Analysis of Lenvatinib's Efficacy against Intermediate-Stage Unresectable Hepatocellular Carcinoma.

Transarterial chemoembolization (TACE) has been the standard treatment for intermediate-stage, unresectable hepatocellular carcinoma (u-HCC). However, with recent advances in systemic therapy and the emergence of the concept of TACE-refractory or -unsuitable, the effectiveness of systemic therapy, as well as TACE, has been demonstrated for patients judged to be TACE-refractory or -unsuitable. In this study, the efficacy of lenvatinib and its combination with TACE after lenvatinib was investigated in 140 patients with intermediate-stage u-HCC treated with lenvatinib mainly because of being judged to be TACE-refractory or -unsuitable. Median overall survival (OS) and progression-free survival (PFS) were 24.4 and 9.0 months, respectively, indicating a good response rate. In multivariate analysis, modified albumin-bilirubin (mALBI) grade and up to seven criteria were identified as independent factors for OS, and mALBI grade and tumor morphology were identified as independent factors for PFS. While 95% of all patients were TACE-refractory or -unsuitable, the further prognosis was prolonged by the combination with TACE after lenvatinib initiation. These findings suggest that systemic therapy should be considered for intermediate-stage u-HCC, even in patients judged to be TACE-refractory or -unsuitable. The use of TACE after the start of systemic therapy may further improve prognosis.

Analysis of Survival and Response to Lenvatinib in Unresectable Hepatocellular Carcinoma.

The association between radiological response and overall survival (OS) was retrospectively evaluated in patients treated with lenvatinib as a first-line systemic treatment for unresectable hepatocellular carcinoma. A total of 182 patients with Child-Pugh class A liver function and an Eastern Cooperative Oncology Group performance status of zero or one were enrolled. Radiological evaluation was performed using Response Evaluation Criteria in Solid Tumors (RECIST) and modified Response Evaluation Criteria in Solid Tumors (mRECIST). Initial radiological evaluation confirmed significant stratification of OS by efficacy judgment with both RECIST and mRECIST, and that initial radiological response was an independent prognostic factor for OS on multivariate analysis. Furthermore, in patients with stable disease (SD) at initial evaluation, macrovascular invasion at the initial evaluation on RECIST and modified albumin-bilirubin grade at initial evaluation on mRECIST were independent predictors of OS on multivariate analysis. In conclusion, if objective response is obtained at the initial evaluation, continuation of treatment appears desirable because prolonged OS can be expected; but, if SD is obtained at the initial evaluation, one should determine whether to continue or switch to the next treatment, with careful consideration of factors related to the tumor and hepatic reserve at the initial evaluation.

Clinical Outcomes of 2nd- and 3rd-Line Regorafenib for Advanced Hepatocellular Carcinoma.

INTRODUCTION: This study compared clinical outcomes of 2nd- and 3rd-line regorafenib in patients with unresectable hepatocellular carcinoma. METHODS: In this retrospective cohort study, 48 patients were treated with regorafenib for unresectable hepatocellular carcinoma. Thirty-five and 13 patients were initiated on 2nd- and 3rd-line therapy, respectively. We assessed the responses to and safety of the therapy. RESULTS: There were no statistically significant differences in clinical characteristics at the start of 2nd- or 3rd-line regorafenib therapy. The overall response rate of 2nd- and 3rd-line regorafenib was 20 and 8%, respectively. The disease control rate was 57 and 54%, respectively. Median overall survival (mOS) from the start of 2nd-line regorafenib was 17.5 months. mOS from the start of 3rd-line regorafenib was not obtained. Median progression-free survival of 2nd- and 3rd-line regorafenib was 4.9 and 2.3 months, respectively. mOS from 1st-line therapy with tyrosine kinase inhibitor plus sorafenib-regorafenib-lenvatinib was 29.5 months; that with lenvatinib-sorafenib-regorafenib was not obtained. Patients on 3rd-line therapy tended to have better Child-Pugh scores and tumor factors at the start of 1st-line therapy than other patients. CONCLUSION: Patients on 2nd- and 3rd-line regorafenib showed favorable responses. Good Child-Pugh scores and tumor factors may be associated with a better response rate and OS.

Analysis of Post-Progression Survival in Patients with Unresectable Hepatocellular Carcinoma Treated with Lenvatinib.

BACKGROUND: Although a strong antitumor effect of lenvatinib (LEN) has been noted for patients with unresectable hepatocellular carcinoma (HCC), there are still no reports on the prognosis for patients with disease progression after first-line LEN therapy. METHODS: Patients (n = 141) with unresectable HCC, Child-Pugh class A liver function, and an Eastern Cooperative Oncology Group performance status (ECOG-PS) of 0 or 1 who were treated with LEN from March 2018 to December 2019 were enrolled. RESULTS: One hundred and five patients were treated with LEN as first-line therapy, 53 of whom had progressive disease (PD) at the radiological evaluation. Among the 53 patients with PD, there were 27 candidates for second-line therapy, who had Child-Pugh class A liver function and an ECOG-PS of 0 or 1 at progression. After progression on first-line LEN, 28 patients were treated with a molecular targeted agent (MTA) as second-line therapy (sorafenib: n = 26; ramucirumab: n = 2). Multivariate analysis identified modified albumin-bilirubin grade 1 or 2a at LEN initiation (odds ratio 5.18, 95% confidence interval [CI] 1.465-18.31, p = 0.011) as a significant and independent factor for candidates. The median post-progression survival after PD on first-line LEN was 8.3 months. Cox hazard multivariate analysis showed that a low alpha-fetoprotein level (<400 ng/mL; hazard ratio [HR] 0.297, 95% CI 0.099-0.886, p = 0.003), a relative tumor volume <50% at the time of progression (HR 0.204, 95% CI 0.07-0.592, p = 0.03), and switching to MTAs as second-line treatment after LEN (HR 0.299, 95% CI 0.12-0.746, p = 0.01) were significant prognostic factors. CONCLUSION: Among patients with PD on first-line LEN, good liver function at introduction of LEN was an important and favorable factor related to eligibility for second-line therapy. In addition, post-progression treatment with MTAs could improve the prognosis for patients who had been treated with first-line LEN.

Autopsy of anaplastic carcinoma of the pancreas producing granulocyte colony-stimulating factor.

A 50-year-old man presented to a nearby hospital with high fever and anorexia. An abdominal tumor was detected, and he was referred to our hospital. A pancreatic tumor was detected by computed tomography and abdominal ultrasonography. He had high fever, leukocytosis, and high serum granulocyte colony-stimulating factor (G-CSF). We performed a tumor biopsy and histological examination revealed anaplastic carcinoma of the pancreas. Based on the diagnosis, we initiated chemotherapy using gemcitabine plus S-1. However, the tumor rapidly progressed and he deteriorated and died 123 days after admission. As immunohistochemical study showed positive staining for G-CSF in the tumor cell, we diagnosed the tumor producing G-CSF during autopsy. Anaplastic carcinoma of the pancreas producing G-CSF is very rare, with 10 cases, including ours, reported in the literature.

Postprocedural combined treatment using the coagulation plus artery-selective clipping (2C) method for the prevention of delayed bleeding after ESD.

BACKGROUND: The incidence of delayed bleeding after endoscopic submucosal dissection (ESD) for gastric neoplasms is reported to be approximately 5 %. We examined whether postprocedural combined treatment using the coagulation plus artery-selective clipping (2C) method is a useful measure for preventing delayed bleeding after ESD. METHODS: A total of 234 gastric epithelial neoplasms were treated from June 2007 to May 2012. Post-ESD coagulation (PEC) and clipping for part of the vessels was performed for 154 lesions from June 2007 to June 2010. A total of 80 lesions were treated using the 2C method from July 2010 to May 2012. During ESD, the locations of the arteries were recorded on a schematic diagram of the lesion. Arteries were defined as regions of arterial bleeding that required coagulation or apparent arteries in which preventive coagulation was performed. When ESD was completed, soft coagulation was performed for arteries in the resection area using hemostatic forceps, followed by arterial clipping for additional strength. Coagulation also was performed continuously for visible vessels in the resection area. This was a retrospective study. The incidence rates of delayed bleeding after ESD, as evidenced by hematemesis or melena, or the presence of anemia (decline in Hb >2 g/dl) that required emergency endoscopy were recorded. RESULTS: Delayed bleeding occurred in 7 (4.5 %) of the 154 cases treated using PEC and in 1 (1.3 %) of the 80 cases treated using the 2C method. The mean time required for the 2C method was 15.0 ± 7.0 min (range, 5-44 min). The mean number of clippings per lesion was 3.8 ± 2.8 (range, 0-13). Almost all clips fell off within 2 months of the procedure. CONCLUSIONS: Coagulation plus artery-selective clipping (the 2C method) of post-ESD ulcers might effectively reduce the incidence of delayed bleeding after ESD for gastric neoplasms.

Clinical outcome of esophageal varices after hepatic arterial infusion chemotherapy for advanced hepatocellular carcinoma with major portal vein tumor thrombus.

AIM: To analyze the clinical outcome of esophageal varices (EV) after hepatic arterial infusion chemotherapy (HAIC) in patients with advanced hepatocellular carcinoma (HCC) and major portal vein tumor thrombus (Vp3/4). METHODS: The study subjects were 45 consecutive patients who received HAIC for HCC with Vp3/4 between January 2005 and December 2009. HAIC comprised the combination therapy of intra-arterial 5-FU with interferon-α (5-FU/IFN) in 23 patients and low-dose cisplatin plus 5-FU (FP) in 22. Radiotherapy (RT) was also provided in 19 patients for portal vein tumor thrombosis. Aggravation rate for EV and overall survival rate were analyzed. RESULTS: The aggravation rates for EV were 47% and 64% at 12 and 24 months, respectively. The survival rates were 47% and 33% at 12 and 24 months, respectively. The response rates to 5-FU/IFN and FP were 35% and 41%, while the disease control rates in these two groups were 57% and 50%, respectively. There were no significant differences in the objective response and disease control between 5-FU/IFN and FP. Multivariate analysis identified size of EV (F2/F3) (HR = 7.554, P = 0.006) and HCC disease control (HR = 5.948, P = 0.015) as significant and independent determinants of aggravation of EV, and HCC disease control (HR = 12.233, P < 0.001), metastasis from HCC (HR = 11.469, P = 0.001), ascites (HR = 8.825, P = 0.003) and low serum albumin (HR = 4.953, P = 0.026) as determinants of overall survival. RT for portal vein tumor thrombosis tended to reduce the aggravation rate for EV in patients with these risk factors. CONCLUSIONS: Hepatocellular carcinoma disease control was the most significant and independent factor for aggravation of EV and overall survival in HCC patients with major portal vein tumor thrombosis treated with HAIC.

Eradication of hepatitis C virus genotype 1 after liver transplantation by interferon therapy before surgery: Report of three patients with analysis of interleukin-28 polymorphism, hepatitis C virus core region and interferon-sensitivity determining region.

The achievement of sustained viral response (SVR) with interferon (IFN) therapy before liver transplantation (LT) is difficult due to liver dysfunction, pancytopenia and frequent side-effects. Here, we report eradication of hepatitis C virus (HCV) genotype 1 after LT in three patients by IFN therapy before surgery. All three patients achieved virological response (VR), namely, fall in serum HCV RNA titer below the detection limit of real-time polymerase chain reaction (PCR) during IFN administration. However, HCV RNA rebound after cessation of treatment in all three patients; namely, they could not achieve SVR despite treatment with pegylated (PEG) IFN plus ribavirin. All three patients had wild-type amino acids (a.a.) at either aa70 or aa91 in the core region. Genotyping of IL-28 single nucleotide polymorphisms (rs8099917) showed TT genotype in two patients and TG genotype in one. All three patients developed multiple hepatocellular carcinomas during the clinical course, and requested living donor LT using liver grafts from their relatives. The patients were treated with IFN to immediately before LT, at which time they remained negative for HCV RNA in serum by real-time PCR. The three patients were followed-up for 14-15 months after LT, during which they remained negative for HCV RNA despite no further IFN therapy. In conclusion, it is possible to eradicate HCV after LT by inducing VR with continuous IFN therapy to before LT in spite of viral and host evidences reflecting low susceptibility to IFN treatment.

Common genetic polymorphism of ITPA gene affects ribavirin-induced anemia and effect of peg-interferon plus ribavirin therapy.

An association between a single nucleotide polymorphism (SNP) in the inosine triphosphate pyrophosphatase (ITPA) gene and reduction of hemoglobin during peg-interferon plus ribavirin combination therapy for patients with chronic hepatitis C virus (HCV) infection has been reported. However, the effect of the SNP on outcome of therapy has not been fully elucidated. Factors associated with anemia during combination therapy, including rs1127354 genotype, were analyzed in 1,002 treated patients. The effect of the SNP on outcome of therapy was analyzed in a subset of 830 patients with genotype 1. A rapid initial decrease in hemoglobin levels was observed in patients with rs1127354 genotype CC compared with a slow decrease in non-CC patients. Cumulative reduction of ribavirin was significantly more frequent in genotype CC patients than non-CC patients (odds ratio 1.928, P = 8.6 × 10(-8) ). The frequency of patients who received at least the recommended 80% of scheduled ribavirin was significantly lower among genotype CC patients, especially among those who had pretreatment hemoglobin levels between 13.5 and 15 g/dl (P < 0.03), and the sustained viral response rate was significantly lower in this group of patients. Independent predictive factors for sustained virological response included a SNP in the IL28B locus (rs809991), age, fibrosis, ITPA SNP rs1127354 as well as pretreatment hemoglobin levels. Our data suggests that measures to prevent anemia should be considered for patients who have pretreatment hemoglobin levels less than 13.5 g/dl or who have rs1127354 genotype CC and pretreatment hemoglobin levels between 13.5 and 15 g/dl.

Clinical features and prognosis in patients with hepatocellular carcinoma that developed after hepatitis C virus eradication with interferon therapy.

BACKGROUND: We evaluated the clinical features and the prognostic factors of hepatocellular carcinoma (HCC) developed after hepatitis C virus (HCV) eradication with interferon (IFN) therapy. METHODS: Forty-one consecutive patients who developed HCC after HCV eradication with IFN therapy were enrolled. Clinical features were reviewed, and overall survival and associated factors were analyzed. The recurrence rate in 26 patients receiving radical therapy was also analyzed. RESULTS: Twenty patients developed HCC within 5 years after the end of IFN therapy, 9 patients developed the disease from 5 to 10 years after the end of the therapy, 9 patients developed the disease from 10 to 15 years after the end of the therapy, and 3 patients developed the disease from 15 years after the end of the therapy. Multivariate analysis of independent variables for the development of HCC within 5 years identified age >55 years at HCV eradication (P = 0.007) and heavy alcohol intake (P = 0.009). The 5-year survival rate was 64%. On multivariate analysis of overall survival for the 41 patients, the only risk factor with prognostic influence was radical therapy (P = 0.010), which was associated with a cumulative 5-year survival rate of 91%. The only independent factor for the receipt of radical therapy was regular surveillance for HCC (P = 0.004). Among patients receiving radical therapy, the 3- and 5-year recurrence rates were 18 and 18%, respectively. CONCLUSION: We found that, despite HCV eradication, patients with the risk factors of high age at HCV eradication and heavy alcohol intake might be at heightened risk for the development of HCC within 5 years after HCV eradication. In contrast, risk factors for the development of HCC more than 10 years after HCV eradication were uncertain. These findings indicate the need for long-term surveillance for HCC after HCV eradication.

[Case of double cancer of the liver, cholangiocarcinoma and hepatocellular carcinoma detected in a patient with hepatitis C 13 years after diminution of HCV-RNA by interferon treatment].

A 56-year-old man with chronic hepatitis C (HCV) was treated with interferon therapy and achieved sustained virological response (SVR) in 1993. Thirteen years later, in 2006 two liver tumors, 35-mm and 11-mm in diameter respectively, were detected in liver segment 6. Hepatic resection was performed, and pathologically one nodule was diagnosed as cholangiocellular carcinoma (CCC) and the other hepatocellular carcinoma (HCC). Continuity was not recognized between these tumors, thus, we diagnosed this case as double cancer (CCC and HCC). Here, we report a rare case of double cancer (CCC and HCC) that developed 13 years after achieving SVR for HCV infection.

The first Japanese case of COACH syndrome.

COACH syndrome is a disorder characterized by hypoplasia of cerebellar vermis, oligophrenia, congenital ataxia, coloboma and hepatic fibrosis, and 21 cases have been reported to date. Here we describe the first Japanese case of COACH syndrome, who was diagnosed at the age of 37 years and never progressed to liver failure. The patient was found to have delayed developmental milestones at the age of 5 months and mental retardation at the age of 7 years. She had been treated for hepatopathy of unknown origin from the age of 22 years. She was admitted to Hiroshima University Hospital at the age of 37 years after the identification of esophageal varices on a routine upper endoscopy. Computed tomography of the abdomen revealed portal hypertension and splenomegaly, and liver biopsy showed liver fibrosis. In addition, she had coordination disorder and dysarthria. Brain magnetic resonance images revealed hypoplasia of cerebellar vermis. The final diagnosis was COACH syndrome. She underwent endoscopic injection sclerotherapy for esophageal varices. From that point until her death from ovarian cancer at the age of 41 years, the liver function tests were stable without an episode of hematemesis. Physicians should be aware of COACH syndrome when they examine young patients who present with hepatopathy, portal hypertension of unknown origin and cerebellar ataxia.

Intra-arterial 5-fluorouracil/interferon combination therapy for advanced hepatocellular carcinoma with or without three-dimensional conformal radiotherapy for portal vein tumor thrombosis.

BACKGROUND: The aim of this study was to elucidate the efficacy of intra-arterial 5-fluorouracil (5-FU) and interferon (IFN) alpha combined with three-dimensional conformal radiotherapy (3D-CRT) for portal vein tumor thrombosis (PVTT). METHODS: The study groups were 16 HCC patients with PVTT treated with 5-FU/IFN combined with 3D-CRT (RT group) and 16 matched controls treated with 5-FU/IFN alone (non-RT group). We compared the survival rate, response, time to progression (TTP), portal hypertension-related events (PREs) and safety. RESULT: Complete response (CR) of PVTT, partial response (PR), stable disease (SD) and progressive disease (PR) were noted in three (19%), nine (56%), four (25%) and zero patients of the RT group, one (6%), three (19%), seven (44%) and five (31%) patients of the non-RT group, respectively. The objective response rate of PVTT was higher in the RT group (P = 0.012). The rate of PREs (variceal rupture, worsening of esophagogastric varices and emerging of uncontrollable ascites) was lower in the RT group than in the non-RT group (P = 0.0195). The median survival time of the RT group (7.5 months) was not significantly different from that of the non-RT group (7.9 months). RT-induced liver disease was not observed. CONCLUSION: 5-FU/IFN combination with 3D-CRT for PVTT improved the response rate of PVTT and reduced the incidence of portal hypertension-related events.

FDG positron emission tomography/computed tomography for the detection of extrahepatic metastases from hepatocellular carcinoma.

AIMS: To compare the efficacy of positron emission tomography (PET) computed tomography (CT), multi-detector helical computed tomography (MDCT) and bone scintigraphy for the detection of extrahepatic metastases in patients with hepatocellular carcinoma (HCC). METHODS: Thirty-four patients diagnosed with metastatic HCC were enrolled in this study. The lesions included lung (n = 18), bone (n = 12) and lymph node (n = 16) metastases. For receiver operating characteristic (ROC) analysis, lesions were diagnosed as metastatic HCC by two experienced abdominal radiologists. Another three physicians independently reviewed both positive and negative images. Each physician read three sets of images of MDCT, PET-CT and bone scintigraphy for bone metastasis. RESULTS: The mean sensitivity and specificity for diagnosis of lung metastasis were 85.2 and 88.9% for MDCT, and 59.2 and 92.6% for PET-CT, respectively. For lymph node metastasis, these values were 62.5 and 79.2% for MDCT, and 66.7 and 91.7% for PET-CT, respectively; and for bone metastasis 41.6 and 94.5% for MDCT, 83.3 and 86.1% for PET-CT, and 52.7 and 83.3% for bone scintigraphy, respectively. The mean Az values were 0.95 and 0.77 for MDCT and PET-CT in lung metastasis, respectively, 0.75 and 0.80 for MDCT and PET-CT for lymph node metastasis, respectively, and 0.59, 0.88 and 0.62 for MDCT, PET-CT and bone scintigraphy for bone metastasis, respectively. CONCLUSION: PET-CT has high sensitivity and is more suitable for the detection of bone metastases from primary HCC, relative to MDCT and bone scintigraphy.

Successful treatment of pulmonary metastases associated with advanced hepatocellular carcinoma by systemic 5-fluorouracil combined with interferon-alpha in a hemodialysis patient.

A 54-year-old man maintained on hemodialysis had a relapse of multiple pulmonary metastases after multimodal therapy for primary hepatocellular carcinoma (HCC). He was treated with tegafur-uracil (UFT; 400 mg/day) and interferon alfa (IFN-alpha; 5 x 10(6) units three times per week) for 4 weeks. Following this he was treated with systemic 5-fluorouracil (5-FU; 1000 mg/day, 5 days per week) and cisplatin (CDDP; 10 mg/day, 5 days per week for 2 weeks). The response to the above treatments was inadequate; pulmonary metastasis deteriorated. Finally, we selected systemic chemotherapy of 5-FU (750 mg/day, 5 days per week) and recombinant IFN-alpha-2b (3 x 10(6) units three times per week) for 2 weeks. This therapy resulted in excellent shrinkage of pulmonary metastases, without severe adverse reactions. Hemodialysis was performed three times a week. We report a case of successful treatment of pulmonary metastases by systemic combination chemotherapy of 5-FU-IFN, previously unsuccessfully treated with UFT-IFN and 5-FU-CDDP in a patient on hemodialysis. Further studies are needed to select appropriate drugs with fluoropyrimidine-based systemic chemotherapy, and to analyze the pharmacokinetics of those agents in hemodialysis patients with HCC and extrahepatic metastases.

Combination therapy of oral fluoropyrimidine anticancer drug S-1 and interferon alpha for HCC patients with extrahepatic metastases.

PURPOSE: There is no standard treatment for hepatocellular carcinoma (HCC) patients with extrahepatic metastases. We assessed the efficiency and safety of the oral fluoropyrimidine anticancer drug S-1 combined with interferon alpha (IFN-alpha) for HCC patients with extrahepatic metastases. METHODS: Twenty-nine HCC patients with extrahepatic metastases received S-1/IFN. One cycle of combination therapy represented 2 weeks followed by 2-4 weeks of rest. In each cycle, S-1 was administrated orally at 80-120 mg (depending on body surface area) every day and IFN-alpha intramuscularly at 5 million units thrice weekly. RESULTS: The overall response of 29 patients was complete response (CR) in 4 (14%), partial response (PR) in 1, stable disease in 4, progressive disease in 12, and dropout in 8 patients. Objective response (CR + PR) was 17%. The time to progression and survival rate were significantly higher in patients with lung metastases (n = 19) than in those with painful bone metastases (n = 7; p = 0.0058 and 0.0015). With regard to NCI-CTC grade 3 adverse reactions, 3 (10%), 3 (10%) and 2 (7%) patients developed anorexia, leukopenia, and neutropenia, respectively. No grade 4 adverse reaction or toxicity-related death occurred. CONCLUSION: S-1/IFN is a potentially safe and suitable combination therapy for HCC patients with extrahepatic metastases, especially those with lung metastases.

Clinicopathological features of elderly patients with hepatitis C virus-related hepatocellular carcinoma.

BACKGROUND: It is well known that the incidence of hepatocellular carcinoma (HCC) in patients with hepatitis C virus (HCV) correlates with progression of liver fibrosis. However, there is little information on the impact of aging on hepatocarcinogenesis. The aim of this study was to elucidate the clinicopathological features of elderly patients with HCV-related HCC. METHODS: The study subjects were 693 consecutive patients newly diagnosed with HCC with anti-HCV. First, we divided them into a younger group (<70 years) and an elderly group (> or =70 years) and compared clinicopathological features between the two groups. Next, we selected pure HCV-related HCC patients by excluding the patients with other probable factors for hepatocarcinogenesis (anti-HBc, interferon therapy, and alcohol) and compared the two groups again. RESULTS: Higher platelet count, lower male/female ratio, lower rate of habitual alcohol consumption, and better Child-Pugh class were recognized in the elderly group thant the younger group, statistically. In 133 cases of hepatic resection, fibrosis stage was lower in the elderly than the younger group. After selection of pure HCV-related HCC patients, in a stepwise multi variate analysis, male sex and platelet count <10 x 10(4)/mm3 were significant variables associated with age <70. Regarding the latency period to HCC development, the patients who received a blood transfusion at an older age developed HCC sooner despite their lower grade of fibrosis. CONCLUSIONS: The elderly patients developed HCC more often, despite their lower grade of fibrosis, compared with the younger patients. In addition to fibrosis, aging could be a factor affecting HCV-related hepatocarcinogenesis.

Low-dose intermittent interferon-alpha therapy for HCV-related liver cirrhosis after curative treatment of hepatocellular carcinoma.

AIM: To assess the efficacy of low-dose intermittent interferon (IFN) therapy in patients with hepatitis C virus (HCV)-related compensated cirrhosis who had received curative treatment for primary hepatocellular carcinoma (HCC). METHODS: We performed a prospective case controlled study. Sixteen patients received 3 MIU of natural IFN-alpha intramuscularly 3 times weekly for at least 48 wk (IFN group). They were compared with 16 matched historical controls (non-IFN group). RESULTS: The cumulative rate of first recurrence of HCC was not significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 68.6% vs 80% at 1- and 3-year, P = 0.157, respectively). The cumulative rate of second recurrence was not also significantly different between the IFN group and the non-IFN group (0% vs 6.7% and 35.9% vs 67% at 1- and 3-year, P = 0.056, respectively). Although the difference in the Child-Pugh classification score between the groups at initial treatment of HCC was not significant, the score was significantly worse at the time of data analysis in the non-IFN group than IFN group (7.19 +/- 1.42 vs 5.81 +/- 0.75, P = 0.0008). The cumulative rate of deviation from objects of any treatment for recurrent HCC was also higher in the non-IFN group than IFN group (6.7% and 27% vs 0 and 0% at 1- and 3-year, P = 0.048, respectively). CONCLUSION: Low-dose intermittent IFN-alpha therapy for patients with HCV-related compensated cirrhosis after curative HCC treatment was effective by making patients tolerant to medical or surgical treatment for recurrent HCC in the later period of observation.

Effects of a 24-week course of interferon-alpha therapy after curative treatment of hepatitis C virus-associated hepatocellular carcinoma.

AIM: To assess whether a 24-wk course of interferon (IFN) could prevent hepatocellular carcinoma (HCC) recurrence and worsening of liver function in patients with hepatitis C virus (HCV)-infected patients after receiving curative treatment for primary HCC. METHODS: Outcomes in 42 patients with HCV infection treated with IFN-alpha, after curative treatment for primary HCC (IFN group), were compared with 42 matched curatively treated historical controls not given IFN (non-IFN group). RESULTS: Although the rate of initial recurrence did not differ significantly between IFN group and non-IFN group (0%, 44%, 61%, and 67% vs 4.8%, 53%, 81%, and 87% at 1, 3, 5, and 7 years, P = 0.153, respectively), IFN group showed a lower rate than the non-IFN group for second recurrence (0%, 10.4%, 28%, and 35% vs 0%, 30%, 59%, and 66% at 1, 3, 5 and 7 years, P = 0.022, respectively). Among the IFN group, patients with sustained virologic response (SVR) were less likely to have a second HCC recurrence than IFN patients without an SVR, or non-IFN patients. Multivariate analysis identified the lack of SVR as the only independent risk factor for a second recurrence, while SVR and Child-Pugh class A independently favored overall survival. CONCLUSION: Most intrahepatic recurrences of HCV-related HCC occurred during persistent viral infection. Eradication of HCV is essential for the prevention of HCC recurrence and improvement of survival.