Comprehensive analysis for viral elements and interleukin-28B polymorphisms in response to pegylated interferon plus ribavirin therapy in hepatitis C virus 1B infection.

UNLABELLED: To comprehensively characterize the contribution of virological factors as well as interleukin-28B (IL28B) single-nucleotide polymorphisms (SNPs) in determining treatment responses in pegylated-interferon plus ribavirin (Peg-IFN/RBV) therapy for chronic hepatitis C virus (HCV)-1b infection, we undertook a retrospective cohort analysis for the pretreatment dominant complete HCV open reading frame (ORF) amino-acid (aa) sequence study in 103 consecutive HCV-1b Japanese patients. The dominant HCV sequences classified by the response were subjected to systematic sliding-window comparison analysis to characterize response-specific viral sequences, along with IL28B SNP analyses (rs8099917). In each comparison of the patients between with and without rapid viral response (RVR), nonearly viral response (nEVR), sustained virological response (SVR), or relapse, the following regions were extracted as most significantly associated with the different responses respectively: nonstructural protein 5A (NS5A) aa.2224-2248 (P = 1.2E-07); core aa.70 (P = 4E-04); NS5A aa.2340-2382 (P = 7.0E-08); and NS5A aa.2360-2377 (P = 1.1E-05). Those NS5A regions nearly coincided with the interferon (IFN) sensitivity-determining region (NS5A aa.2209-2248) and the IFN/RBV resistance-determining region (NS5A aa.2339-2379). In a multivariate analysis, the IL28B SNP (odds ratio [OR] = 16.8; P = 0.009) and NS5A aa.2340-2382 (OR = 13.8; P = 0.0003) were extracted as the two most-significant independent variables contributing to the final outcome. CONCLUSION: In Peg-IFN/RBV therapy, polymorphisms in IL28B, NS5A aa.2224-2248, core aa.70, and, most important, NS5A aa.2340-2382 have a tremendous influence on treatment response in association with viral kinetics, resulting in significantly different outcomes in chronic HCV-1b infection.

Characterization of naturally occurring protease inhibitor-resistance mutations in genotype 1b hepatitis C virus patients.

BACKGROUND AND AIMS: Protease inhibitor (PI)-resistant hepatitis C virus (HCV) variants may be present in substantial numbers in PI-untreated patients according to recent reports. However, influence of these viruses in the clinical course of chronic hepatitis C has not been well characterized. METHODS: The dominant HCV nonstructural 3 (NS3) amino acid sequences were determined in 261 HCV genotype 1b-infected Japanese patients before pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, and investigated the patients' clinical characteristics as well as treatment responses including sustained virological response (SVR) rate. HCV-NS3 sequences were also determined in 39 non-SVR patients after completion of the therapy. RESULTS: Four single mutations (T54S, Q80K, I153V, and D168E) known to confer PI resistance were found in 35 of 261 patients (13.4%), and double mutations (I153V plus T54S/D168E) were found in 6 patients (2.3%). Responses to PEG-IFN/RBV therapy did not differ between patients with and without PI-resistance mutations (mutation group, SVR 48%; wild-type group, SVR 40%; P = 0.38). On the other hand, two mutations appeared in two non-SVR patients after PEG-IFN/RBV therapy (I153V and E168D, 5.1%). CONCLUSIONS: PI-resistance-associated NS3 mutations exist in a substantial proportion of untreated HCV-1b-infected patients. The impact of these mutations in the treatment of PIs is unclear, but clinicians should pay attention to avoid further development of PI resistance.

Analysis of viral amino acids sequences and the IL28B SNP influencing the development of hepatocellular carcinoma in chronic hepatitis C.

BACKGROUND AND AIMS: The association between hepatitis C virus (HCV) sequences with interleukin 28B (IL28B) single-nucleotide polymorphism (SNP) in the development of hepatocellular carcinoma (HCC) has not been well clarified. METHODS: Complete HCV open-reading frame sequences were determined in 20 patients developing HCC and 23 non-HCC patients with HCV-1b infection in two distant time points. An additional 230 patients were studied cross-sectionally for core and NS5A sequences with HCC development. Among them, 98 patients with available samples were investigated for changes in viral core sequences over time. Finally, IL28B SNPs and HCC development were investigated in 228 patients. RESULTS: During observation period (HCC for 10.8 years, and non-HCC for 11.1 years), changes in core a.a. 70 and three amino acid positions in NS5A were characteristics of the patients developing HCC. In 230 patients, Q (glutamine) or H (histidine) to R (arginine) ratio at core a.a. 70 was significantly higher in the HCC group (HCC group 43:22 vs. non-HCC group 66:99, p = 0.001). A change in core R70Q was observed over time in 11 patients associated with a decrease in platelets (p = 0.005) and albumin (p = 0.005), while a Q70R change was observed in 4 patients without associated changes in platelets (nonsignificant) and albumin (nonsignificant). IL28B SNP showed significant correlation with the core a.a. 70 residue. There was no evident link between IL28B SNPs and the occurrence of HCC. CONCLUSIONS: Hepatitis C virus core a.a. 70 residue is associated with liver disease progression and is independent factor for HCC development in genotype-1b infection. IL28B SNPs are related to core a.a. 70 residue, but not to HCC. The functional relevance of core a.a. 70 residue in hepatitis C pathogenesis should be further investigated.

Imaging study of early hepatocellular carcinoma: usefulness of gadoxetic acid-enhanced MR imaging.

PURPOSE: To describe imaging findings of early hepatocellular carcinoma (HCC) at gadoxetic acid-enhanced magnetic resonance (MR) imaging, dynamic contrast material-enhanced computed tomography (CT), CT during arterial portography (CTAP), and CT during hepatic arteriography (CTHA) and to compare the diagnostic performance of each modality for small (≤ 2 cm) HCC. MATERIALS AND METHODS: The institute ethics committee deemed study approval unnecessary. One hundred eight resected small lesions in 64 patients were diagnosed as a dysplastic nodule (DN) (n = 12), progressed HCC (n = 66), or early HCC (n = 30). All but two patients underwent all imaging examinations. The imaging characteristics of the lesions with each modality were determined. To evaluate the diagnostic performance of the modalities, two radiologists graded the presence of HCC with use of a five-point confidence scale. The area under the receiver operating characteristic curve (A(z)), sensitivity, and specificity of each modality were compared. RESULTS: The imaging features that are statistically significant for differentiating an early HCC from a DN include fat-containing lesions at dual-echo T1-weighted MR imaging (seen in 16 of the 30 early HCCs and none of the DNs), low attenuation at unenhanced CT (seen in 13 of the 30 early HCCs and none of the DNs), low attenuation at CTAP (seen in 11 of the 30 early HCCs and none of the DNs), and low signal intensity at hepatocyte phase gadoxetic acid-enhanced MR imaging (seen in 29 of the 30 early HCCs and none of the DNs). The diagnostic performance of gadoxetic acid-enhanced MR imaging (A(z), 0.98 and 0.99) was significantly greater than that of contrast-enhanced CT (A(z), 0.87) and CTHA-CTAP (A(z), 0.85 and 0.86) owing to its significantly higher sensitivity (P < .001). CONCLUSION: Gadoxetic acid-enhanced MR imaging is the most useful imaging technique for evaluating small HCC, including early HCC.

Diagnosis of colorectal hepatic metastases: comparison of contrast-enhanced CT, contrast-enhanced US, superparamagnetic iron oxide-enhanced MRI, and gadoxetic acid-enhanced MRI.

PURPOSE: To compare the diagnostic accuracy of contrast-enhanced computed tomography (CE-CT), contrast-enhanced ultrasonography (CE-US), superparamagnetic iron oxide-enhanced magnetic resonance imaging (SPIO-MRI), and gadoxetic acid-enhanced MRI (Gd-EOB-MRI) in the evaluation of colorectal hepatic metastases. MATERIALS AND METHODS: In all, 111 patients with colorectal cancers were enrolled in this study. Of the 112 metastases identified in 46 patients, 31 in 18 patients were confirmed histologically and the remaining 81 in 28 patients were confirmed by follow-up imaging. CE-CT, CE-US, SPIO-MRI, and Gd-EOB-MRI were evaluated. Mean (of three readers, except for CE-US) area under the receiver operating characteristic curve (A(z) ), sensitivities, and positive predictive values (PPV) were calculated. Each value was compared to the others by variance z-test or chi-square test with Bonferroni correction. RESULTS: For all lesions, mean A(z) and sensitivity of Gd-EOB-MRI (0.992, 95% [56/59]) were significantly greater than those of CE-CT (0.847, 63% [71/112]) and CE-US (0.844, 73% [77/106]). For lesions ≤1 cm, mean A(z) and sensitivity of Gd-EOB-MRI (0.999, 92% [22/24]) were significantly greater than those of CE-CT (0.685, 26% [13/50]) and CE-US (0.7, 41% [18/44]). Mean A(z) (95% CI) of SPIO-MRI for all lesions (0.966 [0.929-0.987]) and lesions ≤ 1 cm (0.961 [0.911-0.988]) were significantly greater than those of CE-CT and CE-US. Mean sensitivity of SPIO-MRI for lesions ≤1 cm (63%, 26/41) was significantly greater than that of CE-CT. CONCLUSION: Gd-EOB-MRI and SPIO-MRI were more accurate than CE-CT and CE-US for evaluation of liver metastasis in patients with colorectal carcinoma.

Double-dose gadoxetic Acid-enhanced magnetic resonance imaging in patients with chronic liver disease.

OBJECTIVES: determine the effect of double-dose gadoxetic-acid (Gd-EOB-DTPA) on lesion-liver contrast ratio in arterial- and hepatocyte-phase images and arterial-phase image quality in patients with chronic liver disease. MATERIALS AND METHODS: the ethics committee at our institute approved this study. This study included 28 patients (13 with Child-Pugh class A and 15 with class B) with 54 hepatocellular carcinomas. All patients received the standard Gd-EOB-DTPA dose (0.025 mmol/kg bodyweight) and double dose (0.050 mmol/kg bodyweight). The lesion-liver contrast ratio was evaluated in arterial- and hepatocyte-phase images. The artifacts in arterial-phase images were evaluated with a 4-point scale. Wilcoxon signed-rank test were used for comparisons. RESULTS: the hepatocyte-phase lesion-liver contrast ratio after the double dose was significantly higher than that after the standard dose in patients with Child-Pugh class B disease(standard dose vs. double dose; 0.20 ± 0.16 vs. 0.25 ± 0.17; P < 0.0001); however, the ratio after both the standard and double doses was equivalent in patients with Child-Pugh class A disease (0.35 ± 0.18 vs. 0.35 ± 0.14; P = 0.3038). The double dose significantly increased the arterial-phase lesion-liver contrast ratio (0.34 ± 0.19 vs. 0.58 ± 0.33; P < 0.0001). The artifacts in the arterial-phase images were more prominent after the standard dose (2.7 vs. 2.4 for reader 1, 2.8 vs. 2.4 for reader 2; P = 0.0195 and 0.0010). CONCLUSIONS: administration of double dose of Gd-EOB-DTPA provided better arterial enhancement of hepatocellular carcinomas in patients with chronic liver disease, and also improved the lesion-liver contrast in hepatocyte-phase images in patients with Child-Pugh class B disease.

Diagnosis of colorectal hepatic metastases: Contrast-enhanced ultrasonography versus contrast-enhanced computed tomography versus superparamagnetic iron oxide-enhanced magnetic resonance imaging with diffusion-weighted imaging.

PURPOSE: To compare the diagnostic accuracy of contrast-enhanced ultrasonography (CE-US), contrast-enhanced CT (CE-CT), and superparamagnetic iron oxide-enhanced MRI (SPIO-MRI) with diffusion-weighted imaging (DWI) in the evaluation of colorectal hepatic metastases. MATERIALS AND METHODS: Thirty-six patients with colorectal cancers were prospectively enrolled and retrospectively evaluated. Of the 86 metastases identified, 16 were confirmed histologically and the remaining 70 were confirmed by follow-up imaging. CE-CT and SPIO-MRI + DWI were independently evaluated by two readers, whereas CE-US was evaluated by consensus reading of two different readers. Area under receiver operating characteristic curve (A(z)), sensitivities, and positive predictive values (PPVs) were calculated and compared. RESULTS: For both readers, SPIO-MRI+DWI had significantly greater A(z) (0.879 and 0.904) and sensitivity (78% and 87%) for all lesions compared with CE-CT (0.779 and 0.793; 59% and 59%) and CE-US (0.811; 69%), and significantly greater A(z) (0.783 and 0.837) and sensitivity (56% and 73%) for lesions ≤1 cm compared with CE-CT (0.562 and 0.601; 20% and 22%) and CE-US (0.66; 37%). For lesions >1 cm, there was no significant difference in A(z), sensitivity and PPV between all the image sets. CONCLUSION: SPIO-MRI with DWI was the most reliable modality for evaluation of liver metastases particularly for lesions ≤1 cm.

High-b-value diffusion-weighted MR imaging of hepatocellular lesions: estimation of grade of malignancy of hepatocellular carcinoma.

PURPOSE: To evaluate the effectiveness of diffusion-weighted magnetic resonance imaging (DWI) in estimating the grade of malignancy of hepatocellular carcinoma. MATERIALS AND METHODS: Dynamic contrast-enhanced computed tomography (CE-CT) and DWI (b value, 1000 s/mm(2)) were performed on 73 patients. Using DW images, the lesions were classified as "visible" or "invisible." The apparent diffusion coefficient (ADC) of the lesions was measured. Furthermore, the lesions were classified as hypervascular or iso-hypovascular using arterial phase CE-CT images. The image findings for each lesion type were compared. RESULTS: The 73 patients had 98 hepatocellular lesions, of which 12 were histologically diagnosed as dysplastic nodules; 39, well-differentiated HCCs; 33, moderately differentiated HCCs; and 14, poorly differentiated HCCs. The mean ADC values of moderately poorly-differentiated HCCs were significantly lower than well-differentiated HCCs and dysplastic nodules (P < 0.01). On DW images, >90% of moderately (30/33) and poorly differentiated HCCs (13/14) were visible, while 51% of well-differentiated HCCs (20/39) and all dysplastic nodules were invisible. Of 22 iso-hypovascular lesions, 4 were visible on DW images and were poorly differentiated HCCs, whereas 18 were invisible and were dysplastic nodules (12/18) or well-differentiated HCCs (6/18). CONCLUSION: A combination of hypovascularity and visibility on DW images can help distinguish poorly differentiated HCCs from low-grade hepatocellular lesions (dysplastic nodules and well-differentiated HCCs).

Liver parenchymal enhancement of hepatocyte-phase images in Gd-EOB-DTPA-enhanced MR imaging: which biological markers of the liver function affect the enhancement?

PURPOSE: To clarify the factors that predict enhancement of the liver parenchyma in hepatocyte-phase of gadolinium ethoxybenzyl diethylenetriaminepentaacetic acid (Gd-EOB-DTPA)-enhanced MR imaging. MATERIALS AND METHODS: Gd-EOB-DTPA-enhanced hepatocyte-phase MR images of 198 patients with chronic liver diseases (Child-Pugh class A in 112 patients, class B in 74 patients, and class C in 12 patients) were retrospectively analyzed. The hepatocyte-phase images were obtained using fat-suppressed T1-weighted gradient-echo images with a 3D acquisition sequence 10 min and 20 min after IV administration of Gd-EOB-DTPA (0.025 mmol/kg body weight). The quantitative liver-spleen contrast ratio (Q-LSC) was calculated using the signal intensities of the liver and spleen. Serum albumin levels, total bilirubin levels, prothrombin activity, and the results of indocyanine green clearance tests (ICGs) were recorded and correlated with the Q-LSC. Logistic regression analysis was performed to analyze which factors predict sufficient liver enhancement using a Q-LSC of 1.5 as a cutoff value. RESULTS: Only ICGs and Child-Pugh classifications showed a statistically significant correlation with the Q-LSC. Logistic regression analysis showed that ICGs were the only factors that accurately predicted liver enhancement on hepatocyte-phase images. CONCLUSION: ICGs were found to be predictors of sufficient liver enhancement on hepatocyte-phase images.

Detection of hypervascular hepatocellular carcinoma with multidetector-row CT: single arterial-phase imaging with computer-assisted automatic bolus-tracking technique compared with double arterial-phase imaging.

PURPOSE: To compare single arterial-phase (SAP) computed tomography (CT) imaging with bolus tracking (BT) with double arterial-phase (DAP) CT imaging for detecting hypervascular hepatocellular carcinoma. MATERIALS AND METHODS: The DAP images were obtained at 25 (DAP-early) and 40 seconds (DAP-late) after the start of contrast material injection. All patients underwent SAP-BT imaging where images were obtained 10 seconds after the CT attenuation value of the aorta reached the threshold value of 120 Hounsfield unit (HU) in 29 (group 120-HU), 160 HU in 30 (group 160-HU), and 200 HU in 32 patients (group 200-HU). Attenuation conspicuity with SAP-BT technique was compared with that with DAP technique using repeated-measures analysis of variance. Attenuation conspicuity and mean scan delays with SAP-BT images obtained with different threshold values were compared using analysis of variance. The sensitivities were compared using McNemar and Fisher exact tests. RESULTS: Within all groups, mean attenuation conspicuity with SAP-BT and DAP-late was significantly higher than that with DAP-early. Regarding SAP-BT, mean attenuation conspicuity in group 200-HU (42 +/- 18 HU) was significantly higher than those in groups 120-HU (23 +/- 11 HU) and 160-HU (25 +/- 11 HU). Mean scan delays for SAP-BT were 24.2 seconds in group-120 HU, 26.8 seconds in group-160 HU, and 31.1 seconds in group-200 HU (P < 0.001). The mean sensitivity with SAP-BT technique in group 200-HU (92.7%) was significantly higher than those in groups 120-HU (72.4%) and 160-HU (71.1%). CONCLUSIONS: Single arterial-phase CT scanning with bolus tracking can be effectively used to detect hepatocellular carcinoma when a threshold value of 200 HU is used.

[New diagnostic imaging for navigation surgery].

Progress in diagnostic computed tomography (CT) and magnetic resonance (MR) imaging has been remarkable. Multidetector-row CT provides thin-slice images through the upper abdomen, multiphase abdominal imaging, and 3D images of high quality including CT angiography and multiplanar reformation. The development of MR units provides diffusion-weighted images for detecting abdominal tumors, and the steady-state coherent echo method can be used for imaging of vessels without using contrast media. The 3D images provided in CT and MR imaging facilitate anatomic understanding of tumors and vessels and are useful for preoperative navigation. However, we must be careful when using 3D images for diagnosis, because the subjectivity of the 3D image creator may affect the results. Therefore the original axial images should also be referred to.

Targeting lipid metabolism in the treatment of hepatitis C virus infection.

Recently, microdomains of organelle membranes rich in sphingomyelin and cholesterol (called "lipid rafts") have been considered to act as a scaffold for the hepatitis C virus (HCV) replication complex. Using the HCV cell culture system, we investigated the effect of myriocin, a sphingomyelin synthesis inhibitor, on HCV replication. We also investigated the combined effect of myriocin with interferon (IFN) and myriocin with simvastatin. Myriocin suppressed replication of both a genotype 1b subgenomic HCV replicon (Huh7/Rep-Feo) and genotype 2a infectious HCV (JFH-1 HCV) in a dose-dependent manner (for subgenomic HCV-1b, maximum of 79% at 1000 nmol/L; for genomic HCV-2a, maximum of 40% at 1000 nmol/L). Combination treatment with myriocin and IFN or myriocin and simvastatin attenuated HCV RNA replication synergistically in Huh7/Rep-Feo cells. Our data demonstrate that the sphingomyelin synthesis inhibitor strongly suppresses replication of both the subgenomic HCV-1b replicon and the JFH-1 strain of genotype 2a infectious HCV, indicating that lipid metabolism could be a novel target for HCV therapy.

Repeated radiofrequency ablation for the distant recurrence in the liver in patients with chronic hepatitis C virus infection achieving long-term survival.

Recurrence of hepatocellular carcinoma (HCC) is frequently observed in patients with hepatitis C virus (HCV) infection and the incidence of HCC recurrence is as high as 20% in these patients even after a complete curative treatment is given for the HCC nodules. We report a 57-year-old female who was referred to our hospital for the treatment of a HCC nodule of 1.8 cm diameter in S5 and having liver cirrhosis of Child-Pugh A classification with HCV infection in April 1999. The HCC nodule showed hypervascularity by computed tomography during hepatic arteriography (CTHA) and was coagulated by microwave under peritoneoscopy. Complete necrosis was confirmed by enhanced-CT scan after microwave coagulation. Thereafter, interferon alfa-2b (3MU, twice weekly) was given but HCV RNA continued to be positive. Thereafter, recurrence of HCC was noted five times in S1, S2, S6; treatment by radiofrequency ablation was given four times; and transarterial chemoembolization was carried out once. Since January 2004, peg-interferon alfa-2a (90 microm/week) has been administered, and no recurrence has been detected until August 2005. She is currently 63 years old, and quite well. Five-year-survival rate in HCC patients treated by radiofrequency ablation is 62.7% in our hospital, however, the recurrence rate is as high as 26.4% per year in the patients with chronic HCV infection. It is a point of controversy when liver transplantation should be recommended in HCC patients with liver cirrhosis of Child-Pugh A classification having chronic HCV infection because of the high incidence of recurrence.

Serum KL-6 as a novel tumor marker for hepatocellular carcinoma in hepatitis C virus infected patients.

The up-regulation of MUC1 protein is associated with malignant phenotype of cancer. We investigated the significance of KL-6, one of the MUC1 antigens, as a tumor marker in hepatitis C virus positive hepatocellular carcinoma (HCC). Serum KL-6 was determined in 203 patients with chronic hepatitis (CH), 47 patients with liver cirrhosis (LC) and 78 patients with HCC. KL-6 was higher in HCC compared to non-HCC (p=0.0005) and was higher in patients with multiple HCC nodules compared to a single nodule (p=0.02). There was no correlation between KL-6 and existent tumor markers for HCC such as alpha-fetoprotein, lens culinaris agglutinin-reactive alpha-fetoprotein or des-gamma-carboxyprothrombin. In the prospective analysis, the cumulative incidence of HCC was significantly greater in CH and LC patients with high initial KL-6 (above 400U/ml) compared to the others (p=0.02). Moreover, in the prospective observation of 25 patients whose HCC was completely cured by radiofrequency ablation therapy, the cumulative incidence of distant recurrences was significantly greater in patients with high initial KL-6 compared to the others (p=0.005). These results suggest that serum KL-6 could be a novel tumor marker in the diagnosis and the prediction of prognosis of HCC that may have additive value to the existent markers.

Mutagenic effects of ribavirin and response to interferon/ribavirin combination therapy in chronic hepatitis C.

BACKGROUND/AIMS: To elucidate whether ribavirin acts as a mutagen in the clinical setting and to clarify the relationship between ribavirin-induced mutations and virological response to combined therapy. METHODS: Thirty-four patients with hepatitis C virus (HCV) genotype 1b received ribavirin monotherapy for 4 weeks, followed by a 24-week course of IFN/ribavirin therapy. HCV mutations during a non-treatment observation period and during subsequent ribavirin monotherapy were determined, and the relationship between mutations and response to subsequent IFN/ribavirin therapy was evaluated. RESULTS: Serum HCV significantly decreased from 6.90 to 6.56 log10copy/ml in response to ribavirin monotherapy (P < 0.0001). Nucleotide mutations in the NS5A and NS5B regions occurred during ribavirin monotherapy at a rate of 2.9 x 10(-2)/site/year and 1.3 x 10(-2)/site/year, respectively, a significantly higher rate than the mutation rates during the prior non-treatment observation period (0.60 x 10(-2)/site/year and 0.24 x 10(-2)/site/year, P = 0.02, respectively). Mutation rates in the NS5A region were significantly higher in sustained viral responders (SVRs, n = 10) than in non-responders (8.8 x 10(-2)/site/year vs. 0.38 x 10(-2)/site/year, P = 0.0005, respectively). In the NS5A region, non-synonymous mutations only occurred in SVRs. CONCLUSIONS: Ribavirin may act as a mutagen, and mutations occurring during ribavirin therapy correlate with the virological response to subsequent IFN/ribavirin combination therapy.

Polymerase domain B mutation is associated with hepatitis relapse during long-term lamivudine therapy for chronic hepatitis B.

Breakthrough hepatitis remains the major issue in long-term lamivudine therapy for chronic hepatitis B. However, the emergence of drug-resistant hepatitis B virus (HBV) is not always accompanied by a relapse of hepatitis. To elucidate factors predictive of breakthrough hepatitis, 53 patients with genotype C of HBV on long-term lamivudine therapy were analyzed. HBV reappeared during therapy in 19 patients with a cumulative incidence of 15% at 1 year, 34% at 2 years, and 60% at 3 years. Within this group, breakthrough hepatitis developed in 12 patients (63%). A polymerase gene domain B mutation (rt180M) emerged in 13 patients, and domain C mutations (rt204I, rt204V) were found in 19 patients. The rt180M mutation was associated with breakthrough hepatitis (p < 0.05) with a positive predictive value of 85% and a negative predictive value of 83%. Patients with the rt180M mutation had higher HBV-DNA levels during viral breakthrough compared to patients with rt180wt (p < 0.05). The mutational pattern of rt204 was not associated with breakthrough hepatitis. In conclusion, genotypic assays for the rt180M mutation after viral breakthrough may be useful in predicting the risk of breakthrough hepatitis and in deciding when to initiate alternative or additive nucleoside analogue therapy.

[Follow-up dynamic CT study for hypovascular nodules in patients with cirrhotic liver].

It is important to clarify the process by which hypovascular nodules progress to hypervascular hepatocellular carcinoma (HCC). In this study, we used dynamic computed tomography(CT) to retrospectively investigate serial changes in 24 hypovascular nodules of 24 patients until they progressed to hypervascular HCC. The mean time to hypervascular transformation(THT) was 726 days, with a minimum of 208 days and maximum of 2,728 days. Mean nodular diameter at the final examination was 21.2 +/- 8.0 mm, and was significantly larger than that(11.4 +/- 4.8 mm) at the initial time. THT was the shortest(463 days) in a group that had an initial nodular diameter larger than 15 mm. In a group with the low-iso-low contrast enhancement pattern, THT was 361 days, and was shorter than that in the other groups. In a group with the low-low-low contrast enhancement pattern, nodules containing fat were frequently detected(5 patients, 75%). In patients with HCC apart from the nodules, THT for the nodules was 464 days, shorter than that(767.5 days) in other patients. The findings suggest that hypovascular nodules larger than 15 mm in diameter with the low-iso-low contrast enhancement pattern and HCC progress to hypervascular HCC at an early stage.

[Improving diffusion-weighted imaging of liver with SENSE technique: a preliminary study].

Diffusion-weighted imaging (DWI) has not commonly been performed for assessment of the liver because of technical and physiologic problems. The sensitivity-encoding (SENSE) technique enables the acquisition time to be shortened and reduces artifacts on DWI. We compared the DWI without SENSE, with SENSE only, and with SENSE and half-Fourier technique using a 1.5 Tesla MRI unit. In general, imaging quality was improved and fewer artifacts were observed in DWI with SENSE. DWI of liver with SENSE is expected to be a useful tool for clinical application.

Persistence of hepatitis B viremia after recovery from acute hepatitis B: correlation between anti-HBc titer and HBV DNA in serum.

During the follow-up of 19 patients with self-limited acute hepatitis B for more than 2 years, clearance of hepatitis B surface antigen from the sera was observed in all patients within 6 months after disease onset, and the corresponding antibody (anti-HBs) appeared in 17 of the 19 patients within 12 months. However, upon performing nested polymerase chain reaction with the estimated sensitivity of 120-200 copies/ml, using two independent pairs of primers derived from the well-conserved sequences in the S gene or C gene region of the hepatitis B virus (HBV) genomes of all seven genotypes, HBV DNA was detected over a period of at least 12 months in serum samples obtained from five (26%) of the 19 patients, although it became undetectable in all five patients at 2-3 years after disease onset. The titer of antibody against hepatitis B core antigen (anti-HBc), assayed by the hemagglutination inhibition (HI, 2(N)) test, was significantly lower at the initial examination in the five patients who remained viremic for at least 12 months, than in the remaining 14 patients who cleared HBV DNA from their sera within 12 months after disease onset (10.6+/-2.7 vs. 13.6+/-0.7, P<0.02). Furthermore, these five patients showed a significantly lower rate of decrease of anti-HBc titer during the 12-month period after disease onset than the remaining 14 patients (55.0+/-32.6 vs. 91.0+/-7.9%, P<0.01). These results indicate that the initial titer and dynamics of anti-HBc may reflect the evolution of HBV viremia after clinical recovery from acute hepatitis B.

Hypervascular hepatocellular carcinoma: can double arterial phase imaging with multidetector CT improve tumor depiction in the cirrhotic liver?

OBJECTIVE: We assessed the efficacy of double arterial phase CT with multidetector CT for the detection of hypervascular hepatocellular carcinoma in the cirrhotic liver. MATERIALS AND METHODS: Double arterial phase images with multidetector CT were evaluated using quantitative, qualitative, and receiver operating characteristic analyses for 59 patients with 78 hepatocellular carcinomas. Early and late arterial phase (double arterial phase) CT scans were obtained at a fixed time of 25 and 40 sec, respectively, after administration of contrast material. Total dose and injection rate of contrast material were 100 mL and 3 mL/sec, respectively. RESULTS: On the basis of the receiver operating characteristic curves, the mean area under the curve values of the late (0.98) and combined arterial phase CT scans (0.98) were equivalent, and both were significantly greater than the mean of the early arterial phase CT scans (0.842) for detecting hepatocellular carcinoma (p < 0.05). The mean relative sensitivity values obtained with the late (69/78, 88%) and combined arterial phase CT scans (70/78, 90%) were also equivalent and were significantly greater than those obtained with the early arterial phase CT scans (52/78, 67%; p < 0.001). CONCLUSION: Double arterial phase CT with multidetector CT showed no significant improvement in effectiveness compared with single late arterial phase CT used alone for detecting hypervascular hepatocellular carcinoma in the cirrhotic liver.