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).

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.

Reversal of hepatocyte senescence after continuous in vivo cell proliferation.

UNLABELLED: A better understanding of hepatocyte senescence could be used to treat age-dependent disease processes of the liver. Whether continuously proliferating hepatocytes could avoid or reverse senescence has not yet been fully elucidated. We confirmed that the livers of aged mice accumulated senescent and polyploid hepatocytes, which is associated with accumulation of DNA damage and activation of p53-p21 and p16(ink4a)-pRB pathways. Induction of multiple rounds continuous cell division is hard to apply in any animal model. Taking advantage of serial hepatocyte transplantation assays in the fumarylacetoacetate hydrolase-deficient (Fah(-/-)) mouse, we studied the senescence of hepatocytes that had undergone continuous cell proliferation over a long time period, up to 12 rounds of serial transplantations. We demonstrated that the continuously proliferating hepatocytes avoided senescence and always maintained a youthful state. The reactivation of telomerase in hepatocytes after serial transplantation correlated with reversal of senescence. Moreover, senescent hepatocytes harvested from aged mice became rejuvenated upon serial transplantation, with full restoration of proliferative capacity. The same findings were also true for human hepatocytes. After serial transplantation, the high initial proportion of octoploid hepatocytes decreased to match the low level of youthful liver. CONCLUSION: These findings suggest that the hepatocyte "ploidy conveyer" is regulated differently during aging and regeneration. The findings of reversal of hepatocyte senescence could enable future studies on liver aging and cell therapy.

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.

Elevated SHOX2 expression is associated with tumor recurrence of hepatocellular carcinoma.

BACKGROUND: SHOX2 (short stature homeobox 2) is a crucial transcriptional regulator in several genetic disorders and has been demonstrated to be an excellent biomarker in the diagnosis and evaluation of lung cancer. However, its expression pattern and prognostic value for hepatocellular carcinoma (HCC) are still unknown. METHODS: Expression of SHOX2 gene and protein in HCC tissues and cell lines were evaluated by RT-qPCR and western blot. Impact of RNAi-mediated SHOX2 silence on the proliferation and invasion ability of Huh7 cell line in vitro was determined by CCK-8 assay and matrigel invasion assay, respectively. RESULTS: Elevated expression of SHOX2 gene was significantly associated with higher incidence of tumor recurrence (n = 60, p = 0.001), absence of tumor capsule (p = 0.015), presence of tumor thrombi (p < 0.0001), and advanced TNM stage (p < 0.0001) of HCC. SHOX2 protein expression was more abundant in HCC cell lines compared with hepatic cell line (p = 0.001), which was associated with tumor recurrence (n = 40, p = 0.046). RNAi-mediated silence of SHOX2 expression significantly inhibited the proliferation (p < 0.001) and invasion (p = 0.006) of Huh7 cell line in vitro. CONCLUSIONS: Elevated SHOX2 expression was associated with HCC recurrence, probably by enhancing proliferation and invasion capability of cancer cells.

Alpha-fetoprotein: the predictor of microvascular invasion in solitary small hepatocellular carcinoma and criterion for anatomic or non-anatomic hepatic resection.

BACKGROUND/AIMS: This study aimed to identify the preoperative predictors of microvascular invasion (MVI) in solitary small hepatocellular carcinoma (HCC) and evaluate their application in surgical treatment. METHODOLOGY: We retrospectively analyzed 161 patients with solitary small HCC who underwent curative hepatic resection. Overall and disease-free survival rates were calculated by Kaplan-Meier method and compared by log-rank test. The independent predictors were identified by Cox proportional hazards model. RESULTS: MVI was an independent predictor of both overall and disease-free survival. In 51 patients with MVI, anatomic resection achieved better survival than non-anatomic resection. However, anatomic resection and non-anatomic resection brought similar survival in patients without MVI. Alpha-fetoprotein (AFP) was identified as the unique predictor of MVI (HR=2.773, p=0.004). Anatomic resection achieved better survival outcome than non-anatomic resection when AFP >100µg/L (5-year overall survival rate: 85% vs. 55%, p=0.024; 5-year disease-free survival rate: 37% vs. 21%, p=0.025), while there was no statistical survival difference between anatomic and non-anatomic resection when AFP <=100µg/L (5-year overall survival rate: 85% vs. 76%, p=0.838; 5-year disease-free survival rate: 48% vs. 49%, p=0.921). CONCLUSIONS: Compared with non-anatomic resection, anatomic hepatic resection improves overall and disease-free survival of solitary small HCC patients with AFP >100µg/L.

[Expression of CD90/EpCAM/CD24 in hepatocellular carcinoma cell lines at various stages of differentiation].

OBJECTIVE: To confirm the malignant phenotype of hepatocarcinoma cell (HCC) lines at various stages of differentiation (MHCC97L, MHCC97H and HCCLM3) and to explore their expression levels of cancer stem cell (CSC) markers. METHODS: The invasive and proliferative properties of each HCC line were assessed by transwell assay and the Cell Counting Kit-8 (CCK-8) colorimetric assay. Sensitivity to chemotherapy was assessed by treatment with oxaliplatin and determination of the half inhibitory concentration (IC50). The expression of CD90, EpCAM and CD24 was measured by flow cytometry. RESULTS: The number of cells that migrated through the invasion assay membrane were significantly different between the three HCC lines: HCCLM3 (30.57 +/- 8.95) more than MHCC97H (21.33 +/- 4.17) more than HCC97L (9.33 +/- 3.85), P less than 0.01. The IC50 was significantly different between the three HCC lines: HCCLM3 (36.57 +/- 6.95) mumol/L more than MHCC97H (26.35+/-3.88) mumol/L more than MHCC97L (17.68 +/- 3.25) mumol/L. The CSC marker with the highest expression on all three HCC lines was CD90 (HCCLM3: 0.92% +/- 0.21%, MHCC97H: 1.98% +/- 0.23%, and MHCC97L: 2.55% +/- 0.34%), followed by EpCAM (2.11% +/- 0.32%, 3.23% +/- 0.18%, and 4.38% +/-0.49%, respectively), and CD24 as the lowest (0.68% +/- 0.37%, 1.22% +/- 0.26%, and 1.36% +/- 0.24%, respectively). CONCLUSION: Higher expression of CSC markers on HCC lines is associated with a stronger invasive ability and higher sensitivity to chemotherapy.

Long noncoding RNA high expression in hepatocellular carcinoma facilitates tumor growth through enhancer of zeste homolog 2 in humans.

UNLABELLED: In recent years, long noncoding RNAs (lncRNAs) have been shown to have critical regulatory roles in cancer biology. However, the contributions of lncRNAs to hepatitis B virus (HBV)-related hepatocellular carcinoma (HCC) remain largely unknown. Differentially expressed lncRNAs between HBV-related HCC and paired peritumoral tissues were identified by microarray and validated using quantitative real-time polymerase chain reaction. Liver samples from patients with HBV-related HCC were analyzed for levels of a specific differentially expressed lncRNA High Expression In HCC (termed lncRNA-HEIH); data were compared with survival data using the Kaplan-Meier method and compared between groups by the log-rank test. The effects of lncRNA-HEIH were assessed by silencing and overexpressing the lncRNA in vitro and in vivo. The expression level of lncRNA-HEIH in HBV-related HCC is significantly associated with recurrence and is an independent prognostic factor for survival. We also found that lncRNA-HEIH plays a key role in G(0) /G(1) arrest, and further demonstrated that lncRNA-HEIH was associated with enhancer of zeste homolog 2 (EZH2) and that this association was required for the repression of EZH2 target genes. CONCLUSIONS: Together, these results indicate that lncRNA-HEIH is an oncogenic lncRNA that promotes tumor progression and leads us to propose that lncRNAs may serve as key regulatory hubs in HCC progression.

Patients with multiple hepatocellular carcinomas within the UCSF criteria have outcomes after curative resection similar to patients within the BCLC early-stage criteria.

BACKGROUND: Surgical strategies for the treatment of multiple hepatocellular carcinomas (HCC) remain controversial. This study compared the prognostic power of the University of California, San Francisco (UCSF) criteria with the Barcelona Clinic Liver Cancer (BCLC) early-stage criteria. METHODS: Clinical and survival data of 162 multiple-HCC patients in Child-Pugh class A who underwent curative resection were retrospectively reviewed. Prognostic risk factors were analyzed using univariate and multivariate analyses. RESULTS: UCSF criteria were shown to independently predict overall and disease-free survival. In patients within the UCSF criteria, 3-year overall and disease-free survivals were significantly better than in those exceeding the UCSF criteria (68 vs. 34 % and 54 vs. 26 %, respectively; both p < 0.001). There were no significant differences in 3-year overall and disease-free survival between patients within the UCSF criteria but exceeding the BCLC early stage and patients with BCLC early-stage disease (71 vs. 66 %, p = 0.506 and 57 vs. 50 %, p = 0.666, respectively). Tumors within the UCSF criteria were associated with a lower incidence of high-grade tumor (p = 0.009), microvascular invasion (p = 0.005), 3-month death (p = 0.046), prolonged Pringle's maneuver (p = 0.005), and surgical margin <0.5 cm (p < 0.001) than those exceeding the UCSF criteria. Tumors within the UCSF criteria but exceeding the BCLC early stage had invasiveness and surgical difficulty similar to those within the BCLC early-stage criteria. CONCLUSIONS: Multiple HCC patients within the UCSF criteria benefit from curative resection. Expansion of curative treatment is justified.

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.

Diagnosis and treatment of hepatic angiomyolipoma.

BACKGROUND AND OBJECTIVE: Hepatic angiomyolipoma is more frequently encountered in clinical practice, its diagnosis is difficult, its treatment remains controversial. We review a single-center experience in the treatment of hepatic angiomyolipoma. METHOD: The clinical data of 79 patients with hepatic angiomyolipoma treated at the authors' institute between January 1992 and December 2006 were retrospectively reviewed. RESULTS: During a period of 15 years, a total of 79 patients with hepatic angiomyolipoma underwent liver resection at our hospital. There are 58 women and 21 men. The tumor size varied from 1 to 25 cm in diameter (6.1 ± 4.08). Fifty-four patients (68%) were asymptomatic. Accurate preoperative diagnosis was made in 41 patients (52%). Tumors less than 6 cm in size were more frequently misdiagnosed. Spontaneous rupture occurred in one patient. One patient had tumor recurrence 6 years after the surgery, and died of the disease 1 year later. Symptom relief was achieved in 92% of the symptomatic patients. Median survival was 90 months (90.12 ± 30.84). CONCLUSIONS: Hepatic angiomyolipoma poses a diagnostic challenge clinically and radiologically. Surgical resection is a safe and effective treatment option. It is important to realize the potential of malignant transformation and risk of rupture as life-threatening complications.

Risk factors influencing postoperative outcomes of major hepatic resection of hepatocellular carcinoma for patients with underlying liver diseases.

BACKGROUND: Major hepatic resection of more than three segments in patients with hepatocellular carcinoma (HCC) is a high-risk operation, especially in patients with co-existing underlying liver diseases. The present study evaluated risk factors for postoperative morbidity and mortality after major hepatic resection in HCC patients with underlying liver diseases. METHODS: Perioperative data of 305 HCC patients with underlying liver diseases who underwent major hepatic resection were evaluated by univariate and multivariate analyses to identify risk factors for postoperative morbidity and mortality. RESULTS: The overall morbidity rate was 37.0% (n = 113), caused by pleural effusion (n = 56), ascites (n = 43), subphrenic effusion/infection (n = 23), hepatic dysfunction (n = 22), bile leakage (n = 10), respiratory infection (n = 7), incision infection (n = 7), intra-abdominal hemorrhage (n = 5), and others. The hospital mortality rate was 2.6% (n = 8), primarily caused by liver failure (4/8). Multivariate logistic regression analysis showed that preoperative platelet count <100 × 10(9)/l (P = 0.006), and increased intraoperative blood loss (≥ 800 ml) (P = 0.008) were independent risk factors of postoperative morbidity, and that preoperative prothrombin time >14 s (P = 0.015) and preoperative platelet count <100 × 10(9)/l (P = 0.007) were independent risk factors for significant hospital mortality. CONCLUSIONS: Careful preoperative selection of patients in terms of the Child-Pugh classification and decrease of intraoperative blood loss are important measures to reduce postoperative morbidity after major hepatic resection in HCC patients with underlying liver diseases. Moreover, we should be aware that preoperative platelet count is independently associated with postoperative morbidity and mortality for those patients following major hepatic resection.

Hepatectomy for bilateral primary hepatolithiasis: a cohort study.

OBJECTIVE: This study aimed to evaluate the perioperative and long-term results of partial hepatectomy for patients with complicated bilateral primary hepatolithiasis. SUMMARY BACKGROUND DATA: Hepatolithiasis is best managed by a multidisciplinary approach. Definitive treatment can be offered using endoscopic, percutaneous, laparoscopic, or open surgical approaches. Partial hepatectomy is only indicated for recurrent, troublesome, localized, and severe disease affecting the liver. METHODS: From January 2000 to December 2006, 136 consecutive patients who underwent bilateral (n = 54) or unilateral (n = 82) hepatectomy for biliary strictures and bilateral primary hepatolithiasis in our center were included in this study. All patients had concomitant bile duct exploration. Their perioperative and long-term outcomes were analyzed. RESULTS: The immediate stone clearance rates after bilateral and unilateral hepatectomy were 81.5% and 65.9%, respectively. Additional postoperative choledochoscopic lithotripsy raised the clearance rates to 85.2% and 81.7%, respectively. The hospital mortality rates were 5.6% and 0%, respectively, and the complication rates were 46.3% and 46.3%, respectively. The 5-year overall survival rates were 98% and 91.5%, respectively. CONCLUSION: In selected patients with biliary strictures and bilateral hepatolithiasis, partial hepatectomy associated with choledochoscopic lithotripsy is a safe and efficacious treatment, with a high immediate stone clearance rate, a low long-term stone recurrence rate and good long-term survival.

[Therapeutical effect of combined hepatic resection and fenestration on patients with severe adult polycystic liver disease].

OBJECTIVE: To evaluate therapeutical effect of combined hepatic resection and fenestration on patients with severe adult polycystic liver disease (APLD). METHODS: Preoperative clinical symptoms, postoperative complications and prognoses from 33 patients with severe adult polycystic liver disease (APLD) treated with combined hepatic resection and fenestration were recorded. According to the number and location of cysts before surgery and the remnant liver parenchyma after operation, all patients were classified into two types: class A and B. And patients in each type were further classified into three grades: Grade I, II and III. The frequency of postoperative complications of two types patients was compared. RESULTS: The mean follow-up time was 57 months. There were three patients with recurrence of symptoms at 81, 68 and 43 mouths after operation. Two patients died of renal failure due to polycystic kidney disease at 137 and 85 mouths after operation. And one patient with postoperative hepatic inadequacy received an orthotopic liver transplantation. The total number of patients with postoperative complications was 26 cases, including one patient with bleeding, two patients with bile leakage, fourteen patients with mild ascites, twelve patients with severe ascites and eighteen patients with pleural effusion, and the overall incidence was 78.8%. There were 22 patients with imaging data, including 6 patients within A type and sixteen patients within B type. The frequencies of postoperative complications were 4 and 31, respectively, and the difference was statistically significant (Chi-square test = 4.99, P less than 0.05). CONCLUSION: Combined hepatic resection and fenestration is a safe and acceptable procedure for the treatment of severe APLD.

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.

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.

Orthotopic liver transplantation as a rescue operation for recurrent hepatocellular carcinoma after partial hepatectomy.

AIM: To compare post-orthotopic liver transplantation (OLT) survival between patients with recurrent hepatocellular carcinoma (HCC) after partial hepatectomy and those who received de novo OLT for HCC and to assess the risk factors associated with post-OLT mortality. METHODS: From July 2003 to August 2005, 77 consecutive HCC patients underwent OLT, including 15 patients with recurrent HCC after partial hepatectomy for tumor resection (the rescue OLT group) and 62 patients with de novo OLT for HCC (the de novo OLT group). Thirty-three demographic, clinical, histological, laboratory, intra-operative and post-operative variables were analyzed. Survival was calculated by the Kaplan-Meier method. Univariable and multivariable analyses were also performed. RESULTS: The median age of the patients was 49.0 years. The median follow-up was 20 mo. Three patients (20.0%) in the rescue OLT group and 15 patients (24.2%) in the de novo OLT group died during the follow-up period (P = 0.73). The 30-day mortality of OLT was 6.7% for the rescue OLT group vs 1.6% for the de novo OLT group (P = 0.27). Cox proportional hazards model showed that pre-OLT hyperbilirubinemia, the requirement of post-OLT transfusion, the size of the tumor, and family history of HCC were significantly associated with a higher hazard for mortality. CONCLUSION: There are no significant differences in survival/mortality rates between OLT as de novo therapy and OLT as a rescue therapy for patients with hcc. Pre-OLT hyperbilirubinemia, post-OLT requirement of transfusion, large tumor size and family history of HCC are associated with a poor survival outcome.

Treatment of polycystic liver disease with resection-fenestration and a new classification.

AIM: To evaluate outcomes in patients with autosomal dominant polycyst liver disease (APLD) treated by combined hepatic resection and fenestration. A new classification was recommended to presume postoperative complications and long outcome of patients. METHODS: Twenty-one patients with APLD were treated by a combined hepatic resection and fenestration technique. All patients were reviewed retrospectively, and clinical symptoms, performance status and morbidity were recorded. A new classification of APLD is recommended here. RESULTS: All patients were discharged when free of symptoms. The mean follow-up time was 55.7 mo and three patients had a recurrence of symptoms at 81, 68 and 43 mo after operation, respectively. The overall morbidity rate was 76.2%. Two patients with Type B-II and Type B-I developed biliary leakage. Four patients had severe ascites, including three with Type B-III and one with Type B-II. Nine patients had pleural effusion, including one with Type A-I; one with Type B-I; five with Type B-II; one with Type A-III and one with Type B-III. Three patients with Type B had recurrence of symptoms, while none with Type A had severe complications. CONCLUSION: Combined hepatic resection and fenestration is an acceptable procedure for treatment of APLD. According to our classification, postoperative complications and long outcome can be predicted before surgery.

Micrometastasis in surrounding liver and the minimal length of resection margin of primary liver cancer.

AIM: To describe the distribution of micrometastases in the surrounding liver of patients with primary liver cancer (PLC), and to describe the minimal length of resection margin (RM) for hepatectomy. METHODS: From November 2001 to March 2003, 120 histologically verified PLC patients without macroscopic tumor thrombi or macrosatellites or extrahepatic metastases underwent curative hepatectomy. Six hundreds and twenty-nine routine pathological sections from these patients were re-examined retrospectively by light microscopy. In the prospective study, curative hepatectomy was performed from November 2001 to March 2003 for 76 histologically verified PLC patients without definite macroscopic tumor thrombi or macrosatellites or extrahepatic metastases in preoperative imaging. Six hundreds and forty-five pathological sections from these patients were examined by light microscopy. The resected liver specimens were minutely examined to measure the resection margin and to detect the number of daughter tumor nodules, dominant lesions, and macroscopic tumor thrombi inside the lumens of the major venous system. The paraffin sections were microscopically examined to detect the microsatellites, microscopic tumor thrombi, fibrosis tumor capsules, as well as capsule invasion and the distance of histological spread of the micrometastases. RESULTS: In the retrospective study, 70 micrometastases were found in surrounding liver in 26 of the 120 cases (21.7%). The farthest distance of histological micrometastasis was 3.5 mm, 5.3 mm and 6.0 mm in 95%, 99% and 100% cases, respectively. Macroscopic tumor thrombi or macrosatellites were observed in 18 of 76 cases, and 149 micrometastases were found in the surrounding live in 25 (43.1%) of 58 cases with no macroscopic tumor thrombi. The farthest distance of histological micrometastasis was 4.5 mm, 5.5 mm and 6.0 mm in 95%, 99% and 100% cases, respectively. Two hundred and sixty-seven micrometastases were found in surrounding liver in 14 (77.8%) out of 18 cases with macroscopic tumor thrombi or macrosatellites. The farthest distance of histological micrometastasis was 18.5 mm, 18.5 mm and 19.0 mm in 95%, 99% and 100% cases, respectively. CONCLUSION: The required minimal length of RM is 5.5 mm and 6 mm respectively to achieve 99% and 100% micrometastasis clearance in surrounding liver of PLC patients without macroscopic tumor thrombi or macrosatellites, and should be greater than 18.5 mm to obtain 99% micrometastasis clearance in surrounding liver of patients with macroscopic tumor thrombi or macrosatellites.