[Diagnosis and treatment of primary hepatic angiosarcoma: a report of 7 cases with a literature review].

OBJECTIVE: To explore the clinical features, diagnosis, treatment and prognosis of primary hepatic angiosarcoma (PHA). METHODS: The clinical data of 7 PHA patients admitted to our hospital from December 2004 to December 2010 were retrospectively analyzed and the relevant literatures reviewed. RESULTS: Seven cases (5 males and 2 females) were diagnosed as PHA among 1027 (0.68%) patients with primary hepatic malignant tumors. Their mean age was 43.3 years old (range: 33 - 74). Four cases were of solitary lesion and three of multiple lesions. No specific clinical features were observed. The PHA lesions were easily misdiagnosed as benign or hepatic metastatic tumors. Contrast enhanced ultrasound (CEUS) showed the lesions with characteristic manifestations. And the positron emission tomography (PET-CT) could confirm the hepatic lesions as malignant tumors. The survival time for two untreated cases was 3 & 5 months, for two cases with liver transplantation (LTx) 3 & 8 months and for two cases treated with surgical resection & targeted therapy was 14 & 19 months respectively. One case was lost to follow-up at 6 months after hepatic resection. CONCLUSION: PHA is a clinically rare and highly malignant tumor with a rapid progression and a poor prognosis. Both CEUS and PET-CT are helpful for its differential and confirmative diagnosis. LTx should be considered as a contraindication for PHA. Hepatic resection has proven to be beneficial for PHA patients with solitary lesion. Surgical resection plus targeted medicines may improve their survival.

[A survival analysis of patients with early-stage hepatocellular carcinoma fulfilling Milan criteria and undergoing hepatectomy].

OBJECTIVE: To summarize the experience of hepatectomy in patients with hepatocellular carcinoma fulfilling the Milan criteria and analyze the clinicopathological factors for patient survival and tumor recurrence. METHODS: The clinicopathological data of 104 patients with early-stage hepatocellular carcinoma fulfilling the Milan criteria and underwent hepatectomy at Peking Union Medical College Hospital between April 2003 and June 2009 were retrospectively analyzed. RESULTS: The median follow-up was 24 months. There were 54 recurrent cases. The 1-, 3- and 5-year cumulative disease-free survival rate were 63.0%, 32.6% and 22.4% respectively. Neither univariate analysis nor multivariate analysis indicated any factor significantly correlated with recurrence (P>0.05). The cumulative overall survival rate at 1, 3 and 5 years were 88.8%, 68.1% and 68.1% respectively. Univariate analysis revealed that blood transfusion (P=0.000), involvement of hepatic capsule (P=0.000) and postoperative transarterial chemotherapy (P=0.049) were significantly correlated with survival. And multivariate analysis indicated that blood transfusion (P=0.001) and involvement of hepatic capsule (P=0.000) were independent prognostic factors for survival. CONCLUSION: For the patients with early-stage hepatocellular carcinoma and compensated liver function fulfilling the Milan criteria, hepatectomy serves as the preferred treatment strategy.

[Diagnosis and treatment of pancreatic metastasis from renal cell carcinoma].

OBJECTIVE: Pancreatic metastasis from renal cell carcinoma (RCC) is a rare event and has not been reported in our country. We report a series of 3 patients with metastatic RCC to the pancreas after radical nephrectomy at our institution. The published reports in the literature were reviewed, and the diagnosis, treatment as well as prognosis of this rare event were discussed. METHODS: The data of 3 RCC patients with metastasis to the pancreas were reviewed retrospectively, including radical nephrectomy, metastatic interval, the second and third surgical removal. Survival of the three patients was analyzed and the reports in the literature were compared as well. RESULTS: The average interval from radical nephrectectomy to the comfirmed pancreatic metastasis was 6.6 years (range, 1.2 to 12 years). The pathological stage revealed T2N0M0 (n = 2) or T3N0M0 (n = 1), with right-sided tumor in 2 patients and left side in 1. One patient was asymptomatic, while the other two cases were symptomatic at presentation, including upper abdominal pain, weight loss, slight xanthochromia of the skin and titillation, clay stool (n = 1); irregular fever, weight loss and jaundice (n = 1). All pancreatic metastases were hypervascular on arterial stage of CT imaging. One patient had only a solitary pancreatic metastasis (n = 1), the another showed two metastatic lesions (n = 1), the third one had multiple lesions (n = 1). Surgical removal was accomplished in 2 patients: including pylorus-preserving pancreaticoduodenectomy in one, and pylorus-preserving pancreaticoduodenectomy together with partial tail resection in another one. The third one only received interventional therapy due to widespread extrapancreatic metastasis, and died of disseminated disease 11 months after the therapy. One of the above two surgically treated patients underwent the second removal due to local recurrence 2.5 years after the first removal of pancreatic metastasis. These two patients were still alive after follow-up of 8.6 years and 16.1 years, respectively. CONCLUSION: Renal cell carcinoma is an unpredictable tumor that may demonstrate very delayed metastasis even from early-stage of the disease. The pancreas is a rare site of metastasis from renal cell carcinoma. We advocate careful long-term follow-up of patients with a history of RCC. Aggressive surgical management of pancreatic metastatic lesions may provide a chance of long-term survival.

[Clinical experiences of surgical manipulations for hepatic masses in difficult sites].

OBJECTIVE: To summarize the surgical experiences, risks, complications, and managements for hepatic masses in difficult sites. METHODS: Totally 47 patients were divided into three groups based on the liver tumor sites: primary porta hepatis group, secondary porta hepatis group, and caudate lobe group. All patients underwent different portion of hepatectomy. RESULTS: The surgery duration was (289.6 +/- 62.2) ml-nutes, intra-operative blood loss was (602.3 +/- 256.4) ml, and intra-operative blood transfusion was (524.0 +/- 325.9) ml. Incidence of surgical complications in each group was 61.5%, 26.9%, and 25%, respectively. Serious complications observed were biliary leakage (27.7%), bleeding (6.4%), and post-operative liver failure (2.1%). Three perioperative deaths were reported: two patients died of bleeding, and one patient died from liver failure. CONCLUSIONS: Dissection of the liver and exposure of major blood vessels and biliary ducts are of critical importance in the surgeries for hepatic masses in difficult sites, and post-operative complications may be remarkably reduced through delicate manipulations of the small intra-hepatic vessels and biliary ducts during resection. A thorough pre-operative evaluation plays a key role in predicting the feasibility and risks of the surgery. Damage to the major blood vessels adjacent to the tumor, in addition to bleeding, may result in in-flow or outflow obstruction and cause necrosis of the corresponding hepatic lobe. Compared with damage to the primary portal area, vascular damage to the secondary porta is generally associated with higher fatality.

[Preoperative evaluation of liver function using 99mTc-diethyl iminodiacetic acid based on single photon emission computed tomography].

OBJECTIVE: To establish a three-dimentional liver function evaluation system using 99mTc-diethyl iminodiacetic acid (99mTc-EHIDA) scintigraphy based on single photon emission computed tomography (SPECT). METHODS: Totally 16 patients with liver lesions were divided into cirrhosis group and non-cirrhosis group. SPECT was performed 2 days before operation and 5 days after operation. Serum liver functions were examined on the same day of scintigraphy. SPECT images of areas of interest of heart and liver were aquired. Time of the peak of EHIDA density in liver (Tpeak), five-minutes heart liver index (HLI5), blood clearance index (HH15), receptor index (LHL15), and the predictive values were calculated. RESULTS: Tpeak was not significantly different between two groups, while HLI5, HH15, and LHL15 were significantly different (P = 0.033, P = 0.001, and P = 0.005). HLI, and LHL15 were significantly correlated with preoperative total protein and prealbumin levels (P = 0.003, P = 0.015, P = 0.022, P = 0.038) and post-operative prealbumin (P = 0.037, P = 0.042). The predictive values of HLI5 and LHL15 correlated well with postoperative HLI5 and LHL15 (r = 0.675, P = 0.016; r = 0.629, P = 0.028). CONCLUSION: The three-dimentional liver function evaluation system using 99mTc-EHIDA based on liver SPECT may facilitate the further studies of risks of liver surgery.

[Early recurrence after the resection of hepatocellular carcinoma].

OBJECTIVE: To observe the precise time of the recurrence after resection of hepatocellular carcinoma (HCC) and to further explore the risk factors associated with postoperative recurrence. METHODS: Totally 94 patients who had undergone resection of HCC were divided into three groups based on the time of recurrence, which was indicated by the digital subtraction angiography (DSA) examination: recurrence between 1 to 6 months, recurrence between 7 to 12 months, and tumor-free after 12 months. Patients with intra-hepatic recurrence were treated with transcatheter arterial chemoembolization and confirmed by CT scans after embolization, contrast-enhanced ultrasound, or magnetic resonance imaging. RESULTS: The recurrence rates of 6 months and 1 year were 30.9% and 36.2%, respectively. No statistically significant difference between 6-month and 1-year recurrence rates was observed. Nine (26.5%) patients with recurrence and five (8.3%) patients free of tumor had previously presented as multifocal HCC, which showed a statistical significance (P = 0.032). The diagnostic accuracy of DSA was 87.2%, which was eventually confirmed by the other investigations. CONCLUSIONS: Most recurrences occure within the first six months postoperatively and multifocal carcinogenesis is one of the risk factors associated with early recurrence after liver resection for advanced HCC. DSA is an important surveillance for early detection of intra-hepatic recurrence after surgery; meanwhile, it also provides information for early management to control the disease progression and for future active therapies.

Establishment of a doxycycline-regulated cell line with inducible, doubly-stable expression of the wild-type p53 gene from p53-deleted hepatocellular carcinoma cells.

p53 is important in the development of hepatocellular carcinoma (HCC) and in therapeutic approaches, but the mechanism whereby it inhibits HCC growth is still unclear. The aim of the present study was to establish a HCC cell system in which p53 levels can be regulated. Full-length wild-type p53 cDNA obtained by PCR was cloned into a retroviral response vector controlled by the tetracycline responsive element (RevTRE-p53). The regulatory vectors RevTet-Off and RevTRE-p53 were transfected into a packaging cell line, PT67. Hep3B cells in which the p53 gene was deleted were infected with RevTet-Off viral particles from the PT67. Three G418-resistant cell clones with high luciferase expression and low background were infected with RevTRE-p53. By screening dozens of RevTRE-p53-infected clones with hygromycin we identified the one with the highest expression of p53 and the lowest background after doxycycline treatment. The results showed that p53 expression in this cell clone could be simply turned on or off by removing or adding doxycycline. Furthermore, it was found that the level of p53 protein was negatively and sensitively related to the doxycycline concentration. In conclusion, we have established a HCC cell line in which p53 expression can be switched on or off and regulated in a dose- and time-dependent manner.

Different levels of p53 induced either apoptosis or cell cycle arrest in a doxycycline-regulated hepatocellular carcinoma cell line in vitro.

Induction of p53 gene expression in cancer cells can lead to both cell cycle arrest and apoptosis. To clarify whether the level of p53 expression determines the apoptotic response of hepatocellular carcinoma (HCC) cells, we assessed the effect of various levels of expression of p53 gene on a p53-deficient HCC cell line, Hep3B, utilizing a doxycycline (Dox)-regulated inducible p53 expression system. Our results showed that apoptosis was induced in HCC cells with high levels of p53 expression. However, lower level of p53 expression induced only cell cycle arrest but not apoptosis. Bax expression was up-regulated following high levels of p53 expression, while bcl-2 expression was not altered by the level of p53 expression. Moreover, p21 expression was observed in both high and low expression of p53. These results suggest the level of p53 expression could determine if the HCC cells would go into cell cycle arrest or apoptosis. Bax may participate, at least in part, in inducing p53-dependent apoptosis and the induction of p21 alone was able to cause cell cycle arrest but not apoptosis.

Outcomes and prognostic factors of cirrhotic patients with hepatocellular carcinoma after radical major hepatectomy.

BACKGROUND: Radical major hepatectomy (RMH) has been suggested as one of main options for cure of large/advanced hepatocellular carcinoma (HCC). However, its operative risk remains high and its effectiveness is still controversial, especially for patients with liver cirrhosis. The present study aims to investigate short- and long-term outcomes and to identify prognostic factors for cirrhotic patients with HCC after RMH. MATERIALS AND METHODS: Prospectively collected clinicopathological data of 81 consecutive cirrhotic HCC patients who underwent RMH were reviewed retrospectively. The Kaplan-Meier method was adopted for evaluating long-term survival. Prognostic factors were identified by univariate and multivariate analyses. RESULTS: After RMH, perioperative mortality, overall morbidity, and life-threatening morbidity were 1.2%, 24.7%, and 12.3%, respectively. Overall and disease-free 5-year survival rates were 39.4% and 28.1%, respectively. Univariate analysis showed that presence of portal vein tumor thrombosis (PVTT) and satellite nodules, late TNM staging, high Edmondson-Steiner grading, and blood transfusion was associated with worsened prognosis. Of them, Edmondson-Steiner grading was identified as the sole independent prognostic factor for both overall and disease-free survival by multivariate analysis, whereas blood transfusion and the presence of PVTT independently predicted unfavorable overall or disease-free survival, respectively. CONCLUSIONS: These data indicated that RMH was safe and appeared to be effective in treating cirrhotic patients with HCC. Some tumor-related and clinical variables influenced long-term outcome of these patients after RMH.

Factors predictive for long-term survival of male patients with hepatocellular carcinoma after curative resection.

BACKGROUND AND OBJECTIVES: Curative hepatic resection (CHR) was a modality that provides possibility of long-term survival for hepatocellular carcinoma (HCC). So far, prognostic factors of male patients with HCC after CHR remain unclear. Purposes of the present study were to identify these factors and to compare them with those for females. METHODS: Consecutive 151 male and 23 female patients with HCC undergoing CHR were enrolled in this retrospective study. Their prognostic factors were identified by uni- and multi-variate statistical analysis. RESULTS: One-, three- and five-year overall and disease-free survival of male patients were 82.4, 51.5, and 43.6%, and 65.8, 33.7, and 21.7%, respectively, with no significant differences compared to females. Univariate analysis showed that tumor size, TNM staging, Edmondson-Steiner grade, serum alpha-fetoprotein (AFP) level, presence of portal vein tumor thrombosis (PVTT) and satellite nodule were significant for males with HCC, but only Edmondson-Steiner grade, presence of PVTT and satellite nodule were independent. For females, Edmondson-Steiner grade was the single potential indicator for survival. CONCLUSIONS: Malignant degree and invasive phenotypes were main factors that independently influenced survival of male patients with HCC after CHR. Among them, histological grade, which was also potentially significant for females, was the most powerful survival predictor.

Eicosapentaenoic acid induces Fas-mediated apoptosis through a p53-dependent pathway in hepatoma cells.

Eicosapentaenoic acid (EPA) has been demonstrated to induce apoptosis and cell cycle arrest in various cancer cell lines in vitro. In this study, we investigated the anti-tumor effects of EPA on hepatoma cell lines and the mechanisms responsible for induced cell death. Three hepatoma cell lines tested had different p53 status: HepG2 with a wild-type p53; Hep3B, of which the endogenous p53 was deleted; and Huh7 with its p53 mutated. MTT assay showed reduced viability of HepG2 cells after exposure to EPA, and the cytotoxicity of EPA was time and dose dependent. However, EPA had no effect on the viability and cell death in the two other hepatoma cell lines containing dysfunctional p53. DNA fragmentation analysis and TUNEL (terminal deoxynucleotidyl transferase [TdT]-mediated deoxyuridine diphosphate [dUTP] nick end labeling) staining showed a typical pattern of DNA laddering and DNA breaks staining, respectively, in wild-type p53-containing HepG2 cells after EPA treatment. We also observed that EPA induced transient nuclear accumulation of P53 protein that subsequently up-regulated the expression of Fas messenger RNA and protein in HepG2 cells. In contrast, these findings were not observed in Hep3B and Huh7 cells exposed to EPA. Most notably, EPA-induced apoptosis in HepG2 cells could be reduced almost completely by treatment with FasL antisense oligonucleotides. We conclude that EPA inhibits the growth of HepG2 cells and mediates its effect, at least in part, via the Fas-mediated apoptosis. It appears that the effects of EPA on hepatoma cells are determined by the status of p53 and that wild-type p53 is a prerequisite for the anticancer effect of EPA.