Outcomes after liver transplantation using deceased after circulatory death donors: A comparison of outcomes in the UK and the US.

BACKGROUND AND AIMS: Identifying international differences in utilization and outcomes of liver transplantation (LT) after donation after circulatory death (DCD) donation provides a unique opportunity for benchmarking and population-level insight. METHODS: Adult (≥18 years) LT data between 2008 and 2018 from the UK and US were used to assess mortality and graft failure after DCD LT. We used time-dependent Cox-regression methods to estimate hazard ratios (HR) for risk-adjusted short-term (0-90 days) and longer-term (90 days-5 years) outcomes. RESULTS: One-thousand five-hundred-and-sixty LT receipts from the UK and 3426 from the US were included. Over the study period, the use of DCD livers increased from 15.7% to 23.9% in the UK compared to 5.1% to 7.6% in the US. In the UK, DCD donors were older (UK:51 vs. US:33 years) with longer cold ischaemia time (UK: 437 vs. US: 333 min). Recipients in the US had higher Model for End-stage Liver Disease (MELD) scores, higher body mass index, higher proportions of ascites, encephalopathy, diabetes and previous abdominal surgeries. No difference in the risk-adjusted short-term mortality or graft failure was observed between the countries. In the longer-term (90 days-5 years), the UK had lower mortality and graft failure (adj.mortality HR:UK: 0.63 (95% CI: 0.49-0.80); graft failure HR: UK: 0.72, 95% CI: 0.58-0.91). The cumulative incidence of retransplantation was higher in the UK (5 years: UK: 11.9% vs. 4.6%; p < .001). CONCLUSIONS: For those receiving a DCD LT, longer-term post-transplant outcomes in the UK are superior to the US, however, significant differences in recipient illness, graft quality and access to retransplantation were seen between the two countries.

Disparities in the Use of Older Donation After Circulatory Death Liver Allografts in the United States Versus the United Kingdom.

BACKGROUND: This study aimed to assess the differences between the United States and the United Kingdom in the characteristics and posttransplant survival of patients who received donation after circulatory death (DCD) liver allografts from donors aged >60 y. METHODS: Data were collected from the UK Transplant Registry and the United Network for Organ Sharing databases. Cohorts were dichotomized into donor age subgroups (donor >60 y [D >60]; donor ≤60 y [D ≤60]). Study period: January 1, 2001, to December 31, 2015. RESULTS: 1157 DCD LTs were performed in the United Kingdom versus 3394 in the United States. Only 13.8% of US DCD donors were aged >50 y, contrary to 44.3% in the United Kingdom. D >60 were 22.6% in the United Kingdom versus 2.4% in the United States. In the United Kingdom, 64.2% of D >60 clustered in 2 metropolitan centers. In the United States, there was marked inter-regional variation. A total of 78.3% of the US DCD allografts were used locally. One- and 5-y unadjusted DCD graft survival was higher in the United Kingdom versus the United States (87.3% versus 81.4%, and 78.0% versus 71.3%, respectively; P < 0.001). One- and 5-y D >60 graft survival was higher in the United Kingdom (87.3% versus 68.1%, and 77.9% versus 51.4%, United Kingdom versus United States, respectively; P < 0.001). In both groups, grafts from donors ≤30 y had the best survival. Survival was similar for donors aged 41 to 50 versus 51 to 60 in both cohorts. CONCLUSIONS: Compared with the United Kingdom, older DCD LT utilization remained low in the United States, with worse D >60 survival. Nonetheless, present data indicate similar survivals for older donors aged ≤60, supporting an extension to the current US DCD age cutoff.

Extracellular Vesicle-Mediated Mitochondrial Reprogramming in Cancer.

Altered metabolism is a defining hallmark of cancer. Metabolic adaptations are often linked to a reprogramming of the mitochondria due to the importance of these organelles in energy production and biosynthesis. Cancer cells present heterogeneous metabolic phenotypes that can be modulated by signals originating from the tumor microenvironment. Extracellular vesicles (EVs) are recognized as key players in intercellular communications and mediate many of the hallmarks of cancer via the delivery of their diverse biological cargo molecules. Firstly, this review introduces the most characteristic changes that the EV-biogenesis machinery and mitochondria undergo in the context of cancer. Then, it focuses on the EV-driven processes which alter mitochondrial structure, composition, and function to provide a survival advantage to cancer cells in the context of the hallmarks of cancers, such as altered metabolic strategies, migration and invasiveness, immune surveillance escape, and evasion of apoptosis. Finally, it explores the as yet untapped potential of targeting mitochondria using EVs as delivery vectors as a promising cancer therapeutic strategy.

Liver transplantation for HCC: validation of prognostic power of the RETREAT score for recurrence in a UK cohort.

BACKGROUND: The Risk Estimation of Tumor Recurrence After Transplant (RETREAT) score as a prognostic index for recurrence has been reported previously and has not been validated outside the USA. Our study has validated the score in a single center UK cohort of patients being transplanted for HCC. METHODS: LT for HCC between 2008 and 2018 at our center were analyzed. Recurrence-free survival (RFS) was compared by the RETREAT score and validated using Net Reclassification Improvement (NRI) by comparing it to Milan criteria. RESULTS: 346 adult HCC patients were transplanted of whom 313 were included. 28 (8.9%) had a recurrence. Summation of largest diameter and total number of viable tumors (HR = 1.19, p < 0.001), micro-/macro-vascular invasion (HR = 3.74, p = 0.002) and AFP>20 ng/ml (HR = 3.03, p = 0.005) were associated with recurrence on multivariate analysis. RFS decreased with increasing RETREAT score (log-rank p = 0.016). RETREAT performed better than Milan with significant NRI at 1- and 2-years post-transplant (0.43 (p = 0.004) and 0.38 (p = 0.03) respectively). CONCLUSION: LT outcomes using the revised UK criteria are equivalent to Milan criteria. Further, RETREAT score was validated as a prognostic index for the first time in a UK cohort and may assist risk stratification, selection for adjuvant therapies and guide surveillance.

Comparable graft survival is achievable with the usage of donation after circulatory death liver grafts from donors at or above 70 years of age: A long-term UK national analysis.

The aim of the study was to assess the UK donation after circulatory death (DCD) liver transplant experience from donors ≥70 years. Nationwide UK DCD retrospective analysis was conducted between 2001 and 2015 (n = 1163). Recipients were divided into group 1 vs. group 2 (donors 70≥ vs. <70 years, respectively). group 1 (n = 69, 5.9%) recipients were older (median 59 vs. 55 years, p = .001) and had longer waitlist time (128 vs. 84 days; p = .039). 94.2% of group 1 clustered in London and Birmingham, where the two busiest centers are located. group 1 allografts had higher UKDRI and UK DCD Risk Scores but similar WIT and CIT and were more likely to have been imported. Both groups had similar 1-, 3-, and 5-year graft survival (group 1, 90%, 81.4%, and 74% vs. group 2, 88.6%, 81.4%, and 78.6%, respectively; p = .54). Both groups had similar ICU stay length (p = .22), 3-month hepatic artery thrombosis rates (4.4% vs 4.0%; p = .9), and 12-month readmission rates for all biliary complications (20.3% vs 25.7%; p = .32). This study demonstrates that acceptable outcomes are achievable using older grafts in a highly selected cohort at experienced centers. Advanced age should not be an absolute contraindication to utilizing a DCD graft from donors aged ≥70 years.

A unique type of fully covered metal stent for the management of post liver transplant biliary anastomotic strictures.

BACKGROUND: We report our experience of treating anastomotic strictures using a novel type of fully covered metal stent (FCSEMS). This stent, known as the Kaffes Stent, is short-length with an antimigration waist and is easily removable due to long retrieval wires deployed within the duodenum. METHODS: Sixty-two patients underwent ERCP and Kaffes stent insertion for post-transplant anastomotic strictures following confirmation of a stricture on MRCP. These patients were retrospectively analysed for immediate and long-term stricture resolution, improvement in symptoms and liver function tests (LFTs), stricture recurrence and complication rates. RESULTS: Of the 56 patients who had their stent removed at the time of analysis, 54 (96%) had immediate stricture resolution and 42 continued to have long-term resolution (mean follow-up period was 548 days). Of the 16 patients with symptoms of biliary obstruction, 13 had resolution of their symptoms. Overall, there was a significant improvement in LFTs after stent removal compared to before stent insertion. Complication rates were 15% with only one patient requiring biliary reconstruction. CONCLUSIONS: The Kaffes stent is effective and safe at resolving post liver transplant biliary anastomotic strictures.

Interaction between tacrolimus, MELD score and acute kidney injury after liver transplantation. Analysis on a large contemporary bicenter meld-era series.

BACKGROUND: Acute kidney injury (AKI) after liver transplantation (LT) is a common problem with complex management. The aims were to analyze the profile of AKI-RIFLE categories in the post-transplant setting of a wide multicentre cohort of patients in the MELD era and to specifically determine the effect of tacrolimus-based (TACRO) immunosuppressive regimes on the development of AKI. METHODS: A retrospective analysis of 550 (2007-2012) consecutive patients transplanted at Reina Sofia, Cordoba, and King's College Hospital, London, was performed. Inclusion criterion was to have CNI as part of initial immunosuppression immediately after LT. RESULTS: After exclusion criteria, a total of 477 patients were analyzed. Incidence of AKI within the first 2 weeks after LT was 65.8% (AKI-Risk), 41.3% (AKI-Injury), and 12.3% (AKI-Failure). The development of any type of AKI had no impact on short- and/or long-term survival up to 3 years after the transplant. Moreover, AKI was almost universal in the early post-transplant period and TACRO trough concentrations during the first 2 weeks after the transplant were not predictors of AKI in none of its categories in the multivariate analyses. CONCLUSIONS: Low-TACRO-based regimes were not as useful as expected in the prevention of AKI when analyzed in the context of a large contemporary LT series.

Effects of thyroid hormone on mitochondria and metabolism of human preimplantation embryos.

Thyroid hormones are regarded as the major controllers of metabolic rate and oxygen consumption in mammals. Although it has been demonstrated that thyroid hormone supplementation improves bovine embryo development in vitro, the cellular mechanisms underlying these effects are so far unknown. In this study, we investigated the role of thyroid hormone in development of human preimplantation embryos. Embryos were cultured in the presence or absence of 10-7 M triiodothyronine (T3) till blastocyst stage. Inner cell mass (ICM) and trophectoderm (TE) were separated mechanically and subjected to RNAseq or quantification of mitochondrial DNA copy number. Analyses were performed using DESeq (v1.16.0 on R v3.1.3), MeV4.9 and MitoMiner 4.0v2018 JUN platforms. We found that the exposure of human preimplantation embryos to T3 had a profound impact on nuclear gene transcription only in the cells of ICM (1178 regulated genes-10.5% of 11 196 expressed genes) and almost no effect on cells of TE (38 regulated genes-0.3% of expressed genes). The analyses suggest that T3 induces in ICM a shift in ribosome and oxidative phosphorylation activity, as the upregulated genes are contributing to the composition and organization of the respiratory chain and associated cofactors involved in mitoribosome assembly and stability. Furthermore, a number of genes affecting the citric acid cycle energy production have reduced expression. Our findings might explain why thyroid disorders in women have been associated with reduced fertility and adverse pregnancy outcome. Our data also raise a possibility that supplementation of culture media with T3 may improve outcomes for women undergoing in vitro fertilization.

Modern Outcomes Following Treatment of Hepatocellular Carcinoma in Hereditary Hemochromatosis: A Matched Cohort Study.

OBJECTIVE: Hepatocellular carcinoma (HCC) is a complication of the common genetic condition hereditary hemochromatosis (HH). It is unknown whether HH as an etiology of liver disease impacts the outcome. We compared the results of liver transplantation (LT), surgical resection and locoregional therapies in a matched cohort study and investigated whether HH as an etiology has an impact on survival. MATERIALS AND METHODS: Consecutive patients with HH and HCC (2000 to 2015) were compared with age, sex and Barcelona Clinic Liver Cancer (BCLC) stage-matched non-HH HCC cases. Patients were offered curative or noncurative treatment according to BCLC stage and Milan criteria. The primary endpoint was all-cause mortality. RESULTS: A total of 102 patients (52 HH; total cohort median age: 67 [44 to 78] y, 97% male, Model for End-stage Liver Disease: 9 [5 to 31]) were studied with a median follow-up of 22 (3 to 126) months. Of the HH cases, the median serum ferritin at diagnosis of HCC was 326 (27 to 5718) µg/L and α-fetoprotein 33 (2 to 197,926) kIU/L. Five-year survival for HH patients receiving curative therapy was 77% (80% for LT, 67% for resection/radiofrequency ablation), and 15% (23% for transarterial chemoembolization) for those undergoing noncurative therapy. Survival for HH patients compared with controls was similar (hazard ratio=0.949; P=0.839). On multivariate Cox regression survival analysis, BCLC stage, and diagnosis of ischemic heart disease (but not HH diagnosis) were independently associated with reduced survival. CONCLUSIONS: Patients with HCC and HH can achieve comparable survival rates following curative or LRT modalities to other liver diseases. The BCLC staging system accurately stratifies survival and excellent 5-year survival is possible following LT in selected patients.

Outcomes of Liver Transplantation in Small Infants.

Liver transplantation (LT) for small infants remains challenging because of the demands related to graft selection, surgical technique, and perioperative management. The aim of this study was to evaluate the short-term and longterm outcomes of LT regarding vascular/biliary complications, renal function, growth, and patient/graft survival in infants ≤3 months compared with those of an age between >3 and 6 months at a single transplant center. A total of 64 infants ≤6 months underwent LT and were divided into 2 groups according to age at LT: those of age ≤3 months (range, 6-118 days; XS group, n = 37) and those of age >3 to ≤6 months (range, 124-179 days; S group, n = 27) between 1989 and 2014. Acute liver failure was the main indication for LT in the XS group (n = 31, 84%) versus S (n = 7, 26%). The overall incidence of hepatic artery thrombosis and portal vein thrombosis/stricture were 5.4% and 10.8% in the XS group and 7.4% and 11.1% in the S group, respectively (not significant). The overall incidence of biliary stricture and leakage were 5.4% and 2.7% in the XS group and 3.7% and 3.7% in the S group, respectively (not significant). There was no significant difference between the 2 groups in terms of renal function. No significant difference was found between the 2 groups for each year after LT in terms of height and weight z score. The 1-, 5-, and 10-year patient survival rates were 70.3%, 70.3%, and 70.3% in the XS group compared with 92.6%, 88.9%, and 88.9% in the S group, respectively (not significant). In conclusion, LT for smaller infants has acceptable outcomes despite the challenges of surgical technique, including vascular reconstruction and graft preparation, and perioperative management.

Cryopreserved neonatal hepatocytes may be a source for transplantation: Evaluation of functionality toward clinical use.

Neonatal livers are a potential source of good-quality hepatocytes for clinical transplantation. We compared viability and function of neonatal hepatocytes (NHs) and adult hepatocytes (AHs) and report their clinical use both intraportally and in alginate microbeads. Following isolation from donor livers, hepatocyte function was assessed using albumin, alpha-1-antitrypsin, and factor VII. Metabolic function was investigated by measuring resorufin conjugation, ammonia metabolism, uridine diphosphate glucuronosyltransferase enzyme activity, and cytochrome P450 (CYP) function following induction. Activation of the instant blood-mediated inflammatory reaction by NHs and AHs was investigated using an in vitro blood perfusion model, and tissue factor expression was analyzed using real-time polymerase chain reaction (RT-PCR). Clinical hepatocyte transplantation (HT) was undertaken using standard protocols. Hepatocytes were isolated from 14 neonatal livers, with an average viability of 89.4% ± 1.8% (mean ± standard error of the mean) and average yield of 9.3 × 106 ± 2.0 × 106 cells/g. Hepatocytes were isolated from 14 adult livers with an average viability of 78.6% ± 2.4% and yield 2.2 × 106 ± 0.5 × 105 cells/g. NHs had significantly higher viability after cryopreservation than AHs, with better attachment efficiency and less plasma membrane leakage. There were no differences in albumin, alpha-1-antitrypsin, and factor VII synthesis between NHs and AHs (P > 0.05). Neonatal cells had inducible phase 1 enzymes as assessed by CYP function and functional phase 2 enzymes, in which activity was comparable to AHs. In an in vitro blood perfusion model, AHs elicited increased thrombus formation with a greater consumption of platelets and white cells compared with NHs (28.3 × 109 versus 118.7 × 109 and 3.3 × 109 versus 6.6 × 109 ; P < 0.01). Intraportal transplantation and intraperitoneal transplantation of alginate encapsulated hepatocytes was safe, and preliminary data suggest the cells may activate the immune response to a lesser degree than adult cells. In conclusion, we have shown NHs have excellent cell viability, function, and drug metabolism making them a suitable alternative source for clinical HT. Liver Transplantation 24 394-406 2018 AASLD.

Massive ascites and the heterozygous alpha 1 antitrypsin (α1 AT) living related donor liver in the homozygous child.

The following is a short report on the use of a heterozygous (PiMZ) alpha 1 antitrypsin (α1AT) living related donor liver in a homozygous (PiZ) child that was complicated by massive ascites early after transplant. This clinical report is then followed by a brief summary of present knowledge on the α1 AT protein and management of massive ascites in the pediatric liver transplant recipient.

Predictors of early graft survival after pediatric liver transplantation.

The objective of this study was to identify peritransplant predictors of early graft survival and posttransplant parameters that could be used to predict early graft outcomes after pediatric liver transplantation (PLT). The response of children to liver dysfunction after liver transplantation (LT) is poor. No data have been reported for early predictors of poor graft survival, which would potentially be valuable for rescuing children at risk after LT. A retrospective cohort study of 422 PLT procedures performed from 2000 to 2010 at a single center was conducted. Multiple peritransplant variables were analyzed. Univariate and multivariate analyses using receiver operating characteristic curves were performed to identify predictors of early graft loss (ie, at 30, 60, and 90 days). The number needed to treat (NNT) was calculated when the risk factors were identified. Comparisons with the Olthoff criteria for early graft dysfunction in adults were performed. The overall 30-, 60-, and 90-day graft survival rates were 93.6%, 92.6%, and 90.7%, respectively. A recipient age of 0 to 2 or 6 to 16 years, acute liver failure, and a posttransplant day 7 serum bilirubin level > 200 µmol/L were risk factors for graft loss in the 3-strata Cox models. The product of the peak aspartate aminotransferase (AST) level, day 2 international normalized ratio (INR) value, and day 7 bilirubin level [with 30-, 60-, and 90-day areas under the receiver operating characteristic curve (AUROCs) of 0.774, 0.752, and 0.715, respectively] and a day 7 bilirubin level > 200 µmol/L (with 30-, 60-, and 90-day AUROCs of 0.754, 0.661, and 0.635, respectively) provided excellent prediction rates for early graft loss (30-days for Day-7-bilirubin level > 200) in the pediatric population (sensitivity = 72.7%, specificity = 96.6%, positive predictive value = 95.5%, negative predictive value = 78%). The NNT with early retransplantation when the day 7 bilirubin level was >200 µmol/L was 2.17 (unadjusted) or 2.76 (adjusted for graft survival). In conclusion, 2 scores-the product of the peak AST level, day 2 INR value, and day 7 bilirubin level and a posttransplant day 7 bilirubin level > 200 µmol/L-have been identified as clinically valuable tools with high accuracy for predicting early graft loss. A more aggressive attitude to considering early retransplantation in this group may further improve survival after LT.

Cholangiocarcinoma complicating recurrent primary sclerosing cholangitis after liver transplantation.

De novo cholangiocarcinoma associated with recurrent primary sclerosing cholangitis in the transplanted liver is rare. This case report reviews the literature and highlights the need to consider cholangiocarcinoma in transplanted patients with PSC that clinically/biochemically deteriorate.

Pilot study for a new bipolar radiofrequency ablation/aspirator device in the management of primary and secondary liver cancers.

BACKGROUND: In the US, the thermal ablation workload for cancer involving the liver is predicted to more than double in the next 5 years, emphasising the need to develop and improve the current technology. STUDY DESIGN: A multicentre nonrandomised prospective clinical trial (NCT00514930) was undertaken, to assess the efficacy and safety of a new bipolar radiofrequency ablation/aspirator device, in the treatment of primary and secondary cancers of the liver. RESULTS: A total of 34 lesions in 16 patients were ablated at laparotomy and followed up at 4 weeks. The mean diameter of lesion before ablation was 3.2+/-2.22 (range 1-10) cm, the mean volume aspirated during ablation was 9.25+/-7.3 (range 0-25) ml and the mean operative time was 145.95+/-40.7 (range 60-215) min. There was one major complication of a pleural effusion, which required drainage. The mean length of stay was 8+/-3.2 (range 3-14) days. In 11 patients, the ablated tumour was resected. On histological assessment, there was no evidence of viable cancer at the tumour edge. On follow-up computed tomography, the ablation zone fully encompassed the targeted tumour and there were no local complications related to ablation. CONCLUSION: Initial analysis of the data from this small cohort, with only a short-term follow-up, shows this device to be safe and effective.

Endoscopic radiofrequency ablation in colorectal cancer: initial clinical results of a new bipolar radiofrequency ablation device.

PURPOSE: There are a number of alternative approaches to palliate cancers of the rectosigmoid, which may not be well tolerated or produce effective symptom relief. Therefore, there is a continuing need to develop alternative techniques for palliation. This paper reports our initial assessment of a new bipolar radiofrequency probe (Endoblate). METHODS: Twelve patients with rectosigmoid tumors were treated with Endoblate during transanal endoscopic microsurgery. In ten patients, this was followed by surgical resection and two patients were treated with Endoblate alone. This study was designed to assess the technical utility of the device, immediate complications, and histologic effect. RESULTS: There were no technical problems. In the patients who had resection of the tumor immediately after ablation (n = 10), there were no local complications evident at surgery. Histology of the resected specimens showed that, on average, 82 (range, 60-99) percent of the tumor mass was destroyed in the ablation zone. In the remaining two patients, Endoblate alone was used successfully to stop bleeding from the tumor. CONCLUSIONS: These preliminary results illustrate the evolution and endoscopic application of bipolar radiofrequency technology. Endoblate showed potential as a useful and safe tool for the palliation of lower gastrointestinal malignancy.

Management of delayed postoperative hemorrhage after pancreaticoduodenectomy: a meta-analysis.

OBJECTIVE: To determine whether interventional radiology (IR) or laparotomy (LAP) is the best management of delayed postoperative hemorrhage (DPH) after pancreaticoduodenectomy. Data Source We undertook an electronic search of MEDLINE and selected for analysis only original articles published between January 1, 1990, and December 31, 2007. STUDY SELECTION: Two of us independently selected studies reporting on clinical presentation and incidence of postoperative DPH and the following outcomes: complete hemostasis, morbidity, and mortality. DATA EXTRACTION: Two of us independently performed data extraction. Data were entered and analyzed by means of dedicated software from The Cochrane Collaboration. A random-effects meta-analytical technique was used for analysis. DATA SYNTHESIS: One hundred sixty-three cases of DPH after pancreaticoduodenectomy were identified from the literature. The incidence of DPH after pancreaticoduodenectomy was 3.9%. Seventy-seven patients (47.2%) underwent LAP; 73 (44.8%), IR; and 13 (8%), conservative treatment. On meta-analysis comparing LAP vs IR for DPH, no significant difference was found between the 2 treatment options for complete hemostasis (73% vs 76%; P = .23), mortality (43% vs 20%; P = .14), or morbidity (77% vs 35%; P = .06). CONCLUSIONS: This meta-analysis, although based on data from small case series, is unable to demonstrate any significant difference between LAP and IR in the management of DPH after pancreaticoduodenectomy. The management of this life-threatening complication is difficult, and the appropriate treatment pathway ultimately will be decided by the clinical status of the patient and the institution preference.