Effectiveness of triple therapy with simeprevir for chronic hepatitis C genotype 1b patients with prior telaprevir failure.

Favourable efficacy and safety profiles for simeprevir in combination with pegylated interferon alpha (PEG-IFNα) and ribavirin (triple therapy) have been shown in clinical trials. This study was carried out to evaluate the effectiveness of simeprevir-based triple therapy for patients with prior telaprevir treatment failure. This multicentre, observational cohort consisted of 345 consecutive Japanese patients infected with HCV genotype 1b, including 20 who had experienced telaprevir-based triple therapy. Amino acid substitutions in the NS3/4A region were identified by direct sequencing at the time of relapse or breakthrough in treatment with telaprevir and at the initiation of treatment with simeprevir. Patients were stratified according to prior response to PEG-IFNα and ribavirin. Of the 20 patients with telaprevir treatment failure, 10 (50.0%) achieved sustained virological response at week 12 after the end of treatment (SVR12). For patients treatment naïve [3/4 (75.0%)] or with prior relapse [1/1 (100%)] or partial response [5/6 (83.3%)] to PEG-IFNα and ribavirin, almost all achieved SVR12, mainly because of the improvement of treatment adherence, especially to direct-acting antiviral agent and ribavirin. However, of the nine patients with prior null response to PEG-IFNα and ribavirin, only one (11.1%) achieved SVR12, despite all having received an adequate treatment dosage, and five (55.6%) achieved rapid virological response. The treatment outcome of simeprevir-based triple therapy for HCV genotype 1b patients with prior telaprevir failure depended on the prior response to PEG-IFNα and ribavirin. For patients with prior null response to PEG-IFNα and ribavirin, retreatment with simeprevir-based triple therapy is not a useful option.

Short-term risk of hepatocellular carcinoma after hepatitis C virus eradication following direct-acting anti-viral treatment.

BACKGROUND: With the development of direct-acting anti-virals (DAAs), almost all patients with chronic hepatitis C virus (HCV) infection can achieve sustained viral response (SVR). AIM: To evaluate the short-term risk of HCC among patients with SVR by DAAs, including those with cirrhosis or previous HCC. METHODS: This large-scale, multicentre cohort study included 1,675 consecutive patients who achieved SVR by treatment with interferon-free sofosbuvir-based regimens, divided into groups with (n = 152) or without previous HCC (n = 1,523). The Kaplan-Meier method and Cox proportional hazard analysis were used to calculate the cumulative HCC incidence and related factors of HCC. RESULTS: During the follow-up period (median: 17 months), 46 (2.7%) patients developed HCC. The 1-year cumulative rates of de novo HCC were 0.4% and 4.9% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P < 0.001). For cirrhotic patients, serum α-fetoprotein level at the end of treatment (EOT-AFP) was the strongest predictor of de novo HCC. The 1-year cumulative de novo HCC rates were 1.4% and 13.1% in the EOT-AFP < 9.0 ng/mL and ≥ 9.0 ng/mL groups (cut-off value) respectively (log-rank test: P < 0.001). The 1-year cumulative rates of HCC recurrence were 6.5% and 23.1% for the noncirrhosis and cirrhosis groups respectively (log-rank test: P = 0.023). For cirrhotic patients, previous HCC characteristics were significantly associated with HCC recurrence. In contrast, sex, age and metabolic features did not influence de novo HCC or recurrence. CONCLUSIONS: For cirrhotic patients after elimination of HCV, serum EOT-AFP level and previous HCC characteristics would be useful markers for predicting de novo HCC or recurrence.

Interleukin-12 receptor/STAT4 signaling is required for the development of autoimmune myocarditis in mice by an interferon-gamma-independent pathway.

BACKGROUND: Interleukin (IL)-12 exerts a potent proinflammatory effect by stimulating T-helper (Th) 1 responses. This effect is believed to be mediated primarily through the activation of STAT4 and subsequent production of interferon (IFN)-gamma. Methods and Results- We examined the role of IL-12 receptor (IL-12R) signaling in the development of murine experimental autoimmune myocarditis (EAM) induced by cardiac myosin immunization. Both IL-12Rbeta1-deficient mice and STAT4-deficient mice were resistant to the induction of myocarditis. Treatment with exogenous IL-12 exacerbated disease. We questioned whether IFN-gamma is required for the disease-promoting activity of IL-12. On the contrary, we found that IFN-gamma suppresses EAM. Lack of IFN-gamma due to either depletion with an antibody or a genetic deficiency exacerbated myocarditis. Spleens from IFN-gamma-deficient mice immunized with cardiac myosin showed increased cellularity; greater numbers of CD3+, CD4+, CD8+, and IL-2-producing cells; and heightened ability to produce cytokines on stimulation in vitro. Treatment of mice with recombinant IFN-gamma suppressed the development of myocarditis. CONCLUSIONS: IL-12/IL-12R/STAT4 signaling promotes the development of EAM. In contrast, IFN-gamma plays a protective role. The disease-limiting effects of IFN-gamma might be explained by its ability to control the expansion of activated T lymphocytes.

Ultrasound evaluation of the fibrosis stage in chronic liver disease by the simultaneous use of low and high frequency probes.

A liver biopsy is currently considered the definitive diagnostic modality for establishing the severity of hepatic fibrosis. We analysed the diagnostic sensitivity and accuracy of ultrasound (US) using both low frequency and high frequency probes as a repeatable, inexpensive, and reliable method to determine the fibrosis stage in chronic liver disease and then compared our results with the histological findings. A total of 103 patients with chronic liver disease (60 males and 43 females, average age 51 years old) who had undergone both a liver biopsy and US with 2-5 MHz frequency and 5-12 MHz frequency probes were prospectively evaluated in this study. An US scoring system using both the low frequency and high frequency probes was performed by evaluating the edge, surface and parenchymal texture of the liver. Each score was obtained by evaluating three parameters; the bluntness of the liver edge, the irregularity of the surface and the coarseness of the parenchymal texture were evaluated and then compared with the histological findings. The US scores of the liver edge (rs: 0.6668), liver surface (rs: 0.9007) and liver parenchymal texture (rs: 0.8853) correlated significantly with the fibrosis stage obtained based on the biopsy findings. The accumulated US scores of these three parameters, however, was found to be the most reliable indicator (rs: 0.9524). Patients with an accumulated score of 6.5 or more were all found to have fibrosis stage 4 in which the accuracy of our scoring system for correctly predicting cirrhosis was found to be 100% sensitive. When an accumulated US score of 3 was interpreted to indicate mild fibrosis (a fibrosis score of 0 or 1), all 42 patients with stage 0 or 1 fibrosis were found to have an accumulated US score of 3 or less (a probability of 100%) and 42 of 53 patients with a score of 3 or less were found to have stage 0 or 1 fibrosis (specificity of 79.2%). An ultrasound evaluation of the liver fibrosis stage based on the scoring system using both low and high frequency probes was found to be a reliable and effective alternative to the histological staging in chronic liver diseases.

Expression Pattern of Mitochondrial ND2 Gene in Human Leukemia and in HL60 Cells During Growth and Differentiation.

We differentially screened 5,000 clones from a cDNA library of acute myelogenous leukemia (AML) cell line HL60 using cDNA probes derived from normal granulocytes or from acute myelomonocytic leukemia cells, the objective being to identify genes preferentially expressed in myeloid lineage leukemic cells. One clone, corresponding to a mitochondrial DNA fragment, including NADH dehydrogenase subunit 2 (ND2) gene, was selected for use as a probe. We examined expression of the ND2 gene in various leukemic cell populations and in normal peripheral blood cells. DNA-RNA hybridization studies revealed that ND2 messenger RNA (mRNA) was more markedly expressed in AML cells than in other leukemic cells and normal peripheral blood granulocytes. The expression of ND2 mRNA decreased in HL60 cells several hours after treatment with phorbol myristate acetate (PMA), or dimethyl sulfoxide (DMSO). However, the ND2 gene expression did not depend on the growth-state of HL60 cells because the steady-state level of its expression was observed during transitions of growth. These results suggest that ND2 mRNA is involved in the maturation of myeloid cells and in cellular differentiation, in a lineage-preferential manner. A comparison of the nucleotide sequence of this clone with the documented human mitochondrial DNA sequence revealed several single-base substitutions, insertions and a 39-bases insertion.

Rotenone, a mitochondrial NADH dehydrogenase inhibitor, induces cell surface expression of CD13 and CD38 and apoptosis in HL-60 cells.

We previously demonstrated that the mitochondrial NADH dehydrogenase subunit 2 (ND2) gene was overexpressed in human acute myelogenous leukemia (AML) cells. Since this finding suggested that ND2 gene expression was related to myeloid differentiation, we here investigated the effects of rotenone, a specific NADH dehydrogenase inhibitor, on HL-60 cell growth, differentiation and death. Fifty nM rotenone inhibited the growth of HL-60 cells and caused an increase in the cell population in the G(2) +M phase. In the quantitative comparison of myeloid antigen, the expression of CD13 and CD38 were relatively increased in the rotenone-treated cells. These findings suggest that the inhibition of NADH dehydrogenase changes the cell cycle and induces some specific surface antigens of HL-60 cells. On the other hand, the expression of ND2 gene remained unchanged after the rotenone treatment, suggesting the rotenone-mediated mitochondrial inhibition did not affect the mitochondrial gene expression. Five mu M rotenone strongly inhibited the cellular proliferation. Electron microscopy and an electrophoretic analysis of DNA showed that the majority of the HL-60 cells were induced into typical apoptosis within 24-48 hours. On the basis of this and other studies, we believe that mitochondrial function is directly involved in both cellular differentiation and apoptotic cell death.

Manifestation of cutaneous polyarteritis nodosa during interferon therapy for chronic hepatitis C associated with primary biliary cirrhosis.

Interferon alpha-2b was administered to a 50-year-old Japanese woman with chronic hepatitis C associated with primary biliary cirrhosis. Two months after the beginning of the interferon alpha-2b therapy a systemic nodular, erythematous rash developed. Histological analysis of the skin revealed typical features of necrotizing arteritis. Because there was no microhematuria, and no microaneurysms were detected on abdominal angiography, a diagnosis of cutaneous polyarteritis nodosa was made. A good outcome was achieved after interferon alpha-2b was discontinued and prednisolone was administered instead. The cutaneous polyarteritis nodosa in this patient is thus considered to have occurred as an adverse effect of interferon administration. To our knowledge, this is the first reported case of cutaneous polyarteritis nodosa which developed because of interferon therapy for chronic hepatitis C associated with primary biliary cirrhosis.

Post-infantile giant cell hepatitis in an elderly female patient with systemic lupus erythematosus.

A 69-year-old Japanese female was admitted because of general fatigue. Laboratory data showed elevation of serum total bilirubin, transaminase, gamma-glutamyl transpeptidase, and creatinine levels. An immunological study revealed hypergammaglobulinemia, low titer of complement, and high titers of antinuclear antibody, anti-DNA antibody, and circulating immune complexes. Antibodies to parainfluenza virus 3 were positive. Histology of the liver disclosed numerous giant cell hepatocyte transformations with the lobular architecture being slightly distorted by portal inflammation and fibrosis. These findings led us to make a diagnosis of giant cell hepatitis associated with systemic lupus erythematosus. Prednisolone was effective in improving the anemia and the serum immunoglobulin, immune complex, and antinuclear antibody levels. The addition of cyclosporine to the initial corticosteroid therapy was also beneficial in decreasing the transaminase level and in improving liver histology. The patient died of acute pneumonitis and renal failure on the 166th day after admission. Parainfluenza virus 3 and autoimmune mechanisms were thus considered to be the causes of the giant cell hepatitis.

Differences in survival based on the type of follow-up for the detection of hepatocellular carcinoma: an analysis of 547 patients.

The aim of this study was to identify any significant variables in the prognosis of 547 cases with hepatocellular carcinoma (HCC), and simultaneously confirm the survival among the different surveillance modalities for the initial detection of HCC in a closely followed-up group (regular periodic follow-up with monthly alpha-fetoprotein (AFP) and ultrasonography at least every 4 months), a not closely followed-up group (neither performed with AFP nor ultrasonography regularly) and an incidental group (incidentally discovered due to related symptoms). Five hundred and forty-seven consecutive patients with HCC diagnosed at the Internal Medicine Department of Saga Prefectural Hospital Koseikan from January 1989 to December 1998 were retrospectively analyzed. The 1-, 3- and 5-year survivals in all 547 cases were 69.7, 42.4 and 26.9%, respectively. The 1-, 3- and 5-year survivals in the cases found to have solitary HCC measuring 2 cm or less in diameter at the time of diagnosis were 97.3, 76.2 and 52.3%, respectively. Forty-seven point one percent of the closely followed-up group, which was the high-risk group were found to have solitary HCC measuring 2 cm or less in diameter (48 out of the 102 followed-up cases), while only 18.5 and 11.8% were found in the not closely followed-up group (46 out of 248 cases) and the incidental group (22 out of 186 cases), respectively. The 5-year survival in the closely followed-up, the not closely followed-up and the incidental groups were 42.9, 26.1 and 15.3%, respectively. The significant factors obtained in the closely followed-up group compared to those from the not closely followed-up group included AFP, tumor size, tumor number and portal thrombosis. These findings indicate the importance of a close follow-up for high-risk groups in order to identify HCC at an early stage, and thereby have a positive influence on survival.

Colour Doppler ultrasound for the evaluation of bowel wall thickening.

We performed colour Doppler ultrasound to evaluate bowel wall thickening and to determine the effectiveness of this modality. 42 patients (aged 8-83 years old, mean age 43.5 years) with bowel disease underwent both grey scale and colour Doppler ultrasound examinations. The diagnoses were classified into three categories: inflammation, vasculitis or ischaemia. The bowel wall thickness, wall echotexture and location of the involved portion were all recorded by grey scale ultrasound, while the presence of an intramural colour Doppler flow and arterial signal was evaluated by colour Doppler ultrasound. The colour Doppler flow was graded as "absent", "mild", or "abundant", and the resistive index was also calculated. Bowel wall thickening was observed in the bowel diseases demonstrating inflammation, vasculitis and ischaemia. Patients with ischaemia were significantly older than those with inflammation. The difference in bowel wall thickness was not significant among the disease categories. Differences in bowel wall echotexture, colour Doppler flow, arterial signal and resistive index among the disease categories were significant. The absence of a colour Doppler flow and of an arterial signal suggested ischaemia, while in younger patients, an abundant colour Doppler flow and a stratified echotexture suggested inflammation. The mean resistive index in the ischemic group was significantly higher than that in the inflammatory group. In conclusion, both grey scale and colour Doppler ultrasound are considered to provide useful information for evaluating and differentiating bowel wall thickening in various bowel diseases.

The value of colour Doppler ultrasonography for small bowel involvement of adult Henoch-Schönlein purpura.

Three patients presented with a non-thrombocytopenic purpuric rash on their upper and lower limbs, abdominal pain, diarrhoea, and arthralgia. Grey scale ultrasound showed abnormally thickened walls of the small bowel. Colour Doppler showed blood flow signals in the diseased bowel wall in all patients. Subsequent barium and endoscopic studies showed oedematous bowel loops with petechial lesions. Biopsy from the purpuric rash of the skin demonstrated vasculitis of subdermal small vessels. The clinical diagnosis of Henoch-Schönlein purpura was made in each case. This paper describes the efficacy of grey scale and colour Doppler ultrasonography in the assessment of the small bowel involvement of Henoch-Schönlein purpura.

Transcatheter arterial chemoembolization therapy combined with percutaneous ethanol injection for unresectable large hepatocellular carcinoma: an evaluation of the local therapeutic effect and survival rate.

BACKGROUND/AIMS: This study was undertaken to evaluate the effectiveness of combination therapy with transcatheter arterial chemoembolization followed by percutaneous ethanol injection in patients with unresectable large hepatocellular carcinoma by comparing the use of this combined regimen with transcatheter arterial chemoembolization alone. METHODOLOGY: Six hundred and thirty-one consecutive patients with hepatocellular carcinoma lesions observed from Jan 1989 to Dec 1999 (11 years) at the Internal Medicine Department, Saga Prefectural Hospital Koseikan were retrospectively enrolled in the study. The series included 120 patients with large unresectable hepatocellular carcinoma lesions, the largest of which were greater than 3 cm in largest dimension. Fifty-two patients underwent a single transcatheter arterial chemoembolization followed by percutaneous ethanol injection, which were compared with 68 patients treated by transcatheter arterial chemoembolization alone. Both groups of patients with hepatocellular carcinoma did not differ regarding the base-line characteristics. The overall survival rates and recurrence ratio of initially treated lesions were compared in both groups. RESULTS: On overall survival rates by the Kaplan-Meier method, three- and five-year survival in the transcatheter arterial chemoembolization and percutaneous ethanol injection group (59.0%, 32.1%) proved to be significantly longer than those in the transcatheter arterial chemoembolization group (27.1%, 17.0%). In addition, during the follow-up local recurrence in the combination group (23.1%) was significantly lower than that in the transcatheter arterial chemoembolization group (50.0%). CONCLUSIONS: The combined treatment with transcatheter arterial chemoembolization and percutaneous ethanol injection proved to be more effective and safer. Furthermore, a lower incidence of local recurrence was observed than transcatheter arterial chemoembolization alone which resulted in an increased survival of the patients associated with unresectable large hepatocellular carcinoma lesions.

Sibling cases of primary biliary cirrhosis associated with polymyositis, vasculitis and Hashimoto's thyroiditis.

Primary biliary cirrhosis (PBC) was diagnosed in two siblings, a 42-year-old male and his 49-year-old sister. Furthermore, they were complicated with three types of autoimmune diseases: polymyositis, Hashimoto's thyroiditis and vasculitis of the right axillary artery. Although PBC is often associated with other autoimmune diseases, reports of the association with polymyositis and vasculitis syndrome are rare. Familial clustering of PBC with autoimmune diseases is also rare.

[Effectively treated hypertension with minocycline hydrochloride infusion into the cyst in a patient with a multi-septated massive hepatic cyst].

We present a successfully treated case of a multi-septated massive hepatic cyst with repeated injection of minocycline hydrochloride (MINO). A 57-year-old Japanese female complaining of right back pain, hypochondralgia and hypertension had a multi-septated massive hepatic cyst, 25 cm in diameter. Multiple cysts of various sizes were also seen in liver and kidneys. In order to reduce the size of the massive hepatic cyst to relieve the complaints, we performed the reduction therapy of the cyst. After a pig tail catheter was inserted into the cyst, the cystic fluid was aspirated and then a total of 3900 mg of MINO was injected. Red-brownish, serous cystic fluids were obtained. Cytology and bacterial culture were negative, but the LDH (3, 336 IU/l) and CA19-9 (751,500 U/l) concentrations were very high. After the 9 series of the therapy, the cyst was minified on CT and the patient's symptoms were relieved. Furthermore high blood pressure was improved. Thus, the therapy of size-reduction for a massive hepatic cyst is revealed to be very safe and useful.

IgG-kappa type multiple myeloma in alcoholic cirrhosis--a case report.

Transition from polyclonal to monoclonal gammopathy resulted in myeloma in the course of cirrhosis is rare but of interest. We treated such a case of multiple myeloma of IgG-kappa type associated with alcoholic cirrhosis. The case was a 72-year-old Japanese male patient who was admitted because of ascites and edema. Physical examination and laboratory findings including liver histology were compatible with alcoholic cirrhosis. Serum electrophoresis revealed monoclonal hypergammaglobulinemia of IgG-kappa. Bence Jones protein in urine was positive. Bone scintigraphy and roentgenography revealed small punched out lesions in the skull. A bone marrow clot section showed marked infiltration of atypical plasma cells. From these findings multiple myeloma associated with alcoholic cirrhosis was diagnosed. On the basis of a review of the reported cases, the possible relationship between monoclonal gammopathy and chronic liver diseases was discussed.

[A case of Fitz-Hugh-Curtis syndrome confirmed by laparoscopy].

A 25-year-old Japanese female was admitted to the Department of Surgery in Kyushu Koseinenkin Hospital because of serious right hypochondralgia. Gastrofiberscopy, abdominal ultrasonography, intravenous pyelography and irrigoscopy did not reveal the origin of the pain, and she was introduced to the Department of Internal Medicine. Because enzyme immunoassay of the uterine cervical specimen in the Department of Urology showed positive chlamydial antigen, we suspected her of perihepatitis induced by Chlamydia trachomatis (Fitz-Hugh-Curtis syndrome). Laparoscopy revealed typical violin string adhesions between the anterior surface of the liver and the corresponding parietal peritoneum, and the diagnosis was confirmed. After an administration of Ofloxacin was started, the symptom disappeared completely. It is considered to be important to remember this syndrome when examining a young women with right hypochondralgia.

Primary papillary adenocarcinoma in the third portion of the duodenum.

We herein report a rare case of papillary adenocarcinoma which occurred in the third portion of the duodenum. The patient was a 62-year-old Japanese male who was admitted due to vomiting and right lower abdominal pain. No abnormal findings were found in the laboratory examinations. After a diagnosis of primary duodenal carcinoma was made by radiologic, endoscopic and ultrasonographic studies, a pancreatoduodenectomy was performed. The histology of the resected specimen revealed papillary adenocarcinoma, with invasion reaching to the pancreatic body. Some characteristic features of the disease are also reviewed.

[A case of primary biliary cirrhosis with negative anti-mitochondrial antibody anteceded by rheumatoid arthritis].

We report a case of primary biliary cirrhosis with negative anti-mitochondrial antibody which were anteceded by rheumatoid arthritis. The patient was a 46-year-old female who was admitted due to low grade fever and elevated serum alkaline phosphatase (ALP) and gamma-glutamyl transpeptidase (gamma-GTP) levels. She had been diagnosed as having erythema nodosum and rheumatoid arthritis 6 years before. Her family history disclosed that her mother had rheumatoid arthritis and her sister systemic lupus erythematosus. On admission, she had moderately elevated erythrocyte sedimentation rate, and elevated serum ALP, gamma-GTP and IgM levels. Anti-mitochondrial antibody and anti-pyruvate dehydrogenase complex antibody were negative but anti-nuclear antibody was positive. However, the histology of liver showed chronic non-suppurative destructive cholangitis. AMA was always negative and serum ALP and bilirubin levels remained constant during the following two years. The pathogenesis of primary biliary cirrhosis with negative anti-mitochondrial antibody is discussed.

[Five cases of Crow-Fukase syndrome].

We presented five cases of Crow-Fukase syndrome. Plasma cell hyperplasia or dyscrasia in bone marrow were recognized in all cases and localized bone lesion was seen in three cases. Thyroid dysfunction was seen in three cases; hyperthyroidism in one case and hypothyroidism in two cases, which was considered to be one of the characteristics though it has seldom been described in this disease. Two of four cases treated with prednisolone had good responses but two cases treated with interferon had no effect.

Obstructive jaundice due to multiple hepatic abscesses.

A 63-year-old Japanese male with diabetes mellitus developed obstructive jaundice following the onset of multiple hepatic abscesses. Percutaneous transhepatic cholangiography showed intrahepatic bile duct irregularity and dilatations accompanied by a complete obstruction of the right branch of the intrahepatic bile duct. Three kinds of organisms were cultured from the blood and the drained bile. The cholangiographic changes returned to the normal after the liver abscesses subsided following biliary drainage and the administration of intravenous antibiotics.