***TASK*** the task is to summarize an input biomedical literature in six sentences 
    ***INPUT*** the input is a biomedical literature 
    ***OUTPUT*** the output is the summary of an input biomedical literature in six sentences 
    ***DOCUMENTATION*** 
    ***EXAMPLES*** 
    Input: Context Hepatocellular carcinoma often follows hepatitis C virus infection . Currently available treatments for hepatocellular carcinoma are unsatisfactory . Percutaneous ethanol injection therapy into tumor nodules shows some promise , but recurrence rates are high . Contribution In a carefully selected group of 74 patients with multicentric hepatocellular carcinoma , mild hepatitis C , and mild cirrhosis , patients r and omly assigned to receive interferon in addition to ethanol injections  showed improved survival at 5 and 7 years , particularly among patients with a sustained virologic response . Caution s Combined treatment of multicentric hepatocellular carcinoma offers the possibility of enhanced survival for carefully selected patients ; this study is small , however , and enrolled only patients with low virus levels and mild cirrhosis . The Editors Chronic hepatitis C virus ( HCV ) infection is a common , frequently asymptomatic disease . Despite the clinical ly quiescent course of HCV infection , it may slowly progress to cirrhosis and , eventually , to hepatocellular carcinoma ( 1 , 2 ) . Cirrhosis is a major risk factor for the development of hepatocellular carcinoma ( 3 , 4 ) , and 70 % to 80 % of patients with hepatocellular carcinoma in Japan have HCV infection ( 5 ) . Current strategies for treating hepatocellular carcinoma include surgical resection , transarterial embolization , percutaneous ethanol injection therapy , radiofrequency wave ablation , and chemotherapy ( 6 - 9 ) . Recent studies have shown that percutaneous ethanol injection therapy is effective for hepatocellular carcinoma when the tumors are small ( <3 to 5 cm in diameter ) and limited in number ; survival rates are similar to those obtained with surgery ( 10 - 12 ) . Five-year survival rates , however , are poor ( 30 % to 60 % for both hepatectomy and percutaneous ethanol injection therapy ) . Poor prognosis may be the result of the high incidence of tumor recurrence ; the cumulative recurrence rate at 5 years is 60 % to 100 % ( 10 - 13 ) . Several studies have evaluated the factors that contribute to the recurrence of hepatocellular carcinoma ( 12 , 13 ) . Occasionally , early recurrence develops adjacent to the treated lesion ( local recurrence , 6 % to 33 % depending on tumor size ) ( 14 ) , but most tumors ( 80 % to 90 % ) recur at different sites ( 15 ) . Because hepatocellular carcinoma recurrence and decompensation of underlying liver disease are major problems after medical or surgical treatment , liver transplantation is another option for treating small , unresectable hepatocellular carcinomas in patients with cirrhosis . Studies report 5-year survival rates as high as 75 % with liver transplantation ( 16 - 18 ) . Interferon therapy has beneficial effects in chronic HCV infection ( 19 , 20 ) . In long-term follow-up studies , sustained virologic responders have remained in remission with normal liver function and improved histologic features of inflammation ; in some of these responders , fibrosis even regresses ( 21 , 22 ) . Recently , the frequency of hepatocellular carcinoma in patients receiving interferon therapy  has substantially decreased , especially in patients with sustained virologic and biochemical responses ( 23 - 25 ) . This decreased frequency has occurred even in patients with cirrhosis ( 25 , 26 ) . Our study evaluated whether complete ablation of neoplastic nodules and administration of antiviral therapy could increase survival rates . Methods Study Design Our prospect i ve study was design ed by an eight-member committee in December 1992 . The Ethics Committee of the University of Tokyo approved the study . We obtained informed consent from each patient in accordance with the Helsinki declaration . Patients with compensated cirrhosis , three or fewer nodules of hepatocellular carcinoma , and low HCV RNA loads were recruited after complete ablation of the lesions . Eligibility Criteria Inclusion Criteria Hepatitis C virus infection was diagnosed on the basis of identification of anti-HCV antibody using the passive hemagglutination test ( Dinabbot , Tokyo , Japan ) or enzyme-linked immunosorbent assay ( ELISA ; Ortho Diagnostic Systems , Tokyo , Japan ) . Hepatitis C virus RNA was identified by reverse transcriptase polymerase chain reaction ( RT-PCR ) . The serum HCV RNA level was measured by competitive reverse transcriptase (CRT)-PCR according to the method of Kato and colleagues ( 27 ) ; HCV genotype was determined by the method of Okamoto and colleagues ( 28 ) . Hepatocellular carcinoma was suspected on the basis of several imaging methods , including abdominal ultrasonography , dynamic computed tomography ( CT ) , magnetic resonance imaging ( MRI ) , and arteriography . We confirmed the diagnosis by histologic examination of tumor biopsy specimens obtained from all patients . Evaluation was based on the criteria of the International Working Party ( 29 ) . In addition , we obtained and evaluated biopsy specimens from non-neoplastic lesions according to the methods of Desmet and colleagues ( 30 ) . Hepatocellular carcinoma was treated with percutaneous ethanol injection therapy ( 7 , 8 , 10 ) . Real-time linear-array scanners were used with 3.5-MHz transducers for the sonographic guidance of needles [ 21-gauge with a 15-cm or 20-cm needle ; Hanako , Tokyo , Japan ] into the tumors . Two to 10 mL of 99.5 % ethanol was injected into each lesion . Ethanol injection was repeated several times at different sessions . Complete destruction of the nodules was confirmed on dynamic CT 1 month after ethanol injection according to the following criteria : 1 ) The destructive area was larger than the area of the tumor nodule shown on pretreatment dynamic CT and 2 ) dynamic CT showed no early-phase contrast enhancement of nodules ( 7 , 8 , 10 ) . Inclusion criteria were as follows : 1 ) hepatocellular carcinoma with three or fewer lesions [ verified by histologic examination ] and dynamic CTconfirmed complete ablation of hepatocellular carcinoma lesions by percutaneous ethanol injection therapy , 2 ) detection of HCV RNA by RT-PCR and an HCV RNA load of 2 106 copies/mL or less by CRT-PCR ( the cutoff value was based on unpublished data indicating that interferon treatment was effective in patients with HCV RNA loads of 105 copies/50 L of serum by CRT-PCR [ 27 ] ] , 3 ) platelet count of 50 109 cells/L , 4 ) leukocyte count of 3 109 cells/L or greater , 5 ) compensated cirrhosis in ChildPugh stage A , 6 ) age younger than 70 years , 7 ) no previous treatment with interferon , and 8) su bmi ssion of informed consent . Exclusion Criteria Exclusion criteria were as follows : 1 ) liver diseases due to other causes , such as hepatitis B or primary biliary cirrhosis ; 2 ) HCV RNA load of 2 106 copies/mL or greater by CRT-PCR ; 3 ) severe comorbid diseases , such as heart disease , lung disease , or diabetes mellitus ; 4 ) decompensated cirrhosis in ChildPugh stage B or C ; and 5 ) failure to obtain informed consent . R and omization Patients who enrolled in the study were r and omly assigned in a 2:1 ratio to the interferon group or the control group by the controller . We assigned patients to the treatment group or control group by using a r and omization list . Interferon Therapy and Follow-up of Patients Interferon Therapy We started interferon therapy with natural interferon- ( Sumitomo Pharmaceuticals , Tokyo , Japan ) 2 to 3 months after tumor ablation was confirmed . Patients received 6 million U of interferon by intramuscular injection three times weekly for 48 weeks as out patients . If patients could not tolerate this dose , the interferon dose was reduced to 3 million U. If HCV RNA in serum was still detected by RT-PCR ( detection limit , 102 copies/mL ) after 24 weeks of interferon therapy and serum alanine aminotransferase ( ALT ) levels were higher than pretreatment ALT levels , therapy was discontinued . Criteria for Interferon Response We defined the efficacy of interferon therapy virologically and biochemically . Patients who were negative for HCV RNA ( as determined by RT-PCR ; detection limit , 102 copies/mL ) more than 6 months after the completion of interferon therapy were classified as showing a sustained virologic response .  Patients with persistently normal ALT levels after the completion of interferon therapy  were classified as showing a sustained biochemical response ; patients with abnormal ALT levels  were classified as showing a nonsustained biochemical response . Follow-up Patients attended a monthly medical consultation at the University of Tokyo Hospital outpatient clinic .  Blood biochemical measures , including -fetoprotein ( AFP ) tumor markers , were measured every 1 to 2 months ; ultrasonography was performed every 2 to 3 months ; and dynamic CT was performed every 6 months . Recurrence of hepatocellular carcinoma was detected by the finding of abnormal nodules with low or high echogenic appearance on abdominal ultrasonography or by the finding of abnormal density on dynamic CT . The diagnosis was confirmed histologically through ultrasonography-guided fine-needle biopsy of the tumor . Recurrent nodules were divided into two categories [ 14 , 15 ] : 1 ) local recurrence , in which the nodule appeared adjacent to the previously treated nodules , suggesting that residual tumor cells had not been completely ablated by percutaneous ethanol injection therapy , or 2 ) new foci developing at a distant site . New foci of hepatocellular carcinoma , as well as local recurrent nodules at tumor , node , metastasis ( TNM ) stage I , II , and III , were mainly treated by a second course of percutaneous ethanol injection therapy ; local recurrent nodules at TNM stage IV were treated with transarterial chemoembolization or chemotherapy .  New development of hepatocellular carcinoma and survival of the patients ( tumor recurrence rate and survival rate ) were analyzed in relation to the time interval after initial treatment . Statistical Analysis When estimating the sample size , we assumed that 5-year survival in the control group would be 40 % according to the data of our previous unpublished study . We predicted that 5-year survival would be increased by 35 % as a result of BACKGROUND / AIMS Vitamin K2 ( VK2 ) appears to have a potent inhibitory activity for cell growth including HCC cells . We investigated whether VK2 could reduce incidence of tumor recurrence after treatment of HCC . Forty-five patients with cured or possibly cured HCC were r and omly selected , assigning patients to treatment ( n=21 ) or control group ( n=24 ) with r and omization list . METHODOLOGY For the treatment group , forty-five mg of Glakay was given orally every day after therapy for HCC . No patients complained of adverse effects .  Abdominal ultrasonography and dynamic CT were performed at 3-month intervals . Recurrence was confirmed by abdominal angiography . RESULTS Recurrence of HCC occurred in 7 cases ( 33.3 % ) for the treatment group and 12 cases ( 50.0 % ) for the control group during mean observation periods of 19.5 and 16.5 months , respectively . Administration of VK2 was not an independent variable for the recurrence on univariate analysis . Cumulative incidence of HCC recurrence did not differ between the two groups , and the cumulative survival rate tended to be high in treatment group ( p = 0.054 ) . Cox regression analysis revealed that serum albumin concentration alone was an independent factor affecting the recurrence . CONCLUSIONS These findings suggest that VK2 does not appear to prevent recurrence of HCC after curative treatment . Our study is preliminary and large-scale trials are needed to determine whether VK2 is of benefit to decrease the recurrence of HCC BACKGROUND Despite the progression of therapeutic approaches , a high frequency of recurrence is what determines the long-term prognosis of patients with hepatocellular carcinoma ( HCC ) . In this study , the chemopreventive effects of vitamin K2 on the recurrence and survival of patients with HCC after curative therapy were evaluated . METHODS Sixty patients who were diagnosed to be free of HCC after radiofrequency ablation therapy or surgery were r and omly assigned to either the vitamin K2 group ( n = 30 patients ) or the control group ( n = 30 patients ) . All patients were positive for the hepatitis C virus ( HCV ) antibody and hepatitis B surface antigen positive patients were excluded from this study . Patients in the vitamin K2 group received an oral dose of menatetrenone at 45 mg per day . Disease recurrence and the survival rates were analyzed in patients with HCC . RESULTS The cumulative recurrence-free rates in the vitamin K2 group were 92.3 % at 12 months , 48.6 % at 24 months and 38.8 % at 36 months ; and those in the control group were 71.7 % , 35.9 % and 9.9 % , respectively ( P = 0.045 ) . The cumulative survival rates in the vitamin K2 group were 100 % at 12 months , 95.0 % at 24 months and 
    Output:
    
The meta- analysis of all five studies , failed to confirm significantly better tumor recurrence- free survival at 1 year .
Improved tumor recurrence at 2nd and 3rd year may be just due to insufficient data .
There was no beneficial effect on the overall survival .