Autoimmune hepatitis and primary sclerosing cholangitis after direct-acting antiviral treatment for hepatitis C virus: A case report.

BACKGROUND: Chronic hepatitis C virus (HCV) infection is a major global health concern that leads to liver fibrosis, cirrhosis, and cancer. Regimens containing direct-acting antivirals (DAAs) have become the mainstay of HCV treatment, achieving a high sustained virological response (SVR) with minimal adverse events. CASE SUMMARY: A 74-year-old woman with chronic HCV infection was treated with the DAAs ledipasvir, and sofosbuvir for 12 wk and achieved SVR. Twenty-four weeks after treatment completion, the liver enzyme and serum IgG levels increased, and antinuclear antibody became positive without HCV viremia, suggesting the development of autoimmune hepatitis (AIH). After liver biopsy indicated AIH, a definite AIH diagnosis was made and prednisolone was initiated. The treatment was effective, and the liver enzyme and serum IgG levels normalized. However, multiple strictures of the intrahepatic and extrahepatic bile ducts with dilatation of the peripheral bile ducts appeared on magnetic resonance cholangiopancreatography after 3 years of achieving SVR, which were consistent with primary sclerosing cholangitis. CONCLUSION: The potential risk of developing autoimmune liver diseases after DAA treatment should be considered.

Risk Factors of Proteinuria in Patients with Hepatocellular Carcinoma Receiving Lenvatinib.

Proteinuria is one of the most frequently reported adverse events leading to the discontinuation of lenvatinib treatment in patients with advanced hepatocellular carcinoma (HCC). However, there are no reports regarding the risk factors of proteinuria in patients with HCC or patients receiving lenvatinib. We retrospectively reviewed the medical records of patients with HCC receiving lenvatinib at the Kobe City Medical Center General Hospital between April 2018 and December 2020. The severity of proteinuria was graded based on the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. A multivariate Cox proportional hazards model was employed to identify the risk factors of developing grade ≥2 proteinuria. Among the 37 patients included, 3 patients had grade-1 proteinuria at baseline and 10 patients had estimated glomerular filtration rate (eGFR) <60 mL/min/1.73 m2 at baseline. Grades 1, 2, and 3 proteinuria were observed in 15 (40.5%), 10 (27.0%), and 2 (5.4%) patients, respectively, during lenvatinib treatment. The median value of eGFR was significantly lower in patients who developed grade ≥2 proteinuria than those with grade ≤1 proteinuria (59.6 vs. 78.1 mL/min/1.73 m2, p = 0.045). Multivariate analysis revealed that pre-existing proteinuria at baseline (hazard ratio (HR), 9.72; 95% confidence interval (CI), 1.29-52.21; p = 0.030), and eGFR <60 mL/min/1.73 m2 at baseline (HR, 4.49; 95% CI, 1.32-16.07; p = 0.017) were significantly associated with developing grade ≥2 proteinuria. These patients should be monitored carefully, and our preliminary data should be confirmed by further studies.

Autoimmune hepatitis and IgG4-related disease.

IgG4-related disease (IgG4-RD) is a chronic-fibroinflammatory disorder affecting a wide range of organs. Elevation of serum IgG4 concentrations and abundant infiltration of IgG4-expressing plasma cells are key diagnostic features of this autoimmune disease. Although common organ involvement of IgG4-RD includes the salivary glands, pancreas, and bile duct, hepatic involvement is less well established. Recently, five studies identified a subtype of autoimmune hepatitis (AIH), called IgG4-associated AIH (IgG4-AIH). IgG4-AIH is diagnosed based on significant accumulation of IgG4-expressing plasmacytes in the liver in patients who met the diagnostic criteria for classical AIH. Although four of the five reports regarded IgG4-AIH based on hepatic accumulation of IgG4-positive cells alone, one report diagnosed IgG4-AIH based on both hepatic accumulation of IgG4-positive cells and elevated serum concentrations of IgG4. IgG4-AIH diagnosed based on the latter criteria may be a hepatic manifestation of IgG4-RD whereas IgG4-AIH diagnosed based on the former criteria may be a subtype of AIH. In this review article, we summarize and discuss clinicopathological features of IgG4-AIH.

Evaluation of pharmaceutical intervention in direct-acting antiviral agents for hepatitis C virus infected patients in an ambulatory setting: a retrospective analysis.

BACKGROUND: Direct-acting antivirals (DAAs) are known to improve tolerability and have higher efficacy and shorter treatment durations compared with conventional interferon (IFN)-based treatments for hepatitis C virus (HCV) infection. Management of drug interactions and maintenance of patient adherence are important to achieve adequate therapeutic effects, sustained virological response (SVR). In order to maximize the benefits of oral DAA therapy, we established an ambulatory care pharmacy practice, a model of integrated collaboration between physicians and pharmacists, for patients receiving IFN-free DAA therapy. In this study, we evaluated pharmaceutical intervention for patients visiting the ambulatory care pharmacy practice. METHODS: HCV-infected outpatients who visited our ambulatory care pharmacy practice between September 2014 and May 2017 were eligible for inclusion in the study. When IFN-free DAAs were first prescribed, the physicians recommended all patients to visit the ambulatory care pharmacy practice after their clinical examination. Subsequently, at the second visit or later, the patients visited the pharmacy service before the physician's examination. The primary endpoint was SVR, defined as HCV RNA below the lower limit of quantification after the completion of treatment. We also evaluated the adherence rate to DAAs, suggestions to the physicians by the pharmacists, and questions from the patients. All data were obtained retrospectively using an electronic medical record system. RESULTS: Among the 401 study subjects, 386 patients completed the IFN-free DAA therapy. A total of 365 patients have reached 12 or 24 weeks after completing the treatment. The overall SVR rate was 98.1% (358/365). The proportion of patients with adherence ≥90% was 99.3% (398/401). Two-hundred and sixty-seven (84%) among 318 suggestions of prescription made by the pharmacists mainly to manage the adverse events were accepted by the physicians. The pharmacists received and answered 1072 questions on DAA therapy from the patients. CONCLUSIONS: This study indicates that the pharmaceutical intervention may contribute to enhanced adherence to DAAs and higher SVR rates in comparison with previous reports. This study also demonstrates that collaboration between physicians and pharmacists in an ambulatory setting provides favorable outcomes for patients receiving IFN-free DAAs.

Serum IFN-λ3 Levels Correlate with Serum Hepatitis C Virus RNA Levels in Symptomatic Patients with Acute Hepatitis C.

BACKGROUND: Recent genome-wide association studies demonstrated that 2 single nucleotide polymorphisms (SNPs), upstream of the interferon-λ (IFNL) 3 gene, are associated with the spontaneous clearance of hepatitis C virus (HCV) in symptomatic patients with acute hepatitis C (AHC). Although these 2 SNPs, rs8099917 and rs12979860, have established their significant roles in the innate immunity response to spontaneously clear HCV in patients with AHC, the detailed mechanisms of their roles remain largely unknown. AIM: This study is aimed at clarifying the factors affecting IFNL3 production and assessing the roles of IFNL3 in AHC. MATERIALS AND METHODS: A total of 21 AHC patients who visited the hospital within 10 days after symptom onset were assessed. As controls, 23 healthy volunteers (HVs) were examined. Serum IFNL3 levels were quantified using an in-house, IFNL3-specific chemiluminescence enzyme immunoassay (CLEIA) kit. Serum IFNL1, IFN-α, IFN-ß, and IFN-γ induced protein-10 (IP-10) levels were assayed using commercial enzyme-linked immunosorbent assay (ELISA) kits. RESULTS: At baseline, serum IFNL3 levels were higher in AHC patients than in HVs (p < 0.0001). The higher levels in AHC patients did not differ between patients with the rs8099917 TT genotype and those with the non-TT (TG/GG) genotype (p = 0.546). Serial measurement of serum IFNL3 levels did not predict the outcome of conventional AHC. However, serum IFNL3 levels at baseline correlated positively with the HCV RNA levels (p = 0.005). Following HCV eradication, serum IFNL3 levels reduced to within the range obtained for HVs. Baseline serum IFNL1 levels did not differ significantly between AHC patients and HVs (p = 0.284). Serum levels of IFNL1 and IFNL3 at baseline also showed no correlative power (p = 0.288). Serum IFN-α and IFN-ß were detected together with remarkably high serum IFNL3 levels in only one patient who progressed to acute liver failure (ALF). CONCLUSION: These findings indicate that serum IFNL3 levels at baseline are higher in AHC patients regardless of the rs8099917 polymorphism, and primary HCV infection triggers the production of IFNL3. As a first line of defense in the innate immune system against invading HCV, increased IFNL3 levels play an important role, but serum IFNL3 levels are not the principal determinant of the clinical course of conventional AHC.

CD68-Positive Cells in Hepatic Angiomyolipoma.

Four resected specimens of hepatic angiomyolipoma in which uptake of Sonazoid was observed in the postvascular phase of Sonazoid-enhanced ultrasonography were analyzed. Macrophage localization in the tumor was revealed pathologically by immunohistochemical staining for CD68. CD68-positive cells were observed in the tumor in all cases. The density of CD68-positive cells was 100/mm2, and the ratio of CD68-positive cell density in the tumor to that in the surrounding parenchyma was 32-171%. These results suggested that the uptake of the contrast agent Sonazoid was related to the density of CD68-positive cells.

[A case of jejunal ectopic pancreatic cancer: the diagnostic usefulness of MRI].

A 70-year-old man was referred to our hospital because of elevated CA19-9. Magnetic resonance imaging revealed a jejunal tumor having duct and retention cyst-like structures, which suggested ectopic pancreatic cancer. We resected that part of the jejunum and the lymph nodes around the tumor. Pathological examination revealed an adenocarcinoma originating from a Heinrich type I ectopic pancreas in the jejunum. Adjuvant chemotherapy with gemcitabine was performed for half a year. After 8 months, CA19-9 remained elevated, and liver metastasis occurred. We began treatment with tegafur/gimeracil/oteracil potassium (S-1) and particle beam therapy. After 7 months, CA19-9 was normal, and the patient has remained in partial remission with S-1 treatment. Ectopic pancreas tissues typically occur in the stomach and duodenum and rarely become cancerous. Here, we report the features of a rare and illustrative case of jejunal ectopic pancreatic cancer.

Outcomes and Prognostic Factors in Patients with Spontaneously Ruptured Hepatocellular Carcinoma.

BACKGROUND/AIMS: Spontaneous rupture is a life-threatening complication of hepatocellular carcinoma (HCC). Although hemostasis can be achieved by transarterial embolization (TAE), the prognosis remains poor. The aims of this study were to evaluate the effectiveness of emergent TAE for ruptured HCC and to clarify the prognostic factors. METHODOLOGY: Thirty-six patients with spontaneously ruptured HCC were retrospectively analyzed. Prognostic factors of short-term (57 days) and long-term (>7 days) survival after HCC rupture were investigated by univariate and multivariate analyses. RESULTS: Emergent TAE was performed in 22 patients and conservative treatment was applied in 14. The hemostasis rate of TAE was 86.4%, and median survival time in patients with TAE was significantly longer than that in patients with conservative treatment (142 days vs. 5 days, p = 0.0006). In multivariate analysis, high serum creatinine (p = 0.036) was a significant independent predictor of poor 7-day survival, and low serum albumin (p = 0.050) and absence of emergent TAE (p = 0.061) tended to be associated with poor 7-day survival. HCC treatment within the past 12 months (p = 0.048) and, high serum total bilirubin (p = 0.016) were predictors of poor long-term survival. Conclusions: We identified some survival predictors after HCC rupture. Emergent TAE appears to be effective for improving short-term oroLnosis after HCC ruoture.

Phase I/II Study of Sorafenib in Combination with Hepatic Arterial Infusion Chemotherapy Using Low-Dose Cisplatin and 5-Fluorouracil.

We conducted a phase I/II study in patients with advanced hepatocellular carcinoma (HCC) to determine the recommended dose, as well as the safety and efficacy, of combination therapy of sorafenib with hepatic arterial infusion chemotherapy (HAIC) using low dose cisplatin (CDDP) and 5-fluorouracil (5FU). Cohorts consisting of 3-6 patients with HCC received an escalated dose of CDDP and 5-FU until a maximum-tolerated dose was achieved. The treatment regimen was as follows: oral administration of sorafenib (400 mg twice daily for 28 days) combined with HAIC using CDDP (14-20 mg/m(2), on days 1 and 8) and 5-FU (170-330 mg/m(2), continuously on days 1-5 and 8-12) via an implanted catheter system). Each treatment cycle consisted of 28 days and three cycles of combination therapy. At the end of the first cycle, adverse events were evaluated and future dose escalation was determined. Eighteen patients with advanced HCC were enrolled. Dose-limiting toxicity was observed in two patients from cohort 1 (erythema multiforme and grade 4 thrombocytopenia) and in one patient from cohort 2 (erythema multiforme). Seven of the 18 patients achieved a partial response, seven showed stable disease, two were diagnosed as progressive disease, and two were not assessable. The response rate was 38.9% and the disease control rate was 77.8%. The time-to-progression was 9.7 months and the 1-year survival rate was 88.2%. Oral administration of 400 mg of sorafenib twice daily, 20 mg/m(2) of intra-arterial infusion of CDDP, and 5-FU at 330 mg/m(2) are the recommended doses for combination therapy, which was well tolerated and efficacious. This combination therapy may be a promising treatment for patients with advanced HCC. A large prospective randomized multicenter study (ClinicalTrials.gov Identifier NCT01214343) is ongoing.

Case of primary hepatic gastrinoma: Diagnostic usefulness of the selective arterial calcium injection test.

Gastrinomas mainly occur in the duodenum and pancreas. Primary hepatic gastrinoma is rare and difficult to diagnose because the liver is a frequent site of metastatic gastrinomas. Clinical factors were assessed in a 28-year-old man with diarrhea and heartburn who was hospitalized for recurrent duodenal ulcers. Abdominal ultrasound, endoscopic ultrasound and computed tomography (CT) could not detect a tumor in the duodenum or pancreas. His gastrin level was 846 pg/mL and magnetic resonance imaging showed a mass 12 mm in diameter in the right robe of the liver. A selective intra-arterial calcium injection (SACI) test and 68-gallium edotreotide positron emission tomography CT (Ga-DOTATOC PET-CT) were therefore performed. Calcium gluconate injection into the proper hepatic artery resulted in a marked increase in serum gastrin concentration in the right hepatic vein, with Ga-DOTATOC PET-CT showing uptake only by the liver mass. Following a diagnosis of primary hepatic gastrinoma, the tumor was resected. A histopathological examination indicated gastrinoma. Six months postoperatively, he has no symptoms, is not taking proton-pump inhibitors and his gastrin level remains within the normal range. The SACI test and the clinical course of this patient strongly suggest that the tumor was a primary hepatic gastrinoma. The SACI test is helpful in the diagnosis of primary hepatic gastrinoma.

The gross classification of hepatocellular carcinoma: usefulness of contrast-enhanced US.

BACKGROUND: This study investigated the usefulness of postvascular images of contrast-enhanced ultrasonography (CE-US) in the gross classification of hepatocellular carcinoma (HCC) in comparison with contrast-enhanced CT (CE-CT) findings. METHODS: This is a prospective study with consecutive HCC patients who had both CE-US and CE-CT prior to surgical resection. Fifty-one patients (32 men, 19 women; mean age, 68.9 years) with 61 HCCs were enrolled. The maximal diameters of all tumors ranged from 1.0 to 5.0 cm (mean ± SD, 2.5 cm ± 1.1). Weighted kappa statistics were used to assess the agreement of the sonographic or CT findings versus the results of macroscopic configurations. RESULTS: Thirty-nine tumors were macroscopically diagnosed as simple nodule type; 19 tumors were macroscopically diagnosed as simple nodular type with extranodular growth, and 3 were macroscopically diagnosed as confluent multinodular type from the resected specimen. The diagnostic accuracy was 86.9% (53/61) for CE-US and 65.6% (40/61) for CE-CT. The differences in accuracy between CE-US and CE-CT were statistically significant (McNemar; p = 0.007). Agreement analysis between gross classification using CE-US and final macroscopic results gave a kappa value of 0.74 (95% CI: 0.65­0.82), which was considered a good agreement. On the other hand, kappa coefficient value was 0.38 (95% CI: 0.28­0.48) between gross classification using CE-CT and final macroscopic results. CONCLUSIONS: CE-US is a more reliable tool than CE-CT to evaluate the gross type of HCC than CE-CT. Accurate gross classification using imaging is considered to be essential for the determination of the correct treatment strategy and the estimates of the patients' prognosis.

Autoimmune hepatitis and immunoglobulin G4-associated autoimmune hepatitis.

Autoimmune hepatitis (AIH) is a disease that is characterized by the presence of autoantibodies and elevated levels of serum immunoglobulin G (IgG) and hepatic enzymes. Its characteristic findings in the liver include interface hepatitis, infiltration of lymphocytes and plasma cells, and rosette formation, and is treated with immunosuppressive drugs. Autoimmune pancreatitis, a pancreatic disease caused by an autoimmune mechanism, is associated with elevated levels of serum IgG4 and the infiltration of IgG4-positive cells into the pancreatic parenchyma, and it is occasionally accompanied by systemic features. This systemic inflammatory disease characterized by the infiltration of IgG4-positive plasma cells and elevated serum IgG4 levels was recently classified as an IgG4-related disease. A few studies have reported AIH cases with infiltrated IgG4-positive plasma cells in the liver, suggesting the involvement of IgG4 in the pathogenesis of AIH. This feature was called IgG4-associated AIH and only two studies have been published. However, the diagnostic criteria of IgG4-associated AIH has not been defined and the epidemiology and clinical features remain uncertain. The degree of IgG4-positive plasma cell infiltration in the liver was different in each article. The serum IgG4 level was not elevated in one study, whereas it was severely elevated in the other. Corticosteroid therapy normalized liver enzymes in both studies. Further studies are needed to define the epidemiological features or diagnostic criteria.

Assessment of Gd-EOB-DTPA-enhanced MRI for HCC and dysplastic nodules and comparison of detection sensitivity versus MDCT.

BACKGROUND: We aimed to evaluate gadolinium ethoxybenzyl diethylenetriamine pentaacetic acid (Gd-EOB-DTPA)-enhanced magnetic resonance imaging (MRI) for the detection of hepatocellular carcinomas (HCCs) and dysplastic nodules (DNs) compared with dynamic multi-detector row computed tomography (MDCT), and to discriminate between HCCs and DNs. METHODS: Eighty-six nodules diagnosed as HCC or DNs were retrospectively investigated. Gd-EOB-DTPA-enhanced MRI and dynamic MDCT were compared with respect to their diagnostic ability for hypervascular HCCs and detection sensitivity for hypovascular tumors. The ability of hepatobiliary images of Gd-EOB-DTPA-enhanced MRI to discriminate between these nodules was assessed. We also calculated the EOB enhancement ratio of the tumors. RESULTS: For hypervascular HCCs, the diagnostic ability of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of MDCT for tumors less than 2 cm (p = 0.048). There was no difference in the detection of hypervascular HCCs between hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI (43/45: 96%) and dynamic MDCT (40/45: 89%), whereas the detection sensitivity of hypovascular tumors by Gd-EOB-DTPA-enhanced MRI was significantly higher than that by dynamic MDCT (39/41: 95% vs. 25/41: 61%, p = 0.001). EOB enhancement ratios were decreased in parallel with the degree of differentiation in DNs and HCCs, although there was no difference between DNs and hypovascular well-differentiated HCCs. CONCLUSION: The diagnostic ability of Gd-EOB-DTPA-enhanced MRI for hypervascular HCCs less than 2 cm was significantly higher than that of MDCT. For hypovascular tumors, the detection sensitivity of hepatobiliary phase images of Gd-EOB-DTPA-enhanced MRI was significantly higher than that of dynamic Gd-EOB-DTPA-enhanced MRI and dynamic MDCT. It was difficult to distinguish between DNs and hypovascular well-differentiated HCCs based on the EOB enhancement ratio.

Activation of c-Jun N-terminal kinase in non-cancerous liver tissue predicts a high risk of recurrence after hepatic resection for hepatocellular carcinoma.

AIM: Hepatocellular carcinoma (HCC) ranks as the third leading cause of cancer deaths worldwide. Hepatic resection is the mainstay of curative treatment for early stage HCC. Although c-Jun N-terminal kinase (JNK) activation contributes to hepatocyte proliferation and HCC development in mice, the extent of involvement of JNK in human HCC development is unknown. The aim of this study is to assess the predictive value of JNK for postoperative recurrence in HCC. METHODS: From April 2005 to March 2008, 159 patients underwent curative resection for HCC. From the 159 patients, 20 patients each matched for age, gender and etiology were registered as three groups: (i) without recurrence (no recurrence group), (ii) with recurrence within one year after surgery (early recurrence group), and (iii) with recurrence at one year or more after surgery (late recurrence group) (a cross-sectional control study). We investigated factors contributing to postoperative early and late phase recurrence. RESULTS: Multivariate analysis using a Logistic regression model showed that JNK activity in non-cancerous liver tissue was correlated with postoperative late recurrence. (P = 0.02, odds ratio; 5.79, 95% confidence interval [CI]; 1.33-25.36). CONCLUSIONS: JNK activity in non-cancerous liver tissue is considered as a reliable predictive biomarker for post-operative recurrence in HCC.

Association of interleukin-28B and hepatitis C genotype 1 with a high viral load and response to pegylated interferon plus ribavirin therapy.

BACKGROUND: Pegylated interferon (PEG-IFN) plus ribavirin therapy is the current standard treatment for chronic hepatitis C (CHC) genotype 1 with high viral load. A common genetic variation near the IL28B gene has been found to affect the response to PEG-IFN plus ribavirin therapy for CHC. The aims of this study were to analyze the association between the rs8099917 genotype and treatment response in a cohort study of CHC. METHODS: This study evaluated clinical and laboratory parameters retrospectively in a cohort of 122 patients with chronic hepatitis C with genotype 1 and a high viral load who received PEG-IFN plus ribavirin therapy. We carried out univariate and multivariate statistical analyses of parameters and clinical responses. RESULTS: Sixty-three of 122 patients (51.6%) had sustained virological responses (SVRs). Patients with the rs8099917 genotype TT achieved significantly higher SVR rates (p < 0.01). Univariate analysis revealed that SVRs were associated with BMI, fibrosis, albumin, total cholesterol, PEG-IFN dose, ribavirin dose and the rs8099917 genotype. Multivariate analysis revealed that the rs8099917 genotype (odds ratio 7.434, 95% CI 2.278-24.257, p = 0.001) and total PEG-IFN dose (odds ratio 7.162, 95% CI 1.565-18.15, p = 0.007) were significant factors. CONCLUSIONS: The rs8099917 genotype and total PEG-IFN dose were associated with SVR in patients with hepatitis C virus genotype 1.

Oral branched-chain amino acid granules reduce the incidence of hepatocellular carcinoma and improve event-free survival in patients with liver cirrhosis.

BACKGROUND: It has been reported that branched-chain amino acid (BCAA) supplementation can improve nutritional status and prevent liver-related complications in patients with decompensated cirrhosis. We investigated the effects of oral BCAA supplementation on the incidence of hepatocellular carcinoma (HCC) and liver-related events in patients with compensated and decompensated cirrhosis. METHODS: We enrolled 211 patients with cirrhosis including 152 patients with Child-Pugh A cirrhosis, but no history of HCC. Of these, 56 received oral administration of 12 g/day BCAA for ≥6 months (BCAA group), and 155 were followed-up without BCAA treatment (control group). The HCC occurrence and event-free survival rates were compared between the two groups. We used a propensity score analysis to overcome selection bias of this retrospective analysis. RESULTS: The HCC occurrence rate was significantly lower and event-free survival rate was significantly higher in the BCAA group than in the control group. Multivariate analyses showed BCAA supplementation was significantly associated with reduced incidence of HCC (hazard ratio (HR) 0.416, 95% confidence interval (CI) 0.216-0.800, p = 0.0085). BCAA supplementation also reduced the incidence of liver-related events in patients with Child-Pugh A cirrhosis, although the difference did not reach statistical significance (HR 0.585, 95% CI 0.336-1.017, p = 0.0575). CONCLUSIONS: Oral BCAA supplementation is associated with reduced incidence of HCC in patients with cirrhosis and seems to prevent liver-related events in patients with Child-Pugh A cirrhosis.

Des-γ-carboxyprothrombin may be a promising biomarker to determine the therapeutic efficacy of sorafenib for hepatocellular carcinoma.

OBJECTIVE: The purpose of this study was to evaluate the role of des-γ-carboxyprothrombin (DCP) as a marker for the efficacy of sorafenib therapy for hepatocellular carcinoma (HCC). METHODS: Patients with advanced HCC treated with sorafenib were retrospectively evaluated, focusing on DCP levels and clinical characteristics. RESULTS: 50 patients with advanced HCC were treated with sorafenib alone. In 25 of these patients, the serum levels of DCP were evaluated twice (pretreatment and within 2 weeks after starting therapy). The time to progression was significantly longer in patients in whom the DCP level at 2 weeks after starting sorafenib was ≥2-fold higher than the pretreatment levels, as compared with patients without an increase in DCP (p = 0.0296). CONCLUSIONS: The serum level of DCP is a surrogate marker for tissue hypoxia and can be a predictive marker to assess the tumor response to sorafenib therapy.

The cancer stem cell marker CD133 is a predictor of the effectiveness of S1+ pegylated interferon α-2b therapy against advanced hepatocellular carcinoma.

BACKGROUND: Combination therapy with the oral fluoropyrimidine anticancer drug S1 and interferon is reportedly effective for the treatment of advanced hepatocellular carcinoma (HCC), but selection criteria for this therapy have not been clarified. In this study, we attempted to identify factors predicting the effectiveness of this combination therapy. METHODS: Pathological specimens of HCC were collected before treatment from 31 patients with advanced HCC who underwent S1+ pegylated-interferon (PEG-IFN) α-2b therapy between January 2007 and January 2009. In these pathological specimens, the expression levels of CD133, thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and interferon-receptor 2 (IFNR2) proteins were determined by Western blot assay. The presence or absence of p53 gene mutations was determined by direct sequencing. The relationships between these protein expression levels and the response rate (RR), progression-free survival (PFS), and overall survival (OS) were evaluated. RESULTS: The CD133 protein expression level was significantly lower in the responder group than in the nonresponder group. Comparing the PFS and OS between high- and low-level CD133 expression groups (n = 13 and 18, respectively) revealed that both parameters were significantly prolonged in the latter group. The expression levels of TS, DPD, and IFNR2 protein and the presence of p53 gene mutations did not correlate with the RR. CONCLUSIONS: CD133 was identified as a predictor of the therapeutic effect of S1+ PEG-IFN α-2b therapy against advanced HCC.

Usefulness of combination of imaging modalities in the diagnosis of hepatocellular carcinoma using Sonazoid®-enhanced ultrasound, gadolinium diethylene-triamine-pentaacetic acid-enhanced magnetic resonance imaging, and contrast-enhanced computed tomography.

OBJECTIVE: To clarify the diagnostic ability of combining imaging methods to diagnose hepatocellular carcinoma (HCC) using Sonazoid®-enhanced ultrasound (US), gadolinium diethylene-triamine-pentaacetic acid-enhanced (Gd-EOB-DTPA) magnetic resonance imaging (MRI), and contrast-enhanced computed tomography (CECT). METHODS: A total of 32 patients who underwent surgical resection for HCC were studied. Sonazoid-enhanced US, Gd-EOB-DTPA MRI, CECT, and intraoperative contrast-enhanced ultrasonography were done for all patients. The definitive diagnosis of HCC in those patients was based on histopathological confirmation. RESULTS: A total of 50 histologically proven HCCs were obtained from 32 patients; their mean (± SD) age was 68.3 years ± 8.1. The mean (± SD) nodule size was 2.6 cm ± 1.9. Twenty percent were well-differentiated HCC, 64% were moderately differentiated HCC, 10% were poorly differentiated HCC, 4% were combined HCC and CCC, and 2% were HCC with severe necrosis. The overall diagnostic sensitivity of CEUS, CECT, and Gd-EOB-DTPA MRI was 72, 74, and 86%, respectively; however, there was no significant difference between the three imaging modalities in diagnosing typical HCC (p = 0.092). When combining the diagnostic ability of the different imaging modalities, the diagnostic sensitivity of Sonazoid-enhanced US and Gd-EOB-DTPA MRI was 90%, while addition of Sonazoid-enhanced US to CECT and CECT to Gd-EOB-DTPA MRI had a sensitivity of 82 and 88%, respectively. There was no significant difference between the three imaging combinations (p = 0.970). CONCLUSION: Sonazoid-enhanced US and Gd-EOB-DTPA MRI can be confidently used in daily clinical practice for the management of HCC.