Safety and Effectiveness of Lenvatinib in Patients with Unresectable Hepatocellular Carcinoma in Real-World Clinical Practice: An Observational Post-Marketing Study in Japan.

BACKGROUND: Lenvatinib was approved for use in unresectable hepatocellular carcinoma (uHCC) in Japan in 2018. Patients with diverse clinical characteristics receive lenvatinib treatment in clinical practice. Thus, it is crucial to evaluate the safety and effectiveness of lenvatinib in real-world clinical settings. OBJECTIVE: This study aimed to evaluate the real-world safety and effectiveness of lenvatinib for uHCC in clinical practice in Japan. PATIENTS AND METHODS: Between July 2018 and January 2019, patients with uHCC who were administered lenvatinib for the first time were enrolled in this prospective, multicenter, observational post-marketing study (NCT03663114). Patients were orally administered lenvatinib and followed up for 12 months. For safety, adverse drug reactions (ADRs) were evaluated. For effectiveness, the objective response rate (ORR) was calculated to evaluate tumor response. Overall survival (OS) was estimated using the Kaplan-Meier method. RESULTS: Data of 703 patients (median age, 73 years; 80.2% males) were analyzed. The median (range) treatment duration was 25.3 (0.3-68.9) weeks. The mean ± standard deviation initial dose was 7.37 ± 1.65 mg in patients with body weight < 60 kg and 10.43 ± 2.49 mg in those with body weight ≥ 60 kg. ADRs (any grade) were reported in 84.9% of the patients, with Grade ≥ 3 ADRs reported in 42.5% of the patients. The most common ADRs (> 10%) were decreased appetite, fatigue, hypertension, proteinuria, palmar-plantar erythrodysesthesia, hypothyroidism, and diarrhea. The median OS of the 703 patients was 498.0 days. In 494 patients assessed using the modified Response Evaluation Criteria in Solid Tumors (mRECIST), the ORR was 39.5% (95% confidence interval: 35.1-43.9%). Patients with better liver or renal function at baseline achieved significantly higher ORR than those with worse liver or renal function. CONCLUSIONS: In patients with uHCC in real-world clinical practice in Japan, treatment with lenvatinib was generally well tolerated, and no new safety concerns were identified. The ORR and median OS were similar to or better than the results of the Japanese subset of the global Phase III REFLECT trial. Our results demonstrated that clinically meaningful treatment responses were achieved with lenvatinib in real-world clinical practice.

Acute necrotic disorder of the small intestine post-coronavirus disease-2019 vaccination.

The Pfizer-BioNTech coronavirus disease 2019 (COVID-19) vaccine is extensively used worldwide, and its safety has been proven. Herein, we report a case of an acute necrotic disorder in the small intestine post-COVID-19 vaccination. The patient developed severe abdominal pain the day after the first vaccination. Contrast-enhanced computed tomography showed extensive ileum wall thickening and ascites. Colonoscopy revealed a ring-shaped ulcer and stricture in the terminal ileum. Ileocecal resection was performed, and the patient did not have further episodes of a necrotic disorder in the small intestine. Although it is unknown if this event is associated with vaccination, and this occurrence also does not outweigh the efficacy and safety of the Pfizer-BioNTech COVID-19 vaccine, gastroenterologists need to be aware of this rare case, given its noteworthy timing.

Intrahepatic cholangiocarcinoma with clear cell type following laparoscopic curative surgery.

BACKGROUND: Intrahepatic cholangiocarcinoma (ICC) is the second most common malignancy of primary liver cancer. Among the several pathological types of ICC, only five cases of the clear cell type have been reported, including the one presented below. Here we report a unique case of clear cell type ICC following laparoscopic hepatectomy. CASE PRESENTATION: A 67-year-old woman had a history of hepatitis B virus. Computed tomography revealed a ring-like enhanced mass 35 mm in diameter at segment 7 in the early phase. The enhancement was prolonged to the late phase through the portal phase, while the shape was irregular. Ethoxybenzy magnetic resonance imaging revealed that the tumor had a low signal intensity on T1-weighted imaging and a high signal intensity on T2-weighted imaging. Diffusion-weighted images identified that the tumor had remarkably high signal intensity. Tumor enhancement was not detected throughout the tumor in the hepatocyte phase. Upon ICC diagnosis, a laparoscopic S7 subsegmentectomy was performed. The patient's postoperative course was uneventful. An immunohistochemical examination revealed that the cells tested positive for cytokeratin 7 (CK7), CK19, and CD56 and negative for CK20, CD10, α-fetoprotein, thyroid transcription factor-1. At 2 years after surgery, the patient remains alive without recurrence. CONCLUSIONS: Here we presented a case of clear cell ICC that was treated by laparoscopic hepatectomy. Immunological analysis, especially by CD56 and several CK markers, is helpful for diagnosing this disease.

Real-world efficacy of sofosbuvir plus velpatasvir therapy for patients with hepatitis C virus-related decompensated cirrhosis.

AIM: Combination therapy with sofosbuvir (SOF) plus velpatasvir (VEL) is approved for patients with hepatitis C virus (HCV)-related decompensated cirrhosis. We analyzed the real-world efficacy of SOF/VEL therapy. METHODS: Thirty-three patients with HCV-related decompensated cirrhosis (25 and eight patients with Child B and C, respectively) were treated with SOF/VEL for 12 weeks. The HCV non-structural protein (NS)5A and NS5B drug resistance-associated substitutions (RASs) were determined by direct sequencing. RESULT: Thirty-two of 33 patients completed the treatment, but the remaining patient discontinued the therapy during third week of the treatment due to aggravation of hepatic encephalopathy. Serum HCV-RNA became negative during the treatment in all patients but relapsed after the end of therapy in five patients. In total, 28 out of 33 patients (85%) achieved sustained virological response 12 weeks following completion of treatment (SVR12). The SVR12 rate was 96% in patients with Child B, but significantly lower, at 50%, in patients with Child C (P < 0.05). In genotype 1b HCV-infected patients, all eight patients without baseline NS5A RASs, but only three of seven patients with RASs, achieved SVR12. Multivariate analysis identified Child B (odds ratio, 35.8 for Child C; P = 0.045) as an independent predictor of SVR12. Median serum albumin levels significantly increased only in patients who achieved SVR12. Child-Pugh scores improved in 16 of 28 patients (57%) following achievement of SVR12. CONCLUSION: The effect of SOF/VEL therapy is lower for patients with Child C. Improvement of hepatic function is expected after viral eradication with SOF/VEL therapy in patients with decompensated cirrhosis.

Advanced liver fibrosis effects on the response to sofosbuvir-based antiviral therapies for chronic hepatitis C.

BACKGROUND: Sustained virological response (SVR) rates for the treatment of chronic hepatitis C virus (HCV)-infected patients have drastically improved with the use of direct-acting antiviral (DAA) therapies; however, a small minority of patients still fails to eradicate the virus. We analyzed factors associated with SVR in DAA therapy and the effect of age and liver fibrosis on treatment response. METHODS: Nine hundred and eighteen patients with chronic HCV infection were treated with 24 weeks of daclatasvir plus asunaprevir (DCV + ASV) or 12 weeks of sofosbuvir plus ledipasvir (SOF + LDV), ombitasvir, paritaprevir plus ritonavir (OMB + PTV + r) or sofosbuvir plus ribavirin (SOF + RBV). Multivariate logistic regression analysis was used to identify factors associated with SVR. The effect of age and liver fibrosis on SVR was analyzed. RESULTS: The overall SVR rate was 95.4% (876 of 918 patients), and rates by DAA regimen were 93.4%, 95.7%, 100%, and 95.0% in DCV + ASV-treated, SOF + LDV-treated, OMB + PTV + r-treated, and SOF + RBV-treated patients, respectively. Patients older than 75 years achieved a similar SVR rate with those aged 75 years or younger (96.4% and 94.8%, respectively). Multivariate logistic regression analysis identified absence of DAA therapy history (odds ratio [OR], 3.868 for presence; P = 0.002) and FIB-4 index of less than 3.25 (OR, 5.042 for ≥3.25; P = 0.001) as independent predictors for SVR. SVR rates were significantly lower in patients with FIB4 index of 3.25 or more compared with those with less than 3.25, especially in sofosbuvir-based therapies such as SOF + LDV-treated or SOF + RBV-treated patients. CONCLUSION: Both older and younger patients respond similarly to DAA therapy. Advanced liver fibrosis affects the virological response to sofosbuvir-based therapy.

Hepatic arterial infusion chemotherapy followed by sorafenib in patients with advanced hepatocellular carcinoma (HICS 55): an open label, non-comparative, phase II trial.

BACKGROUND: In patients with advanced hepatocellular carcinoma (HCC), evidence is unclear as to whether hepatic arterial infusion chemotherapy (HAIC) or sorafenib is superior. We performed a prospective, open-label, non-comparative phase II study to assess survival with HAIC or HAIC converted to sorafenib. METHODS: Fifty-five patients were prospectively enrolled. Patients received HAIC as a second course if they had complete response, partial response, or stable disease (SD) with an alpha fetoprotein (AFP) ratio < 1 or a des-γ-carboxy prothrombin (DCP) ratio < 1. Patients were switched to sorafenib if they had SD with an AFP ratio > 1 and a DCP ratio > 1 or disease progression. The primary endpoint was the 1-year survival rate. Secondary endpoints were the 2-year survival rate, HAIC response, survival rate among HAIC responders, progression-free survival, and adverse events. RESULTS: Of the 55 patients in the intent-to-treat population, the 1-year and 2-year survival rates were 64.0 and 48.3%, respectively. After the first course of HAIC, one (1.8%) patient showed complete response, 13 (23.6%) showed partial response, 30 (54.5%) had SD, and 10 (18.1%) patients had progressive disease. Twenty-three patients (41.8%) had SD with AFP ratios < 1 or DCP ratios < 1, and 7 (12.7%) had SD with AFP ratios > 1 and DCP ratios > 1. Thirty-seven patients (68.5%) were responders and 17 (30.9%) were non-responders to HAIC. In responders, the 1-year and 2-year survival rates were 78 and 62%, respectively. CONCLUSION: Given the results of this study, this protocol deserves consideration for patients with advanced HCC. This trial was registered prospectively from December 12. 2012 to September 1. 2016.

Daclatasvir and asunaprevir in hemodialysis patients with hepatitis C virus infection: a nationwide retrospective study in Japan.

BACKGROUND: Hepatitis C virus (HCV) infection is common in hemodialysis patients and worsens their prognosis, while antiviral therapy options are limited. Recently, clinical trial and real-world, small-scale studies have reported excellent responses to direct-acting antivirals in patients with advanced chronic kidney diseases. However, real-world, large-scale data were lacking. This large multicenter analysis included HCV-infected hemodialysis patients receiving combination therapy with a nonstructural protein 5A (NS5A) inhibitor, daclatasvir (DCV), and a protease inhibitor, asunaprevir (ASV). METHODS: Twenty-three centers in Japan participated in this study of 123 hemodialysis patients with genotype 1 HCV infection, who received DCV/ASV combination therapy between November 2014 and March 2016. We collected and analyzed data relating to treatment outcome, baseline clinical information, laboratory measurements (during and after the treatment), and adverse events. RESULTS: Thirty-nine patients (31.7%) had advanced liver fibrosis, 12 (9.8%) had histories of hepatocellular carcinoma (HCC), and 18 (14.6%) had baseline resistance-associated variants (RAVs) of NS5A. The overall sustained virological response (SVR)12 rate was 95.9% (118/123). Notably, all patients with HCC and 94.4% (17/18) of those with NS5A RAVs achieved SVR12. Significant factors associated with non-SVR were advanced fibrosis and the interleukin-28B non-TT genotype at rs8099917. Four patients (3.3%) discontinued therapy because of adverse events including elevated serum alanine transaminase levels (n = 2), rash (n = 1), and HCC (n = 1); all of these achieved SVR12. CONCLUSIONS: This real-world, nationwide study revealed that DCV/ASV combination therapy was safe and highly effective for hemodialysis patients with genotype 1 HCV infections. This study was registered at the UMIN Clinical Trials Registry (UMIN000024227).

Efficacy and safety of ledipasvir/sofosbuvir with ribavirin in chronic hepatitis C patients who failed daclatasvir/asunaprevir therapy: pilot study.

BACKGROUND: In Japan, daclatasvir (DCV) and asunaprevir (ASV) therapy was the first IFN-free treatment to be approved, and thousands of patients have since been successfully treated, with an SVR rate of around 90%. The converse, however, is that around 10% of patients fail to achieve viral eradication and must be retreated using a different approach. This study is to evaluate treatment efficacy of ledipasvir/sofosbuvir and ribavirin in patients who failed to respond to DCV and ASV therapy. METHODS: Thirty patients were treated with 12 weeks of ledipasvir/sofosbuvir and ribavirin. We evaluated the rate of sustained virological response 12 weeks after the end of treatment (SVR12) and examined the incidence of adverse events during ledipasvir/sofosbuvir and ribavirin treatment. NS5A and NS5B resistance-associated variants (RAVs) in treatment failure cases were examined. RESULTS: The overall SVR12 rate was 86.7% (26/30). Large decreases in mean log10 HCV RNA levels were observed in patients without cirrhosis, and the SVR12 rate for these patients was 100% (12/12). In cases of cirrhosis, SVR12 rate was 72.2% (13/18). The common factors in treatment failure cases were the presence of liver cirrhosis and both NS5A L31M/I and Y93H RAVs. The frequency of RAVs did not change before and after treatment among patients who relapsed. CONCLUSION: Ledipasvir/sofosbuvir with ribavirin is an effective retreatment option for patients with chronic hepatitis C who failed to respond to prior daclatasvir and asunaprevir therapy.

A trial of the use of patency capsules in combination with overnight capsule endoscopy.

BACKGROUND: The PillCam® patency capsule (PPC) was developed to minimize the risk of capsule retention during capsule endoscopy (CE). Typically, the use of patency capsules prior to CE requires patients to be monitored over a period of time. To reduce the need for frequent outpatient visits during PPC examination and CE, we developed the overnight CE (ON-CE) procedure. METHODS: Between October 2012 and January 2014, a total of 19 patients (15 males and 4 females, mean age 48.4 years) were administered PPC to assess the patency of the small intestine prior to ON-CE at JA Onomichi General Hospital in Hiroshima, Japan. RESULTS: PPC confirmed patency of the small intestine in 15 of the 19 patients. Of these 15 patients, 14 proceeded to ON-CE. The CE was cancelled in 1 patient and the cecal intubation time exceeded 8 h in another patient. For the remaining 12 patients, the mean small intestine observation coverage was 92.3% and the mean cecal intubation time was 325 min. There were no adverse events and the discharge of the capsule was confirmed in all cases. CONCLUSION: When patency of the gastrointestinal tract was confirmed with the PPC, ON-CE was performed safely and effectively.

Targeting of αv integrin identifies a core molecular pathway that regulates fibrosis in several organs.

Myofibroblasts are the major source of extracellular matrix components that accumulate during tissue fibrosis, and hepatic stellate cells (HSCs) are believed to be the major source of myofibroblasts in the liver. To date, robust systems to genetically manipulate these cells have not been developed. We report that Cre under control of the promoter of Pdgfrb (Pdgfrb-Cre) inactivates loxP-flanked genes in mouse HSCs with high efficiency. We used this system to delete the gene encoding α(v) integrin subunit because various α(v)-containing integrins have been suggested as central mediators of fibrosis in multiple organs. Such depletion protected mice from carbon tetrachloride-induced hepatic fibrosis, whereas global loss of ß3, ß5 or ß6 integrins or conditional loss of ß8 integrins in HSCs did not. We also found that Pdgfrb-Cre effectively targeted myofibroblasts in multiple organs, and depletion of the α(v) integrin subunit using this system was protective in other models of organ fibrosis, including pulmonary and renal fibrosis. Pharmacological blockade of α(v)-containing integrins by a small molecule (CWHM 12) attenuated both liver and lung fibrosis, including in a therapeutic manner. These data identify a core pathway that regulates fibrosis and suggest that pharmacological targeting of all α(v) integrins may have clinical utility in the treatment of patients with a broad range of fibrotic diseases.

Long-term outcomes of hepatic arterial port implantation using a coaxial microcatheter system in 176 patients with hepatocellular carcinoma.

The purpose of this study is to evaluate the feasibility of hepatic arterial port implantation using a 2.9-Fr coaxial microcatheter for hepatic arterial infusion chemotherapy (HAIC) in patients with unresectable hepatocellular carcinoma (HCC) in the long-term follow-up period. Our study subjects were 176 patients with unresectable HCC who underwent hepatic arterial port implantation using a 2.9-Fr coaxial microcatheter via the femoral approach. A 2.9-Fr microcatheter with a side hole was introduced into the hepatic artery through a 5-Fr catheter. We determined the possible length of HAIC, starting with hepatic arterial port implantation and ending with the manifestation of technical difficulties or patient death. We also recorded the technical success rate, the time required for the procedure, and the complications encountered. The median duration of HAIC was 4.3 months (range 0.4-51.6 months) and the predictable cumulative rate of hepatic arterial port functioning at 6-, 12-, and 24 months was 75.1%, 60.9%, and 44.6%, respectively. Our technical success rate was 99.4% (175/176), and the mean time required for the procedure was 121 min. Complications were migration of the infusion hole (8.6%, 15/175), hepatic artery damage (5.7%, 10/175), port-catheter system occlusion (5.7%, 10/175), and problems involving the port or the puncture site (8.0%, 14/175). Our study demonstrates that the technical success rate of hepatic arterial port implantation using a coaxial microcatheter was high but that the incidence of port-catheter system occlusion and catheter dislocation was higher than in conventional methods. Our technique is another option to treat patients with HCC for whom conventional techniques cannot be used.

Hepatic arterial infusion chemotherapy using 5-fluorouracil and systemic interferon-α for advanced hepatocellular carcinoma in combination with or without three-dimensional conformal radiotherapy to venous tumor thrombosis in hepatic vein or inferior vena cava.

AIM: We investigated the efficacy of hepatic arterial infusion chemotherapy (HAIC) using 5-fluorouracil (5-FU) and systemic interferon (IFN)-α (HAIC-5-FU/IFN) for advanced hepatocellular carcinoma (HCC) with venous tumor thrombosis (VTT) in the hepatic vein trunk (Vv2) or inferior vena cava (Vv3). METHODS: Thirty-three patients with HCC/Vv2/3 underwent HAIC with 5-FU (500 mg/body weight/day, into hepatic artery on days 1-5 on the first and second weeks) and IFN-α (recombinant IFN-α-2b 3 000 000 U or natural IFN-α 5 000 000 U, intramuscularly on days 1, 3 and 5 of each week). Three-dimensional conformal radiotherapy (3D-CRT) was used in combination with HAIC-5-FU/IFN in 14 of 33 patients to reduce VTT. RESULT: The median survival time (MST) was 7.9 months, and 1- and 2-year survival rates were 30% and 20%, respectively. Evaluation of intrahepatic response after two cycles of HAIC-5-FU/IFN showed complete response (CR) in three (9%) and partial response (PR) in seven (21%), with an objective response rate of 30%. Multivariate analysis identified reduction of VTT (P = 0.0006), size of largest tumor (P = 0.013) and intrahepatic response CR/PR (P = 0.030) as determinants of survival. CR/PR correlated significantly with tumor liver occupying rate (P = 0.016) and hepatitis C virus Ab (P = 0.010). Reduction of VTT correlated significantly with radiotherapy (P = 0.021) and platelet count (P = 0.015). Radiotherapy-related reduction in VTT significantly improved survival of 16 patients with Vv3 and non-CR/PR response of HAIC-5-FU/IFN (P = 0.028). CONCLUSION: As for advanced HCC with VTT of Vv2/3, HAIC-5-FU/IFN responsive patients could obtain favorable survival. Despite ineffective HAIC-5-FU/IFN, the combination with effective radiotherapy to VTT might improve patients' prognosis.

Achievement of sustained viral response after switching treatment from pegylated interferon α-2b to α-2a and ribavirin in patients with recurrence of hepatitis C virus genotype 1 infection after liver transplantation: a case report.

We report a case in which sustained viral response was achieved after switching treatment from pegylated interferon (PEG-IFN) α-2b to α-2a and ribavirin (RBV) in patients with recurrence of hepatitis C virus (HCV) infection after living donor liver transplantation. The patient was a 62-year-old man with liver cirrhosis due to HCV genotype 1b infection. The patient had 8 amino acid (aa) substitutions in the interferon sensitivity-determining region, and had substitutions for mutant and wild-type at aa70 and aa91, respectively, in the core region. The patient had minor genotype (GG) IL28B single nucleotide polymorphisms (rs8099917). He had initially received interferon α-2b and RBV for 2 years, and later developed hepatocellular carcinoma (HCC). After surgical resection of HCC, he subsequently received PEG-IFN α-2b and RBV for 1.5 years, without undetectable viremia during the treatment course. Due to recurrence of HCC, the patient received a living donor liver transplantation. Later on, hepatitis C relapsed. For the management of relapse, he received another course of PEG-IFN α-2b and RBV. However, breakthrough viremia occurred. PEG-IFN was thus switched from α-2b to α-2a and RBV for another 17 months. The patient eventually achieved a sustained viral response.

Multicentric hepatocarcinogenesis at 6 and 13 years after sustained viral response to hepatitis C virus.

A 68-year-old Japanese woman with chronic hepatitis C infection who achieved sustained viral response (SVR) was followed up regularly. Six years after SVR, alpha fetoprotein (AFP) was increased. Hepatocellular carcinoma (HCC) was diagnosed by computed tomography and was excised by hepatic resection. Thirteen years after SVR, AFP increased again, and HCC recurrence was detected, which was excised by hepatic resection. Each HCC was <2 cm in diameter, with no vascular invasion. The primary HCC was moderately differentiated, while the secondary was well-to-moderately differentiated. Based on the clinicopathological features, the hepatocarcinogenesis was considered multicentric. Our case illustrates the importance of long-term follow-up of patients who achieve SVR.

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.

[Significant regression of a cavernous hepatic hemangioma to a sclerosed hemangioma over 12 years: a case study].

A sixties woman was found to have diagnosed by abdominal ultrasonography with a tumor in the left lobe of the liver and was referred to our institution in 1998. Abdominal magnetic resonance imaging (MRI) showed a typical, 70×45 mm cavernous hemangioma, which was followed up by annual MRI. In 2006, 8 years after the initial diagnosis, the MRI showed that the tumor had reduced to 30×15 mm. Although atypical of hemangioma, review of the annual observations indicated a diagnosis of regressive hemangioma, which also accorded with clinical observations. In 2009, a liver biopsy was performed by laparotomy during gastrectomy for gastric cancer. Pathological examination of the biopsy revealed sclerosed hemangioma tissue, confirming the diagnosis of regression of a cavernous hemangioma to a sclerosed hemangioma over 12 years.

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.

A first case of hepatic angiosarcoma treated with recombinant interleukin-2.

A 60 year-old woman was admitted to our hospital because of management of multiple liver tumors. According to image findings and liver biopsy, she was diagnosed as having epithelioid hemangioendothelioma of the liver accompanied by metastases in the spleen, lungs and bones. Based on the spread of the liver tumors and the extensive systemic metastases, she was considered inoperable. Instead, she received hepatic arterial infusion therapy using recombinant interleukin-2. However, she died due to liver failure about two months after admission. Autopsy revealed that the liver tumor was angiosarcoma. It is difficult to differentiate angiosarcoma from epithelioid hemangioendothelioma based on the image findings and pathological findings of percutaneous liver biopsy. Many cases are diagnosed as angiosarcoma at autopsy. There is no established effective treatment for hepatic angiosarcoma, because the tumor stage at the time of diagnosis is often progressive. To date, immunotherapy with recombinant interleukin-2 has been reported to be effective clinically for cutaneous angiosarcoma, such as of the scalp and facial skin. To our knowledge, there have been no reported cases of hepatic angiosarcoma treated with recombinant interleukin-2. Our case is important should recombinant interleukin-2 be considered effective for hepatic angiosarcoma in the future.