Yukihiro Kishimoto

FibroIndex, a practical index for predicting significant fibrosis in patients with chronic hepatitis C

Diagnosis of the stage of liver fibrosis in chronic hepatitis C is essential for making a prognosis and deciding on antiviral therapy. In the present study a simple model consisting of routine laboratory tests was constructed and then validated in cross‐sectional and longitudinal investigations. Consecutive treatment‐naive patients with chronic hepatitis C who had undergone liver biopsy were divided into 2 cohorts: an estimation set (n = 240) and a validation set (n = 120). A longitudinal set consisted of 30 patients who had undergone a liver biopsy twice, before and after IFN treatment. The FibroIndex was derived from the platelet count, AST, and gamma globulin measurements in the estimation set. The areas under the ROC curves of the FibroIndex for predicting significant fibrosis were 0.83 and 0.82 for the validation set, better than those of the Forns index and the aminotransferase‐to‐platelet ratio index (APRI). Using the best cutoff values, whether significant fibrosis was present was diagnosed with high positive predictive values, and 35% of patients could avoid liver biopsy. In the longitudinal set, there was a significant decrease in the FibroIndex of 14 patients whose fibrosis stage improved, and a significant increase in that of 5 patients whose fibrosis stage deteriorated. Change in the FibroIndex correlated significantly with variation in fibrosis stage. There was no such correlation with the Forns index or the APRI. Conclusion: The FibroIndex is a simple and reliable index for predicting significant fibrosis in chronic hepatitis C and could also be used as a surrogate marker during antifibrotic treatment for chronic hepatitis C. (HEPATOLOGY 2007;45:297–306.)

Sensitive Detection of Human Telomerase Reverse Transcriptase mRNA in the Serum of Patients with Hepatocellular Carcinoma

Background/Aim: Telomerase reverse transcriptase protein (hTERT) mRNA has been reported to be detectable by reverse transcription polymerase chain reaction (RT-PCR) in the serum of patients with breast cancer. We measured serum hTERT mRNA in patients with hepatocellular carcinoma (HCC), and examined its clinical usefulness. Methods: We performed RT-PCR to detect the expression of hTERT mRNA in 78 patients with HCC, 10 with liver cirrhosis (LC), 12 with chronic hepatitis (CH), and 34 healthy individuals without any liver diseases and cancers, and statistically analyzed the association with clinical parameters which include age, sex, etiology, Child classification, underlying liver disease, biochemical data, α-fetoprotein (α-AFP) number and size of tumor, and histological differentiation of HCC regarding HCC patients. Results: 70 of 78 (89.7%) patients with HCC, 7 of 10 (70.0%) with LC, and 5 of 12 (41.7%) with CH were positive for hTERT expression, whereas all healthy individuals were negative for it. A multivariate analysis showed that positivity of hTERT mRNA was independently associated with AFP, tumor size, and differentiation degree. Conclusions: These results suggest that this assay is sensitive enough to detect hTERT mRNA in serum, and that it would be applicable for early detection and diagnosis of HCC or other cancers by a quantitative method.

Interferon alpha inhibits intrahepatic recurrence in hepatocellular carcinoma with chronic hepatitis C: a pilot study.

The aim of the present study is to evaluate whether interferon alpha (IFNalpha) therapy can inhibit intrahepatic recurrence after the curative treatment of small HCC with underlying chronic hepatitis C. Forty patients were enrolled in this study. They had solitary, small HCC</=3 cm in diameter, underlying chronic hepatitis C, and were </=70 years old. Of the patients, 18 were treated with IFNalpha for 6 months after the treatment of HCC, and 22 patients who did not receive IFNalpha therapy were used as controls. Six (33%) patients in the IFN group showed sustained response. The incidence of local recurrence was not different in the IFN and non-IFN groups (6 vs. 9%). The cumulative incidences of distant recurrence in the non-IFN and IFN groups were 9 and 6% at 1 year, 27 and 11% at 2 years, 63 and 18% at 3 years, 76 and 28% at 4 years, and 82 and 28% at 5 years; they were significantly different (P<0.01). Six (27%) patients in the non-IFN group died from the progression of HCC, but all IFN-treated patients were alive (P<0.05). The pilot study demonstrates that IFNalpha therapy after the curative treatment of small HCC can inhibit intrahepatic recurrence in the remnant liver and improve the prognosis of hepatitis C virus-related HCC.

Mechanism of the protective action of thiol compounds in ethanol-induced liver injury

The protective action of cysteine or mercaptopropionylglycine (MPG) in acute ethanol-induced liver injury has been investigated in the rat. Cysteine accelerated clearance of ethanol and acetaldehyde from blood and liver and prevented an increase in hepatic content of triglyceride and serum ornithine carbamoyl transferase activity. MPG accelerated clearance of ethanol and acetaldehyde less efficiently but prevented an increase in these variables to the same degree. The mode of action of thiol compounds in acute ethanol-induced liver injury has been discussed.

A novel biomarker TERTmRNA is applicable for early detection of hepatoma

BackgroundsWe previously reported a highly sensitive method for serum human telomerase reverse transcriptase (hTERT) mRNA for hepatocellular carcinoma (HCC). α-fetoprotein (AFP) and des-γ-carboxy prothrombin (DCP) are good markers for HCC. In this study, we verified the significance of hTERTmRNA in a large scale multi-centered trial, collating quantified values with clinical course.MethodsIn 638 subjects including 303 patients with HCC, 89 with chronic hepatitis (CH), 45 with liver cirrhosis (LC) and 201 healthy individuals, we quantified serum hTERTmRNA using the real-time RT-PCR. We examined its sensitivity and specificity in HCC diagnosis, clinical significance, ROC curve analysis in comparison with other tumor markers, and its correlations with the clinical parameters using Pearson relative test and multivariate analyses. Furthermore, we performed a prospective and comparative study to observe the change of biomarkers, including hTERTmRNA in HCC patients receiving anti-cancer therapies.ResultshTERTmRNA was demonstrated to be independently correlated with clinical parameters; tumor size and tumor differentiation (P < 0.001, each). The sensitivity/specificity of hTERTmRNA in HCC diagnosis showed 90.2%/85.4% for hTERT. hTERTmRNA proved to be superior to AFP, AFP-L3, and DCP in the diagnosis and underwent an indisputable change in response to therapy. The detection rate of small HCC by hTERTmRNA was superior to the other markers.ConclusionshTERTmRNA is superior to conventional tumor markers in the diagnosis and recurrence of HCC at an early stage.

Development of a Novel Assay to Quantify Serum Human Telomerase Reverse Transcriptase Messenger RNA and Its Significance as a Tumor Marker for Hepatocellular Carcinoma

Currently available tumor markers for hepatocellular carcinoma (HCC) are α-fetoprotein (AFP), lens culinaris agglutinin-reactive AFP (AFP-L3), and Des-γ-carboxy prothrombin (DCP). However, their positive rate can not surpass abdominal ultrasonography (US) as modalities to detect small HCC at early stage, resulting in a possible delay of its diagnosis. There is a need to develop an additional sensitive marker to improve the early detection of HCC. We here introduced a newly developed quantitative detection method for serum hTERT mRNA, which has a clinical significance in HCC diagnosis. Briefly, we examined its sensitivity and specificity in HCC diagnosis, clinical significance in comparison with other tumor markers, and its correlations with the clinical parameters. Serum hTERT mRNA showed higher values in patients with HCC than those with chronic liver diseases. hTERT mRNA expression independently correlated with clinical parameters such as differentiation degree (p < 0.001). The sensitivity/specificity of hTERT mRNA in HCC diagnosis showed 88.2/70.0%. hTERT mRNA proved to be expectedly superior to AFP mRNA , AFP and DCP in HCC diagnosis. Importantly, hTERT mRNA in serum correlated with that in HCC tissue. Thus, we report that serum hTERT mRNA is a novel and available marker for HCC diagnosis.

Expression of oxidative stress-related molecules in circulating leukocytes and urine in patients with chronic viral hepatitis

Abstract: Aims: Oxidative stress plays a role in pathogenesis of chronic viral hepatitis. Expression of oxidative stress‐related molecules remains to be clarified.

Plasma carcinoembryonic antigen and acinar cell carcinoma of the pancreas

Seventeen patients with histologically proven pancreatic cancers were studied in order to clarify the relationship of histologic types to plasma carcinoembryonic antigen (CEA) values. Two cases with marked elevation of plasma CEA values having 6100 ng/ml and 2500 ng/ml, respectively, disclosed histologically acinar cell carcinoma and mixed acinar and ductal cell carcinoma, respectively. Despite of massive hepatic metastases, the other 15 cases with ductal cell carcinoma, including 3 cases with cystadenocarcinoma, adenoacanthoma, and undifferentiated pancreatic cancer, respectively, showed normal or very modest elevation of plasma CEA values. No correlation was obtained between plasma CEA values and several biochemical tests. Two patients with marked elevation of plasma CEA value revealed strong staining in the cancerous areas of the pancreas by using a peroxidase‐antiperoxidase staining technique. These findings suggest that acinar cell carcinoma of the pancreas may contribute to increase the circulating plasma CEA value. Cancer 53:1137‐1142, 1984.

Adult-type neuroblastoma originated in retroperitoneum beginning with obstructive jaundice

Abdominal neuroblastoma in adults is a rare neoplasm and only 30 patients have been described in Japan since 1985. The patient was a 43-year-old woman with jaundice. The tumor originated from retroperitoneum. The enlarged gall bladder and dilatation of intrahepatic bile ducts were noted by ultrasonography and computed tomography. We report the first adult-type neuroblastoma with obstructive jaundice.

Increase in serum 7S domain of type IV collagen and N-terminal propeptide of type III procollagen levels with normal serum transaminase levels after long-term oral administration of Tegaful-Uracil.

To evaluate whether oral administration of Tegaful-Uracil (UFT(R)), a biochemical modulator of 5-fluorouracil that contains tegafur and uracil, can induce hepatic fibrosis, serum 7S domain of type IV collagen and N-terminal propeptide of type III procollagen levels were measured in 63 UFT(R)-treated, 38 tegafur-treated and 40 untreated patients. Serum transaminase and bilirubin levels were normal in almost all patients. Serum levels of 7S collagen and type III propeptide increased in 25 and 17% of the UFT(R)-treated patients, respectively, although a majority of tegafur-treated and untreated patients showed no increase in these markers. The patients with the elevated levels demonstrated mild or moderate hepatic fibrosis without necroinflammation in the liver. Both serum levels decreased markedly after the discontinuation of UFT(R). These findings suggest that long-term oral administration of UFT(R) can induce hepatic fibrosis without the elevation of serum transaminase levels and necroinflammation in the liver, and serum 7S collagen and type III procollagen are of diagnostic value for UFT(R)-induced hepatotoxicity.