Hepatocellular adenoma in a woman who was undergoing testosterone treatment for gender identity disorder.

A 32-year-old Japanese woman was admitted to our hospital for the diagnosis and treatment of multiple liver tumors. She had been receiving 125 mg testosterone enanthate every 2 weeks following female-to-male gender identity disorder (GID) diagnosis at 20 years of age. Ultrasonography, computed tomography, and magnetic resonance imaging showed 11 hepatic nodular tumors with a maximum diameter of 28 mm. Liver tumors with hepatocellular adenoma (HCA) were diagnosed with needle biopsy. Segmentectomy of the left lateral lobe including two lesions, subsegmentectomy of S6 including two lesions, enucleation of each tumor in S5 and S7, and open surgical radiofrequency ablation for each tumor in S4 and S7 were performed. Immunohistochemical specimens showed that the tumor cells were diffusely and strongly positive for glutamine synthetase and that the nuclei were ectopically positive for ß-catenin. Thus, the tumors were diagnosed as ß-catenin-activated HCA (b-HCA). Transcatheter arterial chemoembolization plus subsequent radiofrequency ablation was performed for the 3 residual lesions in S4 and S8. Although testosterone enanthate was being continued for GID, no recurrence was observed until at least 22 months after the intensive treatments. HCA development in such patients receiving testosterone should be closely monitored using image inspection.

C-Arm Cone Beam Computed Tomography Guidance for Radiofrequency Ablation in Hepatocellular Carcinoma.

OBJECTIVE: To assess the usefulness of C-arm cone beam computed tomography (CBCT) combined with ultrasound for the treatment of hepatocellular carcinoma (HCC) by radiofrequency ablation (RFA). METHODS: Patients underwent RFA following transcatheter arterial chemoembolization (TACE) or RFA alone under ultrasound or CBCT guidance combined with ultrasound-based techniques. They were divided into 2 groups based on the use (C group) and nonuse (NC group) of CBCT guidance. The technical success of RFA and local tumor progression after the first RFA session were evaluated by dynamic contrast-enhanced imaging methods. Between-group differences were assessed retrospectively. RESULTS: We enrolled 198 patients with 260 HCC nodules. The complete ablation rates were 63.0 and 89.4% in the NC and C groups, respectively. In log-rank testing, local tumor progression occurred significantly more often in the NC group when RFA was used without TACE, in males when des-gamma-carboxy prothrombin was ≥29 mAU/mL, and when the diameter of a nodule was ≥18 mm. On Cox proportional-hazards regression analysis, the NC group, RFA alone without TACE, and male gender were significant independent variables. CONCLUSION: TACE followed by RFA under CBCT and ultrasound guidance improves the reliability of ablation of target HCC nodules, reduces the need for additional treatment sessions, and prevents local tumor progression.

A 48-week telaprevir-based triple combination therapy improves sustained virological response rate in previous non-responders to peginterferon and ribavirin with genotype 1b chronic hepatitis C: A multicenter study.

AIM: The sustained virological response (SVR) rate of non-responders to peginterferon and ribavirin therapy (PR) is low for 24-week telaprevir-based triple combination therapy (T12PR24), compared to that of treatment-naïve patients or previous-treatment relapsers. This study investigated which characteristics of non-responders were associated with a better SVR rate to 48-week therapy (T12PR48). METHODS: A total of 103 Japanese non-responders with genotype 1b chronic hepatitis C received telaprevir-based therapy. Among them, 81 patients (50 partial and 31 null responders) received T12PR24 and 22 (seven partial and 15 null responders) who agreed to the extended therapy received T12PR48. RESULTS: Multivariate logistic regression analysis for SVR identified the interleukin-28B (IL28B) rs8099917 TT genotype (P = 0.0005, odds ratio [OR] = 10.38), extended rapid virological response (P = 0.0008, OR = 7.02), T12PR48 regimen (P = 0.0016, OR = 9.31) and previous partial responders (P = 0.0022, OR = 5.89). Among partial responders, the SVR rate did not differ significantly between T12PR48 (85.7%) and T12PR24 (70.0%). Among null responders, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 22.6%, P = 0.0037). Among patients with the IL28B non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (68.8% vs 37.7%, P = 0.0288). Moreover, among null responders with the non-TT genotype, the SVR rate was significantly higher with T12PR48 than T12PR24 (66.7% vs 9.1%, P = 0.0009). CONCLUSION: T12PR48 improves the SVR rate in null responders, patients with the non-TT genotype, and null responders with a non-TT genotype.

Impact of IL28B polymorphisms on 24-week telaprevir-based combination therapy for Asian chronic hepatitis C patients with hepatitis C virus genotype 1b.

BACKGROUND AND AIM: The aim of this study was to clarify which or how factors could influence the probability of sustained virological response (SVR) in 24-week telaprevir-based triple combination therapy for East Asian chronic hepatitis C patients infected with hepatitis C virus genotype 1b. METHODS: Of 140 patients who were enrolled in this study, 137 received 12-week telaprevir combined with 24-week pegylated interferon alpha-2b plus ribavirin and were subjected to the analysis. Factors associated with SVR were analyzed by multiple logistic regression analysis. RESULTS: Of the 137 patients, 112 (82%) achieved SVR. Of 87 patients with IL28B single nucleotide polymorphism rs8099917 genotype TT, 84 (97%) achieved SVR. By contrast, 28 of 50 (56%) patients with the genotype TG/GG had SVR (P = 3.29 × 10(-9) ). Fifty-three of 60 (88%) naïve patients and 50 of 54 (93%) prior relapsers achieved SVR. Nine of 13 (69%) prior partial responders and none of 10 (0%) prior null responders achieved SVR. Multivariable analysis identified four independent factors that were significantly associated with SVR: IL28B SNP rs8099917 genotype (P = 6.90 × 10(-5) ), pre-existence of cirrhosis (P = 3.99 × 10(-3) ), prior treatment response (P = 0.0126), and rapid virological response (P = 0.0239). CONCLUSIONS: The IL28B single nucleotide polymorphism still remained informative as a predictor of SVR to 24-week telaprevir-based triple combination therapy for East Asian patients infected with hepatitis C virus genotype 1b.

α-Fetoprotein is a surrogate marker for predicting treatment failure in telaprevir-based triple combination therapy for genotype 1b chronic hepatitis C Japanese patients with the IL28B minor genotype.

Even when treated with telaprevir-based triple therapy, some patients fail to achieve a sustained virological response. This study identified factors related closely to treatment failure. A total of 146 Japanese genotype 1b chronic hepatitis C patients were enrolled in this prospective, multicenter study and received a 24-week regimen of triple therapy. The end-of-treatment response rate was significantly lower in patients with the interleukin 28B (IL28B) (rs8099917) non-TT genotype (85.2%) than in those with the TT genotype (100%, P = 0.0002). Multiple logistic regression analysis identified high α-fetoprotein levels as an independent factor related to non-end-of-treatment response in patients with the non-TT genotype. A cut-off value of 20 ng/ml was determined for a non-end-of-treatment response; sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and accuracy were 75.0%, 95.7%, 75.0%, 75.0%, and 92.6%, respectively. Multiple logistic regression analysis for a sustained virological response identified the IL28B TT genotype, low α-fetoprotein levels, non-responders, and a rapid virological response. The sustained virological response rate was significantly lower in patients with the non-TT genotype (59.3%) than in those with the TT genotype (96.7%, P < 0.0001). In patients with the non-TT genotype, α-fetoprotein was the most significant predictor for non-sustained virological response by univariate analysis. A cut-off value of 7.4 ng/ml α-fetoprotein was determined for non-sustained virological response; sensitivity, specificity, PPV, NPV, and accuracy were 63.6%, 87.5%, 77.8%, 77.8%, and 77.8%, respectively. For the non-TT patients, serum α-fetoprotein levels may be a surrogate marker for predicting treatment failure in telaprevir-based therapy for genotype 1b chronic hepatitis C.

Serum lipoprotein profiles and response to pegylated interferon plus ribavirin combination therapy in patients with chronic HCV genotype 1b infection.

BACKGROUND: Abnormal serum lipid profiles have been noted in patients with chronic hepatitis C virus (HCV) infection. Moreover, many reports suggest that serum lipoprotein profiles are more profoundly distorted in patients with HCV G1b infection who have an unfavorable response to pegylated interferon (peg-IFN) plus ribavirin (RBV) combination therapy. However, after the discovery of single nucleotide polymorphisms near the IL28B gene (rs8099917 and rs12979860) as potent predictive factors affecting the response to peg-IFN plus RBV, lipid factors are thought to be confounding factors. OBJECTIVES: To re-examine the significance of lipoprotein profiles on virological response to peg-IFN plus RBV combination therapy in patients with chronic HCV G1b infection, we examined cholesterol and triglyceride concentrations in each lipoprotein fraction separated by high performance liquid chromatography. PATIENTS AND METHODS: Lipoprotein profiles were examined using fasting sera from 108 patients infected with HCV G1b who had chronic hepatitis, as determined by liver biopsy. Results of lipoprotein profiles and clinical data, including IL28B genotype and amino acid substitution at aa70 of HCV G1b, were compared between patients with a sustained virological response (SVR) and non-SVR or a non-virological response (NVR) and virological responses other than NVR (non-NVR). In addition, significant predictive factors independently associated with virological response to peg-IFNα-2b plus RBV were determined by logistic regression analysis. RESULTS: An increased ratio of cholesterol/triglyceride in very low-density lipoprotein (odds ratio (OR) 3.03; 95% confidence interval (CI) 1.01-9.44) along with a major genotype of rs8099917 (OR 9.09; 95% CI 2.94-33.33), were independent predictive factors for SVR. In contrast, lipid factors were not elucidated as independent predictive factors for NVR. CONCLUSIONS: Examination of the fasting lipid profile has clinical importance in predicting the efficacy of peg-IFN-α-2b plus RBV combination therapy for patients with HCV G1b even after the discovery of the IL28 genotype as a potent predictive factor.

Serum apolipoprotein B-100 concentration predicts the virological response to pegylated interferon plus ribavirin combination therapy in patients infected with chronic hepatitis C virus genotype 1b.

Host lipoprotein metabolism is associated closely with the life cycle of hepatitis C virus (HCV), and serum lipid profiles have been linked to the response to pegylated interferon (Peg-IFN) plus ribavirin (RBV) therapy. Polymorphisms in the human IL28B gene and amino acid substitutions in the core and interferon sensitivity-determining region (ISDR) in NS5A of HCV genotype 1b (G1b) were also shown to strongly affect the outcome of Peg-IFN plus RBV therapy. In this study, an observational cohort study was performed in 247 HCV G1b-infected patients to investigate whether the response to Peg-IFN and RBV combination therapy in these patients is independently associated with the level of lipid factors, especially apolipoprotein B-100 (apoB-100), an obligatory structural component of very low density lipoprotein and low density lipoprotein. The multivariate logistic analysis subsequently identified apoB-100 (odds ratio (OR), 1.602; 95% confidence interval (CI), 1.046-2.456), alpha-fetoprotein (OR, 0.764; 95% CI, 0.610-0.958), non-wild-type ISDR (OR, 5.617; 95% CI, 1.274-24.754), and the rs8099917 major genotype (OR, 34.188; 95% CI, 10.225-114.308) as independent factors affecting rapid initial virological response (decline in HCV RNA levels by ≥3-log10 at week 4). While lipid factors were not independent predictors of complete early or sustained virological response, the serum apoB-100 level was an independent factor for sustained virological response in patients carrying the rs8099917 hetero/minor genotype. Together, we conclude that serum apoB-100 concentrations could predict virological response to Peg-IFN plus RBV combination therapy in patients infected with HCV G1b, especially in those with the rs8099917 hetero/minor genotype.

New proposal for response-guided peg-interferon-plus-ribavirin combination therapy for chronic hepatitis C virus genotype 2 infection.

This study aimed to determine the most suitable duration of pegylated-interferon (Peg-IFN)-plus-ribavirin combination therapy in patients infected with hepatitis C virus (HCV) genotype 2 who had not achieved rapid virological response (serum HCV RNA disappearance after 4 weeks of therapy). HCV genotype 2 patients (n = 182) with a high viral load received >80% of the standard Peg-IFN-plus-ribavirin dose for at least 24 weeks, and their final virological responses were studied. Patients were classified into "rapid virological response" and "non-rapid virological response" groups. The non-rapid virological response group was further divided into a "virological response at 8 weeks" (serum HCV RNA disappearance after 8 weeks of therapy) and a "non-virological response at 8 weeks" group. Factors related to rapid virological response and optimal therapy duration in the non-rapid virological response group were evaluated. Multivariate logistic regression analysis showed that subtype HCV genotype 2a (P = 0.0015) and low concentration of pretreatment serum HCV RNA (P = 0.0058) were independent factors in a rapid virological response. In the virological response at 8 weeks group, the sustained virological response rate after 24 weeks of therapy was significantly lower than after 36 weeks (P = 0.044) or after 48 weeks (P = 0.006), and was similar for 36- and 48-weeks. The cost for achieving (CAS) one sustained virological response was lowest with 36-week therapy. Prolongation of Peg-IFN-plus-ribavirin combination therapy to 36 weeks is suitable for achieving virological response at 8 weeks, given the high, sustained virological response rate and cost benefit.

Several factors including ITPA polymorphism influence ribavirin-induced anemia in chronic hepatitis C.

AIM: To construct formulae for predicting the likelihood of ribavirin-induced anemia in pegylated interferon α plus ribavirin for chronic hepatitis C. METHODS: Five hundred and sixty-one Japanese patients with hepatitis C virus genotype 1b who had received combination treatment were enrolled and assigned randomly to the derivation and confirmatory groups. Single nucleotide polymorphisms at or nearby ITPA were genotyped by real-time detection polymerase chain reaction. Factors influencing significant anemia (hemoglobin concentration < 10.0 g/dL at week 4 of treatment) and significant hemoglobin decline (declining concentrations > 3.0 g/dL at week 4) were analyzed using multiple regression analyses. Prediction formulae were constructed by significantly independent factors. RESULTS: Multivariate analysis for the derivation group identified four independent factors associated with significant hemoglobin decline: hemoglobin decline at week 2 [P = 3.29 × 10(-17), odds ratio (OR) = 7.54 (g/dL)], estimated glomerular filtration rate [P = 2.16 × 10(-4), OR = 0.962 (mL/min/1.73 m(2))], rs1127354 (P = 5.75 × 10(-4), OR = 10.94) and baseline hemoglobin [P = 7.86 × 10(-4), OR = 1.50 (g/dL)]. Using the model constructed by these factors, positive and negative predictive values and predictive accuracy were 79.8%, 88.8% and 86.2%, respectively. For the confirmatory group, they were 83.3%, 91.0% and 88.3%. These factors were closely correlated with significant anemia. However, the model could not be constructed, because no patients with rs1127354 minor genotype CA/AA had significant anemia. CONCLUSION: Reliable formulae for predicting the likelihood of ribavirin-induced anemia were constructed. Such modeling may be useful in developing individual tailoring and optimization of ribavirin dosage.

Contribution of ribavirin transporter gene polymorphism to treatment response in peginterferon plus ribavirin therapy for HCV genotype 1b patients.

BACKGROUND: Standard-dose ribavirin is crucial for the standard-of-care treatment of chronic hepatitis C virus (HCV) infection. Equilibrative nucleoside transporter 1 (ENT1), encoded by SLC29A1 gene, is the main transporter that imports ribavirin into human hepatocytes. AIMS: To determine whether single nucleotide polymorphisms (SNPs) at the SLC29A1 gene could influence the probability of treatment response compared with other baseline and host genetic factors. METHODS: A total of 526 East Asian patients monoinfected with HCV genotype 1b who had received pegylated interferon alpha plus ribavirin therapy were enrolled in this study. They were assigned randomly to the derivation and confirmatory groups. SNPs related to the IL28B, ITPA and SLC29A1 genes were genotyped using real-time detection polymerase chain reaction. Factors associated with sustained virological response (SVR) were analysed using multiple logistic regression analysis. RESULTS: Multivariate analysis for the derivation group identified six baseline variables significantly and independently associated with SVR: age [P = 0.023, odds ratio (OR) = 0.97], gender (P = 0.0047, OR = 2.25), platelet count (P = 0.00017, OR = 1.11), viral load (P = 0.00026, OR = 0.54), IL28B SNP rs12979860 (P = 1.09 × 10(-7) , OR = 8.68) and SLC29A1 SNP rs6932345 (P = 0.030, OR = 1.85). Using the model constructed by these independent variables, positive and negative predictive values and predictive accuracy were 73.3, 70.1 and 71.9% respectively. For the confirmatory group, they were 71.4, 84.6 and 75.3% respectively. The SLC29A1 and IL28B SNPs were also significantly associated with rapid virological response. CONCLUSIONS: The SNP at the major ribavirin transporter ENT1 gene SLC29A1 was one of significantly independent factors influencing treatment response, although the impact on the prediction was small.