After extensive experimentation, outcomes of a first clinical normothermic machine perfusion (NMP) liver trial in the United Kingdom demonstrated feasibility and clear safety, with improved liver ...function compared with standard static cold storage (SCS). We present a preliminary single‐center North American experience using identical NMP technology. Ten donor liver grafts were procured, four (40%) from donation after circulatory death (DCD), of which nine were transplanted. One liver did not proceed because of a technical failure with portal cannulation and was discarded. Transplanted NMP grafts were matched 1:3 with transplanted SCS livers. Median NMP was 11.5 h (range 3.3–22.5 h) with one DCD liver perfused for 22.5 h. All transplanted livers functioned, and serum transaminases, bilirubin, international normalized ratio, and lactate levels corrected in NMP recipients similarly to controls. Graft survival at 30 days (primary outcome) was not statistically different between groups on an intent‐to‐treat basis (p = 0.25). Intensive care and hospital stays were significantly more prolonged in the NMP group. This preliminary experience demonstrates feasibility as well as potential technical risks of NMP in a North American setting and highlights a need for larger, randomized studies.
This paper describes a preliminary Canadian single‐center experience with clinical ex vivo normothermic liver perfusion and transplantation. See the video at amjtransplant.com/videos.
Percutaneous transhepatic portal access avoids surgery but is rarely associated with bleeding or portal venous thrombosis (PVT). We herein report our large, single‐center experience of percutaneous ...islet implantation and evaluate risk factors of PVT and graft function. Prospective data were collected on 268 intraportal islet transplants (122 subjects). A portal venous Doppler ultrasound was obtained on Days 1 and 7 posttransplant. Therapeutic heparinization, complete ablation of the portal catheter tract with Avitene paste and limiting packed cell volume (PCV) to <5 mL completely prevented any portal thrombosis in the most recent 101 islet transplant procedures over the past 5 years. In the previous cumulative experience, partial thrombosis did not affect islet function. Standard liver volume correlated negatively (r =−0.257, p < 0.001) and PCV correlated positively with portal pressure rise (r = 0.463, p < 0.001). Overall, partial portal thrombosis occurred after 10 procedures (overall incidence 3.7%, most recent 101 patient incidence 0%). There were no cases of complete thrombosis and no patient developed sequelae of portal hypertension. In conclusion, portal thrombosis is a preventable complication in clinical islet transplantation, provided therapeutic anticoagulation is maintained and PCV is limited to <5 mL.
In 268 percutaneous islet transplants, complete thrombosis of the portal vein never occurred, partial thrombosis occurred with an incidence of 3.7%, and by limiting the packed tissue volume to <5cc, combined with therapeutic heparin and track plugging, was preventable entirely in the most recent 100 cases.
The presence of an intrahepatic cholangiocarcinoma (iCCA) in a cirrhotic liver is a contraindication for liver transplantation in most centers worldwide. Recent investigations have shown that “very ...early” iCCA (single tumors ≤2 cm) may have acceptable results after liver transplantation. This study further evaluates this finding in a larger international multicenter cohort. The study group was composed of those patients who were transplanted for hepatocellular carcinoma or decompensated cirrhosis and found to have an iCCA at explant pathology. Patients were divided into those with “very early” iCCA and those with “advanced” disease (single tumor >2 cm or multifocal disease). Between January 2000 and December 2013, 81 patients were found to have an iCCA at explant; 33 had separate nodules of iCCA and hepatocellular carcinoma, and 48 had only iCCA (study group). Within the study group, 15/48 (31%) constituted the “very early” iCCA group and 33/48 (69%) the “advanced” group. There were no significant differences between groups in preoperative characteristics. At explant, the median size of the largest tumor was larger in the “advanced” group (3.1 2.5‐4.4 versus 1.6 1.5‐1.8). After a median follow‐up of 35 (13.5‐76.4) months, the 1‐year, 3‐year, and 5‐year cumulative risks of recurrence were, respectively, 7%, 18%, and 18% in the very early iCCA group versus 30%, 47%, and 61% in the advanced iCCA group, P = 0.01. The 1‐year, 3‐year, and 5‐year actuarial survival rates were, respectively, 93%, 84%, and 65% in the very early iCCA group versus 79%, 50%, and 45% in the advanced iCCA group, P = 0.02. Conclusion: Patients with cirrhosis and very early iCCA may become candidates for liver transplantation; a prospective multicenter clinical trial is needed to further confirm these results. (Hepatology 2016;64:1178‐1188)
We studied whether the use of sirolimus with reduced‐dose tacrolimus, as compared to standard‐dose tacrolimus, after liver transplantation is safe, tolerated and efficacious. In an international ...multicenter, open‐label, active‐controlled randomized trial (2000–2003), adult primary liver transplant recipients (n = 222) were randomly assigned immediately after transplantation to conventional‐dose tacrolimus (trough: 7–15 ng/mL) or sirolimus (loading dose: 15 mg, initial dose: 5 mg titrated to a trough of 4–11 ng/mL) and reduced‐dose tacrolimus (trough: 3–7 ng/mL). The study was terminated after 21 months due to imbalance in adverse events. The 24‐month cumulative incidence of graft loss (26.4% vs. 12.5%, p = 0.009) and patient death (20% vs. 8%, p = 0.010) was higher in subjects receiving sirolimus. A numerically higher rate of hepatic artery thrombosis/portal vein thrombosis was observed in the sirolimus arm (8% vs. 3%, p = 0.065). The incidence of sepsis was higher in the sirolimus arm (20.4% vs. 7.2%, p = 0.006). Rates of acute cellular rejection were similar between the two groups. Early use of sirolimus using a loading dose followed by maintenance doses and reduced‐dose tacrolimus in de novo liver transplant recipients is associated with higher rates of graft loss, death and sepsis when compared to the use of conventional‐dose tacrolimus alone.
This study reports the results of the international, multicenter, controlled randomized trial of adult primary liver transplant recipients receiving de novo sirolimus and reduced dose tacrolimus or conventional dose tacrolimus, which formed the basis of a black box warning for use of sirolimus immediately after liver transplantation. See editorial by Levitsky and Feng on page 249.
Abstract Radioembolization with yttrium-90 microspheres offers an alternative treatment option for patients with unresectable intrahepatic cholangiocarcinoma (ICC). However, the rarity and ...heterogeneity of ICC makes it difficult to draw firm conclusions about treatment efficacy. Therefore, the goal of the current study is to systematically review the existing literature surrounding treatment of unresectable ICCs with yttrium-90 microspheres and provide a comprehensive review of the current experience and clinical outcome of this treatment modality. We performed a comprehensive search of electronic databases for ICC treatment and identified 12 studies with relevant data regarding radioembolization therapy with yttrium-90 microspheres. Based on pooled analysis, the overall weighted median survival was 15.5 months. Tumour response based on radiological studies demonstrated a partial response in 28% and stable disease in 54% of patients at three months. Seven patients were able to be downstaged to surgical resection. The complication profile of radioembolization is similar to that of other intra-arterial treatment modalities. Overall survival of patients with ICC after treatment with yttrium-90 microspheres is higher than historical survival rates and shows similar survival to those patients treated with systemic chemotherapy and/or trans-arterial chemoembolization therapy. Therefore, the use of yttrium-90 microspheres should be considered in the list of available treatment options for ICC. However, future randomized trials comparing systemic chemotherapy, TACE and local radiation will be required to identify the optimal treatment modality for unresectable ICC.
Registry data on patients with type 1 diabetes mellitus who undergo pancreatic islet transplantation indicate that only 8 percent are free of the need for insulin therapy at one year.
Seven ...consecutive patients with type 1 diabetes and a history of severe hypoglycemia and metabolic instability underwent islet transplantation in conjunction with a glucocorticoid-free immunosuppressive regimen consisting of sirolimus, tacrolimus, and daclizumab. Islets were isolated by ductal perfusion with cold, purified collagenase, digested and purified in xenoprotein-free medium, and transplanted immediately by means of a percutaneous transhepatic portal embolization.
All seven patients quickly attained sustained insulin independence after transplantation of a mean (+/-SD) islet mass of 11,547+/-1604 islet equivalents per kilogram of body weight (median follow-up, 11.9 months; range, 4.4 to 14.9). All recipients required islets from two donor pancreases, and one required a third transplant from two donors to achieve sustained insulin independence. The mean glycosylated hemoglobin values were normal after transplantation in all recipients. The mean amplitude of glycemic excursions (a measure of fluctuations in blood glucose concentrations) was significantly decreased after the attainment of insulin independence (from 198+/-32 mg per deciliter 11.1+/-1.8 mmol per liter before transplantation to 119+/-37 mg per deciliter 6.7+/-2.1 mmol per liter after the first transplantation and 51+/-30 mg per deciliter 2.8+/-1.7 mmol per liter after the attainment of insulin independence; P<0.001). There were no further episodes of hypoglycemic coma. Complications were minor, and there were no significant increases in lipid concentrations during follow-up.
Our observations in patients with type 1 diabetes indicate that islet transplantation can result in insulin independence with excellent metabolic control when glucocorticoid-free immunosuppression is combined with the infusion of an adequate islet mass.
Human Leukocyte Antigen (HLA) antibodies posttransplant have been associated with an increased risk of early graft failure in kidney transplants. Whether this also applies to islet transplantation is ...not clear. To achieve insulin independence after islet transplants multiple donor infusions may be required. Hence, islet transplant recipients are at risk of sensitization after transplantation. Islet transplant recipients were screened for HLA antibodies posttransplant by flow‐based methods. A total of 98 patients were studied. Twenty‐nine patients (31%) developed de novo donor specific antibodies (DSA) posttransplant. Twenty‐three patients developed DSA while on immunosuppression (IS). Among recipients who have discontinued IS, 10/14 (71%) are broadly sensitized with panel reactive antibody (PRA) ≥50%. The risk of becoming broadly sensitized after transplant was 11/69 (16%) if the recipient was unsensitized prior to transplant. The majority of these antibodies have persisted over time. Appearance of HLA antibodies posttransplant is concerning, and the incidence rises abruptly in subjects weaned completely from IS. This may negatively impact the ability of these individuals to undergo further islet, pancreas or kidney transplantation and should be discussed upfront during evaluation of candidates for islet transplantation.
Recipients of islet transplants become highly sensitized after graft loss and withdrawal of immunosuppression. Also see editorial by Bromberg et al in this issue on page 2217.
Islet transplantation is being offered increasingly for selected patients with unstable type 1 diabetes. Percutaneous transhepatic portal access avoids a need for surgery, but is associated with ...potential risk of bleeding. Between 1999 and 2005, we performed 132 percutaneous transhepatic islet transplants in 67 patients. We encountered bleeding in 18/132 cases (13.6%). In univariate analysis, the risk of bleeding in the absence of effective track ablation was associated with an increasing number of procedures (2nd and 3rd procedures with an odds ratio (OR) of 9.5 and 20.9, respectively), platelets count <150 000 (OR 4.4), elevated portal pressure (OR 1.1 per mm Hg rise), heparin dose ≥45 U/kg (OR 9.8) and pre‐transplant aspirin (81 mg per day) (OR 2.6, p = 0.05). A multivariate analysis further confirmed the cumulative transplant procedure number (p < 0.001) and heparin dose ≥45 U/kg (p = 0.02) as independent risk factors for bleeding. Effective mechanical sealing of the intrahepatic portal catheter tract with thrombostatic coils and tissue fibrin glue completely prevented bleeding in all subsequent procedures (n = 26, p = 0.02). We conclude that bleeding after percutaneous islet implantation is an avoidable complication provided the intraparenchymal liver tract is sealed effectively.
Abstract Safe and effective xenotransplantation would provide a valuable answer to many of the limitations of allogenic transplantation. Such limitations include scarcity of organ supply and ...morbidity to donors in cases of living-related donor transplantation. The main hurdle to the efficacious application of xenotransplantation in clinical medicine is the fierce host immune response to xenografts. This immune response is embodied in 3 different types of xenograft rejection. Both hyperacute rejection and delayed xenograft rejection are mediated by natural antibodies and are concerned primarily with whole organ rejection. Cellular xenograft rejection (CXR), on the other hand, is concerned with both whole organ and CXR and is mediated by innate immunity rather than natural antibodies. Macrophages, which are cells of the innate immune system, play a role in all 3 types of xenograft rejection (not just CXR). They impart their effects both directly and through T-cell activation.
•Acinar cell carcinoma originating in the liver proper remains a diagnostic quandary.•Non-specific imaging features may have led to prior misdiagnosis and poor outcomes.•Ultrastructural electron ...microscopy represents a novel tool for identification.•Heterotopia or metaplastic mechanisms may underlie hepatic acinar cell localization.•The previous literature is summarized in context of the present case of hepatic ACC.
A primary acinar cell carcinoma (ACC) of the liver was incidentally diagnosed in a clinically asymptomatic 80-year-old man. This study aimed to delineate critical diagnostic characteristics of an ACC originating uniquely from the liver to improve its future identification.
Enhanced MRI revealed a heterogenous, cystic 7.7 × 11.1 × 10.4 cm tumour occupying hepatic segments II and III. The mass demonstrated mild diffuse enhancement in hepatic arterial phase with minimal portal venous washout in a liver without cirrhotic features. A central stellate T2-hyperintense necrotic scar and outer capsule were apparent. No primary lesion or metastasis outside the liver was discernable. Post-left hepatic lobectomy, the tumour immunophenotype was atypical for presumptive diagnoses of hepatocellular carcinoma (HCC) or cholangiocarcinoma. Extensive morphologic workup on electron microscopy definitively diagnosed primary hepatic ACC by establishing presence of secretory zymogen-like granules, intracytoplasmic microvilli and acinar cell differentiation. Cytopathology revealed cellular lumen expressing PAS-positive diastase-resistant granular cytoplasmic contents.
This case showcased the novel utility of electron microscopy that was crucial in yielding the definitive diagnosis. The previous literature on hepatic ACC was compiled here in context of the present case. The mechanism of hepatic acinar cell localization was also discussed.
Primary hepatic ACC may easily be confused for other lesions due to nonspecific imaging patterns. Specifically, the presence of a central scar without risk factors for HCC can favour a diagnosis of benign entities such as focal nodular hyperplasia (FNH). Electron microscopy presents an important tool to identify primary hepatic ACC and may improve future patient outcomes.
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