and type of organs received from donors will only make steatosis more of an issue. The aim of this review is to highlight what is known about steatosis in the context of pancreas transplantation identifying potential methods to help its evaluation. Narrative review of literature from inception to June 2017, using OVID interface searching EMBASE and MEDLINE databases as well recent transplant conference data. All studies related to pancreas steatosis examined for clinical relevance with no exclusion criteria. Key ideas extracted and referenced. Pancreatic steatosis is not innocuous and is precariously regarded by transplant surgeons, however its associations with obesity, metabolic syndrome and long list of associated complications clearly show it needs more careful consideration. Radiologic and surgical advances now allow assessment of the fat content of organs, which could be used to quantify organs allowing better optimisation, but there is still much work to be done to refine the optimal method to achieve this.

Novel approaches to preventing ischemia-reperfusion injury during liver transplantation.

Ischemia-reperfusion injury (IRI) results in profound allograft damage during liver transplantation. The process of IRI results in adenosine triphosphatase (ATP) depletion, the production of reactive oxygen species, and progressive tissue destruction. This injury process is accelerated on reperfusion in the recipient. Over the last decade an increasing body of literature has identified a complex interplay of molecular and cellular pathways responsible for causing IRI. This article summarizes recent developments, drawing on preclinical and clinical studies, focusing on how the detrimental effects of IRI can be prevented in liver transplantation. We present a balanced overview on how machine preservation technologies, the coagulation system, antioxidants, cytoprotective agents, cytokines, preservation solutions, and the innate and adaptive immune system can be targeted to prevent IRI in liver transplantation.

Systematic review of total pancreatectomy and islet autotransplantation for chronic pancreatitis.

BACKGROUND: Total pancreatectomy and islet autotransplantation (TP/IAT) is a treatment option in a subset of patients with chronic pancreatitis. A systematic review of the literature was performed to evaluate the outcome of this procedure, with an attempt to ascertain when it is indicated. METHODS: MEDLINE (1950 to present), Embase (1980 to present) and the Cochrane Library were searched to identify studies of outcomes in patients undergoing TP/IAT. Cohort studies that reported the outcomes following the procedure were included. The MOOSE guidelines were used as a basis for this review. RESULTS: Five studies met the inclusion criteria. The techniques reported for pancreatectomy and islet cell isolation varied between studies. TP/IAT was successful in reducing pain in patients with chronic pancreatitis. Comparing morphine requirements before and after the procedure, two studies recorded significant reductions. Concurrent IAT reduced the insulin requirement after TP; the rate of insulin independence ranged from 46 per cent of patients at 5 years' mean follow-up to 10 per cent at 8 years. The impact on quality of life was poorly reported. The studies reviewed did not provide evidence for optimal timing of TP/IAT in relation to the evolution of chronic pancreatitis. CONCLUSION: This systematic review showed that TP/IAT had favourable outcomes with regard to pain reduction. Concurrent IAT enabled a significant proportion of patients to remain independent of insulin supplementation.

Systematic review of outcome of downstaging hepatocellular cancer before liver transplantation in patients outside the Milan criteria.

BACKGROUND: The aim of this systematic review was to assess the evidence on tumour downstaging before liver transplantation in patients with hepatocellular carcinoma (HCC) initially staged beyond the Milan criteria. METHODS: MEDLINE (from 1952), Embase (from 1980) and the Cochrane Library were searched. The review included cohort studies that reported the outcomes of patients with HCC outside the Milan criteria who underwent downstaging before transplantation. RESULTS: Eight studies met the inclusion criteria and included a total of 720 patients who underwent transplantation following downstaging after initial presentation with disease outside the Milan criteria. The rate of successful downstaging varied from 24 to 69 per cent of patients. Reported survival rates ranged from 82 to 100 per cent, 79 to 100 per cent and 54·6 to 94 per cent at 1, 3 and 5 years respectively. These were comparable with results for patients presenting within the Milan criteria. CONCLUSION: Successful downstaging of HCC to within the Milan criteria is feasible in a proportion of patients. Absolute and disease-free survival rates in patients transplanted following downstaging are comparable to those in patients within the Milan criteria.

Polyoma virus infection and urothelial carcinoma of the bladder following renal transplantation.

Renal transplant recipients are at increased risk of bladder carcinoma. The aetiology is unknown but a polyoma virus (PV), BK virus (BKV), may play a role; urinary reactivation of this virus is common post-renal transplantation and PV large T-antigen (T-Ag) has transforming activity. In this study, we investigate the potential role of BKV in post-transplant urothelial carcinoma by immunostaining tumour tissue for PV T-Ag. There was no positivity for PV T-Ag in urothelial carcinomas from 20 non-transplant patients. Since 1990, 10 transplant recipients in our unit have developed urothelial carcinoma, and tumour tissue was available in eight recipients. Two patients were transplanted since the first case of PV nephropathy (PVN) was diagnosed in our unit in 2000 and both showed PV reactivation post-transplantation. In one of these patients, there was strong nuclear staining for PV T-Ag in tumour cells, with no staining of non-neoplastic urothelium. We conclude that PV infection is not associated with urothelial carcinoma in non-transplant patients, and is uncommon in transplant-associated tumours. Its presence in all tumour cells in one patient transplanted in the PVN era might suggest a possible role in tumorigenesis in that case.

Alemtuzumab induction and steroid-free maintenance immunosuppression in pancreas transplantation.

Alemtuzumab is a humanized anti-CD52 antibody that depletes lymphocytes and has been increasingly used as induction agent in transplantation. The impact of alemtuzumab induction immunosuppression in pancreas transplantation was evaluated, with particular reference to steroid avoidance in maintenance. A total of 100 patients who received 102 pancreas transplants (83 simultaneous kidney-pancreas [SPK], 15 pancreas after kidney transplantation [PAK] and 4 pancreas transplant alone [PTA]) were included. All patients received two doses of 30-mg alemtuzumab i.v. with tacrolimus (trough level 8-12 ng/mL) and mycophenolate mofetil (MMF,1g/day) with no maintenance steroids. This analysis included 62 male and 38 female recipients, with mean (+/-SD) age of 42 (+/-7.6) years. Median follow-up was 17 months (range 8-41 months). One-year patient, pancreas and kidney graft survival (actuarial) was 97%, 89% and 94%, respectively. Overall incidence of rejection was 25%. Side effects of alemtuzumab administration included thrombocytopenia (14%), pulmonary edema (2%) and rash (1%). Twenty-five percent required reoperations (12% for bleeding). Infectious complications included Cytomegalovirus (CMV,6.8%) BK viruria (3.8%), fungal infections (4%), primary varicella (1%) and posttransplant lymphoproliferative disorders (PTLD,1%). Eighty-three percent did not require any steroids posttransplant. These results indicate that alemtuzumab is safe and enables pancreas transplantation to be carried out without maintenance steroids in 83% of cases and acceptable rejection rate.

High-intensity focused ultrasound ablation of liver tumours: can radiological assessment predict the histological response?

Cancer therapies usually depend on cross-sectional imaging for the assessment of treatment response. This study was designed to evaluate the ability of MRI to predict zones of necrosis following the use of high-intensity focused ultrasound (HIFU) to treat liver metastases. Patients with liver metastases, who had been scheduled for elective surgical resection of their tumours, were recruited to this non-randomized Phase II study. In each case, a proportion of an index liver tumour target was ablated. The response to HIFU was assessed after 12 days using contrast-enhanced MRI and compared directly with histological analysis at the time of surgery. Eight patients were treated, of whom six were subsequently assessed with both MRI and histology. There were no major complications. MRI predicted complete ablation in three cases. In each case, histological analysis confirmed complete ablation. In one case, the region of ablation observed on MRI appeared smaller than predicted at the time of HIFU, but histology revealed complete ablation of the target region. The predominant characteristic of HIFU-ablated tissue was coagulative necrosis but heat fixation was evident in some areas. Heat-fixed cells appeared normal under haematoxylin and eosin staining, indicating that this is unreliable as an indicator of HIFU-induced cell death. This study demonstrates that HIFU is capable of achieving selective ablation of pre-defined regions of liver tumour targets, and that MRI evidence of complete ablation of the target region can be taken to infer histological success.

More trouble ahead; is gene therapy coming of age?

BACKGROUND: A recent incident, the halting of a Phase I/II trial utilising an adeno-associated vector, highlights the fact that there are more hurdles to overcome prior to a full realisation of gene therapy in the clinical arena. METHODS: The sources of information used to prepare the paper were obtained through published work on Pubmed/Medline and materials published on the US/UK governmental agency websites. RESULTS/CONCLUSION: Over the years, two fatal incidents associated with viral vector usage have been reported. Viral vectors used as carriers for gene therapy have failed in safety trials on two occasions. Also, the human immune response and the oncogenic property of the vectors have restricted the advancement of gene therapy as a therapeutic tool. Nonetheless, gene therapy has now progressed from its infancy 'proof of concept' stage, to the next stage in which we try to overcome the problems associated with therapeutic application. However, this progression has been slow as more and more setbacks have occurred. This calls for a new perspective and radical thinking about future vector development.

Role of transplantation in the management of hepatic malignancy.

BACKGROUND: The acceptance of liver transplantation in the management of hepatic malignancy declined after early poor outcomes. Despite recent developments, including stricter selection criteria and improved adjuvant therapies, the role of liver transplantation in the management of cancer remains controversial. This review explores the evidence for the current role of liver transplantation in the management of hepatic malignancy in the context of recent advances in surgical resection and non-surgical treatments. METHODS: A literature search was conducted using the Cochrane Library and Ovid MEDLINE and EMBASE, using terms for hepatic malignancy and interventions that included liver transplantation, percutaneous interventions, chemotherapy and surgical resection. RESULTS AND CONCLUSION: In patients with primary hepatocellular carcinoma, improved selection has led to outcomes equivalent to those from surgical resection and comparable to those in patients transplanted for non-malignant indications. Recent studies suggest that selection criteria may be refined further. Surgical resection or percutaneous therapies may reduce the risk of progression while waiting for a transplant. Recent improvements have occurred in neoadjuvant therapies for cholangiocarcinoma. Nevertheless, a number of questions regarding the role of liver transplantation for hepatic malignancy remain.

Tamoxifen therapy in encapsulating sclerosing peritonitis in patients after kidney transplantation.

Sclerosing encapsulating peritonitis (SEP) is a serious complication of long-term continuous ambulatory peritoneal dialysis (CAPD) associated with obstructive symptoms and sclerosis of the peritoneal membrane. We present two cases that were successfully treated with tamoxifen and corticosteroids. Case 1: A 40-year-old patient developed end-stage renal failure (ESRF) and was managed with CAPD. He was hospitalized with symptoms of small bowel obstruction. He underwent laparotomy confirming the diagnosis of SEP. The patient was given tamoxifen 20 mg twice a day. Case 2: A 55-year-old patient with ESRF secondary to membranous glomerulonephritis. After having a cadaveric renal transplant in 1978 that failed 20 years later, the patient returned to CAPD. Six years later he had an uneventful kidney transplant and the peritoneal dialysis catheter was removed. However, 8 months later he presented with symptoms of small bowel obstruction and gross blood stained ascites. He also underwent a laparotomy that confirmed the diagnosis of SEP after biopsy. The patient was started on 20 mg of tamoxifen twice a day. Both patients' symptoms were improved gradually with an increase of serum albumin and body weight. Tamoxifen may be useful in the treatment of patients diagnosed with SEP.

PBS140: new competition in the organ preservation market?

PBS140 offers good cold preservation in renal transplantation and now, crucially, has been shown to promote immediate function following warm ischemia. For a new cold preservation solution to compete with UW solution, improved efficacy and lower price may not be enough. Reducing rates of delayed graft function in organs from non-heart-beating and marginal donors might be the key.

Retrieval of abdominal organs for transplantation.

BACKGROUND: Organ retrieval and donor management are not yet standardized. Different transplant centres apply various techniques, such as single or dual organ perfusion, dissection in the cold or warm, and single or en bloc organ removal. These different approaches may cause inconvenience, especially when more than one organ retrieval team is involved. METHODS: Cochrane Library, Medline and PubMed were searched for publications on multiorgan donor/donation, retrieval technique and procurement. Levels of evidence and grades of recommendation were evaluated based on current advice from the Oxford Centre for Evidence-Based Medicine. RESULTS: Multiorgan donation itself does not compromise the outcome of individual organ transplants. Dissection of abdominal organs for transplantation is best performed after cold perfusion. Abdominal organs should be removed rapidly, en bloc, and separated during back-table dissection in the cold, particularly if pancreas or intestine is included. Perfusion itself should be carried out after single cannulation of the aorta with an increased pressure. CONCLUSION: Although the literature on organ retrieval is extensive, the level of evidence provided is mainly low. Nevertheless, optimized donor treatment and organ retrieval should increase the number and quality of cadaveric donor organs and improve graft function and survival.

Alemtuzumab induction and sirolimus plus mycophenolate mofetil maintenance for CNI and steroid-free kidney transplant immunosuppression.

We performed a pilot study in which 22 kidney recipients (14 LD: 8 DCD) were given alemtuzumab induction (30 mg day 0 and 1), steroids (500 mg mp day 0 and 1, none thereafter), mycophenolate mofetil (MMF) maintenance (500 mg b.i.d) and sirolimus (concentration controlled 8-12 ng/mL). With a mean follow-up of 15.9 months, patient survival is (21/22) 96% and graft survival (19/22) 87%. Acute rejections occurred in (8) 36.3% (two humoral). Of 19 surviving grafts, 18 (95%) remain steroid and 15 (79%) CNI-free. At 1 year, mean creatinine was 1.43 mg/dL. Overall infection rates were low, but 2 patients developed severe acute respiratory distress syndrome (ARDS) at month 3 and 7, respectively, resulting in mortality in one and a graft loss in the other. No cancer or PTLD was observed. Leukopenia was common and MMF dose was reduced or eliminated in 6/22 (27%) patients. The reported higher than expected rate of acute rejection, leukopenia and possible pulmonary toxicity suggests excessive morbidity. Modifications such as an initial period of CNI use should be considered.

The safety and feasibility of extracorporeal high-intensity focused ultrasound (HIFU) for the treatment of liver and kidney tumours in a Western population.

High-intensity focused ultrasound (HIFU) provides a potential noninvasive alternative to conventional therapies. We report our preliminary experience from clinical trials designed to evaluate the safety and feasibility of a novel, extracorporeal HIFU device for the treatment of liver and kidney tumours in a Western population. The extracorporeal, ultrasound-guided Model-JC Tumor Therapy System (HAIFU Technology Company, China) has been used to treat 30 patients according to four trial protocols. Patients with hepatic or renal tumours underwent a single therapeutic HIFU session under general anaesthesia. Magnetic resonance imaging 12 days after treatment provided assessment of response. The patients were subdivided into those followed up with further imaging alone or those undergoing surgical resection of their tumours, which enabled both radiological and histological assessment. HIFU exposure resulted in discrete zones of ablation in 25 of 27 evaluable patients (93%). Ablation of liver tumours was achieved more consistently than for kidney tumours (100 vs 67%, assessed radiologically). The adverse event profile was favourable when compared to more invasive techniques. HIFU treatment of liver and kidney tumours in a Western population is both safe and feasible. These findings have significant implications for future noninvasive image-guided tumour ablation.

Adult small intestinal transplantation in England and Wales.

BACKGROUND: In 1996 two transplantation centres in the UK were commissioned by the National Specialist Commissioning Advisory Group for England and Wales to assess small intestinal transplantation in adults. The joint experience of the two centres is presented. METHODS: Patients with irreversible small intestinal failure and complications of parenteral nutrition, and those with abdominal disease requiring extensive visceral resection, were assessed as candidates and where appropriate listed for surgery. RESULTS: Thirty-six patients were assessed for small intestinal transplantation and, of these, 14 underwent surgery. Twelve patients survived the transplantation procedure. Of these, seven patients were alive at 1 year, five at 3 years and three at 5 years. Three patients remain alive. Patient and graft survival improved with experience; the 1-year survival rate improved in the last 4 years of this experience from 43 to 57 per cent, and the 3-year survival rate from 29 to 43 per cent. CONCLUSION: Small intestinal transplantation is associated with a high mortality rate but may benefit carefully selected patients in whom conservative management is likely to carry a greater mortality rate.

Hepatic control of perfusate homeostasis during normothermic extrocorporeal preservation.

BACKGROUND: We investigated the ability of the isolated porcine liver to maintain acid-base homeostasis in the perfusate and the impact of ischemia-reperfusion injury without or with extracorporeal perfusion. METHODS: Harvested livers were either stored for 24 hours in cold University of Wisconsin solution or preserved by continuous, normothermic, oxygenated sanguineous perfusion with supplemental nutrition, prostacyclin, and bile salts. After a further 24-hour period of reperfusion of both groups on an extracorporeal circuit, the perfusate was assessed for both biochemical indices of synthetic and metabolic liver function as well as hepatocellular injury and blood gas analysis. RESULTS: Livers injured by cold ischemia during preservation displayed inferior synthetic and metabolic functions. Perfused livers, which displayed minimal ischemic injury, produced more bicarbonate than the cold-stored organs, suggesting autoregulation of pH homeostasis in perfused livers in contrast to progressively worsening acidosis in cold-stored organs. CONCLUSIONS: Given proper physiologic substrate the porcine liver has the ability to maintain acid-base homeostasis, provided there is not a significant ischemia-reperfusion injury.

Extended preservation of non-heart-beating donor livers with normothermic machine perfusion.

BACKGROUND: Non-heart-beating donor (NHBD) livers represent an important organ pool, but are seldom utilized clinically and require rapid retrieval and implantation. Experimental work with oxygenated perfusion during preservation has shown promising results by recovering function in these livers. This study compared sanguinous perfusion with cold storage for extended preservation of the NHBD liver in a porcine model. METHODS: Porcine livers were subjected to 60 min of in vivo total warm ischaemia before flushing, after which they were preserved by one of two methods: group 1 (n = 4), University of Wisconsin (UW) solution by standard cold storage for 24 h; group 2 (n = 4), oxygenated autologous blood perfusion on an extracorporeal circuit for 24 h. All livers were subsequently tested on the circuit during a 24-h reperfusion phase. RESULTS: Livers in group 1 showed no evidence of viability during the reperfusion phase with no bile production or glucose utilization; they also displayed massive necrosis. Livers in group 2 demonstrated recovery of function by synthetic function, substrate utilization and perfusion haemodynamics; these livers displayed less cellular injury by hepatocellular enzymes. All differences in parameters between the two groups were statistically significant (P < 0.05). These findings were supported by histological examination. CONCLUSION: Warm ischaemia for 1 h and simple cold storage (UW solution) for 24 h renders the liver non-viable. Oxygenated, sanguinous perfusion as a method of preservation recovers liver function to a viable level after 24 h of preservation.

Prope tolerance with induction using Campath 1H and low-dose cyclosporin monotherapy in 31 cadaveric renal allograft recipients.

The last 40 years has been a period of remarkable evolution of organ transplantation from nothing to a well-established form of treatment with good short-term and tolerable long-term results. Nevertheless by ten years approximately 50% of grafts will have been lost due, mainly, to chronic rejection or the side-effects of immunosuppressive therapy. We now have a number of extremely powerful immunosuppressive drugs and antibodies with different mechanisms of action and the stage is set for a move from current continuous high dose immunosuppressive maintenance therapy to low dose or no maintenance immunosuppression. True tolerance can occur in man, examples being successful bone marrow transplantation and patients with liver grafts who have stopped immunosuppression after years of good function. The antibody Campath 1H with a unique target CH52 on T & B lymphocytes and monocytes has been used to eliminate lymphocytes from the blood for a month in patients with renal allografts who have then been maintained on half dose Cyclosporin without any other maintenance drug. The results with a mean two year follow-up have been encouraging, 29 patients having good function without receiving maintenance steroids. It is likely that this protocol could be improved since dosage timing and various minimal maintenance immunosuppressive protocols have not been fully investigated. This almost or "Prope" tolerance could be a major step forward providing a better quality of life for patients and inexpensive maintenance immunosuppression.

Xenotransplantation.

BACKGROUND: The success of clinical transplantation has led to a large discrepancy between donor organ availability and demand; considerable pressure exists to develop an alternative source of organs. The use of animal organs for donation is a possible solution that is not yet clinically applicable. METHODS AND RESULTS: A literature review was performed based on a Medline search to find articles on xenotransplantation. Keywords included hyperacute, acute vascular, xenograft rejection combined with concordant and discordant. Additional references cited in these articles from journals not included in Medline were obtained from the British Library. Limited information on unpublished, preliminary work has been included from sources known to the authors, based on their research work in the field. One hundred and forty-six references and four personal communications have been included in this review article. CONCLUSION: A greater understanding of the pathogenesis of xenograft rejection is developing rapidly. Strategies to abrogate hyperacute rejection have proved successful, but control of antibody-driven acute vascular rejection has not yet been achieved. The safety and viability of xenotransplantation as a therapeutic modality are still unproven.