[Is Balloon-Occluded Transcatheter Arterial Chemoembolization Effective in Patients with Hepatocellular Carcinoma That Is Unresponsive to Conventional Transcatheter Arterial Chemoembolization ?]

We previously reported that the antitumor response of balloon-occluded transcatheter arterial chemoembolization(BTACE) is better than that of conventional transcatheter arterial chemoembolization(C-TACE). Thus far, little attention has been paid on the efficacy of B-TACE using the same antitumor agents for hepatocellular carcinoma(HCC)that is unresponsive to C-TACE, which is defined as C50% necrosis of the targeted nodules or the appearance of new lesions in the liver 1-3 months following one C-TACE procedure. Therefore, this study focused on the efficacy of B-TACE using the same antitumor agents for HCC that is unresponsive to C-TACE. Fourteen patients treated with B-TACE at our institution were retrospectively investigated between January 2011 and August 2015. The median age was 76(interquartile range[IQR]70-79)years, and 9 patients(64.3%)were men. A total of 9(64.3%)and 5(35.7%)patients had the Child-Pugh class A and B, respectively. The median maximum tumor diameter was 30(IQR 18-40)mm, and 4(28.6%), 3(21.4%), 0(0.0%), and 7(50.0%) patients had 1, 2, 3, andB4 tumors, respectively. The antitumor effects were CR, PR, SD, and PD in 6(42.9%), 1(7.1%), 3 (21.4%), and 7(28.6%)patients, respectively. The response and disease control rates were 50% and 71.4%, respectively. Our results suggest that B-TACE is an effective modality for the treatment of HCC that is unresponsive to C-TACE.

Factors predicting overall response and overall survival in hepatocellular carcinoma patients undergoing balloon-occluded transcatheter arterial chemoembolization: A retrospective cohort study.

AIM: This study aimed to investigate the factors predicting overall response and overall survival in hepatocellular carcinoma patients undergoing balloon-occluded transcatheter arterial chemoembolization (B-TACE). METHODS: Sixty-six patients treated with B-TACE at a Japanese tertiary referral hospital between January 2011 and August 2015 were included in this retrospective cohort study. RESULTS: The overall response was classified as complete response, partial response, stable disease, and progressive disease in 35 (53.0%), 7 (10.6%), 13 (19.7%), and 11 (16.7%) patients, respectively. The response rate was 63.6%, and the disease control rate was 83.3%. The number of tumors (hazard ratio [HR], 4.44; 95% confidence interval [CI], 1.26-15.7; P = 0.021) and α-fetoprotein level (HR, 11.40; 95% CI, 2.75-46.9; P < 0.001) were significantly associated with the tumor response in a multivariate analysis. The 1-, 2-, and 3-year survival rates were 76.8% (95% CI, 64.5-85.3%), 57.3% (95% CI, 42.3-69.7%), and 46.7% (95% CI, 30.7-61.2%), respectively. The median survival time was 902 days. Albumin (≥3.4 g/dL) (HR, 0.28; 95% CI, 0.12-0.63; P = 0.002) and overall response (complete response and partial response) (HR, 0.33; 95% CI, 0.16-0.71; P = 0.004) were factors significantly associated with overall survival in a multivariate analysis. No mortalities were observed, but biloma requiring percutaneous transhepatic biliary drainage occurred in one patient (1.5%). CONCLUSION: Balloon-occluded transcatheter arterial chemoembolization may exert a good antitumor effect and result in good overall survival in select hepatocellular carcinoma patients.

Safety and efficacy of balloon-occluded transcatheter arterial chemoembolization using miriplatin for hepatocellular carcinoma.

AIM: Balloon-occluded transcatheter arterial chemoembolization (B-TACE) using a microballoon catheter was performed to administrate miriplatin, and the early therapeutic efficacy and safety of the procedure were evaluated. METHODS: Out of 158 patients who received miriplatin using B-TACE for hepatocellular carcinoma, 49 patients with a single lesion at either stage I or II (according to the Liver Cancer Study Group of Japan) were evaluated in comparison with 48 matched patients who received miriplatin using conventional TACE (C-TACE). RESULTS: The mean total dose and median dose of miriplatin in each group were 32.5 ± 31.7 mg and 20 mg (C-TACE) and 50.1 ± 31.3 mg and 40 mg (B-TACE), respectively (P < 0.01). The treatment effect (TE) on the target nodule classified as TE4, TE3, TE2 or TE1 was 39.6%, 33.3%, 25.0% and 2.1%, respectively, in the C-TACE group, and 55.1%, 38.8%, 4.1% and 2.0%, respectively, in the B-TACE group. Therefore, the TE was significantly higher in the B-TACE group (P < 0.05). Although abdominal blood tests revealed adverse, increased levels of serum alanine aminotransferase (ALT) in a significantly higher number of B-TACE-treated patients, serum ALT levels returned to baseline levels in all patients within 1 month. There were no significant differences in clinical symptoms between the two groups. CONCLUSION: Compared with C-TACE, B-TACE significantly improved cancer nodule control, and it was satisfactory in terms of safety. B-TACE is an effective procedure that enhances the effects of catheterization with miriplatin.

Spleen stiffness correlates with the presence of ascites but not esophageal varices in chronic hepatitis C patients.

Although spleen stiffness has recently been identified as potential surrogate marker for portal hypertension, the relationship between spleen stiffness and portal hypertension has not been fully elucidated. We attempted to determine the relationship between the liver or spleen stiffness and the presence of ascites or esophageal varices by acoustic radiation force impulse (ARFI) imaging. A total of 33 chronic hepatitis C (CHC) patients (median age 68; range 51-84) were enrolled. We evaluated the relationship between the liver or spleen stiffness and indicators of portal hypertension as well as clinical and biochemical parameters. Fourteen healthy volunteers were used for validating the accuracy of AFRI imaging. The liver and spleen stiffness increased significantly with progression of liver disease. A significant positive correlation was observed between the liver and spleen stiffness. However, spleen stiffness, but not liver stiffness, was significantly associated with the presence of ascites (P < 0.05), while there was no significant association between the spleen stiffness and spleen index/presence of esophageal varices in CHC patients. The area under the receiver operating characteristic curve based on the spleen stiffness was 0.80. In conclusion, spleen stiffness significantly correlates with the presence of ascites but not esophageal varices in CHC patients.

Transileocolic vein obliteration for bleeding rectal varices with portal thrombus.

We report a case of rectal varices treated successfully with transileocolic vein obliteration (TIO). A 70-year-old man was admitted to our hospital for evaluation of fresh bloody stools in January 2011. Emergent colonoscopy revealed fresh blood in the rectum and tortuous rectal varices. Three-dimensional computed tomography was used as a non-invasive method for the identification of rectal varices and thrombus in the extrahepatic portal vein. Angiography demonstrated that rectal varices were supplied with backward blood flow by the inferior mesenteric vein. Transileocolic variceal obliteration was performed using coils and 5% ethanolamine oleate with iopamidol. Complete hemostasis was achieved without complications. We conclude that TIO is a safe and effective hemostatic measure for ruptured rectal varices with portal thrombus.

[Clinical evaluation of transcatheter arterial chemolipiodolization of miriplatin for multiple hepatocellular carcinoma].

The safety and efficacy of miriplatin-lipiodol suspension were investigated in 174 patients with hepatocellular carcinoma(HCC). We assessed 29 patients who underwent transarterial chemoembolization(TACE)for whole-liver multinodular HCC(mHCC), compared with 145 patients who underwent TACE for non-multinodular HCC(n-mHCC)as the controls. In the mHCC group, a treatment effect(TE)of 4 was obtained in 0%, TE3 in 38%, TE2 in 31%, and TE1 in 31%. In the n-mHCC group, TE4 was obtained in 24%, TE3 in 40%, TE2 in 32%, and TE1 in 4%. Efficacy was significantly higher in the mHCC group. In the mHCC group, Grade 3 adverse events(fever, elevated alanine aminotransferase, and thrombocytopenia)occurred in 4 patients(13. 7%). In the n-mHCC group, Grade 3 adverse events(ascites, elevated serum transaminase, and cytopenia)occurred in 33 patients(22. 7%). There was no significant difference in the change of Child-Pugh scores over time in 6 patients who underwent repetitive TACE for mHCC. In conclusion, TACE for whole-liver mHCC is generally safe, but its short-term therapeutic effects were not satisfactory. Variation in the TACE protocol using miriplatin, such as repetitive administration of miriplatin and a reduction in the treatment interval, can be alternative treatment choices for patients with whole-liver mHCC.

Respiratory effects of balloon occluded retrograde transvenous obliteration of gastric varices: a prospective controlled study.

BACKGROUND AND AIM: We evaluated the respiratory effects of balloon-occluded retrograde transvenous obliteration (BRTO) performed for the treatment of gastric varices complicating liver cirrhosis. METHODS: From 2005 to 2009, we performed BRTO in 20 patients with gastric fundal varices, by intravariceal injection of 5% ethanolamine oleate (EO) as the sclerosant. We studied the effect of BRTO on the respiratory gas exchange, chest X-ray findings, computed tomography (CT) findings, pulmonary function parameters, and (99m) Tc-MAA lung perfusion scintigraphy findings. Subjects undergoing balloon-occluded retrograde transvenous varicerography (BRTV) without injection of the sclerosant served as the controls. RESULTS: Arterial blood gas analysis revealed a decrease in the mean arterial partial oxygen tension (PaO(2)) (P < 0.01), and increase in the alveolar-arterial oxygen tension difference (AaDO(2)) after BRTO (P < 0.01), as compared with the results obtained before the BRTO, while breathing room air. No changes were observed after BRTV as compared with the previous findings. In addition, a significant correlation was observed between the change of the PaO(2) and the volume of the sclerosant injected (rs = 0.511, P = 0.011). Left-pleural effusion was noted on the chest CT in 20% of the patients. On pulmonary function testing, decrease of the vital capacity was noted in two of the 20 patients after BRTO. CONCLUSION: The aforementioned results suggest that BRTO performed using EO as the sclerosant induces pulmonary function disorders. The effect was found to depend on the total amount of EO injected. Therefore, careful respiratory monitoring seems necessary in patients undergoing BRTO, particularly those in whom large volumes of the sclerosant are used.

Clinical characteristics and treatment for patients presenting with bleeding duodenal varices.

BACKGROUND AND AIM: Bleeding from ectopic varices, including duodenal varices, is uncommon, but it can be difficult to manage. The clinical data of patients diagnosed and treated for duodenal varices were reviewed to investigate the strategy for treatment. METHODS: The present study reviewed the clinical data of 10 patients with duodenal varices (mean age, 58.2 ± 15.6 years) at our associated institutes during the period between January 1996 and December 2008. RESULTS: Nine patients had duodenal varices located in the second portion, whereas in one case they were located in the duodenal bulbus. The underlying diseases included liver cirrhosis in eight patients, and extrahepatic portal vein obstruction in two patients. The lesions were identified with bleeding from varices in eight of 10 patients. Initial hemostasis was achieved in all eight patients. However, among four patients treated endoscopically only, two patients died from rebleeding from varices and two died from hepatic failure resulting from variceal bleeding. Additional interventional radiology (IVR) was used in three patients and additional surgery was carried out in one case. One patient who was treated with balloon-occluded retrograde transvenous obliteration rebled during IVR and died from bleeding. Two patients who underwent double balloon-occluded embolotherapy and one case who had surgery achieved good clinical outcomes. CONCLUSIONS: Although endoscopic treatment is useful for initial hemostasis of hemorrhagic duodenal varices, the patients who underwent additional IVR after endoscopic treatment achieved good outcomes.

Hepatocyte growth factor protects against Fas-mediated liver apoptosis in transgenic mice.

BACKGROUND: Apoptosis via the Fas/Fas ligand signalling system plays an important role in the development of various liver diseases. The administration of an agonistic anti-Fas antibody to mice causes massive hepatic apoptosis and fulminant hepatic failure. Several growth factors including hepatocyte growth factor (HGF) have been found to prevent apoptosis. METHODS: In this study, we demonstrated the overexpression of HGF to have a protective effect on Fas-mediated hepatic apoptosis using a transgenic mice (Tg mice) model. RESULTS: In HGF Tg mice, the elevation of alanine aminotransferase was dramatically inhibited at 12 and 24 h after the administration of 0.15 mg/kg anti-Fas antibody. HGF Tg mice showed a significantly lower number of apoptotic hepatocytes at 12 h compared with wild-type (WT) mice. Furthermore, 85% (six of seven) HGF Tg mice were able to survive after the administration of 0.3 mg/kg anti-Fas antibody, while none of the WT mice survived. The Bcl-xL expression was increased in HGF Tg mice, while there was no difference in the expression of Bax, Bid, Mcl-1 and bcl-2 between WT mice and HGF Tg mice. In addition, the HGF Tg mice showed more Akt phosphorylation than the WT mice both before and after the anti-Fas antibody injection. CONCLUSIONS: Taken together, our findings suggest that HGF protects against Fas-mediated liver apoptosis in vivo, and the upregulation of Bcl-xL via Akt activation may also play a role in the protective effects of HGF.

Gastric cancer with features of submucosal tumor: a case report.

A case of stomach carcinoma showing the features of a submucosal tumor (SMT) is reported. The patient was a 65-year-old woman admitted to the Internal Medicine Department with autoimmune hepatitis and complaining of anemia and tarry stools. Endoscopy revealed a submucosal tumor-like lesion with central ulceration. The lesion was the suspected cause of the anemia; therefore, a partial resection of the stomach was performed. The histopathologic examination revealed a mucinous adenocarcinoma (MUC). The tumor extended to the submucosa. Accordingly, a subtotal gastrectomy with regional lymph node dissection was performed. In stomach carcinoma simulating an SMT, generally preoperative diagnosis is important. However, in this patient, surgery was selected as the best treatment.

[Clinical study of low-dose cisplatin and 5-fluorouracil chemotherapy via implanted fusion port in 20 patients with advanced hepatocellular carcinoma with portal vein tumor thrombosis].

We experienced 20 cases of advanced hepatocellular carcinoma with portal vein tumor thrombosis treated with low-dose cisplatin and 5-fluorouracil (5-FU) chemotherapy via implanted fusion port between August 1999 and September 2003. A fusion port was implanted by inserting an intraarterial catheter into the hepatic artery. Cisplatin (10 mg/day, 5 times/week, 4 weeks) and 5-FU (250 mg/day, 5 times/week, 4 weeks) were administered for one cycle. The treatment was performed repeatedly until the patient showed progressive disease (PD) with an off period of 4 to 12 weeks. The average number of cycles was 1.7+/-0.73. Responses were complete response (CR) 0/20, partial response (PR) 6/20, no change (NC) 8/20, and PD 6/20, and the overall response rate was 30%. The 1-year survival rate was 48.5%, and the average observation period was 357 days. The toxicities of grade 3 and above were leukocytopenia (2 cases; 10%), thrombocytopenia (2 cases; 10%), nausea (1 case; 5%), and epigastralgia (1 case; 5%). Complications with reservoir implantation included 2 cases of catheter dislocation, 1 case of wound separation,1 case of bleeding from the port implantation site, 1 case of development of collateral circulation,and 1 case of catheter occlusion. The outcomes were survival in 5 cases (25%) and death in 15 cases (75%). The causes of death included cancer (12 cases; 60%), varices rupture (2 cases; 10%),and hemoptysis (1 case; 5%). The group with a CLIP score of 3 or less showed a significantly higher survival rate than the group with a CLIP score of 4 or more (survival rates were 80% and 12.5%, respectively; p=0.0032, logrank test). Among CLIP score factors, tumor morphology (TM) was particularly related to life convalescence,and TM 1 group with the tumor occupying less than half of the liver showed a significantly higher survival rate than the TM 2 group with the tumor occupying more than half of the liver (p=0.0003, logrank test) with one-year survival rates of 88.9% and 10.9%, respectively. CLIP score and TM were also significantly reflected in life convalescence on multivariate analysis. While low-dose cisplatin and 5-FU chemotherapy via an implanted fusion port were regarded as a useful therapeutic regimen to improve life convalescence for cases of progressive hepatocellular carcinoma with portal vein tumor thrombosis (Vp 3/4), life convalescence in those with a CLIP score of 3 and above,particularly in the TM 2 group, was poor. We consider that treatment in such cases should be decided carefully, taking into consideration their quality of life.

Hepatocyte growth factor accelerates thrombopoiesis in transgenic mice.

Hepatocyte growth factor (HGF) is one of the potent growth factors for liver regeneration and has a strong effect on epithelial and nonepithelial cells. As one of the pleiotropic functions, HGF acts as a hematopoietic regulator in the proliferation and differentiation of hematopoietic progenitors. However, the effect of HGF on the thrombopoietic function remains unclear. The correlation between HGF and thrombopoiesis was investigated in transgenic (TG) mice overexpressing murine HGF controlled by the murine HGF by the metallothionein promoter. Furthermore, the mechanism of thrombocytosis induced by HGF in vitro was analyzed in hepatoma cell line HepG2. Both the platelet count and the serum thrombopoietin (TPO) concentration were significantly higher in TG than in the wild type (WT) control mice. In the liver and spleen, the expression of TPOmRNA in TG was higher than that in WT by real-time polymerase chain reaction. The expressions of transcriptional factor of TPO, GABP-alpha/beta were more increased in TG liver compared to WT. In an in vitro study, HGF induced TPO and GABP-alpha/beta expression and enhanced TPO promoter activity. Therefore, HGF induced thrombopoiesis accompanied with the overexpression of TPO through GABP stimulation.

Lack of macrophage migration inhibitory factor protects mice against concanavalin A-induced liver injury.

BACKGROUND: Macrophage migration inhibitory factor (MIF) is involved in inflammatory and immune-mediated diseases but the role of MIF in liver injury has not yet been elucidated. METHODS: We investigated biochemically, histologically and immunologically the character of MIF in concanavalin A (Con A)-induced T-cell-mediated liver injury using MIF knockout (KO) mice and wild-type (WT) mice. RESULTS: MIF KO mice showed significantly decreased serum alanine aminotransferase values and suppressed histological change with massive necrosis of the hepatic parenchymal cells and infiltration of inflammatory cells compared with their WT counterparts. This protection was not mediated by either tumor necrosis factor-alpha or interferon-gamma, which are critical mediators of Con A-induced liver injury, as their serum concentrations were shown to be similar in MIF KO and WT mice. On the other hand, a flow cytometric analysis demonstrated that the number of activated hepatic leukocytes decreased more in the MIF KO mice than in the WT mice. CONCLUSIONS: A lack of MIF protected the mice from Con A-induced liver injury. Controlling the MIF activity may be a useful therapeutic strategy for treating such T-cell activation-associated liver diseases as autoimmune hepatitis and viral hepatitis.

Computed tomography-guided transpulmonary radiofrequency ablation for hepatocellular carcinoma located in hepatic dome.

AIM: To determine the feasibility of performing computed tomography (CT)-guided transpulmonary radiofrequency ablation (RFA) for hepatocellular carcinoma (HCC) located in the hepatic dome. METHODS: A total of seven patients with HCC comprising seven nodules located in the hepatic dome were treated from April 2004 to December 2004. CT-guided transpulmonary RFA was performed using a cool-tip type electrode (Radionics Company) based on a standardized energy protocol. All tumors located in the hepatic dome were not detectable by the usual ultrasound (US) methods. The lesion diameters ranged from 15 to 27 mm. RESULTS: RFA was technically feasible in all the patients. The puncture procedure was performed twice or less and the total average performance time was 40.6 min. Local tumor control was achieved in all the patients. The necrosis diameter ranged from 25 to 35 mm. The mean follow-up period was 9.6 (7-14 mo) mo. There was no local recurrence at the follow-up points. Pneumothorax requiring pleural drainage was the main complication, which was observed in two of the seven patients (28.6%). However, it improved with chest drainage tube, and the tube could be removed within 2-3 d. No other major complications were observed. CONCLUSION: CT-guided puncture is useful for the treatment of tumors located in the hepatic dome which are hardly detectable by US, even though pneumothorax sometimes may occur as a complication. In the cases with adhesion in the pleura for which artificial pleural effusion methods are not appropriate, CT-guided RFA is thus considered to be an alternative treatment for HCC located in the hepatic dome.

Hepatocellular carcinoma in extremely elderly patients: an analysis of clinical characteristics, prognosis and patient survival.

AIM: To identify the clinical and prognostic features of patients with hepatocellular carcinoma (HCC) aged 80 years or more. METHODS: A total of 1310 patients with HCC were included in this study. Ninety-one patients aged 80 years or more at the time of diagnosis of HCC were defined as the extremely elderly group. Two hundred and thirty-four patients aged > or = 50 years but less than 60 years were regarded as the non-elderly group. RESULTS: The sex ratio (male to female) was significantly lower in the extremely elderly group (0.90:1) than in the non-elderly group (3.9:1, P < 0.001). The positive rate for HBsAg was significantly lower in the extremely elderly group and the proportion of patients negative for HBsAg and HCVAb obviously increased in the extremely elderly group (P < 0.001). There were no significant differences in the following parameters: diameter and number of tumors, Child-Pugh grading, tumor staging, presence of portal thrombosis or ascites, and positive rate for HCVAb. Extremely elderly patients did not often receive surgical treatment (P < 0.001) and they were more likely to receive conservative treatment (P < 0.01). There were no significant differences in survival curves based on the Kaplan-Meier methods in comparison with the overall patients between the two groups. However, the survival curves were significantly worse in the extremely elderly patients with stage I/II, stage I/II and Child-Pugh grade A cirrhosis in comparison with the non-elderly group. The causes of death did not differ among the patients, and most cases died of liver-related diseases even in the extremely elderly patients. CONCLUSION: In the patients with good liver functions and good performance status, aggressive treatment for HCC might improve the survival rate, even in the extremely elderly patients.

Immune thrombocytopenic purpura in patients with hepatitis C virus infection.

BACKGROUND/AIMS: Immune thrombocytopenic purpura could occur as an extrahepatic manifestation of hepatitis C virus infection. The aim of this study was to clinically analyze hepatitis C virus-positive cases with immune thrombocytopenic purpura and to examine the relationship between hepatitis C virus and immune thrombocytopenic purpura. METHODOLOGY: Eight hepatitis C virus-positive patients with immune thrombocytopenic purpura were compared with 67 cases with chronic hepatitis C without immune thrombocytopenic purpura. We examined various clinical and hematological parameters including platelet and platelet-associated immunoglobulin G. RESULTS: Two men and 6 women with hepatitis C virus infection (age 58.0 +/- 11.8) were diagnosed with immune thrombocytopenic purpura. Platelet counts (x10(4)/mm3) were significantly lower in these 8 patients (2.9 +/- 2.1) than in chronic hepatitis C patients without immune thrombocytopenic purpura (16.7 +/- 0.3) (P<0.001). Hepatitis C virus infection predated immune thrombocytopenic purpura in 6 patients and none of the patients with immune thrombocytopenic purpura was infected with hepatitis C virus after the diagnosis. Three of the 6 patients with chronic hepatitis C, which predated immune thrombocytopenic purpura, were treated with interferon and 2 developed immune thrombocytopenic purpura after the treatment. None of them eradicated hepatitis C virus by interferon. CONCLUSIONS: The fact that hepatitis C virus infection predated immune thrombocytopenic purpura in 6 of 8 patients suggests that hepatitis C virus could potentially induce immune thrombocytopenic purpura and interferon itself might induce immune thrombocytopenic purpura.

CCl4-induced acute liver injury in mice is inhibited by hepatocyte growth factor overexpression but stimulated by NK2 overexpression.

Hepatocyte growth factor (HGF) inhibits acute liver injury. NK2 acts as an antagonist to HGF in vitro, but its in vivo function has reached no consensus conclusions. We have investigated in vivo effects of HGF and NK2 on CCl4-induced acute liver injury. Elevation of the serum alanine aminotransferase level and extension of centrilobular necrosis were inhibited in HGF transgenic mice but were promoted in NK2 transgenic mice. Hepatocyte proliferation after liver injury was not inhibited in NK2 transgenic mice. Thus, this study indicates that HGF inhibits liver injury, and NK2 antagonizes HGF on liver injury, however, NK2 may not antagonize HGF on hepatocyte proliferation.

Absence of specific symptoms in chronic hepatitis C.

BACKGROUND: No systematic research has been carried out on the symptoms of chronic hepatitis C, although the disease is believed to induce subjective symptoms such as fatigue or dullness in the legs. METHODS: The Todai Health Index has been developed as a symptom checklist that is used for screening particular diseases or for health management. The index was chosen as the most suitable questionnaire for measuring characteristic symptoms of chronic hepatitis C. Sixty patients with chronic hepatitis C who did not have any severe complications were compared with healthy control subjects who were selected randomly from the residents of Isesaki City, Gunma, Japan. RESULTS: The major findings were as follows: (1) male and female patients with chronic hepatitis C had no characteristic subjective physical symptoms when compared with the healthy controls, except for a significant difference in aggression, and (2) the severity of the hepatitis was not associated with the patients' symptoms after adjusting for age and treatments. CONCLUSIONS: Patients with chronic hepatitis C who did not have any severe complications did not show specific subjective physical symptoms.

Transforming growth factor alpha protects against Fas-mediated liver apoptosis in mice.

The Fas/Fas ligand interaction plays a crucial role in various liver diseases, and administration of agonistic anti-Fas antibody to mice causes massive hepatic apoptosis and fulminant hepatic failure. Several growth factors have recently been found to function in preventing apoptosis. In this study, we demonstrated that overexpression of transforming growth factor alpha (TGFalpha) has a dramatic protective effect on Fas-mediated hepatic apoptosis at the biochemical and histological levels. Moreover, 85.7% (six out of seven) of TGFalpha transgenic mice survived the lethal liver damage, whereas all wild-type mice died. Expression of Bcl-xL, an anti-apoptotic protein, was greatly increased in the transgenic mice. Taken together, our findings suggest that TGFalpha protects against Fas-mediated liver apoptosis in vivo and up-regulation of Bcl-xL may participate in protective effect of TGFalpha.