BACKGROUNDTransplantation of livers obtained from donors after circulatory death is associated with an increased risk of nonanastomotic biliary strictures. Hypothermic oxygenated machine perfusion of livers may reduce the incidence of biliary complications, but data from prospective, controlled studies are limited.

BackgroundIslet cell transplantation can cure type 1 diabetes (T1D), but only a minority of recipients remains insulin–independent in the following years. We tested the hypothesis that allograft rejection and recurrent autoimmunity contribute to this progressive loss of islet allograft function.Methodology/Principal FindingsTwenty-one T1D patients received cultured islet cell grafts prepared from multiple donors and transplanted under anti-thymocyte globulin (ATG) induction and tacrolimus plus mycophenolate mofetil (MMF) maintenance immunosuppression. Immunity against auto- and alloantigens was measured before and during one year after transplantation. Cellular auto- and alloreactivity was assessed by lymphocyte stimulation tests against autoantigens and cytotoxic T lymphocyte precursor assays, respectively. Humoral reactivity was measured by auto- and alloantibodies. Clinical outcome parameters - including time until insulin independence, insulin independence at one year, and C-peptide levels over one year- remained blinded until their correlation with immunological parameters. All patients showed significant improvement of metabolic control and 13 out of 21 became insulin-independent. Multivariate analyses showed that presence of cellular autoimmunity before and after transplantation is associated with delayed insulin-independence (p = 0.001 and p = 0.01, respectively) and lower circulating C-peptide levels during the first year after transplantation (p = 0.002 and p = 0.02, respectively). Seven out of eight patients without pre-existent T-cell autoreactivity became insulin-independent, versus none of the four patients reactive to both islet autoantigens GAD and IA-2 before transplantation. Autoantibody levels and cellular alloreactivity had no significant association with outcome.Conclusions/SignificanceIn this cohort study, cellular islet-specific autoimmunity associates with clinical outcome of islet cell transplantation under ATG-tacrolimus-MMF immunosuppression. Tailored immunotherapy targeting cellular islet autoreactivity may be required. Monitoring cellular immune reactivity can be useful to identify factors influencing graft survival and to assess efficacy of immunosuppression.Trial RegistrationClinicaltrials.gov NCT00623610

This article has been accepted for publication and undergone full peer review but has not been through the copyediting, typesetting, pagination and proofreading process. Oxygenated versus standard cold perfusion preservation in kidney transplantation (COMPARE): a randomised, double-blind, paired, phase 3, superiority trial. Authorship Ina Jochmans (PhD), Aukje Brat (Medical degree), Lucy Davies (PhD) 4 , H. Sijbrand Hofker (Medical degree), Fenna E.M. van de Leemkolk (Medical degree), Henri G.

Background Tumor recurrence after radical resection of hepatic tumors is not uncommon, suggesting that malignant lesions are missed during surgery. Intraoperative navigation using fluorescence guidance is an innovative technique enabling real-time identification of (sub)capsular liver tumors. The objective of the current study was to compare fluorescence imaging (FI) and conventional imaging modalities for laparoscopic detection of both primary and metastatic tumors in the liver. Methods Patients undergoing laparoscopic resection of a malignant hepatic tumor were eligible for inclusion. Patients received standard-of-care, including preoperative CT and/or MRI. In addition, 10 mg indocyanine green was intravenously administered one day prior to surgery. After introduction of the laparoscope, inspection, FI, and laparoscopic ultrasonography (LUS) were performed. Histopathological examination of resected suspect tissue was considered the gold standard. Results Twenty-two patients suspected to have hepatocellular carcinoma (n=4), cholangiocarcinoma (n=2) or liver metastases from colorectal carcinoma (n=12), uveal melanoma (n=2) and breast cancer (n=2) were included. Two patients were excluded because their surgery was unexpectedly postponed several days. Twenty-six malignancies were resected in the remaining 20 patients. Sensitivity for various modalities was 80% (CT), 84% (MRI), 62% (inspection), 86% (LUS) and 92% (FI), respectively. Three metastases (12%) were identified solely by FI. All 26 malignancies could be detected by combining LUS and FI (100% sensitivity). Conclusion This study demonstrates added value of FI during laparoscopic resections of several hepatic tumors. Although larger series will be needed to confirm long-term patient outcome, the technology already aids the surgeon by providing real-time fluorescence guidance.

OBJECTIVEThe metabolic outcome of islet cell transplants in type 1 diabetic patients is variable. This retrospective analysis examines whether differences in recipient characteristics at the time of transplantation are correlated with inadequate graft function.RESEARCH DESIGN AND METHODSThirty nonuremic C-peptide–negative type 1 diabetic patients had received an intraportal islet cell graft of comparable size under an ATG-tacrolimus–mycophenolate mofetil regimen. Baseline patient characteristics were compared with outcome parameters during the first 6 posttransplant months (i.e., plasma C-peptide, glycemic variability, and gain of insulin independence). Correlations in univariate analysis were further examined in a multivariate model.RESULTSPatients that did not become insulin independent exhibited significantly higher counts of B-cells as well as a T-cell autoreactivity against insulinoma-associated protein 2 (IA2) and/or GAD. In one of them, a liver biopsy during posttransplant year 2 showed B-cell accumulations near insulin-positive β-cell aggregates. Higher baseline total lymphocytes and T-cell autoreactivity were also correlated with lower plasma C-peptide levels and higher glycemic variability.CONCLUSIONSHigher total and B-cell counts and presence of T-cell autoreactivity at baseline are independently associated with lower graft function in type 1 diabetic patients receiving intraportal islet cells under ATG-tacrolimus–mycophenolate mofetil therapy. Prospective studies are needed to assess whether control of these characteristics can help increase the function of islet cell grafts during the first year posttransplantation.

SummaryAn immunogenic peptide (p277) from the 60-kDa heat shock protein (hsp60) arrested beta-cell destruction in non-obese diabetic mice. A randomized, double-blind, phase Ib/II clinical trial of DiaPep277 peptide treatment was performed in recent-onset type 1 diabetes patients with remaining insulin production. We studied the immunological efficacy of this peptide therapy and correlated this with clinical outcome. Forty-eight C-peptide-positive patients were assigned subcutaneous injections of 0·2, 1·0 or 2·5 mg p277 (n = 12 per dosage) at entry, and 1, 6 and 12 months, or four placebo injections (n = 12). T cell autoimmunity to hsp60, DiaPep277, glutamic acid decarboxylase and tetanus toxoid (recall response control) were assayed by proliferation and cytokine secretion assays (enzyme-linked immunospot) at regular intervals until 18 months after the first injection. All treated patients at each dosage of peptide demonstrated an altered immune response to DiaPep277, while the majority of placebo-treated patients remained non-responsive to treatment (P = 0·00001), indicating a 100% efficacy of immunization. Cytokine production in response to therapy was dominated by interleukin (IL)-10. IL-10 production before therapy and decreasing autoantigen-specific T cell proliferation were associated with beta-cell preservation. Third-party control immune responses were unaffected by therapy. No potentially adverse immunological side effects were noted. DiaPep277 is immunogenic in type 1 diabetic subjects and has immune modulating properties. Immunological monitoring distinguished therapy from placebo treatment and could determine immunological efficacy. Declining or temporary proliferative responses to peptide DiaPep277 treatment may serve as an immunological biomarker for clinical efficacy.

Background: Fluorescence cholangiography using indocyanine green (ICG) can enhance orientation of bile duct anatomy during laparoscopic cholecystectomy. To ensure clear discrimination between bile ducts and liver, the fluorescence ratio between both should be sufficient. This ratio is influenced by the ICG dose and timing of fluorescence imaging. We first systematically identified all strategies for fluorescence cholangiography. Second, we aimed to optimize the dose of ICG and dosing time in a prospective clinical trial. Methods: PubMed was searched for clinical trials studying fluorescence cholangiography. Furthermore, 28 patients planned to undergo laparoscopic cholecystectomy were divided into 7 groups, receiving different intravenous doses (5 or 10 mg ICG) at different time points (0.5, 2, 4, 6, or 24 hours prior to surgery). Results: The systematic review revealed 27 trials including 1057 patients. The majority of studies used 2.5 mg administered within 1 hour before imaging. Imaging 3 to 24 hours after ICG administration was never studied. The clinical trial demonstrated that the highest bile duct-to-liver ratio was achieved 3 to 7 hours after administration of 5 mg and 5 to 25 hours after administration of 10 mg ICG. Up to 3 hours after administration of 5 mg and up to 5 hours after administration of 10 mg ICG, the liver was equally or more fluorescent than the cystic duct, resulting in a ratio ≤1.0. Conclusion: This study shows for the first time that the interval between ICG administration and intraoperative fluorescence cholangiography should be extended. Administering 5 mg ICG at least 3 hours before imaging is easy to implement in everyday clinical practice and results in bile duct-to-liver ratios >1.0.

Multiple DiaPep277 peptide administration seems safe and may have a beneficial effect on C-peptide levels over time, but this finding is not supported by lower HbA1c levels or daily insulin requirement. Further investigation on a larger scale is warranted.