Routine utilization of machine perfusion in liver transplantation: Ready for prime time?

The last decade has been notable for increasing high-quality research and dramatic improvement in outcomes with dynamic liver preservation. Robust evidence from numerous randomized controlled trials has been pooled by meta-analyses, providing the highest available evidence on the protective effect of machine perfusion (MP) over static cold storage in liver transplantation (LT). Based on a protective effect with less complications and improved graft survival, the field has seen a paradigm shift in organ preservation. This editorial focuses on the role of MP in LT and how it could become the new "gold standard". Strong collaborative efforts are needed to explore its effects on long-term outcomes.

Rate of prophylactic anti-Xa achievement and impact on venous thromboembolism following oncologic hepato-pancreatico-biliary surgery: A prospective cohort study.

BACKGROUND: Hepato-pancreatico-biliary (HPB) patients experience competing risk of venous thromboembolism (VTE) and bleeding. We sought to evaluate the effect of anti-Xa levels on VTE and bleeding, and to characterize factors associated with subprophylaxis. METHODS: This prospective cohort study evaluated adult HPB surgical patients; cohorts were described by anti-Xa levels as subprophylactic (<0.2 IU/mL), prophylactic (0.2-0.5 IU/mL), and supraprophylactic (>0.5 IU/mL). Primary outcome evaluated bleeding and VTE complications. Secondary outcomes evaluated factors associated with subprophylaxis. RESULTS: We included 157 patients: 68 (43.6%) attained prophylactic anti-Xa and 89 (56.7%) were subprophylactic. Subprophylactic patients experienced more VTE compared to prophylactic patients (6.9% vs 0%; p = 0.028) without differences in bleeding complications (14.6% vs 5.9%; p = 0.081). Factors associated with subprophylactic anti-Xa included female sex (OR 2.90, p = 0.008), and Caprini score (OR 1.30, p = 0.035). Enoxaparin was protective against subprophylaxis compared to tinzaparin (OR 0.43, p = 0.029). CONCLUSIONS: Many HPB patients have subprophylactic anti-Xa levels, placing them at risk of VTE. Enoxaparin may be preferential, however, studies evaluating optimized prophylaxis are needed.

Bioengineered stem cells as an alternative for islet cell transplantation.

Type 1 diabetes is an autoimmune and increasingly prevalent condition caused by immunological destruction of beta cells. Insulin remains the mainstay of therapy. Endeavours in islet transplantation have clearly demonstrated that type 1 diabetes is treatable by cellular replacement. Many challenges remain with this approach. The opportunity to use bioengineered embryonic or adult pluripotential stem cells, or islets derived from porcine xenograft sources could address future demands, but are still associated with considerable challenges. This detailed review outlines current progress in clinical islet transplantation, and places this in perspective for the remarkable scientific advances now occurring in stem cell and regenerative medicine approaches in the treatment of future curative treatment of diabetes.

Islet cell transplantation for the treatment of type 1 diabetes: recent advances and future challenges.

Islet transplantation is a well-established therapeutic treatment for a subset of patients with complicated type I diabetes mellitus. Prior to the Edmonton Protocol, only 9% of the 267 islet transplant recipients since 1999 were insulin independent for >1 year. In 2000, the Edmonton group reported the achievement of insulin independence in seven consecutive patients, which in a collaborative team effort propagated expansion of clinical islet transplantation centers worldwide in an effort to ameliorate the consequences of this disease. To date, clinical islet transplantation has established improved success with insulin independence rates up to 5 years post-transplant with minimal complications. In spite of marked clinical success, donor availability and selection, engraftment, and side effects of immunosuppression remain as existing obstacles to be addressed to further improve this therapy. Clinical trials to improve engraftment, the availability of insulin-producing cell sources, as well as alternative transplant sites are currently under investigation to expand treatment. With ongoing experimental and clinical studies, islet transplantation continues to be an exciting and attractive therapy to treat type I diabetes mellitus with the prospect of shifting from a treatment for some to a cure for all.

Impact of adverse pancreatic injury at surgical procurement upon islet isolation outcome.

The consequence of a pancreas injury during the procurement for islet isolation purpose is unknown. The goal of this work was to assess the injuries of the pancreata procured for islet isolation, and to determine their effect on the islet yield. Between January 2007 and October 2013, we prospectively documented every injury of the pancreata processed in our centre for islet isolation. Injuries involving the main duct were classified as major, the others as minor. Donors' characteristics and islet yields were compared between the groups of injuries. A pancreas injury was identified in 42 of 452 pancreata received for islet isolation (9.3%). In 15 cases, the injury was major (3.3% of all pancreata). Although a minor injury did not affect the islet yield, a major injury was significantly associated with unfavourable outcomes (postpurification mean islet equivalent of 364 ± 181, 405 ± 190 and 230 ± 115 × 10(3) for absence of injury, minor injury and major injury, respectively). A major injury was significantly more prevalent in lean and short donors. We recommend assessing the quality of the pancreas in the islet isolation centre before starting the isolation procedure. Each centre should determine its own policy based on its financial resources and on the wait list.

Current status of clinical islet transplantation.

Islet transplantation (IT) is today a well-established treatment modality for selected patients with type 1 diabetes mellitus (T1DM). After the success of the University of Alberta group with a modified approach to the immune protection of islets, the international experience grew along with the numbers of transplants in highly specialized centers. Yet, long-term analysis of those initial results from the Edmonton group indicated that insulin-independence was not durable and most patients return to modest amounts of insulin around the fifth year, without recurrent hypoglycemia events. Many phenomena have been identified as limiting factor for the islet engraftment and survival, and today all efforts are aimed to improve the quality of islets and their engrafting process, as well as more optimized immunosuppression to facilitate tolerance and ultimately, better long term survival. This brief overview presents recent progress in IT. A concise historical perspective is provided, along with the latest efforts to improve islet engraftment, immune protection and ultimately, prolonged graft survival. It is apparent that as the community continues to work together further optimizing IT, it is hopeful a cure for T1DM will soon be achievable.

Characterization of the transcriptome in isolated and transplanted mouse pancreatic islets: associations with engraftment and dysfunction.

The transplantation of pancreatic islets is an option for therapeutic management of hypoglycemia unawareness in select patients with type 1 diabetes mellitus. Characteristics of the transcriptome of freshly isolated islets, islet allografts, and islet isograft are reported in the literature. However, no single experiment has undertaken a comparison of the islet allograft to isograft. Potential implications of the latter are the use in diagnosis of rejection and to discover the molecular pathways in islet allograft dysfunction after transplant. Here, the mouse model of islet transplant is used to characterize the transcriptome of freshly isolated islets and compare islet graft in an isogeneic vs. allogeneic host using an Affymetrix GeneChip® Array assay. A set of islet associated transcripts (IAT) was developed, and subsequently shown to have high level of expression in islet allografts and isografts harvested either five- or ten-days after transplant. Furthermore, specific analysis of transcriptome differences between islet isografts and pre-rejection allografts (ten-day), reveal a series of islet rejection associated transcripts (IRAT). Nearly half of IRAT show overlap with previously described pathogenesis based transcript sets identified in the setting of mouse kidney allograft rejection. The novel transcripts identified to be associated with islet rejection include those involved in chemotaxis or lymphocyte function. Although use of biopsy based monitoring of humans islet transplants remains difficult at the present time, this study provides proof of principle for a transcriptome based technique for islet graft rejection monitoring and describes the transcripts associated with islet graft dysfunction.

Immune monitoring of pancreatic islet graft: towards a better understanding, detection and treatment of harmful events.

IMPORTANCE OF THE FIELD: Long-term clinical outcomes of islet transplantation are hampered by rejection and recurrence of autoimmunity, which lead to a gradual decrease in islet function usually taking place over the first five years after transplantation. An accurate monitoring strategy could allow for the detection and treatment of harmful immune events, potentially resulting in higher rates of insulin-independence. AREAS COVERED IN THIS REVIEW: This article provides a critical review of the various assays currently available for the assessment of allo- and autoimmunity both prior to and after islet transplantation. The accuracy in predicting clinical outcome is specifically addressed. WHAT THE READER WILL GAIN: Most current tests based on the assessment of allo- and auto-immune antibody are of minimal help in clinical practice. Cell-based tests (including the assessment of cytotoxic T lymphocyte precursors, proliferation tests, enzyme-linked immunospot) have the potential to allow earlier and more accurate detection of harmful events. TAKE HOME MESSAGE: A specific and accurate immune monitoring has the potential to significantly improve islet transplant outcomes. The development and use of such tests (favouring cell-based tests) should be promoted.

A patient with severe, recurrent hypoglycemia and glycemic lability who underwent islet transplantation.

BACKGROUND: A 48-year-old woman who was diagnosed with type 1 diabetes at 5 years of age presented to our Clinical Islet Transplant Program with severe, recurrent hypoglycemia and glycemic lability. She was diligent with her diet, used a continuous subcutaneous insulin infusion pump (32 U per day), and monitored her glucose levels typically eight times a day. The patient usually had one hypoglycemic reaction a day, experienced a severe reaction once a month, and had marked variability of her glucose values. On presentation, her HYPO score was 584 and her lability index was 868 mmol/l(2)/h per week. INVESTIGATIONS: HYPO score, lability index score, screening for diabetes complications, and routine pretransplant evaluation. DIAGNOSIS: Severe, recurrent hypoglycemia and glycemic lability associated with type 1 diabetes. MANAGEMENT: The patient underwent islet transplantation. Post-transplant, the problems with hypoglycemia abated and excellent stable glycemic control was attained, although some side effects from the immunosuppressive drug, sirolimus, were evident. Insulin was reinstituted 2.5 years after surgery, at lower doses than before the transplant because of deterioration in graft function. Occasional episodes of hypoglycemia have occurred and some glycemic lability has recurred, although endogenous insulin secretion is still preserved.

Pancreatic Transplantation: Beta Cell Replacement.

Diabetes is a leading cause of morbidity and mortality worldwide. Complications of diabetes including renal failure, retinopathy, neuropathy, and cardiovascular disease limit both survival and quality of life. Pancreatic transplantation can restore euglycemia thereby stabilizing or even reversing secondary complications of diabetes as well as improving quality of life particularly in patients with labile diabetes. Recent evidence also shows an improved survival in diabetic patients that undergo pancreatic transplantation when combined with a kidney transplant. Pancreatic transplantation should more properly be referred to as beta cell replacement as the field today encompasses both whole organ and islet cell transplantation. We have outlined herein the indications and contraindications to islet or whole organ pancreas transplantation and we have described periprocedure care and short- and long-term prognosis.