Integrated Bioinformatics Analysis and Validation of the Prognostic Value of RBM10 Expression in Hepatocellular Carcinoma.

Background: RBM10's function in hepatocellular carcinoma (HCC) has rarely been addressed. We intend to explore the prognostic significance and therapeutic meaning of RBM10 in HCC in this study. Methods: Multiple common databases were integrated to analyze the expression status and prognostic meaning of RBM10 in HCC. The relationship between RBM10 mRNA level and clinical features was also assessed. Multiple enrichment analyses of the differentially expressed genes between RBM10 high- and low- transcription groups were constructed by using R software (version 4.0.2). A Search Tool for Retrieval of Interacting Genes database was used to construct the protein-protein interaction network between RBM10 and other proteins. A tumor immune estimation resource database was employed to identify the relationship between RBM10 expression and immune cell infiltrates. The prognostic value of RBM10 expression was validated in our HCC cohort by immunohistochemistry test. Results: The transcription of RBM10 mRNA was positively correlated with tumor histologic grade (p < 0.001), T classification (p < 0.001), and tumor stage (p < 0.001). High transcription of RBM10 in HCC predicted a dismal overall survival (p = 0.0037) and recurrence-free survival (p < 0.001). Kyoto Encyclopedia of Genes and Genomes, Gene Ontology, and Gene Set Enrichment Analysis all revealed that RBM10 was involved in the regulation of cell cycle, DNA replication, and immune-related pathways. Tumor immune estimation analysis revealed that RBM10 transcription was positively related to multiple immune cell infiltrates and the expressions of PD-1 and PD-L1. Conclusion: RBM10 was demonstrated to be a dismal prognostic factor and a potential biomarker for immune therapy in HCC in that it may be involved in the immune-related signaling pathways.

Proteomics analysis identified TPI1 as a novel biomarker for predicting recurrence of intrahepatic cholangiocarcinoma.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common tumor in primary liver cancer, but the prognostic factors associated with long-term outcomes after surgical resection remain poorly defined. This study aimed to develop a novel prognostic classifier for patients with ICC after surgery. METHODS: Using a proteomics approach, we screened tumor markers that up-regulated in ICC tissues, and narrowed down by bioinformatics analysis, western blot and immunohistochemistry. Prognostic markers were identified using Cox regression analyses in primary training cohort and the predictive models for time to recurrence (TTR) were established. The predictive accuracy of predictive model was validated in external validation cohort and prospective validation cohort. MTT assay, clonal formation assay and trans-well assays were used to verify the effect on the proliferation and migration in ICC cell line. RESULTS: Triosephosphate isomerise (TPI1) was significantly up-regulated in ICC tissues and Kaplan-Meier analysis reveals that higher TPI1 expression was strongly correlated with higher recurrence rate of ICC patients. In the primary training cohort, mean TTR was significantly longer (p < 0.0001) than in the low-risk group (26.9 months for TTR, 95% CI 22.4-31.5) than in the high-risk group (14.5 months for TTR, 95% CI 10.6-18.4). Similar results were observed in two validation cohorts. In addition, a nomogram to predict recurrence was developed. Moreover, Knockdown of TPI1 by shRNA inhibited ICC cell growth, colony information, migration, invasion in vitro. CONCLUSIONS: Current prognostic models were accurate in predicting recurrence for ICC patients after surgical resection.

Extensively expanded murine-induced hepatic stem cells maintain high-efficient hepatic differentiation potential for repopulation of injured livers.

BACKGROUND & AIM: Shortage of donor hepatocytes limits hepatocyte transplantation for clinical application. Induced hepatic stem cells (iHepSCs) have capacities of self-renewal and bipotential differentiations. Here, we investigated whether iHepSCs could be extensively expanded, and whether they could differentiate into sufficient functional hepatocytes as donors for transplantation therapy after their extensive expansions. METHODS: Murine extensively expanded iHepSCs (50-55 passages) were induced to differentiate into iHepSC-Heps under a chemically defined condition. iHepSC-Heps were proved for carrying morphological hepatocyte characters and hepatocytic functions including low-density lipoprotein uptake, glycogen storage, CLF secretion, ICG uptake and release, Alb secretion, urea synthesis and metabolism-relative gene expressions respectively. Next, both iHepSCs and iHepSC-Heps were transplanted into Fah-/- mice respectively. Both liver repopulation and alleviation of liver function were compared between two transplantation groups. RESULTS: Murine iHepSCs still maintained the capacities of self-renewal and bipotential differentiations after extensive expansion. The efficiency for the functional hepatocyte differentiation from extensively expanded iHepSCs reached to 72.64%. Transplantations of both extensively expanded iHepSCs and iHepSC-Heps resulted in liver engraftment in Fah-/- mice. Survival rate of Fah-/- mice recipients and level of liver repopulation were 50% and 20.32 ± 4.58% respectively in iHepSC-Heps group, while 33% and 10.4 ± 4.3% in iHepSCs group. CONCLUSIONS: Extensively expanded iHepSCs can efficiently differentiate into hepatocytes in chemical defined medium. Transplantation of iHepSC-Heps was more effective and more efficient than transplantation of iHepSCs in Fah-/- mice. Our results suggested an innovative system to obtain sufficient hepatocytes through hepatic differentiation of iHepSCs generated by lineage reprogramming.

Safety and Efficacy of Radiofrequency Ablation for Solitary Hepatocellular Carcinoma (3-5 cm): a Propensity Score Matching Cohort Study.

BACKGROUND: We aim to investigate the safety and efficacy of radiofrequency ablation in the treatment of solitary hepatocellular carcinoma (3-5 cm) in comparison with surgical resection. METHODS: Included in this study were 388 patients with primary and solitary hepatocellular carcinoma, of whom 196 patients underwent surgical resection and the other 192 patients received radiofrequency ablation. Clinicopathological characteristics, prognosis, post-treatment complications, hospital stay, and financial expenditures between the two groups were compared retrospectively. RESULTS: The result of propensity score matching and subgroup analysis showed that the 1-, 3-, and 5-year overall survival and disease-free survival were comparable in patients with tumors of 3-4 cm in diameter between surgical resection and radiofrequency ablation groups. However, when the tumor size exceeded 4 cm in diameter, surgical resection exhibited a superior long-term prognosis compared with radiofrequency ablation. Nevertheless, hepatectomy was associated with high occurrences of postoperative complications, long hospital stay, and high hospitalization cost as compared with radiofrequency ablation. Further analysis of the relationship between tumor size and pathological features of hepatocellular carcinoma showed that tumors larger than 4 cm were positively correlated with a high rate of microvascular invasion and satellite nodule formation. CONCLUSION: For solitary hepatocellular carcinoma of 3-4 cm in diameter, radiofrequency ablation could achieve a comparable prognosis with a low incidence of post-treatment complications and low hospitalization costs, while surgical resection is recommended for solitary hepatocellular carcinoma tumors of 4-5 cm in diameter when long-term prognosis is considered.

Specific risk factors contributing to early and late recurrences of intrahepatic cholangiocarcinoma after curative resection.

BACKGROUND: Most intrahepatic cholangiocarcinoma (ICC) patients experienced tumor recurrences even after curative resection, but the optimal cut-off time point and the specific risk factors for early and late recurrences of ICC have not been clearly defined. The objective of the current study was to define specific risk factors for early and late recurrences of ICC after radical hepatectomy. METHODS: Included in this study were 259 ICC patients who underwent curative surgery at our hospital between January 2005 and December 2009. Recurrences in these patients were followed-up prospectively. Piecewise regression model and the minimum P value approach were used to estimate the optimal cut-off time point for early and late recurrences. Then, Cox's proportional hazards regression model was used to identify specific independent risk factors for early and late recurrences. RESULTS: Early and late recurrences occurred in 130 and 74 patients, respectively, and the 12th month was confirmed as the optimal cut-off time point for early and late recurrences. Cox's proportional hazards regression model showed that microvascular invasion (HR = 2.084, 95% CI 1.115-3.897, P = 0.021), multiple tumors (HR = 2.071, 95% CI 1.185-3.616, P = 0.010), abnormal elevation of serum CA19-9 (HR = 1.619, 95% CI 1.076-2.437, P = 0.021), and the negative hepatitis B status (HR = 1.650, 95% CI 1.123-2.427, P = 0.011) were independent risk factors for early recurrence, and HBV-DNA level > 106 IU/mL (HR = 1.785, 95% CI 1.015-3.141, P = 0.044) and a hepatolithiasis history (HR = 2.538, 95% CI 1.165-5.533, P = 0.010) contributed to late recurrence independently. CONCLUSION: Specific risk factors and mechanisms may relate to early and late recurrences of ICC after curative resection.

ß-catenin deficiency in hepatocytes aggravates hepatocarcinogenesis driven by oncogenic ß-catenin and MET.

Both activating and inactivating mutations in catenin ß1 (ctnnb1), which encodes ß-catenin, have been implicated in liver tumorigenesis in humans and mice, although the underlying mechanisms are not fully understood. Herein, we show that deletion of endogenous ß-catenin in hepatocytes aggravated hepatocellular carcinoma (HCC) development driven by an oncogenic version of ß-catenin (CAT) in combination with the hepatocyte growth factor receptor MET proto-oncogene receptor tyrosine kinase (MET). Although the mitogenic signaling and cell cycle progression was modestly impaired after CAT/MET transfection, the ß-catenin-deficient livers displayed changes in transcriptomes, increased DNA damage response, expanded Sox9+ cells, and up-regulation of protumorigenic cytokines, including interleukin-6 and transforming growth factor ß1. These events eventually exacerbated CAT/MET-driven hepatocarcinogenesis in ß-catenin-deficient livers, featured by up-regulation of extracellular signal-regulated kinase (Erk), protein kinase B (Akt), and Wnt/ß-catenin signaling and cyclin D1 expression. The resultant mouse tumors showed similar transcriptomes to human HCC samples with concomitant CTNNB1 mutations and MET overexpression. CONCLUSION: These data argue that while dominantly activating mutants of ß-catenin are oncogenic, inhibiting the oncogenic signaling pathway generates a pro-oncogenic microenvironment that may facilitate HCC recurrence following a targeted therapy of the primary tumor. An effective therapeutic strategy must require disruption of the oncogenic signaling in tumor cells and suppression of the secondary tumor-promoting stromal effects in the liver microenvironment. (Hepatology 2018;67:1807-1822).

SVCT-2 determines the sensitivity to ascorbate-induced cell death in cholangiocarcinoma cell lines and patient derived xenografts.

Cholangiocarcinoma (CC) is a devastating malignancy with late diagnosis and poor response to conventional chemotherapy. Recent studies have revealed anti-cancer effect of vitamin C (l-ascorbic acid, ascorbate) in several types of cancer. However, the effect of l-ascorbic acid (AA) in CC remains elusive. Herein, we demonstrated that AA induced cytotoxicity in CC cells by generating intracellular reactive oxygen species (ROS), and subsequently DNA damage, ATP depletion, mTOR pathway inhibition. Moreover, AA worked synergistically with chemotherapeutic agent cisplatin to impair CC cells growth both in vitro and in vivo. Intriguingly, sodium-dependent vitamin C transporter 2 (SVCT-2) expression was inversely correlated with IC50 values of AA. Knockdown of SVCT-2 dramatically alleviated DNA damage, ATP depletion, and inhibition of mTOR pathway induced by AA. Furthermore, SVCT-2 knockdown endowed CC cells with the resistance to AA treatment. Finally, the inhibitory effects of AA were further confirmed in patient-derived CC xenograft models. Thus, our results unravel therapeutic potential of AA alone or in combination with cisplatin for CC. SVCT2 expression level may serve as a positive outcome predictor for AA treatment in CC.

Overexpression of Sox3 is associated with promoted tumor progression and poor prognosis in hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a common malignant tumor lacking sensitive biomarkers for prognosis. Sox3, a member of the Sex determining region Y box gene superfamily, has been demonstrated to be an oncogene in many cancers. However, the expression and clinical importance of Sox3 in HCC remains elusive. In this study, fifty pairs of HCC tissues with adjacent non-tumor samples were collected for detecting Sox3 expression by qPCR and immunoblotting analyses. A total of 104 HCC tissues were included for immunohistochemistry assay and analyzed by immunostaining scores. The correlation of Sox3 expression with clinicopathological factors and prognosis of HCC patients were calculated. Sox3 expression in HCC tissues was significantly higher than that in the non-tumor counterparts at the mRNA and protein levels. High staining scores of Sox3 was detected in 75.96% of HCC tissues. Statistical analyses demonstrated that highly expressed Sox3 was significantly correlated with low tumor capsule formation, advanced tumor stage and poor tumor differentiation. Moreover, patients with high Sox3 expression showed worse recurrence-free survival and overall survival than those with low Sox3 expression, and multivariate analyses further indicated that status of Sox3 expression is an independent prognostic factor in HCC patients. Therefore, our results suggested that overexpression of Sox3 in HCC tissues is correlated with increased tumor development and poor prognosis in HCC.

Overexpression of RAS-Association Domain Family 6 (RASSF6) Inhibits Proliferation and Tumorigenesis in Hepatocellular Carcinoma Cells.

Ras-association domain family 6 (RASSF6), a member of the RASSF family, is frequently downregulated in various types of cancer. However, the roles of RASSF6 in human hepatocellular carcinoma (HCC) are still unclear. In this study, we investigated the biological functions and related molecular mechanisms in HCC. Our results found that RASSF6 is expressed in low amounts in HCC tissues and cell lines. Overexpression of RASSF6 obviously inhibited the proliferation, invasion, and EMT process in HCC cells. Furthermore, overexpression of RASFF6 greatly downregulated the protein levels of phosphorylated focal adhesion kinase (FAK), MMP-2, and MMP-9 in HepG2 cells. Last, overexpression of RASFF6 significantly attenuated tumor growth in Balb/c nude mice. In conclusion, the present study revealed that RASFF6 can inhibit the proliferation, invasion, and migration of HCC cells both in vivo and in vitro. These inhibitory effects are through suppressing FAK phosphorylation, leading to decreased MMP-2/9 expression. RASFF6 is therefore a potential therapeutic target for treating HCC.

Krüppel-like factor 8 promotes cancer stem cell-like traits in hepatocellular carcinoma through Wnt/ß-catenin signaling.

Krüppel-like factor 8 (KLF8) is highly expressed in hepatocellular carcinoma (HCC) and contributes to tumor initiation and progression by promoting HCC cell proliferation and invasion. However, the role of KLF8 in liver cancer stem cells (LCSCs) is not known. In the current study, we investigated the role of KLF8 in LCSCs to determine if KLF8 is a novel marker of these cells. We found that KLF8 was highly expressed in primary HCC tumors, distant migrated tissues, and LCSCs. Patients with high KLF8 expression had a poor prognosis. KLF8 promoted stem cell-like features through activation of the Wnt/ß-catenin signaling pathway. Cell apoptosis was significantly increased in HCC cells with knockdown of KLF8 compared with the control cells when treated with the same doses of sorafenib or cisplatin. Taken together, our study shows that KLF8 plays a potent oncogenic role in HCC tumorigenesis by maintaining stem cell-like features through activation of the Wnt/ß-catenin signaling pathway and promoting chemoresistance. Thus, targeting KLF8 may provide an effective therapeutic approach to suppress tumorigenicity of HCC. © 2016 Wiley Periodicals, Inc.

STK33 promotes hepatocellular carcinoma through binding to c-Myc.

OBJECTIVE: STK33 has been reported to play an important role in cancer cell proliferation. We investigated the role of STK33 in hepatocellular carcinoma (HCC) and its underlying mechanisms. DESIGN: 251 patients with HCC were analysed for association between STK33 expression and clinical stage and survival rate. Tamoxifen (TAM)-inducible, hepatocyte-specific STK33 transgenic and knockout mice models were used to study the role of STK33 in liver tumorigenesis. HCC cell lines were used to study the role of STK33 in cell proliferation in vitro and in vivo. RESULTS: STK33 expression was found to be frequently upregulated in patients with HCC. Significant associations were found between increased expression of STK33 and advanced HCC staging and shorter disease-free survival of patients. Overexpression of STK33 increased HCC cell proliferation both in vitro and in vivo, whereas suppression of STK33 inhibited this effect. Using a TAM-inducible, hepatocyte-specific STK33 transgenic mouse model, we found that overexpression of STK33 resulted in increased hepatocyte proliferation, leading to tumour cell burst. Using a TAM-inducible, hepatocyte-specific STK33 knockout mouse model, we found that, when subjected to the diethylnitrosamine (DEN) liver cancer bioassay, STK33KO(flox/flox, Alb-ERT2-Cre) mice exhibited a markedly lower incidence of tumour formation compared with control mice. The underlying mechanism may be that STK33 binds directly to c-Myc and increases its transcriptional activity. In particular, the C-terminus of STK33 blocks STK33/c-Myc association, downregulates HCC cell proliferation, and reduces DEN-induced liver tumour cell number and tumour size. CONCLUSIONS: STK33 plays an essential role in hepatocellular proliferation and liver tumorigenesis. The C-terminus of STK33 could be a potential therapeutic target in the treatment of patients with STK33-overexpressed HCC.

Surgery for hepatocellular carcinoma presenting with variceal bleeding: The eastern experience.

BACKGROUND: Variceal bleeding can be the first manifestation of patients with newly diagnosed hepatocellular carcinoma (HCC), and effective treatments deserve to be explored for these patients. METHODS: A prospectively collected database of HCC patients undergoing hepatectomy identified 75 patients who presented with variceal bleeding. Among them, 31 patients underwent concomitant Hassab's operation. The clinical variables and outcomes were compared between the Hassab and non-Hassab groups. RESULTS: The postoperative morbidity and 90-days mortality were 44.0% and 6.7% respectively. Variceal re-bleeding and tumor recurrence occurred in 28.8% and 52.1% of surviving patients after surgery, and the 1-, 3-, and 5-year overall survival rates were 87.7, 66.8, and 50.3%. There were no significant differences in morbidity, mortality and postoperative recurrence between the Hassab and non-Hassab groups. However, patients in the Hassab group had significantly higher 1-, 3-, and 5-year overall survival rates (P = 0.038), and significantly lower rate of re-bleeding (13.3% vs. 39.5%, P = 0.014) than those in the non-Hassab group. On multivariable analysis, concomitant Hassab's operation was independently predicted longer overall survival. CONCLUSION: Liver resection could safely be performed in selected patients with HCC who presented with variceal bleeding, and concomitant Hassab's operation may improve long-term prognosis for these patients.

LincRNA-p21 activates endoplasmic reticulum stress and inhibits hepatocellular carcinoma.

LincRNA-p21 is a downstream long non-coding RNA (lncRNA) transcript of p53. LincRNA-p21 serves as a repressor in p53-dependent transcriptional responses and participates in diverse biological processes, including apoptosis, cell cycle, metabolism and pluripotency. However, the role of lincRNA-p21 in human hepatocellular carcinoma remains to be defined. Here in this work, we demonstrated that lincRNA-p21 acted as a tumor suppressive lncRNA in human hepatocellular carcinoma. We firstly found the downregulation of lincRNA-p21 level in human hepatocellular carcinoma tissues, and showed that low expression of lincRNA-p21 was associated with high disease stage and predicted poor survival. Further we showed that lincRNA-p21 knockdown promoted proliferation and colony formation of HepG2, Huh7 and Bel-7042 cells in vitro, while lincRNA-p21 overexpression obtained oppose results. Using tumor xenograft experiments, we also demonstrated that lincRNA-p21 inhibited HepG2 cell growth in vivo and lincRNA-p21 contributed to sorafenib-induced growth regression of HepG2 cell in vivo. Further mechanism analysis revealed that lincRNA-p21 promoted ER stress both in vitro and in vivo, which facilitated apoptosis of hepatocellular carcinoma cells. Finally, we demonstrated that ER stress accounted for lincRNA-p21 effects on apoptosis, proliferation and in vivo growth of hepatocellular carcinoma. These findings implicate that lincRNA-p21 is a potential prognostic factor and therapeutic target for human hepatocellular carcinoma.

Prognosis after resection for hepatitis B virus-associated intrahepatic cholangiocarcinoma.

AIM: To investigate the prognostic factors after resection for hepatitis B virus (HBV)-associated intrahepatic cholangiocarcinoma (ICC) and to assess the impact of different extents of lymphadenectomy on patient survival. METHODS: A total of 85 patients with HBV-associated ICC who underwent curative resection from January 2005 to December 2006 were analyzed. The patients were classified into groups according to the extent of lymphadenectomy (no lymph node dissection, sampling lymph node dissection and regional lymph node dissection). Clinicopathological characteristics and survival were reviewed retrospectively. RESULTS: The cumulative 1-, 3-, and 5-year survival rates were found to be 60%, 18%, and 13%, respectively. Multivariate analysis revealed that liver cirrhosis (HR = 1.875, 95%CI: 1.197-3.278, P = 0.008) and multiple tumors (HR = 2.653, 95%CI: 1.562-4.508, P < 0.001) were independent prognostic factors for survival. Recurrence occurred in 70 patients. The 1-, 3-, and 5-year disease-free survival rates were 36%, 3% and 0%, respectively. Liver cirrhosis (HR = 1.919, P = 0.012), advanced TNM stage (stage III/IV) (HR = 2.027, P < 0.001), and vascular invasion (HR = 3.779, P = 0.02) were independent prognostic factors for disease-free survival. Patients with regional lymph node dissection demonstrated a similar survival rate to patients with sampling lymph node dissection. Lymphadenectomy did not significantly improve the survival rate of patients with negative lymph node status. CONCLUSION: The extent of lymphadenectomy does not seem to have influence on the survival of patients with HBV-associated ICC, and routine lymph node dissection is not recommended, particularly for those without lymph node metastasis.

Impact of occult hepatitis B virus infection on outcome after resection for non-B non-C hepatocellular carcinoma.

BACKGROUND: To investigate the clinicopathologic characteristics of patients with both hepatitis B virus-surface antigen and hepatitis C virus antibody negative hepatocellular carcinoma (non-B non-C HCC [NBNC-HCC]) and examine the impact of occult hepatitis B virus infection (OBI) on patients' survival. METHODS: All patients with OBI were identified from a database of patients with NBNC-HCC who underwent surgical resection between January 1, 2006, and December 31, 2008. Their clinicopathologic and survival characteristics were compared with NBNC-HCC patients without OBI. RESULTS: Out of the 86 NBNC-HCC patients, 59 patients (68.6%) with OBI. A higher prevalence of hepatitis B core antigen positive rate, low platelet count, portal hypertension, and liver cirrhosis were observed in NBNC-HCC patients with OBI. The 1- and 3-y recurrence free survival rates were 66% and 25% in OBI group and 89% and 70% in the no OBI group, respectively (P < 0.001). The 1-, 3-, and 5-y overall survival rates were 86%, 55%, and 51% in OBI group and 93%, 85%, and 66% in no OBI group, respectively (P = 0.112). Multivariate analysis revealed that OBI (hazard ratio [HR] = 2.122; 95% confidence interval [CI], 1.086-4.149; P = 0.028), liver cirrhosis (HR = 2.411; 95% CI, 1.337-4.345; P = 0.003), and vascular invasion (HR = 5.858; 95% CI, 2.799-12.261; P < 0.001) were independent poor prognostic factors for recurrence free survival of patients with NBNC-HCC. CONCLUSIONS: NBNC-HCC patients with OBI had a poorer prognosis. OBI can be a useful predictor for recurrence in patients with NBNC-HCC after surgery.

The early diagnosis of pancreatic cancer and diabetes: what's the relationship?

Pancreatic cancer (PC) has a dismal prognosis as cancer-specific symptoms occur only at an advanced stage. If the cancer is to be discovered early, it will have to be done in asymptomatic individuals. Since the incidence of PC is low, screening for asymptomatic cancer in the general population will not be feasible. Screening will have to be restricted to subjects at high risk for PC. The proportion of PC patients who also have hyperglycemia or diabetes has previously been under appreciated; new data show that up to 80% are either hyperglycemic or diabetic and this can be evident in the pre-symptomatic phase. Diabetes improves following PC resection suggesting that diabetes is caused by the cancer. Conversely, older subjects with new-onset diabetes have an approximately eight fold higher risk of having PC compared to the general population. Recognition of new-onset diabetes as an early manifestation of PC could lead to diagnosis of asymptomatic, early stage PC. However, primary type 2 diabetes is common and PC is relatively uncommon in the general population and the two forms of diabetes are clinically indistinguishable. The success of the strategy to use new-onset hyperglycemia and diabetes as a screening tool to identify subjects with a high likelihood of having asymptomatic PC will depend largely on our ability to differentiate PC-associated diabetes from the more common type 2 diabetes using a (serologic) biomarker.

Distal bile duct cancers complicated with cholangiobronchopleural fistula after ERCP: A case report.

Distal (lower) bile duct cancers arise in the lower half of the biliary tree closer to the small intestine. Biliary disease complicated with cholangiobronchopleural fistula, which may occur in cases of multiple hepatobiliary stones or biliary ascariasis-associated severe infection, has rarely been reported in the literature, particularly following endoscopic retrograde cholangiopancreatography (ERCP). The present study describes the case of a 60-year-old female with distal cholangiocarcinoma complicated with cholangiobronchopleural fistula after ERCP for this rare disease. This complication was likely due to the inability to control retrograde infection following ERCP and, thus, the infection was disseminated. This resulted in mixed infection involving the diaphragm and pleura, and further penetrating the bronchus. The patient was managed with pancreatoduodenectomy and has since remained in good health.

Graft versus host disease following liver transplantation: A case report.

Graft versus host disease (GVHD) is an uncommon complication following liver transplantation. In the present case report, a 53-year-old male hepatitis B virus carrier was diagnosed with primary liver cancer with post-hepatitis cirrhosis. Preoperative cytomegalovirus (CMV), Epstein-Barr virus, coxsackievirus, herpes simplex virus and autoimmune antibody series were negative. Preoperative human leukocyte antigen type was also negative. Following classic orthotropic liver transplantation, postoperative treatment included immunosuppression therapy, infection protection, anti-human immunodeficiency virus therapy and CMV infection protection therapy. Chemotherapy was initiated at day 16 following surgery. At day 26 following the transplantation, the patient developed a fever of unknown cause, and a scattered red rash was observed behind the left ear and on the neck. The patient presented with a fever of unknown cause, rash, symptoms of the digestive tract, leukocytopenia and pancytopenia. A diagnosis of GVHD was confirmed following a skin biopsy. Symptomatic therapies, including antivirals, anti-anaphylaxis drugs and steroids were administered. However, the patient succumbed to infection, acute respiratory distress syndrome and multiple organ failure at day 46 following surgery. Therefore, an effective therapeutic strategy for the treatment of GVHD following liver transplantation is yet to be established, and further research is required prior to such a regimen being developed.

Loss of expression of MHC class I-related chain A (MICA) is a frequent event and predicts poor survival in patients with hepatocellular carcinoma.

Natural killer (NK) cells are important effector cells for the first line of defense against tumor. Distant MHC class I homolog MICA has been identified as human ligand for NK cell activating receptor NKG2D. Engagement of MICA triggers NK cells and augments antigen-specific CTL anti-tumor immunity. However, the expression level of MICA and its clinical significance in hepatocellular carcinoma remains to be elucidated. In the present study, a hospital-based study cohort of 143 HCC patients was involved. MICA expression levels were determined by immunohistochemical staining. The association of MICA expression with tumor clinicopathologic features, disease-free survival, and overall survival of HCC patients were analyzed. Significantly decreased expression of MICA was detected in tumor specimens. MICA expression was significantly associated with AFP level (P < 0.001) and tumor node metastasis stage (P = 0.003). Patients with reduced level of MICA had a statistically significantly shorter disease-free survival and overall survival duration than patients with preserved expression of MICA. However, in multivariate analysis, MICA expression level was found not to be an independent prognostic factor for both disease-free survival and overall survival of HCC patients. Our findings suggest that decreased MICA expression may play an important role in HCC tumor evasion of host immunity, which warrants further investigation in future studies.

Expression of vascular endothelial growth factor and basic fibroblast growth factor in acute rejection reaction following rat orthotopic liver transplantation.

The aim of the present study was to investigate the expression levels of vascular endothelial growth factor (VEGF) and basic fibroblast growth factor (bFGF) in acute rejection reaction (ARR) following orthotopic liver transplantation in a rat model. Serum VEGF and bFGF levels were detected using ELISA, and their expression levels in liver and spleen tissues were determined using immunohistochemistry. The mRNA expression levels of VEGF and bFGF were detected by conducting a quantitative polymerase chain reaction during the ARR following orthotopic liver transplantation. The expression levels of VEGF and bFGF in the serum 3 days following liver transplantation were significantly higher compared with those in the other groups (1 and 7 days following transplantation; P<0.01). In addition, the numbers of cells in the liver tissue that were shown to be positive for the expression VEGF and bFGF using immunohistochemistry were significantly higher 3 days following transplantation than at the other time points (P<0.0001). Furthermore, the numbers of cells positive for VEGF and bFGF expression in the spleen detected 3 days following the transplantation surgery were also significantly higher compared with those at the other time points (P<0.01). VEGF and bFGF mRNA expression levels were also increased from 1 day following the surgery and reached a peak at day 3, prior to declining gradually and remaining at a relatively high level. VEGF and bFGF mRNA expression levels changed dynamically, by peaking and then declining, in ARR following orthotopic liver transplantation. These changes may have an important impact on angiogenesis and the inflammatory reaction, and the identification of these changes increases the current understanding of ARR following orthotopic liver transplantation.