The real impact of telaprevir dosage on the antiviral and side effects of telaprevir, pegylated interferon and ribavirin therapy for chronic hepatitis C patients with HCV genotype 1.

Triple therapy with telaprevir, pegylated interferon and ribavirin has been reported to improve antiviral efficacy but have potentially severe adverse effects in patients with chronic hepatitis C. To avoid the severe effects of telaprevir, lowering the dose has been suggested. However, impact of dosage changes on antiviral and adverse effects remains unclear. One hundred and sixty-six Japanese patients with HCV genotype 1 were treated with triple therapy. The drug exposure of each medication was calculated by averaging the dose actually taken. The overall SVR rate was 82%. The telaprevir discontinuation rate was 26%. The factors associated with discontinuation were an older age (≥65 y.o.) and a higher average dose during treatment. The telaprevir discontinuation rates were 42%, 25% and 14% in patients at ≥35, 25-35 and <25 mg/kg/day of telaprevir and 58% in older patients at ≥35 mg/kg/day of TVR. The factors associated with SVR were treatment-naïve, relapse to previous treatment, higher average telaprevir dose during treatment and completion of treatment. The SVR rate was higher, at 91%, in patients at 25-35 mg/kg/day of telaprevir than the 71% and 78% observed in those at <25 and ≥35 mg/kg/day of drug. In Japanese patients, a mean telaprevir dose of 25-35 mg/kg/day during treatment can augment its efficacy in triple therapy for patients with HCV genotype 1.

Risk factors for hepatocellular carcinoma in hepatitis C patients with normal alanine aminotransferase treated with pegylated interferon and ribavirin.

Pegylated interferon (Peg-IFN) plus ribavirin combination therapy is effective in patients with hepatitis C virus (HCV) infection and normal alanine aminotransferase levels (NALT). However, it remains unclear whether the risk of hepatocellular carcinoma (HCC) incidence is actually reduced in virological responders. In this study, HCC incidence was examined for 809 patients with NALT (ALT ≤ 40 IU/mL) treated with Peg-IFN alpha-2b and ribavirin for a mean observation period of 36.2 ± 16.5 months. The risk factors for HCC incidence were analysed by Kaplan-Meier method and Cox proportional hazards model. On multivariate analysis among NALT patients, the risk of HCC incidence was significantly reduced in patients with sustained virological response (SVR) or relapse compared with those showing nonresponse (NR) (SVR vs NR, hazard ratio (HR): 0.16, P = 0.009, relapse vs NR, HR: 0.11, P = 0.037). Other risk factors were older age (≥65 years vs <60 years, HR: 6.0, P = 0.032, 60-64 vs <60 years, HR: 3.2, P = 0.212) and male gender (HR: 3.9, P = 0.031). Among 176 patients with PNALT (ALT ≤ 30 IU/mL), only one patient developed HCC and no significant risk factors associated with HCC development were found. In conclusion, antiviral therapy for NALT patients with HCV infection can lower the HCC incidence in responders, particularly for aged and male patients. The indication of antiviral therapy for PNALT (ALT ≤ 30 IU/mL) patients should be carefully determined.

The treatment of refractory atlanto-axial rotatory fixation using a halo vest: results of a case series involving seven children.

We reviewed seven children with torticollis due to refractory atlanto-axial rotatory fixation who were treated in a halo vest. Pre-operative three-dimensional CT and sagittal CT imaging showed deformity of the superior articular process of C2 in all patients. The mean duration of halo vest treatment was 67 days (46 to 91). The mean follow-up was 34 months (8 to 73); at the latest review six patients demonstrated remodelling of the deformed articular process. The other child, who had a more severe deformity, required C1-2 fusion. We suggest that patients with atlanto-axial rotatory fixation who do not respond to conservative treatment and who have deformity of the superior articular process of C2 should undergo manipulative reduction and halo-vest fixation for two to three months to induce remodelling of the deformed superior articular process before C1-2 fusion is considered.

A comparative analysis of incident reporting lag times in academic medical centres in Japan and the USA.

BACKGROUND: Delays in reporting of medical errors may signal deficiencies in the performance of hospital-based incident reporting. We sought to understand the characteristics of hospitals, providers and patient injuries that affect such delays. SETTING AND METHODS: All incident reports filed between May 2004 and August 2005 at the Kyoto University Hospital (KUH) in Japan and the Brigham and Women's Hospital (BWH) in the USA were evaluated. Lag time between each event and the submission of an incident report were computed. Multivariable Poisson regression with overdispersion, to control for previously described confounding factors and identify independent predictors of delays, was used. RESULTS: Unadjusted lag times were significantly longer for physicians than other reporters (3.6 vs 1.8 days, p < 0.0001), longer for major than minor events (4.1 vs 1.9 days, p = 0.0006) and longer at KUH than at BWH (3.1 vs 1.0 days, p < 0.0001). In multivariable analysis, lag times at KUH remained nearly three times longer than at BWH (incidence-rate ratio 2.95, 95% CI 2.84 to 3.06, p < 0.0001). CONCLUSIONS: Lag time provides a novel and useful metric for evaluating the performance of hospital-based incident reporting systems. Across two very different health systems, physicians reported far fewer events, with significant delays compared with other providers. Even after controlling for important confounding factors, lag times at KUH were nearly triple those at BWH, suggesting significant differences in the performance of their reporting systems, potentially attributable to either the ease of online reporting at BWH or to the greater attention to patient safety reporting in that hospital.

Cost analysis of radiotherapy, carbon ion therapy, proton therapy and BNCT in Japan.

The purpose of this study was to estimate the financial costs to start BNCT as a clinical treatment in a hospital. To evaluate more accurate data on the precise costs of BNCT, we analyzed the costs of conventional radiotherapy, carbon ion and proton therapy and compare them to BNCT. An aggregate cost calculation of accelerator, buildings, equipments and staff requirements was performed.

Three-dimensional images for surgical plan of giant sacral schwannoma.

OBJECTIVE: Documentation of three-dimensional (3D) images of a giant sacral schwannoma with intrapelvic expansion. SETTING: Nagoya University, Nagoya, Japan. RESULTS: 3D computed tomography (3D CT) showed a destructed bony region clearly. 3D CT angiography clarified the positional relationship between tumor and iliac arteries. Resection procedure was safely completed based on these 3D evaluations. CONCLUSION: 3D images were helpful to make a surgical plan and to complete this complicated resection combined with sacroiliac reconstruction.

FK506-associated limbic injury following umbilical cord blood transplantation.

A 5-year-old girl with Ph-positive chronic myelogenous leukemia, who underwent umbilical cord blood transplantation, developed two episodes of electrical status epilepticus while receiving tacrolimus (FK506) then cyclosporin A (CsA), as treatment against graft-versus-host disease. MRI including diffusion weighted MR imaging of the brain revealed abnormalities in the hippocampus and posterior white matter following FK506 and CsA treatment, respectively. While posterior white matter injury has been described with both FK506 and CsA, no previous report describes hippocampal injury from either drug. The MRI changes in the hippocampus in our case suggest possible increased susceptibility to hippocampal injury with FK506.

A designed antagonist of the thyroid hormone receptor.

We synthesized an analogue of the thyromimetic GC-1 bearing the same hydrophobic appendage as the estrogen receptor antagonist ICI-164,384. While having reduced affinity for the thyroid hormone receptors compared to GC-1, it behaves in a manner consistent with a competitive antagonist in a transactivation assay.

Significance of serum soluble Fas antigen level in chronic hepatitis C patients treated with interferon: relationship to the therapeutic response.

BACKGROUND AND AIM: Fas system-mediated cytotoxicity is thought to be involved in the development of liver injury in hepatitis C virus (HCV) infection. In this study, we investigated serum soluble Fas antigen levels in chronic hepatitis C patients treated with interferon and their correlation with the therapeutic response. METHODS: The subjects were 67 chronic hepatitis C patients who underwent a 24-week course of alpha-interferon therapy. Patients were categorized into three groups; sustained responders (n = 22), transient responders (n = 24), and non-responders (n = 21), according to changes in the serum alanine aminotransferase level during and after therapy. The viral genotype, viremic level and diversity in the hypervariable region were examined before therapy. Serum soluble Fas antigen levels were assayed by using serum samples taken at the beginning and the end of therapy. RESULTS: In the univariate analysis, serum soluble Fas antigen levels tended to be higher in non-responders (10.0 +/- 3.4 ng/mL) than in sustained responders (8.5 +/- 3.0 ng/mL) and transient responders (8.2 +/- 2.1 ng/mL; P = 0.13 and P < 0.05). The non-response to therapy was observed in eight of the 15 (53%) patients with serum soluble Fas antigen > or = 11 ng/mL, compared with 13 of the 52 (25%) patients with serum soluble Fas antigen < 11 ng/mL (P < 0.05). As for the multivariate analysis, the only significant factor contributing to the sustained response was a low HCV viremic level (P = 0.0046). Significant factors contributing to the non-response were a high serum alanine aminotransferase (P = 0.0407) and a high serum soluble Fas antigen level (P = 0.0483). CONCLUSIONS: High production levels of soluble Fas antigen may be associated with a poor response to interferon therapy in chronic hepatitis C patients.

Histologic analysis of the implanted cartilage in an exact-fit osteochondral transplantation model.

PURPOSE: Osteochondral transplantation is one of the useful treatments for articular cartilage defect. However, the histologic change of the implanted cartilage has not been reported in detail. We investigated the histology of exact-fit osteochondral transplants used to repair articular cartilage defects in an animal model. TYPE OF STUDY: This was a nonrandomized control study using an animal model. METHODS: Sixteen skeletally mature female Japanese white rabbits were used in the study. The region of the femoral groove was selected as the site for the osteochondral defect. A full-thickness cylindrical defect (7 mm in diameter and 7 mm in depth) through the articular cartilage and into the subchondral bone was made using the Osteochondral Autograft Transfer System (Arthrex, Naples, FL). The entire osteochondral fragment was removed and then returned to its original site in the femoral condyle precisely. Thus, the defect was repaired with an autogenous osteochondral transplantation of exactly the same size and configuration as the defect. Specimens were obtained 2, 4, 12, and 24 weeks postoperatively and were analyzed both macroscopically and histologically. RESULTS: Macroscopically, there was smooth continuity of the articular surface and the integration of the graft to the normal host cartilage. However, histologic examination showed that the layer of the grafted cartilage was thicker than that of the normal host cartilage and the extracellular matrix of the implanted cartilage exhibited a stronger staining pattern with safranin-O fast green than the normal cartilage. Cell density was higher in the grafted cartilage, particularly in the middle and the deep zones. Round and polygonal hypertrophic clusters of chondrocytes were observed in the middle and deep zones of the grafted cartilage. CONCLUSIONS: The histologic properties of the exact-fit implanted cartilage were different from that of normal articular cartilage. Further investigation of mechanical and structural properties of grafted cartilage is necessary to verify the long-term effects of osteochondral transplantation.

De novo malignant transformation of giant cell tumor of bone.

Two cases of malignant lesions are reported, both of which arose secondary to an originally benign giant cell tumor (GCT) of bone. The first case was a typical benign GCT, which occurred in the left proximal tibia of a 31-year-old woman. The tumor was treated by curettage and bone grafting. However, it recurred twice during 15 years of follow-up. The second recurrence showed that the lesion histologically had turned into malignant fibrous histiocytoma. The second case also started as an initially benign GCT that arose in the left distal femur of a 41-year-old man. The patient underwent curettage and bone grafting. The lesion recurred 13 years postoperatively. The histological appearance of the recurrent tumor showed it to be an osteogenic sarcoma. In both patients, radiation and never been given. Malignant transformation has rarely been reported in patients with GCT of bone who have not received radiation treatment.

Medical markup language (MML) for XML-based hospital information interchange.

Medical Markup Language (MML) has been developed over the last 6 years in order to create a set of standards by which medical data, within Japan and hopefully worldwide, can be stored, accessed and exchanged in any number of physical locates. The MML version 2.21 is characterized by XML as meta-language, module structure for each document and enhancement of linking function among documents. Data exchange specification has been also added for query and reply. MML instances are composed of MML header and MML body. The MML header includes information for data transmission, while MML body includes several module items. One module item contains two elements: document information and module content. Nine MML module contents are defined at the present time: patient information, health insurance information, diagnosis information, lifestyle information, basic clinic information, particular information at the time of first visit, progress course information, surgery record information and clinical summary information.

Effect of interferon therapy on the incidence of hepatocellular carcinoma and mortality of patients with chronic hepatitis C: a retrospective cohort study of 738 patients.

The effect of interferon on the long-term clinical outcome of patients with chronic hepatitis C remains unclear. This study included 594 patients with chronic hepatitis C who received interferon-alpha therapy (Interferon group) and 144 patients with chronic hepatitis C who did not receive interferon (Control group). The patients in the Interferon group were classified into the following three groups based on the response of the serum aminotransaminase level of the patient during and after completion of the therapy protocol: sustained responders (n = 175), transient responders (n = 165), and non-responders (n = 254). The age, sex, serum aminotransaminase level, platelet count, histological staging, hepatitis C virus (HCV) subtype, and HCV concentration at baseline were adjusted with the Cox proportional hazards model. The length of follow-up for assessment of the risk for developing hepatocellular carcinoma (HCC) was 57.2 +/- 13.9 months in the Interferon group and 67.7 +/- 28.7 months in the Control group. Multivariate analysis showed that interferon therapy decreased the risk for developing HCC by 48% compared with that in the Control group (P = 0.064). The older the age, being male, having a low platelet count, and higher histological stage were independent factors associated with the development of HCC. The hazard rate ratio for development of HCC in the sustained responders, transient responders, and non-responders was 0.16 (95% confidence interval [CI]: 0.04-0.62), 0.27 (95% CI: 0. 09-0.79), and 0.74 (95% CI: 0.37-1.48), respectively. During follow-up, 18 patients in the Interferon group died (10 from liver-related diseases) and 17 patients in the Control group died (10 from liver-related diseases). No sustained responder or transient responder in the Interferon group died of liver-related disease. The cumulative survival rates of the Interferon and Control groups were nearly identical during the first 5 years following diagnosis. Thereafter, the cumulative survival rate of the Control group declined, resulting in an 8-year survival rate in the Interferon and Control groups of 97% and 81%, respectively (P = 0. 061). Similar trends were seen in the survival analysis of those who had died of liver disease: the 8-year survival rates of the Interferon and Control groups were 98% and 88%, respectively (P = 0. 32). Our study demonstrated that interferon therapy significantly lowered the incidence of HCC among patients with chronic hepatitis C who showed sustained normalization and among patients who showed transient normalization of the serum aminotransferase level after completion of interferon therapy. The survival analyses and determination of cause of death suggested that interferon therapy improves the long-term survival of chronic hepatitis C patients who respond to this therapy, possibly by decreasing mortality from liver-related diseases.

[Chemotherapy in hemodialysis patient with metastatic testicular cancer; pharmacokinetics of etoposide and cisplatin].

The pharmacokinetics of intravenously administrated cisplatin and etoposide were studied in a patient with seminoma (stage IIIA) receiving hemodialysis for chronic renal failure. The treatment schedule was as follows: 7 mg/m2 of cisplatin at day 1, 3, 5; 14 mg/m2 of cisplatin at day 2, 4; 70 mg/m2 of etoposide at day 1-5; hemodialysis at day 2, 4. After the treatment myelosuppression was very strong. So the patient were received another treatment of smaller doses of cisplatin and etoposide in three courses. The other schedule was as follows: 14 mg/m2 of cisplatin at day 1, 3, 5; 35 mg/m2 of etoposide at day 1-5; hemodialysis at day 1, 3, 5. The area under the blood concentration-time curve (AUC) of free-cisplatin was 6.82 micrograms.hr/ml in first course, 4.07 micrograms.hr/ml in second course. The peak concentration of peripheral blood free-cisplatin was 0.58 microgram/ml in first course, 0.43 microgram/ml in second course. The AUC of etoposide was 241.9 micrograms.hr/ml in first course, 216.9 micrograms.hr/ml in second course. After treatment CR was observed and there was no recurrence for five years. In conclusion, it was considered that cisplatin and etoposide could be given to the patient receiving hemodialysis for chronic renal failure and smaller doses should be given to prevent side effects.

Risk of non-Hodgkin's lymphoma in patients with hepatitis C virus infection.

Hepatitis C virus (HCV) has been suggested to play an etiological role in the development of B-cell non-Hodgkin's lymphoma (NHL) in Italy. However, another study in Scotland questioned increased risk of development of NHL in patients with chronic HCV infection. A total of 2,162 patients admitted to 3 hospitals in Osaka, where the incidence of HCV-related hepatitis is highest in Japan, during the period from 1957 to 1997 were followed up from the date of diagnosis of chronic HCV-related hepatitis until 30 October 1997. Overall, 12,404.5 person-years of observation were accrued with a follow-up period ranging from 0.25 to 40.4 (average 5.74) years. NHL of the B-cell type developed in 4 patients. The interval between onset of chronic HCV and NHL ranged from 6 to 36 (median 13) years. Expected number of cases of NHL in the sex-, age- and calendar year-matched general population was 1.90, which gave a relative risk (RR) of 2.10 (95% confidence interval 0.57-5.38; p = 0.247). Taking the much higher RR for hepatocellular carcinoma among patients with HCV infection into account, chronic HCV infection was considered to be moderately associated with increased risk of NHL.

Determination of iron(II) and total iron in environmental water samples by flow injection analysis with column preconcentration of chelating resin functionalized with N-hydroxyethylethylenediamine ligands and chemiluminescence detection.

A flow injection analysis (FIA) technique for the determination of Fe(II) and total-Fe in environmental water samples has been developed with a high sensitivity. The resin used for preconcentration of iron was the macroporous resin, Amberlite XAD-4 functionalized by N-hydroxyethylethylenediamine (HEED) groups. The technique employed was FIA by combination of on-line chelate resin preconcentration and chemiluminescence detection (CL), using brilliant sulfoflavine and hydrogen peroxide reagent solutions. The interference by coexisting Fe(III) could be eliminated by addition of 1x10(-6) mol of deferrioxamine B solution. The detection limits of Fe(II) and total-Fe were 0.80 and 0.36 nmol l(-1) for 5.6-ml seawater samples with a concentration of 2 nmol l(-1). The relative standard deviations for both samples were less than +/-4%. A typical analysis for Fe(II) can be performed in 7.5 min. The technique was ascertained by comparing the analytical value of total-Fe with the certified value of Fe in the reference standard seawater CASS-3.

Gene expression of alpha1-6 fucosyltransferase in human hepatoma tissues: a possible implication for increased fucosylation of alpha-fetoprotein.

The 1-6 fucosylated -fetoprotein (AFP) present in serum of patients with hepatocellular carcinoma (HCC) has been employed for the differential clinical diagnosis of HCC from chronic liver diseases. The molecular mechanism by which this alteration occurs, however, remains largely unknown. To address this issue, we purified GDP-L-Fuc:N-acetyl-beta-D-glucosaminide 1-6 fucosyltransferase (1-6 FucT), an enzyme involved in the 1-6 fucosylation of N-glycans from porcine brain, as well as from a human gastric cancer cell line, and cloned their genes. In this study, levels of 1-6 FucT mRNA expression and the activity of this enzyme for 12 human HCC tissues were examined and compared with that in surrounding tissues and normal livers. The mean +/- SD for 1-6 FucT activity was 78 +/- 41 pmol/h/mg in normal control liver, 202 +/- 127 pmol/h/mg in adjacent uninvolved liver tissues (chronic hepatitis: 181 +/- 106 pmol/h/mg; liver cirrhosis: 233 +/- 164 pmol/h/mg), and 195 +/- 72 pmol/h/mg in HCC tissues. The mRNA expression of 1-6 FucT was also enhanced in proportion to enzymatic activity except for a few cases, suggesting that 1-6 FucT expression is increased in chronic liver diseases, especially liver cirrhosis. Transfection of 1-6 FucT gene into cultured rat hepatocytes markedly increased 1-6 FucT activity and led to an increase in lens culinaris agglutinin (LCA) binding proteins in both cell lysates and condition media. When the 1-6 FucT gene was transfected into a human HCC cell line, Hep3B, which originally showed low levels of 1-6 FucT expression, 1-6-fucosylated AFP was dramatically increased in the condition media. Collectively, these results suggest that the enhancement of 1-6 FucT expression increased the fucosylation of several proteins, including AFP, and that the level of 1-6-fucosylated AFP in patients with HCC was in part caused by up-regulation of the 1-6 FucT gene expression.

Interrelationship between alcohol intake, hepatitis C, liver cirrhosis, and hepatocellular carcinoma.

The discovery of a cDNA clone of hepatitis C virus (HCV) genome in 1989 has resulted in numerous reports of high rates of the prevalence of HCV antibody in patients with alcoholic liver disease, in particular, alcoholic liver cirrhosis and hepatocellular carcinoma. Thus, the interaction between alcohol intake and HCV infection has become of great importance. In terms of the effect of alcohol on HCV-RNA levels, the data are controversial; in some reports, alcohol increases HCV-RNA levels, and in the other reports it does not. There are several reports suggesting the possibility of an elevated quasi-species of hypervariable region 1 in the HCV genome caused by alcohol drinking. Recent studies have documented that alcohol intake exaggerates the responsiveness of interferon therapy for chronic hepatitis C; however, its mechanism is still obscure. Several studies have suggested the promoting effect of alcohol on the development of hepatocellular carcinoma in type C liver cirrhosis, which has been similarly observed in type B chronic liver disease, whereas its mechanism is limited to speculations.