Cholangiocarcinoma (CC) and hepatocellularcarcinoma (HCC) are two main forms of liver malignancies, which exhibit differences in drug response and prognosis. Immunohistotochemical staining for cytokeratin markers has been used to some success in the differential diagnosis of CC from HCC. However, there remains a need for additional markers for increased sensitivity and specificity of diagnosis. In this study, we have identified a p38 MAP kinase, p38d (also known as MAPK13 or SAPK4) as a protein that is upregulated in CC relative to HCC and to normal biliary tract tissues. We performed microarray gene expression profiling on 17 cases of CC, 12 cases of adjacent normal liver tissue, and three case of normal bile duct tissue. p38d was upregulated in 16 out of 17 cases of CC relative to normal tissue. We subsequently performed immunohistochemical staining of p38d in 54 cases of CC and 54 cases of HCC. p38d staining distinguished CC from HCC with a sensitivity of 92.6% and a specificity of 90.7%. To explore the possible functional significance of p38d expression in CC, we examined the effects of overexpression and knockdown of p38d expression in human CC cell lines. Our results indicate that p38d is important for motility and invasion of CC cells, suggesting that p38d may play an important role in CC metastasis. In summary, p38d may serve as a novel diagnostic marker for CC and may also serve as a new target for molecular based therapy of this disease.

Summary Conventional orthotopic liver transplantation (CON‐LT) involves resection of recipient cava, usually with extra‐corporeal circulation (veno‐venous bypass, VVB), while in the piggyback technique (PC‐LT) the cava is preserved. Along with a temporary portacaval shunt (TPCS), better haemodynamic maintenance is purported with PC‐LT. A prospective, consecutive series of 384 primary transplants (2000–2003) were analysed, 138 CON‐LT (with VVB) and 246 PC‐LT (54 without TPCS). Patient/donor characteristics were similar in the two groups. PC‐LT required less usage of fresh‐frozen plasma and platelets, intensive care stay, number of patients requiring ventilation after day 1 and total days spent on ventilator. The results were not different when comparing, total operating and warm ischaemia time (WIT), red cell usage, requirement for renal support, day 3 serum creatinine and total hospital stay. TPCS had no impact on outcome other than WIT (P = 0.02). Three patients in PC‐LT group (three of 246;1.2%) developed caval outflow obstruction (P = 0.02). There was no difference in short‐ or long‐term graft or patient survival. PC‐LT has an advantage over CON‐LT unsing VVB with respect to intraoperative blood product usage, postoperative ventilation requirement and ITU stay. VVB is no longer required and TPCS may be used selectively in adult transplantation.

The most frequent chromosomal structural loss in hepatocellular carcinoma (HCC) is of the short arm of chromosome 8 (8p). Genes on the remaining homologous chromosome, however, are not recurrently mutated, and the identity of key 8p tumor-suppressor genes (TSG) is unknown. In this work, analysis of minimal commonly deleted 8p segments to identify candidate TSG implicated GATA4, a master transcription factor driver of hepatocyte epithelial lineage fate. In a murine model, liver-conditional deletion of 1 Gata4 allele to model the haploinsufficiency seen in HCC produced enlarged livers with a gene expression profile of persistent precursor proliferation and failed hepatocyte epithelial differentiation. HCC mimicked this gene expression profile, even in cases that were morphologically classified as well differentiated. HCC with intact chromosome 8p also featured GATA4 loss of function via GATA4 germline mutations that abrogated GATA4 interactions with a coactivator, MED12, or by inactivating mutations directly in GATA4 coactivators, including ARID1A. GATA4 reintroduction into GATA4-haploinsufficient HCC cells or ARID1A reintroduction into ARID1A-mutant/GATA4-intact HCC cells activated hundreds of hepatocyte genes and quenched the proliferative precursor program. Thus, disruption of GATA4-mediated transactivation in HCC suppresses hepatocyte epithelial differentiation to sustain replicative precursor phenotype.

Liver resection is commonly performed for solitary hepatocellular carcinoma (HCC) in well-compensated cirrhotic and noncirrhotic patients. Data concerning exacerbation of chronic hepatitis B (ECHB) post-liver resection are scant. To determine the incidence, risk factors, and clinical outcomes of ECHB in patients who underwent hepatic resection for HCC. The methods consisted of a retrospective review of consecutive patients with chronic hepatitis B virus (HBV) infection who had undergone liver resection for HCC from January 2002 to December 2004. Seventy-seven patients underwent 82 liver resections; the mean age was 58.0 +/- 12.1 years; 87% male; 20% hepatitis B e-antigen positive. Incidence of all causes of postoperative hepatitis was 25.6% (n = 21), and ECHB was 8.5% (n = 7). Both groups had their peak alanine aminotransferases, 231.0 IU/L (74-1,400) and 312 IU/L (147-1,400), respectively, observed at day 84 postresection. Three patients died as a result of ECHB within 4 months postsurgery. One- and 2-year survival rates were poorest for the ECHB group at 42.9 and 21.4%, compared with those with postoperative hepatitis due to other causes at 60.3 and 45.2% and those without postoperative hepatitis at 87.7 and 73.5% (p < 0.001). Liver resection for HCC in patients with chronic HBV infection carries a risk for ECHB, and affected patients have poorer clinical outcomes. There is a need for close monitoring of these patients preoperatively and in the early postoperative period.

Background/Aim: A cholangiocarcinoma, the second most common primary hepatic malignancy, can present with diagnostic dilemmas. The aim of this study is to assess the role of CA 19-9 in patients with a cholangiocarcinoma without primary sclerosing cholangitis. Methods: The prospectively collected information on patients with biopsy-proven cholangiocarcinomas who had the CA 19-9 level measured was obtained (n = 68) from our computer database and medical records. These patients were compared with patients who had benign liver tumours (n = 25) and benign bile duct strictures (n = 13) who also had their CA 19-9 concentration measured. Results: Sensitivity and specificity of CA 19-9 in the diagnosis of a cholangiocarcinoma were 77.9 and 76.3%, respectively, when using a cut-off value of 35 kU/l, while sensitivity and specificity were 67.5 and 86.8%, respectively, when the cut-off value was raised to 100 kU/l. The specificity was found to be higher in patients with peripheral cholangiocarcinomas (96%) using a CA 19-9 cut-off value >100 kU/l. A CA 19-9 value >600 kU/l was associated with non-resectable tumours (p = 0.05). Conclusions: This study demonstrates that CA 19-9 is a useful adjunct in the diagnosis of cholangiocarcinomas without primary sclerosing cholangitis, especially in the diagnosis of peripheral cholangiocarcinomas. However, it does not provide a reliable guide for the pathological staging of these tumours.