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Background: Pioneered by the Mayo Clinic, multimodal therapy with neoadjuvant chemoradiotherapy and orthotopic liver transplant has emerged as a promising option for unresectable hilar cholangiocarcinoma (hCCA). This study reports the experience of the Irish National Liver Transplant Programme with the Mayo Protocol., Methods: All patients diagnosed with unresectable hCCA between 2004 and 2016, who were eligible for the treatment protocol, were prospectively studied., Results: Thirty-seven patients commenced chemoradiotherapy. Of those, 11 were excluded due to disease progression and 26 proceeded to liver transplantation. There were 24 males, the median age was 49, and 88% had underlying primary sclerosing cholangitis. R0 and pathologic complete response rates were 96% and 62%, respectively. Overall median survival was 53 months and 1-, 3-, and 5-year survival was 81%, 69%, and 55%, respectively. The median survival of patients achieving a pathologic complete response was 83.8 months compared with 20.9 months in the group with residual disease (P = 0.036). Six patients (23%) developed disease recurrence. Among the patients who developed metastatic disease during neoadjuvant treatment, median survival was 10.5 months compared with 53 months in patients who proceeded to transplant (P < 0.001)., Conclusions: Neoadjuvant chemoradiotherapy followed by liver transplantation substantially increases the survival of patients with unresectable hCCA. Achieving a pathologic complete response confers a significant survival benefit.

The adult human liver hosts a complex repertoire of liver resident and transient natural killer (NK) cell populations with diverse phenotypes and functions. Liver resident NK cells are CD56 bright NK cells defined by a unique expression profile of transcription factors and cell surface markers (Eomes hi Tbet lo TIGIT + CD69 + CXCR6 + CD49e - ). Despite extensive characterization of the phenotype of liver resident NK cells, it remains unclear how factors within the liver microenvironment induce and maintain this unique phenotype. In this study, we have explored the factors regulating the phenotype of liver resident NK cells. Isolation of healthy liver resident NK cells from donor liver perfusate and in vitro culture results in the gradual loss of the characteristic Tbet lo phenotype, with the cells increasing Tbet expression significantly at day 7. This phenotypic loss could be halted through the dose-dependent addition of liver conditioned media (LCM), generated from the ex vivo culture of liver biopsies from healthy organ donors. TGF-β, but not IL-10, replicated the Tbet suppressive effects of LCM in both liver resident and peripheral blood NK cells. Furthermore, blocking TGF-β receptor signaling using the inhibitor SB431542, reversed the effect of LCM treatment on liver resident NK cells, causing the loss of tissue resident Eomes hi Tbet lo phenotype. Our findings identify liver-derived TGF-β as an important component of the liver microenvironment, which acts to regulate and maintain the phenotype of liver resident NK cells.

Purpose: We aimed to compare the overall (OS) and disease-free survival (DFS) of patients undergoing orthotopic liver transplant (OLT) for hepatocellular carcinoma who did and did not have neoadjuvant doxorubicin drug-eluting bead transarterial chemoembolization (DEB-TACE)., Methods: This is a retrospective study of 94 patients with HCC transplanted between 2000 and 2014 in a single tertiary center. Pre- and postoperative features, DFS and OS were compared between patients who received pre-OLT DEB-TACE (n=34, DEB-TACE group) and those who did not (n=60, non-TACE group). Radiologic and histologic response to neoadjuvant treatment as well as its complications were also studied., Results: There were no significant differences in post-transplantation DFS and OS rates between groups (5-year DFS: 70% in DEB-TACE group vs. 63% in non-TACE group, P = 0.454; 5-year OS: 70% in DEB-TACE group vs. 65% in non-TACE group, P = 0.532). The DEB-TACE group had longer OLT waiting time compared with the non-TACE group (110 vs. 72 days; P = 0.01). On univariate and multivariate analyses, alpha-fetoprotein (AFP) levels >500 ng/mL prior to OLT were associated with decreased OS and DFS regardless of neoadjuvant approach (hazard ratio of 6, P = 0.001 and 5.5, P = 0.002, respectively)., Conclusion: Patients who underwent neoadjuvant DEB-TACE and OLT for hepatocellular carcinoma had no statistically different OS or DFS at 3 and 5 years from patients undergoing OLT alone.

Background: Unresectable cholangiocarcinoma (CCA) has a dismal prognosis. Initial studies of orthotopic liver transplantation (OLT) alone for CCA yielded disappointing outcomes. The Mayo Clinic demonstrated long-term survival using neoadjuvant chemoradiotherapy followed by OLT in selected patients with unresectable CCA. This study reports the Irish National Liver Transplant Programme experience of neoadjuvant therapy and OLT for unresectable CCA., Materials and Methods: Twenty-seven patients with CCA were selected for neoadjuvant chemoradiotherapy in a single centre from October 2004 to September 2011. Patients were given brachytherapy, external beam radiotherapy and 5-fluorouracil (5-Fu), followed by liver transplantation if progression free (20 patients)., Results: Twenty progression-free patients after neoadjuvant therapy underwent OLT. Hospital mortality was 20%. Of the 16 patients who left hospital, survival rates were 94% and 61% at 1 and 4 years. Seven patients developed recurrent disease and died at intervals of 10-58 months after OLT, whereas 9 are disease free with a median follow-up of 37 months (18-76). Predictors of disease recurrence were a tumour in explant specimen and high CA 19.9 levels., Discussion: In selected patients with unresectable CCA, long-term survival can be achieved using neoadjuvant chemoradiotherapy and OLT although short-term mortality is high. Prospective international registries may aid patient selection and refinement of neoadjuvant regimens., (© 2013 International Hepato-Pancreato-Biliary Association.)

Background: Altered nitric oxide (NO) metabolism has been shown to contribute to ischemia-reperfusion (IR) injury in animal models. However, similar studies have not been performed in human liver transplantation (LT). In this study, we examined nitrate, nitrite, and nitrosothiols (NOx), NO synthases (endothelial [constitutive] nitric oxide synthase [eNOS] and inducible nitric oxide synthase [iNOS]), and nitrotyrosine in early IR injury after human LT., Methods: Paired biopsies were obtained from nine donor livers before cold ischemia (retrieval biopsy) and after reimplantation (reperfusion biopsy). Sections were graded for reperfusion injury using the Suzuki score. NO was detected by chemiluminescence after reduction of NOx. Expression of eNOS and iNOS was by Western blot and reverse transcriptase polymerase chain reaction and peroxynitrite by immunodetection of 3-nitrotyrosine., Results: Reperfusion biopsies showed histologic evidence of injury (median Suzuki score: retrieval 2, reperfusion 6, P=0.008) and neutrophil infiltration. NOx was reduced after reperfusion from 5.41 microM/100 mg (median, range 2.17-13.39 microM) to 3.51 microM (1.45-5.66 microM, P=0.05). eNOS protein was reduced after reperfusion from 0.6 units (median, range 0.45-1 unit) in retrieval biopsies to 0.39 units in reperfusion biopsies (range 0.2-0.79 units, P=0.007). There was no change in eNOS or iNOS mRNA expression or iNOS protein. Western blotting showed increased nitrotyrosine formation after reperfusion, median 0.42 (range 0.16-0.87) units in retrieval biopsies and 0.68 (0.29-1.06) units in reperfusion samples (P=0.007) and localized to periportal regions., Conclusions: iNOS protein may not contribute to early reperfusion injury during human LT. However, reduced NO bioavailability caused by reduced eNOS may contribute significantly to damage at this time point.

Background Involvement of the inferior vena cava (IVC) by neoplasm has traditionally been considered a contra-indication to curative surgery because of high surgical risks and poor long-term prognosis. Advances in surgical and anaesthetic techniques however have made this feasible. The aim of this study is to evaluate the outcome of combined IVC and visceral resection in a single institution. Methods A retrospective review of a prospectively maintained database was performed. Pre-operative clinicopathological data, operative details and post-operative outcomes including overall and disease-free survival were analysed. Clinicopathological data of patients over a seven-year period undergoing combined IVC and visceral resection was reviewed, including overall and disease-free survival. Results Between 2006 and 2012, 14 patients underwent IVC resection was accompanied by major hepatectomy (8), nephrectomy (6) and multivisceral resection (3). Post resection, the IVC was reconstructed primarily (3); with PTFE tube graft (9) or using a Gore-tex patch graft (2). All patients underwent a R0 resection. There were two postoperative deaths within 30 days. 6 patients had postoperative complications. There was 1 early and one late (after 6 months) IVC thrombosis. With a median follow up of 20 months (range 5–84 months), two patients died of tumour recurrence and ten are alive with ( n = 5) or without ( n = 5) disease. Conclusion Combined IVC and visceral resection can be safely performed in selected patients. Surgery provides the possibility of negative margins, acceptable perioperative morbidity/mortality and prolonged survival. These factors combined with lack of alternative treatments justify this approach. However, specialist teams should perform the surgery preferably in centres with expertise in liver transplantation. [ABSTRACT FROM AUTHOR]

The liver is the most frequently injured intra-abdominal organ and is the main cause of death in patients with abdominal injuries (mortality 10–15%). Grades III and IV liver injuries may present a complex problem to the surgeon. Several techniques to prevent exsanguination have been described including perihepatic packing, hepatic artery ligation, liver suturing or resection, and hepatectomy with transplantation. We report a case of a trauma patient who underwent perihepatic packing to control bleeding. Following pack removal, the patient developed severe cardiorespiratory depression resulting from postreperfusion syndrome requiring emergency total hepatectomy and liver transplantation. Types I–III hepatic injuries can safely be treated conservatively. Complex injuries (types IV and V) result in significant mortality, often requiring operative intervention. Indications of transplantion are uncontrollable hemorrhage or irreversible liver dysfunction. Literature reports describe liver transplantation as a second line treatment of complications following initial treatment. Our patient underwent liver transplantation as a second line treatment. The decision to transplant was based on two pathologic findings, ischemic changes of the liver and sudden cardio-respiratory decompensation following restoration of the blood supply to the liver. Both complications are emergencies, leading to death if not recognized and treated instantly. A total hepatectomy with temporary portocaval shunt followed by liver transplantation immediately or at a later stage is a life saving treatment for such cases. [ABSTRACT FROM AUTHOR]

Background & Aims: Extensive populations of liver immune cells detect and respond to homeostatic perturbation caused by damage, infection or malignancy. Dendritic cells (DCs) are central to these activities, governing the balance between tolerance and immunity. Most of our knowledge about human liver DCs is derived from studies on peritumoral tissue. Little is known about the phenotype and function of DCs, in particular the recently described CD141+ subset, in healthy human liver and how this profile is altered in liver disease. Methods: During liver transplantation, healthy donor and diseased explant livers were perfused and hepatic mononuclear cells isolated. Dendritic cell subset frequency and phenotype were characterised in liver perfusates by flow cytometry and the function of CD141+ DCs was evaluated by mixed lymphocyte reactions (MLRs) and measuring cytokine secretion. Results: Almost one third of liver CD11c+ myeloid DCs (mDCs) expressed CD141 compared to <5% of circulating mDCs. Hepatic CD141+ DCs demonstrated pro-inflammatory function in allogeneic MLRs, inducing T cell production of interferon gamma (IFN-γ) and interleukin (IL)-17. While CD123+ plasmacytoid DCs (pDCs) and CD1c+ mDCs were expanded in diseased liver perfusates, CD141+ DCs were significantly depleted. Despite their depletion, CD141+ DCs from explant livers produced markedly increased poly(I:C)-induced IFN lambda (IFN-λ) compared with donor DCs. Conclusions: Accumulation of CD141+ DCs in healthy liver, which are significantly depleted in liver disease, suggests differential involvement of mDC subsets in liver immunity. [Copyright &y& Elsevier]