Machine Perfusion of Donor Livers for Transplantation: A Proposal for Standardized Nomenclature and Reporting Guidelines.

With increasing demand for donor organs for transplantation, machine perfusion (MP) promises to be a beneficial alternative preservation method for donor livers, particularly those considered to be of suboptimal quality, also known as extended criteria donor livers. Over the last decade, numerous studies researching MP of donor livers have been published and incredible advances have been made in both experimental and clinical research in this area. With numerous research groups working on MP, various techniques are being explored, often applying different nomenclature. The objective of this review is to catalog the differences observed in the nomenclature used in the current literature to denote various MP techniques and the manner in which methodology is reported. From this analysis, we propose a standardization of nomenclature on liver MP to maximize consistency and to enable reliable comparison and meta-analyses of studies. In addition, we propose a standardized set of guidelines for reporting the methodology of future studies on liver MP that will facilitate comparison as well as clinical implementation of liver MP procedures

Ultrastructural pathology of primary ciliary dyskinesia: report about 125 cases in Germany

<p>Abstract</p> <p>Background</p> <p>Primary ciliary dyskinesia (PCD) is a rare genetically induced disorder of cilia inducing mainly respiratory diseases. Transmission electron microscopy (TEM) analysis of ciliary ultrastructure is classically used for diagnosis. We report our experience of TEM investigations in a large series of patients.</p> <p>Methods</p> <p>TEM analysis performed of 742 biopsies from patients with suspected PCD was reviewed retrospectively. Ultrastructural defects were analysized further in 125 cases with changes typical for PCD.</p> <p>Results</p> <p>In 18.1% of patients diagnosis of PCD was made because of morphological alterations, in 68.2% secondary changes were seen. In 13.7% material was not feasible for analysis. Mostly defects of dynein arms were detected in PCD (96.8%). In particular defects of the inner arms (51.2%) and combined dynein defects (37.6%) were found. Total loss of dynein arms was dominant. Only in 3.2% deficiencies of central structures were found alone. Associated situs inversus or dextracardia was reported clinically in 21.4%.</p> <p>Conclusions</p> <p>TEM analysis is possible in most patients and a useful tool for diagnosis of PCD. Functional and genetic analysis should be done additionally. Registers should be installed to collect all available informations and push further research.</p

Oxygen persufflation as adjunct in liver preservation (OPAL): Study protocol for a randomized controlled trial

<p>Abstract</p> <p>Background</p> <p>Early graft dysfunction due to preservation/reperfusion injury represents a dramatic event after liver transplantation. Enhancement of donor organ criteria, in order to cope with the ever increasing donor shortage, further increases graft susceptibility to ischemic alterations.</p> <p>Major parts of post-preservation injury, however, occur at the time of warm reperfusion but not during ischemic storage; successful reperfusion of ischemic tissue in turn depends on an adequate redox and intracellular signal homeostasis. The latter has been shown experimentally to be favorably influenced by oxygen persufflation within short time spans. Thus viability of marginally preserved liver grafts could still be augmented by transient hypothermic reconditioning <b><it>even after </it></b>normal procurement and static cold storage. The present study is aimed to confirm the conceptual expectations, that hypothermic reconditioning by gaseous oxygen persufflation is a useful method to suppress injurious cellular activation cascades and to improve post-ischemic recovery of marginally preserved liver grafts.</p> <p>Methods/Design</p> <p>OPAL is a prospective single center randomized proof of concept study, including two parallel groups in a total of 116 liver transplant patients. The effect of an in hospital treatment of the isolated liver graft by 2 hours of oxygen persufflation immediately prior to transplantation will be assesses as compared to standard procedure (cold storage without further intervention). The primary endpoint is the peak transaminase serum level (AST) during the first three days after transplantation as a surrogate readout for parenchymal liver injury. Other outcomes comprise patient and graft survival, time of intensive care requirement, hepatic tissue perfusion 1h after revascularisation, early onset of graft dysfunction based on coagulation parameters, as well as the use of a refined scoring-system for initial graft function based on a multi-parameter (AST, ALT, Quick and bilirubin) score. Furthermore, the effect of OPAL on molecular pathways of autophagy and inflammatory cell activation will be evaluated. Final analysis will be based on all participants as randomized (intention to treat).</p> <p>Trial Registration</p> <p>Current Controlled Trials <a href="http://www.controlled-trials.com/ISRCTN00167887">ISRCTN00167887</a></p

A phase II study of mitomycin C, cisplatin and continuous infusion 5-fluorouracil (MCF) in the treatment of patients with carcinoma of unknown primary site

Carcinoma of unknown primary site remains a common clinical diagnosis, accounting for between 5 and 10% of all cancer patients. Numerous combination chemotherapy regimens have been used in the management of carcinoma of unknown primary site, resulting in response rates of 0–48%. We present the results of a single centre phase II study of the use of the combination of mitomycin C (7 mg m−2 on day 1 of cycles 1, 3 and 5) cisplatin (60 mg m−2 on day 1) and continuous infusion 5-fluorouracil (300 mg m−2 daily), MCF, delivered as a 21-day cycle, in patients with carcinoma of unknown primary site. Thirty-one patients with a diagnosis of carcinoma of unknown primary site were treated in Aberdeen Royal Infirmary between 1997 and 2001 with MCF. In total, 136 cycles of MCF were delivered (median of 5 cycles per patient). Toxicity was acceptable, with 19% grade 3 or 4 neutropenia, 16% grade 3 or 4 thrombocytopenia and 13% grade 3 or 4 nausea and vomiting. No cases of neutropenic sepsis were seen and there were no treatment-related deaths, however, six patients developed thrombotic complications. The overall response rate was 27% (CR 3%; PR 23%). Median time to progression was 3.4 months (95% CI 1.1–5.6 months) and median overall survival was 7.7 months (95% CI 5.7–9.8 months). Survival at 1 year was 28%, and at 2 years, 10%. MCF is a tolerable regimen with comparable toxicity, response rates and survival data to most platinum-based combination chemotherapy regimens in use for this devastating disease

Influence of microenvironment on engraftment of transplanted β-cells

Pancreatic islet transplantation into the liver provides a possibility to treat selected patients with brittle type 1 diabetes mellitus. However, massive early β-cell death increases the number of islets needed to restore glucose homeostasis. Moreover, late dysfunction and death contribute to the poor long-term results of islet transplantation on insulin independence. Studies in recent years have identified early and late challenges for transplanted pancreatic islets, including an instant blood-mediated inflammatory reaction when exposing human islets to the blood microenvironment in the portal vein and the low oxygenated milieu of islets transplanted into the liver. Poor revascularization of remaining intact islets combined with severe changes in the gene expression of islets transplanted into the liver contributes to late dysfunction. Strategies to overcome these hurdles have been developed, and some of these interventions are now even tested in clinical trials providing a hope to improve results in clinical islet transplantation. In parallel, experimental and clinical studies have, based on the identified problems with the liver site, evaluated the possibility of change of implantation organ in order to improve the results. Site-specific differences clearly exist in the engraftment of transplanted islets, and a more thorough characterization of alternative locations is needed. New strategies with modifications of islet microenvironment with cells and growth factors adhered to the islet surface or in a surrounding matrix could be designed to intervene with site-specific hurdles and provide possibilities to improve future results of islet transplantation

Obstacles on the way to the clinical visualisation of beta cells: looking for the Aeneas of molecular imaging to navigate between Scylla and Charybdis

For more than a decade, researchers have been trying to develop non-invasive imaging techniques for the in vivo measurement of viable pancreatic beta cells. However, in spite of intense research efforts, only one tracer for positron emission tomography (PET) imaging is currently under clinical evaluation. To many diabetologists it may remain unclear why the imaging world struggles to develop an effective method for non-invasive beta cell imaging (BCI), which could be useful for both research and clinical purposes. Here, we provide a concise overview of the obstacles and challenges encountered on the way to such BCI, in both native and transplanted islets. We discuss the major difficulties posed by the anatomical and cell biological features of pancreatic islets, as well as the chemical and physical limits of the main imaging modalities, with special focus on PET, SPECT and MRI. We conclude by indicating new avenues for future research in the field, based on several remarkable recent results

How to discuss gene therapy for haemophilia? A patient and physician perspective

Gene therapy has the potential to revolutionise treatment for patients with haemophilia and is close to entering clinical practice. While factor concentrates have improved outcomes, individuals still face a lifetime of injections, pain, progressive joint damage, the potential for inhibitor development and impaired quality of life. Recently published studies in adeno‐associated viral (AAV) vector‐mediated gene therapy have demonstrated improvement in endogenous factor levels over sustained periods, significant reduction in annualised bleed rates, lower exogenous factor usage and thus far a positive safety profile. In making the shared decision to proceed with gene therapy for haemophilia, physicians should make it clear that research is ongoing and that there are remaining evidence gaps, such as long‐term safety profiles and duration of treatment effect. The eligibility criteria for gene therapy trials mean that key patient groups may be excluded, eg children/adolescents, those with liver or kidney dysfunction and those with a prior history of factor inhibitors or pre‐existing neutralising AAV antibodies. Gene therapy offers a life‐changing opportunity for patients to reduce their bleeding risk while also reducing or abrogating the need for exogenous factor administration. Given the expanding evidence base, both physicians and patients will need sources of clear and reliable information to be able to discuss and judge the risks and benefits of treatment