Centrilobular zonal necrosis is a unique subtype of autoimmune hepatitis: A cohort study.

BACKGROUNDS: Centrilobular zonal necrosis (CZN) is described as a histological feature present in a small number of autoimmune hepatitis (CZN-AIH) patients. CZN may be detected in the absence of significant interface hepatitis, which is the most important histological finding of AIH. The clinical and histopathological spectra of CZN-AIH were not homogeneous, and the concept of CZN-AIH as a distinctive subtype of AIH remains controversial, due to the rarity of CZN-AIH and the ambiguous definition of CZN. METHODS: To elucidate the clinical and immunogenetic features of CZN-AIH, a total of 102 biopsy samples of AIH, obtained at The Jikei University Katsushika Medical Center and Jikei University Hospital from 2000 to 2018, were reviewed. The 32 patients whose biopsies showed CZN were selected as the CZN-AIH group, and the remaining 70 were grouped as the non-CZN-AIH controls (control AIH). Data on clinical, histopathologic, and immunogenetic features were statistically compared between the CZN-AIH and the control AIH group. Additionally, the impact of the onset pattern (acute or chronic) and coexistent significant interface hepatitis in CZN-AIH was determined. RESULTS: In CZN-AIH, the frequency of acute-onset cases was significantly higher than that in control AIH (56.2% vs 32.9%; P < .05), and the number of cases with moderate-to-severe interface hepatitis in liver histology was significantly lower (37.5% vs 87.1%; P < .001). Compared to the control AIH, cases of CZN-AIH had lower immunoglobulin G level (P < .001), lower antinuclear antibodies titer (P < .001), and lower AIH score (P < .001). The immunogenetic disproportionate distribution of HLA-DR phenotypes in control AIH (increased HLA-DR4 and decreased HLA-DR9) was not found in CZN-AIH. Moreover, CZN-AIH was less frequently relapsed (P < .05). For the acute-onset CZN-AIH cases, the clinical features were hardly indistinguishable from the chronic CZN-AIH cases. Similarly, the existence of interface hepatitis did not influence on the pathophysiology of CZN-AIH. Moreover, the acute-onset CZN-AIH cases is clinically distinguishable from acute-onset control AIH. CONCLUSION: CZN can characterize as a distinct AIH subtype, regardless of onset-pattern or coexistence of significant interface hepatitis. To further strengthen this hypothesis, collection of more CZN-AIH cases is needed.

Daclatasvir and asunaprevir for genotype 1b chronic hepatitis C patients with chronic kidney disease.

AIM: To evaluate the efficacy and safety of daclatasvir and asunaprevir combined therapy in genotype 1b chronic hepatitis C patients with non-dialysis chronic kidney disease (CKD). METHODS: In a multicenter collaborative study, 249 patients received 60 mg daclatasvir (NS5A inhibitor) once a day and 100 mg of asunaprevir (NS3/4A protease inhibitor) twice a day for 24 weeks between September 2014 and September 2015 and were subjected to this analysis. Virological response and adverse events in non-dialysis patients with CKD (stage 3-5, excluding 5D: dialysis), which was defined as estimated glomerular filtration rate <60 mL/min/1.73 m2 , were compared with those in patients without CKD. RESULTS: Overall, the rates of rapid viral response, end-of-treatment response, and sustained virological response (SVR) were 76.7%, 91.2%, and 86.3%, respectively. Among 55 patients with CKD, the rapid viral response, end-of-treatment response, and SVR rates were 76.4%, 87.3%, and 83.6%, respectively. Among 194 patients without CKD, they were 76.8, 92.3, and 87.1%, respectively. There were no significant differences in the virological response rates between the two groups (P = 0.999, 0.282, and 0.509, respectively). The baseline estimated glomerular filtration rate did not affect the achievement of SVR. The incidence of adverse events in patients with and without CKD were 21.8% and 13.9%, respectively (not significant, P = 0.142). CONCLUSION: The efficacy and safety of daclatasvir and asunaprevir combined therapy in genotype 1b chronic hepatitis C patients with non-dialysis CKD are not inferior to those in patients without CKD.

Mucinous carcinoma of the gallbladder with signet ring cells.

Most gallbladder carcinomas are adenocarcinomas, of which mucinous carcinoma (MC) is a rare pathologic subtype. Signet ring cells are seldom found in MCs. We report an extremely rare case of gallbladder MC with signet ring cells. This is the first radiological case report about this rare type of histologic entity with detailed discussion of imaging findings in the English literature. In addition to the features of MC, linitis plastica-like invasion, which is the key feature of signet ring cells, was confirmed by both imaging and histopathologic analysis. Furthermore, radiologists should know how the imaging findings of MC differ from those of other major subtypes of adenocarcinoma, as there is a risk of delays in diagnosis and underestimation of tumor spread.

Endoscopic submucosal dissection for an atypical small verrucous carcinoma: a case report.

BACKGROUND: Esophageal verrucous carcinoma is a rare variant of esophageal squamous cell carcinoma. In most cases, verrucous carcinoma presents as an exophytic, slow-growing mass with an extensive superficial growth pattern. Symptoms often include an insidious onset of dysphagia resulting in weight loss. In a patient presenting with super early-stage verrucous carcinoma, we were able to eliminate the aberration using endoscopic submucosal dissection. CASE PRESENTATION: An asymptomatic 68-year-old Asian man was found to have an abnormality in his esophagus. The abnormality was discovered, by chance, in a barium study for a health checkup. Esophagogastroduodenoscopy revealed a 1-centimeter polypoid lesion covered with squamous epithelium. Biopsies showed squamous high-grade intraepithelial neoplasia. An endoscopic submucosal dissection was performed and the histopathological findings showed a well-differentiated squamous cell carcinoma with hyperkeratosis with a church spire configuration. These features are consistent with the growth pattern of verrucous carcinoma. CONCLUSIONS: Verrucous carcinoma can manifest as a small mass with nonclinical symptoms and endoscopic submucosal dissection is useful as a curative treatment. We must consider that verrucous carcinoma can manifest as appearance of a polyp that is not papillary or warty-like with and without extensive superficial growth appearance.

Centrilobular zonal necrosis as a hallmark of a distinctive subtype of autoimmune hepatitis.

BACKGROUND AND AIM: Centrilobular zonal necrosis (CZN) is a known histological variant of autoimmune hepatitis (AIH). However, the significance of CZN is yet to be fully elucidated. This study aimed to determine whether CZN is a hallmark of a distinctive subtype of AIH. METHODS: Histological changes in the centrilobular zones of liver biopsies from 113 AIH patients were assessed by a single pathologist and classified into three categories: typical zonal necrosis defined as CZN (15 patients); other necroinflammatory change (NIC; 24 patients); and absence of necrosis (non-NIC; 74 patients). The clinicopathological features and immunogenetic background of CZN patients were then assessed. RESULTS: The clinicopathological features of AIH with CZN were distinct from other types of AIH, including a higher frequency of acute onset, lower frequency of antinuclear antibodies, lower antinuclear antibody titers, lower serum immunoglobulin G levels, lower grade interface hepatitis, less prominent lymphoplasmacytic infiltration, and lower AIH score. Increased and decreased frequencies of HLA-DR9 and HLA-DR4, respectively, were identified as immunogenetic features of AIH with CZN. Conversely, the clinicopathological characteristics of AIH with NIC were similar to those of non-NIC AIH, including the majority of the AIH patients. The therapeutic outcomes of AIH with CZN were excellent when precise diagnoses were made without delay. CONCLUSION: The clinicopathological features and immunogenetic background of AIH with CZN differed from AIH without CZN. CZN may be a hallmark of a distinct subtype of AIH.

[Progress in the Management of NAFLD/NASH].

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases. The con- cept of NAFLD ranges from simple steatosis (NAFL) to non-alcoholic steatohepatitis (NASH) and cirrhosis. The majority of NAFLD has been recognized as a hepatic manifestation of metabolic syndrome with a close association with insulin resistance. Regarding the development of NAFLD/NASH, adiponectin and TNFa are thought to have key roles. Moreover, the gut microbiota may affect energy metabolism in the context of NAFLD. Genetic susceptibility to NAFLD may be determined by polymorphisms of patatin-like phospho- lipase domain-containing 3 (PNPLA3) and methylenetetrahydrofolate reductase (MTHFR). The diagnosis of NAFLD/NASH is made by liver biopsy. The differential diagnosis between NAFL and NASH has been made according to Matteoni's classification, and the progression of liver fibrosis has been determined by Brunt's staging. For the prevention and treatment of NAFLD, the modification of dietary habits and promo- tion of physical activity including aerobic and resistance training are essential. Although vitamin E, pioglita- zone, or liraglutide is used as a first-line treatment for NAFLD, pharmacotherapy for NAFLD has not been established because of the insufficient pharmacological effects of these agents. Among recently developed drugs, farnesoid X nuclear receptor ligand obeticholic acid is the most promising for first-in-class treatment of NASH. In this review, the details of recent advances in knowledge about the epidemiology, etiology, diag- nosis, and treatment of NAFLD/NASH are described. [Review].

Chronic hepatitis C virus infection and lipoprotein metabolism.

Hepatitis C virus (HCV) is a hepatotrophic virus and a major cause of chronic liver disease, including hepatocellular carcinoma, worldwide. The life cycle of HCV is closely associated with the metabolism of lipids and lipoproteins. The main function of lipoproteins is transporting lipids throughout the body. Triglycerides, free cholesterol, cholesteryl esters, and phospholipids are the major components of the transported lipids. The pathway of HCV assembly and secretion is closely linked to lipoprotein production and secretion, and the infectivity of HCV particles largely depends on the interaction of lipoproteins. Moreover, HCV entry into hepatocytes is strongly influenced by lipoproteins. The key lipoprotein molecules mediating these interactions are apolipoproteins. Apolipoproteins are amphipathic proteins on the surface of a lipoprotein particle, which help stabilize lipoprotein structure. They perform a key role in lipoprotein metabolism by serving as receptor ligands, enzyme co-factors, and lipid transport carriers. Understanding the association between the life cycle of HCV and lipoprotein metabolism is important because each step of the life cycle of HCV that is associated with lipoprotein metabolism is a potential target for anti-HCV therapy. In this article, we first concisely review the nature of lipoprotein and its metabolism to better understand the complicated interaction of HCV with lipoprotein. Then, we review the outline of the processes of HCV assembly, secretion, and entry into hepatocytes, focusing on the association with lipoproteins. Finally, we discuss the clinical aspects of disturbed lipid/lipoprotein metabolism and the significance of dyslipoproteinemia in chronic HCV infection with regard to abnormal apolipoproteins.

Aldehyde dehydrogenase 2 polymorphism for development to hepatocellular carcinoma in East Asian alcoholic liver cirrhosis.

BACKGROUND AND AIM: We aimed to clarify the influences of aldehyde dehydrogenase 2 (ALDH2), alcohol dehydrogenase 1B (ADH1B) polymorphisms, and ethanol consumption profile to hepatocellular carcinoma (HCC) development in alcoholic liver cirrhosis without chronic hepatitis B and C virus infection (non-B non-C). METHODS: Of 236 freshly diagnosed non-B non-C alcoholic liver cirrhosis patients, 67 were diagnosed as HCC and the remaining 169 as not having HCC. The relationship between the genetic polymorphisms and development to HCC were evaluated in well-matched patients with HCC (HCC group, n = 67) and without HCC (non-HCC group, n = 67) using propensity scores in age, sex, and prevalence of diabetes mellitus. RESULTS: Daily amount of ethanol consumption was significantly lower (P = 0.005), and consumptive period was significantly longer (P = 0.003) in HCC group than non-HCC group. Of 134 well-matched patients, 113 (84.3%) had ALDH2*1/*1 genotype and 21 (15.7%) had ALDH2*1/*2 genotype. In HCC development, consumptive long period (P = 0.007) and carrying ALDH2*1/*2 genotype (P = 0.026) were identified as significant factors independently participated, while there was no relation to ADH1B polymorphism. In addition, consumptive period was significantly longer in HCC group than non-HCC group in ALDH2*1/*1 genotype patients (P = 0.0005), while there was no difference in profile of ethanol consumption in ALDH2*1/*2 genotype patients. Among HCC group, daily (P = 3.78 × 10(-6) ) and cumulative amount (P = 4.89 × 10(-6) ) of ethanol consumption were significantly higher in ALDH2*1/*1 genotype patients than ALDH2*1/*2 genotype patients. CONCLUSION: In alcoholic liver cirrhosis, investigations of ALDH2 polymorphism and ethanol consumption profile are useful for prediction of HCC development.

Serum cytokeratin 18 fragment level as a noninvasive biomarker for non-alcoholic fatty liver disease.

BACKGROUND AND AIM: We evaluated the usefulness of serum cytokeratin 18 fragment (CK18-F) as a noninvasive biomarker in differentiating nonalcoholic steatohepatitis (NASH) from nonalcoholic fatty liver (NAFL) since the prognosis of the 2 diseases differ. METHODS: 116 Japanese patients with nonalcoholic fatty liver disease (NAFLD) proven by liver biopsy were studied. Histological findings were classified according to the NAFLD activity score (NAS) proposed by the Nonalcoholic Steatohepatitis Clinical Research Network. The correlation between histological findings and serum CK18-F levels was investigated. RESULTS: Serum CK18-F levels showed a positive correlation with histologic steatosis (ρ = 0.271, P = 0.0033), inflammation (ρ = 0.353, P = 0.0005), ballooning (ρ = 0.372, P = 0.0001), and the total NAS (ρ = 0.474, P = 2.68 × 10-7). The serum CK18-F level was significantly lower for NAFL (NAS ≤ 2) than for borderline NASH (NAS of 3-4) or definite NASH (NAS ≥ 5) (P = 0.0294, P = 1.163 × 10-5, respectively). The serum CK18-F level was significantly higher for definite NASH than for borderline NASH (P = 0.0002). The area under the receiver operating characteristic curve of serum CK18-F to predict the presence of NAFL and definite NASH was 0.762 and 0.757, respectively. The optimal cut-off point of serum CK18-F for NAFL and definite NASH was 230 and 270 U/L, respectively. The sensitivity, specificity, positive predict value, and negative predict value of serum CK18-F for NAFL were 0.89, 0.65, 0.34, and 0.97, and those for definite NASH were 0.64, 0.76, 0.72, and 0.67, respectively. Accuracies of diagnosis for both NAFL and definite NASH were 0.70. CONCLUSIONS: Serum CK18-F could be a clinically useful biomarker to discriminate between NAFL and NASH.

A case of peripancreatic tuberculous lymphadenitis diagnosed by endoscopic ultrasound-guided fine-needle aspiration.

Tuberculous lymphadenitis is a rare cause of obstructive jaundice. Here, we report the case of a 33-year-old male with obstructive jaundice caused by tuberculous lymphadenitis around the pancreatic head. The patient was born in China and had immigrated to Japan at 12 years of age. He presented with acute abdominal pain and jaundice. Findings from ultrasonography, computed tomography, and endoscopic retrograde cholangiopancreatography were suggestive of a stenosis of the distal common bile duct caused by multiple low-density masses around the pancreatic head with a contrast-enhanced solid rim. We successfully diagnosed the mass as tuberculous lymphadenitis using endoscopic ultrasound-guided fine-needle aspiration (EUS-FNA). The patient was treated with anti-tuberculous combination chemotherapy for 6 months, and subsequently exhibited clinical improvement. Thus, we found that EUS-FNA was a valuable minimally invasive method for diagnosing masses that cause icterus.

Early syphilitic hepatitis concomitant with nephrotic syndrome followed by acute kidney injury.

Although acute hepatitis and nephrotic syndrome are commonly reported as complications of tertiary syphilis, nephrotic syndrome concomitant with hepatitis in early-stage syphilis is rare. Here, we describe the case of a 46-year-old male who was diagnosed with acute liver dysfunction and nephrotic syndrome after presenting with general malaise, and who subsequently developed acute kidney injury. Laboratory examination showed alkaline phosphatase had a greater magnitude of elevation compared to alanine aminotransferase, suggesting the possibility of syphilitic hepatitis. The rapid plasmin regain test and Treponema pallidum hemagglutination assay were positive, supporting the presence of a syphilis infection. Additionally, liver biopsy examination showed infiltration of inflammatory cells into the portal area and epithelioid cell granulomas. Moreover, kidney biopsy examination by both optical and electron microscopy showed a congestion of neutrophils in the capillary vessels, structural collapse of the tubules, and subepithelial deposits under the epithelium of the glomerular endothelial cells. These pathological changes were consistent with those reported previously for early syphilitic hepatitis and nephrotic syndrome in early-stage syphilis. All the symptoms, including liver and renal dysfunction, resolved after benzyl penicillin treatment was initiated. Hence, we believe early-stage syphilis should be included in the differential diagnosis of unknown liver damage and/or nephrosis.

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.

Alcohol, postprandial plasma glucose, and prognosis of hepatocellular carcinoma.

AIM: To identify factors associated with prognosis of hepatocellular carcinoma (HCC) after initial therapy. METHODS: A total of 377 HCC patients who were newly treated at Katsushika Medical Center, Japan from January 2000 to December 2009 and followed up for > 2 years, or died during follow-up, were enrolled. The factors related to survival were first analyzed in 377 patients with HCC tumor stage T1-T4 using multivariate Cox proportional hazards regression analysis. A similar analysis was performed in 282 patients with tumor stage T1-T3. Additionally, factors associated with the period between initial and subsequent therapy were examined in 144 patients who did not show local recurrence. Finally, 214 HCC stage T1-T3 patients who died during the observation period were classified into four groups according to their alcohol consumption and postprandial glucose levels, and differences in their causes of death were examined. RESULTS: On multivariate Cox proportional hazards regression analysis, the following were significantly associated with survival: underlying liver disease stage [non-cirrhosis/Child-Pugh A vs B/C, hazard ratio (HR): 0.603, 95% CI: 0.417-0.874, P = 0.0079], HCC stage (T1/T2 vs T3/T4, HR: 0.447, 95% CI: 0.347-0.576, P < 0.0001), and mean postprandial plasma glucose after initial therapy (< 200 vs ≥ 200 mg/dL, HR: 0.181, 95% CI: 0.067-0.488, P = 0.0008). In T1-T3 patients, uninterrupted alcohol consumption after initial therapy (no vs yes, HR: 0.641, 95% CI: 0.469-0.877, P = 0.0055) was significant in addition to underlying liver disease stage (non-cirrhosis/Child-Pugh A vs B/C, HR: 0649, 95% CI: 0.476-0.885, P = 0.0068), HCC stage (T1 vs T2/T3, HR: 0.788, 95% CI: 0.653-0.945, P = 0.0108), and mean postprandial plasma glucose after initial therapy (< 200 mg/dL vs ≥ 200 mg/dL, HR: 0.502, 95% CI: 0.337-0.747, P = 0.0005). In patients without local recurrence, time from initial to subsequent therapy for newly emerging HCC was significantly longer in the "postprandial glucose within 200 mg/dL group" than the "postprandial glucose > 200 mg/dL group" (log-rank test, P < 0.05), whereas there was no difference in the period between the "non-alcohol group" (patients who did not drink regularly or those who could reduce their daily consumption to < 20 g) and the "continuation group" (drinkers who continued to drink > 20 g daily). Of 214 T1-T3 patients who died during the observation period, death caused by other than HCC progression was significantly more frequent in "group AL" (patients in the continuation and postprandial glucose within 200 mg/dL groups) than "group N" (patients in the non-alcohol and postprandial glucose within 200 mg/dL groups) (P = 0.0016). CONCLUSION: This study found that abstinence from habitual alcohol consumption and intensive care for diabetes mellitus were related to improved prognosis in HCC patients.

[A long-term survival case of liver epithelioid hemangioendothelioma with multiple lung metastases that regressed by long-term administration of interleukin-2].

A patient was a 46-year-old man. Multiple lung tumors had been pointed out on a medical examination at age 24. He came to our hospital for further examination. Multiple liver and lung tumors were found out, and epithelioid hemangioendothelioma (EHE) derived from the liver was diagnosed by biopsy. At first we gave recombinant interleukin-2 (rIL-2) by intra-arterial and local injection and then continued it by intramuscular injection for 22 years as maintenance therapy. The tumors have regressed, with partial necrosis. EHE is a rare tumor, but we do not have a standard antitumor therapy except surgical resection. This case suggests that rIL-2 may become a new therapy for EHE. We think that the report of the long-term survival of a case of EHE in which rIL-2 treatment was effective is extremely valuable.

Genotype rs8099917 near the IL28B gene and amino acid substitution at position 70 in the core region of the hepatitis C virus are determinants of serum apolipoprotein B-100 concentration in chronic hepatitis C.

The life cycle of the hepatitis C virus (HCV) is closely related to host lipoprotein metabolism. Serum levels of lipid are associated with the response to pegylated interferon plus ribavirin (PEG-IFN/RBV) therapy, while single nucleotide polymorphisms (SNPs) around the human interleukin 28B (IL28B) gene locus and amino acid substitutions in the core region of the HCV have been reported to affect the efficacy of PEG-IFN/RBV therapy in chronic hepatitis with HCV genotype 1b infection. The aim of this study was to elucidate the relationship between serum lipid and factors that are able to predict the efficacy of PEG-IFN/RB therapy, with specific focus on apolipoprotein B-100 (apoB-100) in 148 subjects with chronic HCV G1b infection. Our results demonstrated that both the aa 70 substitution in the core region of the HCV and the rs8099917 SNP located proximal to the IL28B were independent factors in determining serum apoB-100 and low-density lipoprotein (LDL) cholesterol levels. A significant association was noted between higher levels of apoB-100 (P = 1.1 × 10(-3)) and LDL cholesterol (P = 0.02) and the subjects having Arg70. A significant association was also observed between subjects carrying the rs8099917 TT responder genotype and higher levels of apoB-100 (P = 6.4 × 10(-3)) and LDL cholesterol (P = 4.2 × 10(-3)). Our results suggest that apoB-100 and LDL cholesterol are markers of impaired cellular lipoprotein pathways and/or host endogenous interferon response to HCV in chronic HCV infection. In particular, serum apoB-100 concentration might be an informative marker for judging changes in HCV-associated intracellular lipoprotein metabolism in patients carrying the rs8099917 responder genotype.

Expansion of CD4(+)CD25(+)FoxP3(+) regulatory T cells in hepatitis C virus-related chronic hepatitis, cirrhosis and hepatocellular carcinoma.

AIM: Regulatory T (Treg) cells may play a pivotal role in the persistence of hepatitis C virus (HCV) infection and the development of hepatocellular carcinoma (HCC). Therefore, we examined their frequency in peripheral blood from patients with HCV-positive chronic hepatitis (CH), cirrhosis (LC) and HCC. METHODS: Treg cells were identified as CD4(+), CD25(+) and FoxP3(+) T lymphocytes using three-color FACS. The frequency of Treg cells was expressed as a percentage of the total CD4(+) T lymphocytes, and the phenotype of Treg cells was examined using CD45RA. RESULTS: Treg cells were significantly increased in CH (5.88 +/- 0.19%, n = 76; P < 0.01), LC (6.10 +/- 0.28%, n = 40; P < 0.001) and HCC (6.80 +/- 0.30%, n = 57; P < 0.0001) compared to healthy control (5.13 +/- 0.25%, n = 31). However, Treg cells were not increased with the progression of fibrosis or the grade of inflammations. Treg cells were slightly increased in early-stage HCC (6.91 +/- 0.40%) compared with advanced-stage HCC (6.58 +/- 0.39%), but these results were not statistically significant. In a serial examination, a distinct increase in Treg cells after local therapy for early-stage HCC was a hallmark of early recurrence. Most expanded Treg cells in HCC were CD45RA(-), suggesting that a memory-type Treg population had differentiated in the periphery and not in the thymus. CONCLUSION: We observed an increase in Treg cells in HCV-related chronic liver disease, particularly in HCC, and these cells were shown to be memory-type Treg cells.

[A case of primary small cell carcinoma of the esophagus responding remarkably to carboplatin (CBDCA) + etoposide (VP-16) combination therapy and radiation therapy].

A 78-year-old man was admitted to hour hospital because of dysphagia, and primary small cell carcinoma of the esophagus was diagnosed. Carboplatin (CBDCA) + etoposide (VP-16) combination chemotherapy and radiation therapy was performed. After this therapy, endoscopic examination and computed tomographic scan showed the disappearance of the primary esophageal tumor. Endoscopic examination with biopsy confirmed the disappearance of malignant cells. Severe adverse reactions were not observed during this therapy. This patient is alive without recurrence for 6 years and 3 months. This case seems to provide suggestions on deciding on the operative indications for small cell carcinoma of esophagus.

Etiology of non-B non-C hepatocellular carcinoma in the eastern district of Tokyo.

BACKGROUND: This study was carried out to clarify the carcinogenic factors associated with nonviral hepatocellular carcinoma (HCC). METHODS: A total of 320 HCC patients diagnosed and treated from January 2000 to December 2006 were enrolled. The clinical characteristics of non-B non-C HCC patients were examined to determine possible carcinogenic factors. RESULTS: Of 320 HCC patients, 64 were classified as having non-B non-C HCC. The proportion of non-B non-C HCC increased from 17.8% in 2000 to 28.6% in 2006. Non-B non-C HCC patients had a significantly higher rate of early stage cirrhosis (Child-Pugh classification) than viral HCC patients. Significantly fewer non-B non-C HCC patients had periodic intensive medical assessments than viral HCC patients. Forty-five non-B non-C HCC patients were habitual alcohol drinkers, ten had nonalcoholic fatty liver disease (NAFLD), and seven had no apparent etiology. In habitual drinkers, the stage of underlying liver disease varied widely, while most NAFLD patients had early stage cirrhosis. On the other hand, more than half of the patients with HCC of undetermined etiology had noncirrhotic liver disease. Among habitual drinkers, the underlying liver disease was more progressive, and the T stage was more advanced in those with high daily alcohol intake than in those with low daily alcohol intake. Periodic intensive medical assessments were crucial for detecting early stage HCC. CONCLUSIONS: Alcohol consumption and NAFLD may be important etiological factors in non-B non-C HCC. Periodic medical assessments for all patients with non-B non-C cirrhosis are crucial for early diagnosis and curative therapy.

Detection of a new N-oxidized metabolite of flutamide, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine, in human liver microsomes and urine of prostate cancer patients.

Flutamide (2-methyl-N-[4-nitro-3-(trifluoromethyl)phenyl]-propanamide), a nonsteroidal antiandrogen, is used in the treatment of prostate cancer but is occasionally associated with hepatic dysfunction. In the present study, the metabolism of flutamide including the formation of the possible reactive toxic metabolites was investigated using human liver microsomes and 10 isoforms of recombinant human cytochrome P450 (P450). 2-Hydroxyflutamide (OH-flutamide) and 4-nitro-3-(trifluoromethyl)phenylamine (FLU-1) were the main products of flutamide metabolism in human liver microsomes. The formation of OH-flutamide was markedly inhibited by ellipticine, an inhibitor of CYP1A1/1A2, and was mainly catalyzed by the recombinant CYP1A2. FLU-1 was also produced from OH-flutamide, but its metabolic rate was much less than that from flutamide. An inhibitor of carboxylesterase, bis-(p-nitrophenyl)phosphoric acid, completely inhibited the formation of FLU-1 from flutamide in human liver microsomes. A new metabolite, N-[4-nitro-3-(trifluoromethyl)phenyl]hydroxylamine (FLU-1-N-OH), was detected as a product of the reaction of FLU-1 with human liver microsomes and identified by comparison with the synthetic standard. The formation of FLU-1-N-OH was markedly inhibited by the addition of miconazole, an inhibitor of CYP3A4, and was mediated by recombinant CYP3A4. Furthermore, FLU-1-N-OH was detected mostly as the conjugates (glucuronide/sulfate) in the urine of prostate cancer patients collected for 3 h after treatment with flutamide. The formation of FLU-1-N-OH, however, did not differ between patients with and without abnormalities of hepatic functions among a total of 29 patients. The lack of an apparent association of the urinary excretion of FLU-1-N-OH and hepatic disorder may suggest the involvement of an additional unknown factor in the mechanisms of flutamide hepatotoxicity.