Background
Different approaches to surgical treatment of portal vein tumor thrombosis (PVTT) have been advocated. This study investigated the outcomes of different surgical approaches in ...hepatocellular carcinoma (HCC) patients with PVTT.
Methods
We reviewed prospectively collected data for all patients who underwent hepatectomy for HCC at our hospital between December 1989 and December 2010. Patients were excluded from analysis if they had extrahepatic disease, PVTT reaching the level of the superior mesenteric vein, or hepatectomy with a positive resection margin. The remaining patients were divided into three groups for comparison: group 1, with ipsilateral PVTT resected in a hepatectomy; group 2, with PVTT extending to or beyond the portal vein bifurcation, treated by en bloc resection followed by portal vein reconstruction; group 3, with PVTT extending to or beyond the portal vein bifurcation, treated by thrombectomy.
Results
A total of 88 patients, with a median age of 54 years, were included in the analysis. Group 2 patients were younger, with a median age of 43.5 years versus 57 in group 1 and 49 in group 3 (
p
= 0.017). Group 1 patients had higher preoperative serum alpha-fetoprotein levels, with a median of 8,493 ng/mL versus 63.25 in group 2 and 355 in group 3 (
p
= 0.004), and shorter operation time, with a median of 467.5 min versus 663.5 in group 2 and 753 in group 3 (
p
= 0.018). No patient had thrombus in the main portal vein. Two (2.8 %) hospital deaths occurred in group 1 and one (10 %) in group 2, but none in group 3 (
p
= 0.440). The rates of complication in groups 1, 2, and 3 were 31.9, 50.0, and 71.4 %, respectively (
p
= 0.079). The median overall survival durations were 10.91, 9.4, and 8.58 months, respectively (
p
= 0.962), and the median disease-free survival durations were 4.21, 3.78, and 1.51 months, respectively (
p
= 0.363). The groups also had similar patterns of disease recurrence (intrahepatic: 33.8 vs. 28.6 vs. 40.0 %; extrahepatic: 16.9 vs. 14.3 vs. 0 %; both: 28.2 vs. 42.9 vs. 40.0 %; no recurrence: 21.1 vs. 14.3 vs. 20.0 %;
p
= 0.836).
Conclusions
The three approaches have similar outcomes in terms of survival, complication, and recurrence. Effective adjuvant treatments need to be developed to counteract the high incidence of recurrence.
Activation of the stem cell transcriptional circuitry is an important event in cancer development. Although cancer cells demonstrate a stem cell-like gene expression signature, the epigenetic ...regulation of pluripotency-associated genes in cancers remains poorly understood. In this study, we characterized the epigenetic regulation of the pluripotency-associated genes NANOG, OCT4, c-MYC, KLF4, and SOX2 in a variety of cancer cell lines and in primary tumor samples, and investigated the re-activation of pluripotency regulatory circuits in cancer progression. Differential patterns of DNA methylation, histone modifications, and gene expression of pluripotent genes were demonstrated in different types of cancers, which may reflect their tissue origins. NANOG promoter hypomethylation and gene upregulation were found in metastatic human liver cancer cells and human hepatocellular carcinoma (HCC) primary tumor tissues. The upregulation of NANOG, together with p53 depletion, was significantly associated with clinical late stage of HCC. A pro-metastatic role of NANOG in colon cancer cells was also demonstrated, using a NANOG-overexpressing orthotopic tumor implantation mouse model. Demethylation of NANOG promoter was observed in CD133+(high) cancer cells. In accordance, overexpression of NANOG resulted in an increase in the population of CD133+(high) cells. In addition, we demonstrated a cross-regulation between OCT4 and NANOG in cancer cells via reprogramming of promoter methylation. Taken together, epigenetic reprogramming of NANOG can lead to the acquisition of stem cell-like properties. These results underscore the restoration of pluripotency circuits in cancer cells as a potential mechanism for cancer progression.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Laparoscopic liver resection has been reported as a safe and effective approach to the management of liver cancer. However, studies of long-term outcomes regarding tumor recurrence and patient ...survival in comparison with the conventional open approach are limited. The aim of this study was to analyze the survival outcome of laparoscopic liver resection versus open liver resection.
Between October 2002 and September 2009, 32 patients underwent pure laparoscopic liver resection for hepatocellular carcinoma (HCC). Case-matched control patients (n = 64) who received open liver resection for HCC were included for comparison. Patients were matched in terms of cancer stage, tumor size, location of tumor, and magnitude of resection. Immediate operation outcomes, operation morbidity, disease-free survival, and overall survival were compared between groups.
With the laparoscopic group compared with the open resection group, operation time was 232.5 minutes versus 204.5 minutes (P = 0.938), blood loss was 150 mL versus 300 mL (P = 0.001), hospital stay was 4 days versus 7 days (P < 0.0001), postoperative complication was 2 (6.3%) versus 12 (18.8%) (P = 0.184), disease-free survival was 78.5 months versus 29 months (P = 0.086), and overall survival was 92 months versus 71 months (P = 0.142). The disease-free survival for stage II HCC was 22.1 months versus 12.4 months (P = 0.075).
Laparoscopic liver resection for HCC is associated with less blood loss, shorter hospital stay, and fewer postoperative complications in selected patients with no compromise in survival.
Notch signaling, a critical pathway for tissue development, also contributes to tumorigenesis in many cancers, but its pathological function in liver cancer is not well defined. In our study, Notch1 ...expression and its clinicopathological parameters were evaluated in 82 human hepatocellular carcinoma (HCC) patients. Plasmid‐based siNotch1 shRNA was transiently or stably transfected into metastatic HCC cells and subsequently evaluated for the effects on orthotopic liver tumor metastasis in a mouse model as well as the effects on downstream pathways. Aberrant high expression of Notch1 was significantly associated with metastatic disease parameters in HCC patients, such as tumor‐node‐metastasis Stages III–IV and tumor venous invasion. Knocking‐down Notch1 reduced cell motility in vitro and orthotopic tumor metastasis from the liver to the lung in vivo in a mouse model. In metastatic HCC cells, abnormal expression of Notch1 was associated with increased expression of Snail1 and repressed expression of E‐cadherin; the Notch1‐Snail1‐E‐cadherin association can also be found in HCC patient tumors. Inhibition of Notch1 by shRNA abolished Snail1 expression, which further resulted in the re‐establishment of repressed E‐cadherin in metastatic HCC cells. Thus, abnormal Notch1 expression was strongly associated with HCC metastatic disease, which might be mediated through the Notch1‐Snail1‐E‐cadherin pathway. Knock‐down of Notch1 reversed HCC tumor metastasis in a mouse model. Therefore, these data suggest that effective targeting of Notch signaling might also inhibit tumor metastasis.
We previously demonstrated Proline rich tyrosine kinase 2 (Pyk2) plays important roles in regulating tumor progression, migration and invasion in hepatocellular carcinoma (HCC). In this study, we ...aimed to examine the role of proline rich tyrosine kinase 2 (Pyk2) on cisplatin resistance in HCC and to explore its underlying molecular mechanism.
Stable transfectants either overexpressing or suppressing Pyk2 were established in different HCC cell lines. MTT, colony formation and Annexin-V assays were employed to examine their in vitro responses to cisplatin. Xenograft ectopic and orthotopic nude mice models were generated to investigate the in vivo responses of them to cisplatin treatment. cDNA microarray was performed to identify Pyk2-induced genes which were further validated by quantitative real-time RT-PCR using clinical HCC samples. In vitro functional study demonstrated that Pyk2-overexpressing HCC transfectants exhibited relatively lower cytotoxicity, higher colony-forming ability and lower apoptosis to cisplatin compared with the control transfectants. Moreover, Pyk2 overexpressing HCC transfectants had a higher survival rate under cisplatin treatment by up-regulation of AKT phosphorylation. In vivo xenograft nude mice model demonstrated that Pyk2-overexpressing transfectants developed higher tolerance to cisplatin treatment together with less tumor necrosis and apoptosis. cDNA microarray analysis revealed that there were more than 4,000 genes differentially expressed upon overexpression of Pyk2. Several upregulated genes were found to be involved in drug resistance and invasion in cancers. Among them, the expression profiles of MDR1, GAGE1, STAT1 and MAP7 were significantly associated with the expression of Pyk2 in clinical HCC samples.
Our results may suggest a new evidence of Pyk2 on promoting cisplatin resistance of HCC cells through preventing cell apoptosis, activation of AKT pathway and upregulation of drug resistant genes.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
This phase I/II single-arm study evaluated the safety, pharmacokinetics, pharmacodynamics, and activity of foretinib, an oral multikinase inhibitor of MET, ROS, RON, AXL, TIE-2, and VEGFR2, in the ...first-line setting in advanced hepatocellular carcinoma patients.
In the phase I part, advanced hepatocellular carcinoma patients were dose escalated on foretinib (30-60 mg) every day using the standard 3+3 design. Once the maximum tolerated dose (MTD) was determined, an additional 32 patients were dosed at the MTD in the phase II expansion cohort for assessment of efficacy and safety. Exploratory analyses were conducted to assess potential biomarkers that might correlate with clinical efficacy and survival.
The MTD of foretinib was established as 30 mg every day. The most frequent adverse events were hypertension, decreased appetite, ascites, and pyrexia. When dosed at 30 mg every day in the first-line setting, foretinib demonstrated promising antitumor activity. According to the modified mRECIST, the objective response rate was 22.9%, the disease stabilization rate 82.9%, and the median duration of response 7.6 months. The median time to progression was 4.2 months and the median overall survival (OS) was 15.7 months. Fifteen candidate biomarkers whose levels in the circulation were significantly altered in response to foretinib treatment were elucidated. Multivariate analyses identified IL6 and IL8 as independent predictors of OS.
Foretinib demonstrated promising antitumor activity and good tolerability in the first-line setting in Asian advanced hepatocellular carcinoma patients. Baseline plasma levels of IL6 or IL8 might predict the response to foretinib.
.
Background & Aims Patients with hepatocellular carcinoma (HCC) receiving living donor liver transplantation appear to possess significantly higher tumor recurrence than the recipients receiving ...deceased donor liver transplantation. The underlying mechanism for HCC recurrence after transplantation remains unclear. Here, we aim to investigate the impact of small-for-size liver graft injury on HCC recurrence after transplantation. Methods The correlation between tumor recurrence, liver graft injury, CXCL10 expression and endothelial progenitor cell (EPC) mobilization was studied in 115 liver transplant recipients and rat orthotopic liver transplantation (OLT) models. The direct role of CXCL10/CXCR3 signaling on EPC mobilization was investigated in CXCL10−/− mice and CXCR3−/− mice. The role of EPCs on tumor growth and angiogenesis was further investigated in an orthotopic liver tumor model. Results Clinically, patients with small-for-size liver grafts (<60% of standard liver weight, SLW) had significantly higher HCC recurrence ( p = 0.04), accompanied by more circulating EPCs and higher early-phase intragraft and plasma CXCL10 levels, than the recipients with large grafts (⩾60% of SLW), which were further validated in rat OLT models. Circulatory EPC mobilization was reduced after liver injury both in CXCL10−/− mice and CXCR3−/− mice in comparison to wild-type controls. CXCL10 recruited EPCs in dose-dependent and CXCR3-dependent manners in vitro . Early-phase EPC/CXCL10 injection enhanced orthotopic liver tumor growth, angiogenesis and metastasis in nude mice. Conclusions Post-transplant enhanced CXCL10/CXCR3 signaling in small-for-size liver grafts directly induced EPC mobilization, differentiation and neovessel formation, which further promotes tumor growth. Targeting CXCL10/CXCR3 signaling may attenuate early-phase liver graft injury and prevent late-phase tumor recurrence/metastasis after transplantation.
Poor prognosis of hepatocellular carcinoma (HCC) is associated with a high potential of vascular invasion and metastasis. Epithelial-mesenchymal transition (EMT) is a key event in the tumor invasion ...process. Recently, signal transducers and activators of transcription 5 (STAT5) has been linked to tumor progression by EMT induction. However, the precise roles of STAT5 genes (STAT5a and STAT5b) in human epithelial cancers have not been elucidated clearly. The aim of this study is to analyze the roles of STAT5 isoforms in HCC progression using HCC clinical samples. We showed that activation of STAT5b, but not STAT5a, was found in HCC clinical samples and its expression was significantly associated with younger age (P = 0.037), advanced tumor stages (P = 0.003), venous infiltration (P = 0.016), microsatellite formation (P = 0.024), multiple tumor nodules (P = 0.02), and poor patient survival. To specifically investigate the mechanism underlying constitutive activation of STAT5b in HCC, EGFP-HBX was introduced into Huh-7 cells. STAT5b activation in HCC is at least partially mediated by HBX activation. Ectopic STAT5b transfection conferred increased HCC cell motility and invasiveness by induction of EMT changes. In conclusion, STAT5b activation enhanced HCC aggressiveness by induction of EMT, which was possibly mediated by HBX activation. STAT5b could serve as a novel molecular target for HCC treatment.
ObjectiveSerum α-fetoprotein (AFP) is the most commonly used biomarker for screening hepatocellular carcinoma (HCC) but fails to detect about half of the patients. Thus, we investigated if ...circulating microRNAs (miRNAs) could outperform AFP for HCC detection.DesignA retrospective cohort study.SettingTwo clinical centres in China.ParticipantsThe exploration phase included 96 patients with HCC who received primary curative hepatectomy, and the validation phase included 29 hepatitis B carriers, 57 patients with HCC and 30 healthy controls.Main outcome measuresExpression of miRNAs was measured by real-time quantitative reverse transcription–PCR. Areas under receiver operating characteristic curves were used to determine the feasibility of using serum miRNA concentration as a diagnostic marker for defining HCC. A multivariate logistic regression analysis was used to evaluate performances of combined serum miRNAs.ResultsIn the exploration phase, miRNA profiling on resected tumour/adjacent non-tumour tissues identified miR-15b, miR-21, miR-130b and miR-183 highly expressed in tumours. These miRNAs were also detectable in culture supernatants of HCC cell lines and in serum samples of patients. Remarkably, these serum miRNAs were markedly reduced after surgery, indicating the tumour-derived source of these circulating miRNAs. In a cross-centre validation study, combined miR-15b and miR-130b demonstrated as a classifier for HCC detection, yielding a receiver operating characteristic curve area of 0.98 (98.2% sensitivity and 91.5% specificity). The detection sensitivity of the classifier in a subgroup of HCCs with low AFP (<20 ng/ml) was 96.7%. The classifier also identified early-stage HCC cases that could not be detected by AFP.ConclusionThe combined miR-15b and miR-130b classifier is a serum biomarker with clinical value for HCC screening.
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