Artery Reconstruction in Right Lobe Living Donor Liver Transplantation: Donor-Recipient Vessel Ratio Is Key to Choosing Recipient Artery.

BACKGROUND: The aims of this study were to investigate if recipient artery choice in right lobe living donor liver transplant affects postoperative complications and discuss solutions accordingly. METHODS: Three hundred fourteen right lobe living donor liver transplantation patients were divided into 2 groups: 163 patients using right hepatic artery as the recipient vessel and 151 patients using left hepatic artery as the recipient vessel. Cases involving 2 recipient blood vessels or the use of other blood vessels as recipient vessels were excluded. RESULTS: Overall vascular embolism rate in both groups was 1.3%, and our complication rate was lower than those in previous studies. There was no significant difference in complication rate between the groups, but a significant difference in recipient/donor artery size ratio was noted. CONCLUSIONS: Although left hepatic artery's anatomical position makes it less affected by bile duct anastomosis and thus fewer postoperative complications, we believe that the ratio of the donor-recipient blood vessel size and the length of the anastomosis vessel stumps are the key factors that affect the outcome of the vascular anastomosis.

Living donor liver transplantation for hepatocellular carcinoma beyond the Milan criteria: outcome of expanded criteria in tumor size.

BACKGROUND: The Milan criteria are the universal standard of liver transplantation for hepatocellular carcinoma (HCC). Numerous expanded criteria have shown outcomes as good as the Milan criteria. In Taiwan, living donor liver transplant (LDLT) accounts for the majority of transplantations due to organ shortages. METHODS: We retrospectively enrolled 155 patients who underwent LDLT for HCC from July 2005 to June 2017 and were followed up for at least 2 years. Patients beyond the Milan criteria (n = 78) were grouped as recurrent or nonrecurrent, and we established new expanded criteria based on these data. RESULTS: Patients beyond the Milan criteria with recurrence (n = 31) had a significantly larger maximal tumor diameter (4.13 ± 1.96 cm versus 6.10 ± 3.41 cm, p = 0.006) and total tumor diameter (7.19 ± 4.13 cm versus 10.21 ± 5.01 cm, p = 0.005). Therefore, we established expanded criteria involving maximal tumor diameter ≤ 6 cm and total tumor diameter < 10 cm. The 5-year survival rate of patients who met these criteria (n = 134) was 77.3%, and the 5-year recurrence rate was 20.5%; both showed no significant differences from those of the Milan criteria. Under the expanded criteria, the pool of eligible recipients was 35% larger than that of the Milan criteria. CONCLUSION: Currently, patients with HCC who undergo LDLT can achieve good outcomes even when they are beyond the Milan criteria. Under the new expanded criteria, patients can achieve outcomes as good as those with the Milan criteria and more patients can benefit.

Prediction of microvascular invasion of hepatocellular carcinoma: preoperative CT and histopathologic correlation.

OBJECTIVE: The objective of our study was to prospectively investigate whether nonsmooth margins detected on multiphasic CT images correlate with the presence and location of microvascular invasion (MVI) in hepatocellular carcinoma (HCC). SUBJECTS AND METHODS: A total of 102 patients with preoperative CT findings of solitary HCC were prospectively enrolled. Tumor size, tumor capsule, tumor margins, and peritumoral enhancement on preoperative CT images were assessed. Histopathologic results including the following were also recorded: tumor differentiation; liver fibrosis score; presence or absence of MVI; and, if present, the location of MVI. Correlation between tumor margin on preoperative CT images and histopathologic location of MVI was determined. RESULTS: Pathologic examination revealed MVI in 60 of the 102 HCC specimens. Although the results of the univariate analysis showed that tumor size, higher Edmondson-Steiner grade, and nonsmooth tumor margins were associated with MVI, multivariate analysis revealed that only nonsmooth margins correlated with the presence of MVI in HCC (p < 0.001). Of the 60 HCC specimens with histopathologic evidence of MVI, 40 exhibited focal nonsmooth margins. In addition, the locations of the nonsmooth margins and MVI were similar in 36 of the 40 specimens. CONCLUSION: Nonsmooth tumor margins correlated with the histopathologic presence and location of MVI. Therefore, nonsmooth margins detected on multiphasic CT may be predictive of MVI in HCC.

Presence of fibrosis is predictive of postoperative survival in patients with small hepatocellular carcinoma.

BACKGROUND/AIMS: The aim of this study was to evaluate whether liver fibrosis is predictive of survival in patients who require hepatectomy for small hepatocellular carcinoma. METHODOLOGY: In this retrospective study, we enrolled 174 patients with small HCC who underwent major or minor hepatectomy at the Changhua Christian Hospital during the period January 2001 to June 2007. Patients were classified into two subgroups depending on whether tumor recurrence after surgery. Factors influencing overall survival and recurrence were analyzed and compared between the two subgroups. Univariate and multivariate logistic regression analyses were performed to determine the most significant predictors of tumor recurrence or death. The Kaplan-Meier method and the log-rank test were used to detect differences in cumulative survival between the two subgroups based on histopathologic fibrosis scores. RESULTS: Results of the univariate analysis revealed these variables that tumor margin, type of resection, and degree of fibrosis were independent predictors of tumor recurrence or death. However, the multivariate analysis revealed that fibrosis was the only independent predictor of tumor recurrence. Survival analysis showed that low fibrotic scores were predictive of disease-free survival. CONCLUSIONS: The degree of fibrosis is an important predictor of survival among patients who undergo hepatectomy for small HCC.

Clustered DNA methylation changes in polycomb target genes in early-stage liver cancer.

Polycomb-group proteins mark specific chromatin conformations in embryonic and somatic stem cells that are critical for maintenance of their "stemness". These proteins also mark altered chromatin modifications identified in various cancers. In normal differentiated cells or advanced cancerous cells, these polycomb-associated loci are frequently associated with increased DNA methylation. It has thus been hypothesized that changes in DNA methylation status within polycomb-associated loci may dictate cell fate and that abnormal methylation within these loci may be associated with tumor development. To assess this, we examined the methylation states of four polycomb target loci -Trip10, Casp8AP2, ENSA, and ZNF484 - in liver cancer. These four targets were selected because their methylation levels are increased during mesenchymal stem cell-to-liver differentiation. We found that these four loci were hypomethylated in most early-stage liver cancer specimens. For comparison, two non-polycomb tumor suppressor genes, HIC1 and RassF1A, were also examined. Whereas the methylation level of HIC1 did not differ significantly between normal and tumor samples, RassF1A was significantly hypermethylated in liver tumor samples. Unsupervised clustering analysis classified the methylation changes within polycomb and non-polycomb targets to be independent, indicating independent epigenetic evolution. Thus, pre-deposited polycomb marks within somatic stem cells may contribute to the determination of methylation changes during hepatic tumorigenesis.

Using 3D Microscope for Hepatic Artery Reconstruction in Living Donor Liver Transplant.

INTRODUCTION: This study compares the intraoperative process of hepatic artery anastomosis using conventional microscope and novel 3D digital microscope and discusses our technique and operative set-up. METHOD: A retrospective comparative cohort study with 46 hepatic artery reconstructions in living donor liver transplant patients. Either an operational microscope (control group) or a 3D digital microscope Mitaka Kestrel View II (study group) was used for hepatic artery anastomosis. We then discuss and share our institution's experience of improving surgical training. RESULTS: Both operation instruments provide effective and comparable results. There was no statistical difference regarding operational objective results between conventional microscope and exoscope. Both instruments have no hepatic artery size limit, and both resulted in complete vessel patency rate. CONCLUSIONS: There was no statistical differences regarding hepatic artery anastomosis between microscope and exoscope cohorts. Microsurgeons should perform hepatic artery anastomosis efficiently with the instruments they are most proficient with. Yet, exoscope provided better ergonomics in the operation room and lessened musculoskeletal strain, allowing surgeons to work in a more neutral and comfortable posture while allowing the first assistant to learn and assist more effectively. Using exoscope with micro-forceps and modified tie technique make artery reconstruction easier.

Tumor size as a prognostic factor in resected small hepatocellular carcinoma: a controversy revisited.

BACKGROUND AND AIM: The widespread use of screening programs has resulted in an increase in detection of small hepatocellular carcinoma (HCC). Surgical resection generally leads to favorable outcomes in this group of patients; however, the prognostic significance of tumor size and the optimal cutoff point in resected specimens of small HCC have not been well defined. The aim of current study is to evaluate the prognostic significance of tumor size in small resected HCC. METHODS: Patients who underwent surgical resection for small HCC at the Changhua Christian Hospital during January 2001 to June 2007 were enrolled. Small HCC was defined as a single HCC nodule with maximum diameter ≤ 5 cm. Cox regression hazard ratios for cancer-specific death were calculated to survey the prognostic significance of tumor size. We then determined the optimal cut-point for tumor size that could be used to stratify patients into 5-year disease-free survival (DFS) and cancer-specific survival (CSS) groups. RESULTS: A total of 140 patients who underwent resection of small HCC were enrolled. The mean tumor size was 2.9 cm (range 0.9-5.0) and the mean follow-up period was 43.4 months. The 5-year DFS and CSS rates were 46.6% and 81.6%, respectively. Cox regression analysis revealed that tumor size (hazard ratio = 2.973, 95% confidence interval: 1.073-8.239, P = 0.036) was an independent prognostic factor. Our analysis showed that a tumor size of 3 cm was the cut-point that could dichotomize patients into statistically different 5-year DFS and CSS risk groups. CONCLUSIONS: Tumor size is an independent prognostic factor in resected small HCC and the prognostic significance of tumor size may vary according to different cut-off points.

Factors affecting prognosis of small hepatocellular carcinoma in Taiwanese patients following hepatic resection.

BACKGROUND: Small hepatocellular carcinoma (HCC) affects millions of individuals worldwide. Surveillance of high-risk patients increases the early detection of small HCC. OBJECTIVE: To identify prognostic factors affecting the overall survival (OS) and recurrence-free survival (RFS) of patients with small HCC. METHODS: The present prospective study enrolled 140 Taiwanese patients with stage I or stage II small HCC. Clinical parameters of interest included operation type, tumour size, tumour histology, Child- Pugh class, presence of hepatitis B surface antigen and liver cirrhosis, hepatitis C status, alpha-fetoprotein, total bilirubin and serum albumin levels, and administration of antiviral and salvage therapies. RESULTS: Tumour size correlated significantly with poorer OS in patients with stage I small HCC (P=0.014); however, patients with stage II small HCC experienced a significantly poorer RFS (P=0.033). OS rates did not differ significantly between patients with stage I and stage II small HCC. Tumour margins, tumour histology and cirrhosis did not significantly affect OS or RFS (P>0.05). DISCUSSION: Increasing tumour size has generally been associated with poorer prognoses in cases of HCC. The present study verified the relationship between small HCC tumour size and OS; however, a reduction in OS with increasing tumour size was demonstrated for patients with stage I - but not for stage II - small HCC. CONCLUSION: Patients with stage II small HCC may benefit from aggressive surveillance for tumour recurrence and appropriate salvage treatment. Further studies are needed for additional stratification of stage I patients to identify those at increased risk of death.

Ferroptosis as a Major Factor and Therapeutic Target for Neuroinflammation in Parkinson's Disease.

Mounting evidence suggests that ferroptosis is not just a consequence but also a fundamental contributor to the development and progression of Parkinson's disease (PD). Ferroptosis is characterized as iron-dependent regulated cell death caused by excessive lipid peroxidation, leading to plasma membrane rupture, release of damage-associated molecular patterns, and neuroinflammation. Due to the crucial role of intracellular iron in mediating the production of reactive oxygen species and the formation of lipid peroxides, ferroptosis is intimately controlled by regulators involved in many aspects of iron metabolism, including iron uptake, storage and export, and by pathways constituting the antioxidant systems. Translational and transcriptional regulation of iron homeostasis and redox status provide an integrated network to determine the sensitivity of ferroptosis. We herein review recent advances related to ferroptosis, ranging from fundamental mechanistic discoveries and cutting-edge preclinical animal studies, to clinical trials in PD and the regulation of neuroinflammation via ferroptosis pathways. Elucidating the roles of ferroptosis in the survival of dopaminergic neurons and microglial activity can enhance our understanding of the pathogenesis of PD and provide opportunities for the development of novel prevention and treatment strategies.

Using Glissonian sheath as an alternative way to prevent biliary stricture in living-donor liver transplantation.

BACKGROUND: /Objective: The aim of this study was to report a single-institution experience involving a Glissonian sheath-to-duct method for biliary reconstruction in living donor liver transplantation, focusing on the association between surgical techniques and biliary stricture rates. METHODS: Three hundred and twenty adult right lobar living donor liver transplantation procedures were analyzed through a comparison of 200 Glissonian sheath-to-duct (GD) reconstructions and 120 duct-to-duct (DD) reconstructions in biliary anastomosis. RESULTS: At a mean follow-up period of 60.8 months, the GD group had a significantly lower biliary stricture rate (13.5%, 27/200) than the DD group (26.7%, 32/120) (p = 0.003). In biliary anastomosis with single duct anastomosis, the incidence of biliary stricture was significantly greater for the DD group (17/79, 21.5%) than for the GD group (14/141, 9.9%) (p = 0.018). CONCLUSION: This study has shown that GD anastomosis of the bile duct produced outstanding results with respect to the reduction of biliary stricture. The GD technique can therefore be suggested as an alternative method for biliary reconstruction in LDLT.

Comparison of the diagnostic performance of magnetic resonance elastography and Wisteria foribunda agglutinin-positive Mac-2-binding protein in the determination of advanced liver fibrosis stages in patients with chronic liver disease.

The present study aimed to compare the accuracy of Wisteria floribunda agglutinin-positive Mac-2-binding protein (WFA+-M2BP) and magnetic resonance elastography (MRE) in determining the liver fibrosis stage in patients with chronic liver disease. A retrospective review of a prospectively maintained database was performed. The eligible patients had hepatic tumors and chronic liver disease, including hepatitis B (HBV) and HCV. All patients underwent blood sampling, MRE and hepatectomy at Changhua Christian Hospital (Changhua, Taiwan). Surgical specimens were used to determine definitive histopathological diagnoses and liver fibrosis stages. Measurement of liver stiffness was performed via MRI. The value of WFA+-M2BP in each patient was also assessed. The area under the receiver operating characteristic (ROC) curve (AUC) was measured to compare the diagnostic accuracy of the two examinations. The results indicated that the serum WFA+-M2BP levels were able to detect severe liver fibrosis (≥F3) in patients with chronic liver disease and performed as well as MRE in patients with HCV. Of the 238 patients enrolled in the present study, 135 had chronic HBV 75 had chronic HCV, 92 had early liver fibrosis (F1-F2) and 139 patients had advanced liver fibrosis (F3-F4). In predicting fibrosis stages ≥F3, MRE had an AUC of 0.89 with a cutoff value of 3.76 and serum WFA+-M2BP had an AUC of 0.65 with a cutoff value of 1.32. MRE had higher AUCs than serum WFA+-M2BP for predicting the severity based on the fibrosis stage in the total cohort and the HBV subgroup. In patients with HCV, no significant differences in diagnostic performance were identified between MRE and serum WFA+-M2BP. In conclusion, determination of WFA+-M2BP as a biomarker for predicting severe liver fibrosis (≥F3) is a reliable and non-invasive method and performs as well as MRE in patients with chronic liver disease, particularly those with HCV.

A Novel Biomarker Driving Poor-Prognosis Liver Cancer: Overexpression of the Mitochondrial Calcium Gatekeepers.

Several studies have indicated the biological role of mitochondrial Ca2+ uptake in cancer pathophysiology; however, its implications in predicting the prognosis of hepatocellular carcinoma (HCC) are not yet fully understood. Here, we collected tumor specimens and adjacent normal liver tissues from 354 confirmed HCC patients and analyzed the levels of cyclic adenosine monophosphate (cAMP) responsive element binding protein 1 (CREB), mitochondrial calcium uniporter (MCU), mitochondrial calcium uptake 1 and 2 (MICU1, MICU2) using bioinformatics, qRT-PCR, and immunohistochemistry (IHC), and their relationship with clinicopathological characteristics and prognosis. HCC patients with low CREB/MICU1 and high MCU/MICU2 expression exhibited poor survival rate and prognosis in overall survival (OS) and disease-free survival (DFS) analyses. Low CREB/MICU1 and low MICU1 alone indicated poor prognosis in stage I/II and III/IV patients, respectively. In the poor differentiation/undifferentiation group, low expression of MICU1 indicated poor clinical outcomes. Low CREB/MICU1 expression suggested poor outcomes in patients with or without hepatitis B virus (HBV) infection and poor prognosis in the HCV infection group. In the non- hepatitis C virus (HCV) infection group, low MCU1 indicated a poor prognosis. Multivariate analysis demonstrated that CREB and MICU1 expression showed prognostic significance. This study demonstrates the prognostic significance of CREB, MCU, MICU1, and MICU2, in predicting HCC outcomes. Low CREB/MICU1 and high MCU/MICU2 in HCC tissues are associated with poor prognosis, thus offering a novel perspective in the clinical management for HCC patients.

The Phenoxyphenol Compound 4-HPPP Selectively Induces Antiproliferation Effects and Apoptosis in Human Lung Cancer Cells through Aneupolyploidization and ATR DNA Repair Signaling.

Lung cancer is a leading cause of cancer death worldwide, and non-small-cell lung cancer (NSCLC) accounts for 85% of lung cancer, which is highly metastatic, leading to the poor survival rate of patients. We recently reported that 4-[4-(4-hydroxyphenoxy)phenoxy]phenol (4-HPPP), a phenoxyphenol, exerts antihepatoma effects by inducing apoptosis and autophagy. In this study, we further examined the effect of 4-HPPP and its analogs on NSCLC cells. Colony formation assays showed that 4-HPPP exerts selective cytotoxicity against NSCLC H1299 cells; furthermore, the inhibitory effect of 4-HPPP on the proliferation and migration of NSCLC cells was validated using an in vivo zebrafish-based tumor xenograft assay. The flow cytometry-based dichlorofluorescein diacetate (DCF-DA) assays indicated that 4-HPPP caused an increase in reactive oxygen species (ROS) in NSCLC cells, and Western blot assays showed that the major ROS scavenging enzymes superoxide dismutases- (SODs-) 1/2 were upregulated, whereas peroxidase (PRX) was downregulated. Furthermore, 4-HPPP caused both aneuploidization and the accumulation of γH2AX, a sensor of DNA damage, as well as the activation of double-strand break (DSB) markers, especially Ataxia-telangiectasia-mutated and Rad3-related (ATR) in NSCLC cells. Our present work suggests that the antiproliferative effects of 4-HPPP on lung cancer cells could be due to its phenoxyphenol structure, and 4-HPPP could be a candidate molecule for treating NSCLC by modulating ROS levels and lowering the threshold of polyploidy-specific cell death in the future.

Prognostic Role of Serum Wisteria Floribunda Agglutinin-Positive Mac-2 Binding Protein Level in Early Stage Hepatocellular Carcinoma.

The purpose of this study is to evaluate the prognostic value of preoperative Wisteria floribunda agglutinin-positive Mac-2 binding protein (WFA+-M2BP) in predicting overall survival for patients with hepatitis B- and hepatitis C-related early-stage hepatocellular carcinoma (ESHCC) after liver resection. Post-operative survival rates were compared according to WFA+-M2BP level and tumor stage. Six hundred and ten patients were identified and 198 were removed after application of the exclusion criteria; the median follow-up time was 4.33 years, and cancer-related death occurred in 117 (28.4%) patients. Age (p = 0.03), fibrosis grade (p = 0.042), cancer stage (p = 0.01), and WFA+-M2BP level (p = 0.001) were identified as independent risk factors for poor overall survival. The overall survival rates at 3 and 5 years for patients with WFA+-M2BP ≤ 1.12 were 0.92 and 0.90, respectively, and 0.76 and 0.61 for patients with WFA+-M2BP > 1.12 (p < 0.001). During the analysis of survival prediction, serum WFA+-M2BP level exhibited a higher log-likelihood and a lower AIC value compared to TNM stage (log likelihood: -638; AIC: 1279). Pre-operative serum WFA+-M2BP level provided important prognostic information after curative hepatic resection in our study.

Overexpression of dihydrodiol dehydrogenase as a prognostic marker in resected gastric cancer patients.

The cytoplasmic enzyme dihydrodiol dehydrogenase (DDH) plays an important role in detoxification. Patients with DDH overexpression have a significantly higher incidence of early tumor recurrence and distant metastasis. This study evaluated the correlation between clinicopathological data and DDH expression and the prognostic significance of DDH expression in patients with resected gastric cancer. Between January 1998 and September 2004, we retrospectively enrolled 81 patients who received surgical treatment for gastric cancer. Pathology samples were immunostained with monoclonal antibody to DDH. The relationship between DDH expression and clinicopathological data (age, gender, histological type, stage) was analyzed by chi-square analysis. Survival curves were plotted using the Kaplan-Meier method and compared using a log-rank test. The overexpression rate of DDH was 41.9%. Of patients with overexpressed DDH, 13% had stage I, 24% had stage II, 52% had stage III, and 78% had stage IV tumors. Among patients who died, DDH expression level differed significantly between high and low-expression groups (P = 0.042). Survival was significantly better in patients with low DDH expression (P = 0.048). Thus, DDH expression may be useful in identifying high-risk gastric cancer patients and distinguishing future candidates for curative and palliative treatment.

Overexpression of LGR-5 as a Predictor of Poor Outcome in Patients with Hepatocellular Carcinoma.

Hepatocarcinogenesis and distant metastasis pose major challenges for physicians. They are regulated by several genes, such as AKT, JUK, Wnt, and P53, and their expression activates several important processes such as cell proliferation, migration, motility, and interaction in the microenvironment. The leucine-rich repeat-containing G-protein-coupled receptor 5 (LGR-5) is a novel biomarker, particularly in stem cells, and is involved in embryogenesis, tumor development, and tumor cell signal transduction. Here, we investigated LGR-5 expression using immunohistochemistry and analyzed the correlation between clinical features and prognosis in patients with hepatocellular carcinoma (HCC). We found that LGR-5 expression was higher in tumor tissues than in normal liver tissues, and that high LGR-5 expression possibly favored poor outcomes in HCC, especially in well/moderate differentiation grade, hepatitis C virus (HCV)-negative, and hepatitis B virus (HBV)-positive groups. Thus, the LGR-5 marker is suggested to be a routine biomarker for poor prognosis, thereby providing a platform for anti-LGR-5-targeted therapy in the future.

Overexpression of epithelial cell adhesion molecule as a predictor of poor outcome in patients with hepatocellular carcinoma.

Cancer growth, metastasis and development are regulated by a number of genes, whose expression mediates important processes, including cellular plasticity, motility and internal interactions in the tumor microenvironment. The epithelial cell adhesion molecule (EpCAM) serves an important role in cell-cell migration and tumorigenicity, particularly metastasis. The aim of the present study was to measure EpCAM expression using immunohistochemistry and to investigate the association between clinicopathological features and prognosis in hepatocellular carcinoma (HCC). The results revealed that EpCAM expression may be a biomarker for poor prognosis in patients with HCC and may therefore be used to predict clinical outcome. The present study suggests that EpCAM expression in HCC can be considered as a routine biomarker for unfavorable prognosis and may provide a basis for the future development of anti-EpCAM-targeted therapy.