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A 66-year-old woman with rheumatoid arthritis (RA) who had been receiving methotrexate (MTX) for 2 years presented with tarry stools. Contrast-enhanced computed tomography (CT) of the abdomen revealed irregular wall thickening in the ileocecal region and multiple low-contrast masses in both lobes of the liver. Lower gastrointestinal endoscopy revealed a type 2 tumor in the ileocecal region with a semi-peripheral ulcer. Histological examination of liver and colon biopsies showed other iatrogenic immunodeficiency-associated lymphoproliferative disorder (Oi-LPD), diffuse large B-cell lymphoma type, with positivity for Epstein-Barr virus DNA. After withdrawal of MTX, the LPD lesions disappeared and the patient achieved remission. We considered this to be a sporadic case of Oi-LPD, diffuse large B-cell lymphoma type, in the liver and colon due to treatment with MTX. There has been no previous report of this condition with simultaneous hepatic and colonic lesions, and the present case is thought to be highly informative in relation to the pathogenesis. [ABSTRACT FROM AUTHOR]

Objective: There is limited information regarding the benefits of Lenvatinib-transcatheter arterial chemoembolization (LEN-TACE) sequential therapy for unresectable hepatocellular carcinoma (u-HCC). We compared the efficacy and safety of LEN-TACE sequential therapy to LEN monotherapy and investigated the factors contributing to the LEN-TACE sequential therapy deep response. Methods: We enrolled a multicenter cohort of 247 patients with u-HCC treated with LEN between 2018 and 2020. Propensity score matching identified 63 matching pairs of patients with well-balanced characteristics. We retrospectively compared the clinical outcomes, including overall survival (OS), progression-free survival (PFS), and incidence of adverse events (AEs), between the LEN-TACE and LEN monotherapy groups. Additionally, we evaluated the tumor response, change in albumin-bilirubin (ALBI) score, factors affecting PFS and OS, and independent predictors contributing to the LEN-TACE sequential therapy deep response. In this study, at eight weeks after resumption of LEN after initial TACE, "deep response" was defined as achieving complete response or partial response (PR) on modified Response Evaluation Criteria in Solid Tumors (mRECIST), and at least a 30% decrease in the sum of diameters of target lesions, taking the baseline sum diameters as the reference. Results: The OS and PFS in the LEN-TACE group were significantly higher than those in the LEN monotherapy group (p = 0.002 and p = 0.037, respectively). The incidence of AEs related to LEN was not significantly different between the two groups. In LEN-TACE sequential therapy, the objective response rate was 61.9%, and the disease control rate was 74.6%, according to the mRECIST criteria. No significant change in the ALBI score was observed during sequential LEN-TACE therapy. Multivariable analyses revealed that deep response was independently associated with the outcome of the initial response to LEN by mRECIST: PR (odds ratio: 5.176, 95% confidence interval: 1.528–17.537, p < 0.001). Conclusions: LEN-TACE sequential therapy may provide more clinical benefits than LEN monotherapy in u-HCC patients who responded to initial LEN treatment. Objective response according to mRECIST to initial LEN is an independent factor contributing to LEN-TACE sequential therapy deep response. [ABSTRACT FROM AUTHOR]

Sarcopenia is associated with poor prognosis of patients with hepatocellular carcinoma (HCC). We investigated the association of skeletal muscle volume (SMV) and its change in HCC patients taking lenvatinib. In 130 HCC patients, psoas mass index (PMI) was calculated as the left–right sum of the major × minor axis of psoas muscle at the third lumbar vertebra, divided by height squared. Patients were classified into two groups (low and normal PMI) based on indices of < 6.0 cm2/m2 for man and < 3.4 cm2/m2 for women. Change in PMI per month during the lenvatinib administration period (ΔPMI/m) was calculated; and patients were classified into two groups (severe and mild atrophy) based on the ΔPMI/m rate, as ≥ 1% or < 1%, respectively. There was no significant difference in Overall survival (OS) between the low and normal PMI groups at the start of lenvatinib administration. OS was significantly lower in the severe atrophy group than in the mild atrophy group (median; 15.2 vs. 25.6 months, P = 0.005). Multivariate analysis revealed a significant association of severe atrophy with OS (hazard ratio 1.927, P = 0.031). Progressive loss of SMV is a strong predictor of poor prognosis in HCC patients taking lenvatinib. [ABSTRACT FROM AUTHOR]

Sarcopenia is associated with poor prognosis of patients with hepatocellular carcinoma (HCC). We investigated the association of skeletal muscle volume (SMV) and its change in HCC patients taking lenvatinib. In 130 HCC patients, psoas mass index (PMI) was calculated as the left–right sum of the major × minor axis of psoas muscle at the third lumbar vertebra, divided by height squared. Patients were classified into two groups (low and normal PMI) based on indices of < 6.0 cm2/m2 for man and < 3.4 cm2/m2 for women. Change in PMI per month during the lenvatinib administration period (ΔPMI/m) was calculated; and patients were classified into two groups (severe and mild atrophy) based on the ΔPMI/m rate, as ≥ 1% or < 1%, respectively. There was no significant difference in Overall survival (OS) between the low and normal PMI groups at the start of lenvatinib administration. OS was significantly lower in the severe atrophy group than in the mild atrophy group (median; 15.2 vs. 25.6 months, P = 0.005). Multivariate analysis revealed a significant association of severe atrophy with OS (hazard ratio 1.927, P = 0.031). Progressive loss of SMV is a strong predictor of poor prognosis in HCC patients taking lenvatinib. [ABSTRACT FROM AUTHOR]

Background: Rifaximin is commonly used for hepatic encephalopathy (HE). However, the effects of long-term treatment for Japanese people are limited. Therefore, this study aimed to investigate the effects and safety of long-term treatment with rifaximin on HE. Methods: A total of 215 patients with cirrhosis administered with rifaximin developed overt or covert HE, which was diagnosed by an attending physician for >12 months. Laboratory data were extracted at pretreatment and 3, 6, and 12 months after rifaximin administration. The long-term effect of rifaximin was evaluated, and the incidence of overt HE during 12 months and adverse events was extracted. Results: Ammonia levels were significantly improved after 3 months of rifaximin administration and were continued until 12 months. There were no serious adverse events after rifaximin administration. The number of overt HE incidents was 9, 14, and 27 patients within 3, 6, and 12 months, respectively. Liver enzymes, renal function, and electrolytes did not change after rifaximin administration. Prothrombin activity is a significant risk factor for the occurrence of overt HE. The serum albumin, prothrombin activity, and albumin–bilirubin (ALBI) scores were statistically improved after 3 and 6 months of rifaximin administration. Moreover, the same results were obtained in patients with Child–Pugh C. Conclusions: The long-term rifaximin treatment was effective and safe for patients with HE, including Child–Pugh C. [ABSTRACT FROM AUTHOR]

Autonomic nerve fibers in the liver are distributed along the portal tract, being involved in the regulation of blood flow, bile secretion and hepatic metabolism, thus contributing to systemic homeostasis. The present study investigated changes in hepatic nerve fibers in liver biopsy specimens from patients with normal liver, viral hepatitis and non-alcoholic steatohepatitis, in relation to clinical background. The areal ratio of nerve fibers to the total portal area was automatically calculated for each sample. The nerve fiber areal ratios (NFAR) for total nerve fibers and sympathetic nerve fibers were significantly lower in liver affected by chronic hepatitis, particularly viral hepatitis, and this was also the case for advanced liver fibrosis. However, the degree of inflammatory activity did not affect NFAR for either whole nerves or sympathetic nerves. Comparison of samples obtained before and after antiviral treatment for HCV demonstrated recovery of NFAR along with improvement of liver fibrosis. [ABSTRACT FROM AUTHOR]

In recent years, the development of diagnostics using artificial intelligence (AI) has been remarkable. AI algorithms can go beyond human reasoning and build diagnostic models from a number of complex combinations. Using next-generation sequencing technology, we identified hepatitis C virus (HCV) variants resistant to directing-acting antivirals (DAA) by whole genome sequencing of full-length HCV genomes, and applied these variants to various machine-learning algorithms to evaluate a preliminary predictive model. HCV genomic RNA was extracted from serum from 173 patients (109 with subsequent sustained virological response [SVR] and 64 without) before DAA treatment. HCV genomes from the 109 SVR and 64 non-SVR patients were randomly divided into a training data set (57 SVR and 29 non-SVR) and a validation-data set (52 SVR and 35 non-SVR). The training data set was subject to nine machine-learning algorithms selected to identify the optimized combination of functional variants in relation to SVR status following DAA therapy. Subsequently, the prediction model was tested by the validation-data set. The most accurate learning method was the support vector machine (SVM) algorithm (validation accuracy, 0.95; kappa statistic, 0.90; F-value, 0.94). The second-most accurate learning algorithm was Multi-layer perceptron. Unfortunately, Decision Tree, and Naive Bayes algorithms could not be fitted with our data set due to low accuracy (< 0.8). Conclusively, with an accuracy rate of 95.4% in the generalization performance evaluation, SVM was identified as the best algorithm. Analytical methods based on genomic analysis and the construction of a predictive model by machine-learning may be applicable to the selection of the optimal treatment for other viral infections and cancer. [ABSTRACT FROM AUTHOR]

Hepatitis B virus (HBV) genotypes B (HBV/B) and C (HBV/C) are the most prevalent genotypes among Japanese patients with hepatitis. Reportedly, HBV/C infection has been associated with more severe disease progression, manifesting as developing cirrhosis and hepatocellular carcinoma (HCC), than HBV/B infection. However, no long‐term studies have examined the development of HCC in HBV/B‐infected patients in Japan. The aims of our study were to compare the incidence of HCC in HBV/B‐ or HBV/C‐infected patients. A total of 241 patients were followed up among 295 hepatitis B surface antigen (HBsAg)‐positive carriers. Genotypes of HBV were A in 1% (4/295), B in 61% (179/295), C in 37% (110/295) and D in 1% (2/295) patients, and 96% of HBV/B were infected with subgenotype Bj. The mean age at HCC diagnosis was significantly higher in HBV/B than in HBV/C (67.0 ± 10.0 vs 57.7 ± 8.0 years, P < 0.001). The value of FIB‐4 index was significantly higher in HBV/B than in HBV/C (P < 0.01). The rate of HCC was higher in HBV/C than in HBV/B, and a significant difference was observed until the 20‐year observation period (P = 0.048). However, thereafter, HCC associated with HBV/B increased, and no significant difference was observed between HBV/B and HBV/C. HCC development was consistently observed even in HBV/B infection, especially among elderly patients with advanced fibrosis compared with HBV/C. HBV/B‐infected patients developed HCC later in life, and in the long term, we found no differences in incidence of HCC development rates between these two genotypes. [ABSTRACT FROM AUTHOR]

Aim The number of Japanese patients with anorexia nervosa ( AN) is increasing as society changes. Mild liver injury is a complication of AN in around 30% of cases. In some rare instances, patients present with severe liver injury similar to acute liver failure. However, there are numerous uncertainties over the clinical characteristics of this condition. The objective of the present study was to clarify the clinical characteristics of AN complicated by liver injury and to investigate the factors related to hepatic complications. Methods Thirty-seven patients hospitalized at our institution with a diagnosis of AN were enrolled as the study subjects. The study used clinical data obtained at the time of hospitalization. The enrolled patients underwent subgroup analysis and were categorized into three groups: (i) normal alanine aminotransferase ( ALT), (ii) moderately elevated ALT, and (iii) highly elevated ALT. Results All of the study subjects were female with a median age of 24 years and presenting with marked weight loss (mean body mass index, 13 kg/m2). Thirteen of the subjects had liver injury. We found that patients in the highly elevated ALT group had a significantly high blood urea nitrogen ( BUN)/creatinine ratio, and a low blood sugar level. Conclusions Our present findings indicate that AN patients with highly elevated ALT have a severe dehydration. This suggests that dysfunction of hepatic circulation accompanying severe dehydration due to malnutrition may be an important factor in the development of liver injury in AN patients. [ABSTRACT FROM AUTHOR]

Chronic active Epstein−Barr virus infection (CAEBV) can be manifested in a variety of systemic conditions, including interstitial pneumonia, malignant lymphoma, and coronary aneurysm. Sometimes it may be associated with hepatic failure, although the mechanism underlying CAEBV-related hepatotoxicity remains unclear. We encountered a case of autoimmune hepatitis (AIH) associated with CAEBV. A 61-year-old male was referred to our hospital because of abnormal liver enzyme levels after initial diagnosis of CAEBV had been made by laboratory tests and liver biopsy. On admission, positivity for anti-nuclear antibody was evident, and examination of the liver biopsy specimen showed findings compatible with AIH. Steroid administration was initiated, and the liver function parameters subsequently improved. Although phenotypic changes in liver biopsy specimens are rare in this condition, the present case could provide clues to the possible pathogenesis of AIH. [ABSTRACT FROM AUTHOR]

Background: Hepatic steatosis is often seen in patients with chronic hepatitis C (CH-C). It is still unclear whether these patients have an impaired mitochondrial β-oxidation. In this study we assessed mitochondrial β-oxidation in CH-C patients by investigating ketogenesis during fasting.Methods: This study consisted of thirty patients with CH-C. Serum levels of insulin and hepatitis C virus (HCV) core protein were measured by chemiluminescence enzyme immunoassay. The subjects were then fasted, and venous blood samples were drawn 12 h and 15 h after the start of fasting. The levels of blood ketone bodies were measured by an enzymatic cycling method. The rate of change in total ketone body concentration was compared with that in eight healthy volunteers.Results: The rate of change in total ketone body concentration between 12 h and 15 h after the start of fasting was significantly lower in CH-C patients than in healthy volunteers (129.9% (8.5-577.3%) vs. 321.6% (139.6-405.4%); P <0.01). The rate of change in total ketone body concentration in patients with a serum level of HCV core protein of 10000 fmol/L or higher was significantly lower than in patients with a level of less than 10000 fmol/L (54.8% (8.5-304.3%) vs. 153.6% (17.1-577.3%); P <0.05). The rate of change in total ketone body concentration in patients with a homeostasis model assessment of insulin resistance (HOMA-IR) of 2.5 or higher was significantly lower than in patients with a HOMA-IR of less than 2.5 (56.7% (8.5-186.7%) vs. 156.4% (33.3-577.3%); P <0.01).Conclusions: These results suggest that mitochondrial β-oxidation is impaired, possibly due to HCV infection in patients with CH-C. [ABSTRACT FROM AUTHOR]

Prolactin is not only a pituitary hormone but an immunoregulatory hormone secreted from lymphocytes. Prolactin induction in relation to hepatitis C virus (HCV) infection has not been elucidated. The serum levels of prolactin were examined in 232 HCV-infected subjects positive for anti-HCV antibody and 65 healthy controls negative for it, who were recruited in the cohort study. The prolactin mRNAs were measured in peripheral blood mononuclear cells (PBMCs) of eleven healthy volunteers including five men and six women before and after stimulation by HCV in vitro. The serum level of prolactin and prolactin mRNA in PBMCs were measured by chemiluminescence immunoassay and real-time PCR, respectively. The serum levels of prolactin were significantly higher in the HCV-infected subjects (median: 7.5, IQR: 5.7-10.9 ng/ml) than in the controls (median: 5.6, IQR: 4.4-8.3 ng/ml) ( P < 0.01). They were significantly higher in HCV-infected males (median: 8.0, IQR: 5.9-11.8 ng/ml) than in the controls (median: 4.8, IQR: 4.2-5.9 ng/ml) ( P < 0.001), however, the difference was not significant between HCV-infected females (median: 7.3, IQR: 5.6-10.5 ng/ml) and the controls (median: 6.4, IQR: 5.3-9.8 ng/ml). The mRNA expression of prolactin was induced in PBMCs of all males, but it was induced in PBMCs of the two of six females examined in vitro. These results suggest that the serum level of prolactin is higher in HCV-infected males than in healthy males, and that HCV infection induces the mRNA expression of prolactin in PBMCs that is more apparent in male than in females. J. Med. Virol. 85:1199-1205, 2013. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

A 52-year-old man suffering from monocular blindness, with light perception only, was admitted to our hospital. The symptom had begun as low vision and developed rapidly within 3 weeks into monocular blindness in the right eye, with no other systemic manifestations. Imaging examinations revealed multiple hepatocellular carcinomas in the cirrhotic liver, and tumors at the skull base and vertebra. A pathological and immunochemical study of specimens obtained by endoscopic transnasal tumor biopsy and laminectomy revealed them to be metastatic hepatocellular carcinomas (HCCs). Although the patient underwent radiation therapy and chemotherapy, he died 5 months after admission to our hospital. The cranial HCC, involving only the optic canal, may have disturbed the optic nerve in preference to the other cranial nerves. This is the first report of a HCC patient with monocular blindness as the initial presentation of the disease. [ABSTRACT FROM AUTHOR]

We describe a 62-year-old woman with advanced chronic hepatitis C who showed no response to low-dose long-term interferon-beta monotherapy (3 MU, three times a week). The interferon monotherapy was continued for 2 years and 9 months. Despite this lack of response to interferon, the patient's clinical course was good and liver function assessed by Tc-galactosyl human serum albumin single photon emission computed tomography (Tc-GSA SPECT) analysis improved significantly. Improvement of the data obtained by Tc-GSA SPECT analysis justified continuation of the treatment. Tc-GSA SPECT analysis was clinically useful to evaluate the effect of interferon in a patient with interferon non-responsive chronic hepatitis C, despite a lack of reduction of the ALT level and HCV-RNA titer. [ABSTRACT FROM AUTHOR]

The transplantation of bone marrow cells (BMCs) has been applied in liver regenerative cell therapy. However, details of the interaction between the transplanted BMCs and hepatic stem cells have not been elucidated. The aim of the present study was to investigate the interaction of BMCs with hepatic stem-like cells (HSLCs) and to determine the BMC factor that steers HSLC differentiation into the hepatocyte lineage. Both BMCs and HSLCs were obtained from an adult Sprague-Dawley rat, and a co-culture system was established. Cell proliferation was analyzed by a proliferation assay, and the differentiation of HSLCs into the hepatocyte lineage was evaluated by the detection of cellular mRNA for liver-specific proteins. DNA microarray analysis was applied to BMCs co-cultured with HSLCs to determine the genes upregulated by their interaction. The proliferation of HSLCs co-cultured with BMCs was significantly higher than that of HSLCs cultured alone, and the expression of mRNAs for both albumin and tryptophan-2,3-dioxygenase was detectable in the co-cultured HSLCs. DNA microarray analysis showed the upregulated expression of fibroblast growth factor 2 ( FGF2) mRNA in BMCs co-cultured with HSLCs, and the expression of mRNAs for both albumin and tyrosine aminotransferase became detectable in HSLCs cultured with FGF2. Thus, BMCs stimulate both the proliferation of HSLCs and their differentiation into the hepatocyte lineage. FGF2 is one of the factors that is produced by the interacting BMCs and that stimulates this differentiation. [ABSTRACT FROM AUTHOR]

The aim of the study was to identify a predictive marker for the virological response in hepatitis C virus 1b (HCV-1b)-infected patients treated with pegylated interferon plus ribavirin therapy. A total of 139 patients with chronic hepatitis C who received therapy for 48 weeks were enrolled. The secondary structure of the 120 residues of the amino-terminal HCV-1b non-structural region 3 (NS3) deduced from the amino acid sequence was classified into two major groups: A and B. The association between HCV NS3 protein polymorphism and virological response was analyzed in patients infected with group A (n = 28) and B (n = 40) isolates who had good adherence to both pegylated interferon and ribavirin administration (>95% of the scheduled dosage) for 48 weeks. A sustained virological response (SVR) representing successful HCV eradication occurred in 33 (49%) in the 68 patients. Of the 28 patients infected with the group A isolate, 18 (64%) were SVR, whereas of the 40 patients infected with the group B isolate only 15 (38%) were SVR. The proportion of virological responses differed significantly between the two groups ( P < 0.05). These results suggest that polymorphism in the secondary structure of the HCV-1b NS3 amino-terminal region influences the virological response to pegylated interferon plus ribavirin therapy, and that virus grouping based on this polymorphism can contribute to prediction of the outcome of this therapy. J. Med. Virol. 82:1364-1370, 2010. © 2010 Wiley-Liss, Inc. [ABSTRACT FROM AUTHOR]

Aim: Musashi1 is an RNA-binding protein that regulates the Notch signaling pathway in stem cells. Our previous study revealed that Musashi1 is expressed in early hepatocytes during liver development in the mouse. However, whether this unique protein is expressed with Notch signaling markers in adult liver stem-like cells remains unknown. Methods: Established hepatic stem-like cells (HSLC), which were derived from adult Sprague–Dawley rats, were used for experiments in vitro. HSLC were differentiated into mature cells in terms of producing albumin when co-cultured with epidermal growth factor (EGF). The mRNA expression of Musashi1, Notch family ( Notch1 and Notch2), Jagged1 and Hes1 was examined in HSLC before and after cell differentiation using polymerase chain reaction-based techniques. Protein expression of Musashi1 was examined in the HSLC and normal mature hepatocytes by immunofluorescence staining. Results: The mRNA expression of Musashi1, Notch1, Jagged1 and Hes1 was detected in the original HSLC before culturing with EGF but not in primary cultured mature hepatocytes. The mRNA expression of Musashi1 and Hes1 was found to be downregulated in differentiated HSLC that produce albumin. Protein expression of Musashi1 was detectable in the original HSLC but not in both differentiated HSLC and mature hepatocytes. Conclusion: These findings demonstrate that the RNA-binding protein Musashi1 is expressed with Notch signaling markers in adult liver stem-like cells. [ABSTRACT FROM AUTHOR]

Background and Aim: Hematopoietic growth factors including stem cell factor (SCF), thrombopoietin (TPO) and granulocyte colony stimulating factor (G-CSF) have a potential role in inducing bone marrow hematopoietic stem cells to move into the circulation, and the association of these factors with liver regeneration has received a lot of attention recently. The aim of this study was to determine the serum levels of such factors in patients with acute liver injury. Methods: The subjects were 25 patients with acute hepatitis (AH) who had a favorable prognosis and 26 patients with fulminant hepatitis (FH), of whom 11 were alive and 15 had died. Sixty-six healthy subjects matched for age and sex served as controls. Serum samples were collected before treatment, and the levels of SCF, TPO and G-CSF were measured using enzyme-linked immunosorbant assays. Results: The levels of SCF and TPO were significantly lower in FH patients than in AH patients and the controls, and were also significantly lower in the FH patients who died, compared to the surviving patients. The G-CSF levels did not differ among them. Conclusions: These results suggest that low serum levels of SCF and TPO may be linked to poor prognosis in patients with severe liver injury. [ABSTRACT FROM AUTHOR]

Abstract: The asialoglycoprotein receptor (ASGPR) is abundantly expressed on the sinusoidal surfaces of hepatocytes. However, regional expression and clinical significance of the ASGPR in acute hepatic damage is presently unknown. Our aim was to clarify the clinical significance of the regional expression of ASGPR in human livers with acute hepatitis (AH) and fulminant hepatic failure (FHF). Eighteen volunteers, 42 patients with AH and 10 with FHF were studied using a newly developed, conventional 99mTc-GSA SPECT analysis. Using Cantlie''s line as a guide, ASGPR expression was analyzed separately in the right and left hepatic lobes, as well as in the whole liver, using novel indices (the liver uptake ratio [LUR] and liver uptake density [LUD], which reflect the amount and density of ASGPRs in the liver, respectively). Mean LUR and LUD values for the whole liver and the right and left lobes decreased in accordance with the severity of acute hepatic damage. In the FHF group, the reduction in LUR and LUD values in the right lobes was more significant than in the left lobes. The LUR and LUD values for the whole liver correlated well with hepatic functional reserve and total bilirubin levels. The right LUR and LUD values in particular correlated well with these parameters. A time-course observation of 13 patients with either AH or FHF revealed that the expression of ASGPRs in the right lobe recovered faster than in the left. We first evaluated the regional expression of AGSPRs by 99mTc-GSA SPECT analysis in both AH and FHF patients, which is a clinically useful and reliable indicator for assessing the severity of regional hepatic damage and evaluating regional liver regeneration. [Copyright &y& Elsevier]

Background. Bone marrow cells (BMCs) have been shown to differentiate into a liver cell lineage, but little is known about their dynamics following transplantation. BMCs were cultured to investigate the expression of liver-specific genes in vitro and transplanted into in vivo liver-injury models to elucidate their dynamics in the liver. Methods. The mRNA expression of various liver-specific genes in BMCs cocultured with hepatocytes was analyzed using reverse transcription-polymerase chain reaction. BMCs from transgenic rats expressing green fluorescent protein were transplanted into the spleen of rat liver-injury models induced with 2-acetylaminofluorene (2-AAF) or carbon tetrachloride (CCl4). BMCs were also transplanted directly into livers treated with CCl4 to determine which route is better for transplantation. Results. BMCs differentiated into a liver cell lineage in vitro and expressed mRNAs consistent with mature hepatocytes, including albumin. The transplanted BMCs were found in the liver in the CCl4-induced injury model, but not in the 2-AAF-induced model. The hepatocyte growth factor and fibroblast growth factor mRNA levels in the liver were significantly higher in the CCl4-induced model than in the 2-AAF-induced model. Migration of BMCs to the liver was more effective following injection into the liver, rather than into the spleen. Conclusions. Cultured BMCs differentiated into a liver cell lineage are a potential source for cell transplantation. Transplantation is successful in the severely injured liver with a high level of expression of mRNAs for growth factors. Injection of BMCs directly into the liver is the preferred route of administration. [ABSTRACT FROM AUTHOR]

Abstract: Notch signalling pathway plays an important role in cell differentiation. To investigate the implications of Notch signalling in the differentiation of rat bone marrow (BM) cells into a liver cell lineage, we used cultured BM cells to examine the mRNA expression of Musashi-1, which positively regulates Notch signalling, and made a transplant model to examine the protein expression of Notch signalling markers. For the in vivo experiment, BM cells were collected from transgenic rats expressing green fluorescence protein (GFP) and transplanted into the spleens of recipient rats, in which liver damage had been induced with carbon tetrachloride. The expression of Notch receptor 1 (Notch-1), Jagged-1 and Musashi-1, in the transplanted GFP-positive BM cells was investigated by immunohistochemistry. The expression of the liver-specific proteins, alpha-fetoprotein and cytokeratin19 was also investigated. Musashi-1 mRNA became detectable in the BM cells on culture day 7 in vitro. After transplantation, GFP-positive BM cells were observed in the portal areas of the recipient''s livers. Notch-1, Jagged-1, Musashi-1, alpha-fetoprotein and cytokeratin19 were all expressed in the transplanted BM cells. These results suggest that the Notch signalling pathway plays a role in the differentiation of BM cells into a liver cell lineage. [Copyright &y& Elsevier]

To elucidate how hepatitis C virus (HCV) with multiple variants (quasispecies) is transmitted and adapts to the host during infection, we compared nucleotide and deduced amino acid sequences from hypervariable region1 (HVR1) of the E2 gene of HCV between a donor and a recipient who developed hepatitis after a needlestick accident. Thirty clones from each subject were sequenced after PCR amplification, cloning, and purification of plasmid DNA from single colonies of transformed bacteria. Genetic analysis revealed that the recipient''s viral sequences were much less diverse than the donor''s. We found a single predominant HCV HVR1 clone of the recipient in 22/30 isolates with the same amino acid sequence, and mimic clones in 8/30 isolates with only one amino acid substitution. These were all absent in the donor, who had 21 highly diverse sequences. Phylogenetic analysis of virus E1/E2 gene sequences showed that the recipient''s unique sequences were related to the population of variants from the donor, in whom one isolate had 96% similarity to the recipient''s predominant amino acid sequence. These results suggest that a minor subset of the donor''s HCV variants is selectively transmitted to the recipient, and that the selection determines the predominant variant in the new host. [Copyright &y& Elsevier]

Okumoto K, Hattori E, Tamura K, Kiso S, Watanabe H, Saito K, Saito T, Togashi H, Kawata S. Possible contribution of circulating transforming growth factor-β1 to immunity and prognosis in unresectable hepatocellular carcinoma. Liver International 2004: 24: 21–28. © Blackwell Munksgaard, 2004 Transforming growth factor-β1 (TGF-β1) has been implicated in tumor progression. The relationship of this cytokine as measured in plasma to anti-tumor immunity and prognosis was investigated. This study consisted of 70 consecutive patients with unresectable hepatocellular carcinoma (HCC) (median age, 65 years). Forty-four healthy age-matched subjects and 32 patients with cirrhosis but no carcinoma served as controls. Patients with HCC were divided into those with plasma TGF-β1 concentrations above (group A, n=21) or below (group B, n=49) 10 ng/ml (the mean concentration+2SD in the concentrations of the controls with cirrhosis was 8.7 ng/ml). Age, gender, Child-Pugh grade, and tumor stage distributions were similar in groups A and B. Considering all tumor stages together and individually, group A had a significantly shorter survival (median for all stages, 2 months) than group B (median for all stages, 10 months; P<0.01, generalized Wilcoxon's test). Groups A and B had significantly shorter survival than controls with cirrhosis ( P<0.001 for each). Lymphokine-activated killer (LAK) activity in group A was significantly lower than that in group B ( P<0.001). Natural killer (NK) activity in group A was also significantly lower than that in group B ( P<0.05). Plasma TGF-β1 concentration was a significant predictor of survival by Cox's proportional-hazards regression analysis (multivariate analysis, P<0.01). LAK and NK activities were also weak but significant predictors ( P<0.05 and <0.05, respectively). These data suggest that plasma TGF-β1 concentration is a predictor of outcome of patients with unresectable HCC. Circulating TGF-β1 supposedly contributes to the suppression of anti-tumor immunity in the advanced disease. [ABSTRACT FROM AUTHOR]

Objectives: Interleukin-10 (IL-10) has been implicated in immune deficiency in patients with cancer. The relationship of this cytokine as measured in serum to anti-tumor immunity and prognosis was investigated in unresectable hepatocellular carcinoma. Methods: This study consisted of 74 consecutive patients with unresectable hepatocellular carcinoma (median age, 65 years). Forty-four healthy age-matched subjects and 32 patients with cirrhosis but no carcinoma served as controls. Patients with hepatocellular carcinoma were divided into those with serum IL-10 concentrations above (high group, n=39) or below (low group, n=35) 10 pg/ml. Results: Age, gender, Child–Pugh grade, and tumor stage distributions were similar in high and low groups. The patients of high group showed lower in lymphokine-activated killer (LAK) and natural killer (NK) activities than those of low group (P<0.01 and 0.01, respectively). Serum IL-10 concentration was a significant factor contributing to low activities of LAK and NK by logistic regression analysis (P<0.05 and 0.05, respectively). The high group had a significantly shorter survival (median, 3 months) than low group (median, 12 months; P<0.02, generalized Wilcoxon test). Conclusions: These data suggest that serum IL-10 concentration is a possible factor contributing to poor prognosis and low anti-tumor immunity in patients with unresectable hepatocellular carcinoma. [Copyright &y& Elsevier]

The article presents a letter to the editor about percutaneous radiofrequency ablation of adrenal metastasis from hepatocellular carcinoma.