Association of genetic polymorphisms with interferon-induced haematologic adverse effects in chronic hepatitis C patients.

Interferon (IFN)-based combination therapy with ribavirin has become the gold standard for the treatment of chronic hepatitis C virus infection. Haematologic toxicities, such as neutropenia, thrombocytopenia, and anaemia, however, frequently cause poor treatment tolerance, resulting in poor therapeutic efficacy. The aim of this study was to identify host genetic polymorphisms associated with the efficacy or haematologic toxicity of IFN-based combination therapy in chronic hepatitis C patients. We performed comprehensive single nucleotide polymorphism detection in all exonic regions of the 12 genes involved in the IFN signalling pathway in 32 healthy Japanese volunteers. Of 167 identified polymorphisms, 35 were genotyped and tested for an association with the efficacy or toxicity of IFN plus ribavirin therapy in 240 chronic hepatitis C patients. Multiple logistic regression analysis revealed that low viral load, viral genotypes 2 and 3, and a lower degree of liver fibrosis, but none of the genetic polymorphisms, were significantly associated with a sustained virologic response. In contrast to efficacy, multiple linear regression analyses demonstrated that two polymorphisms (IFNAR1 10848-A/G and STAT2 4757-G/T) were significantly associated with IFN-induced neutropenia (P = 0.013 and P = 0.011, respectively). Thrombocytopenia was associated with the IRF7 789-G/A (P = 0.031). In conclusion, genetic polymorphisms in IFN signalling pathway-related genes were associated with IFN-induced neutropenia and thrombocytopenia in chronic hepatitis C patients. In contrast to toxicity, the efficacy of IFN-based therapy was largely dependent on viral factors and degree of liver fibrosis.

Severity analysis of neurovascular contact in patients with trigeminal neuralgia: assessment with the inner view of the 3D MR cisternogram and angiogram fusion imaging.

BACKGROUND AND PURPOSE: Neurovascular contact (NVC) of the trigeminal nerve is not only detected at the affected trigeminal nerve in patients with trigeminal neuralgia (TN) but is also observed at the asymptomatic nerves on the side contralateral to the TN as well as in normal nerves in control subjects. The frequency and severity of the NVC among the affected, contralateral, and normal trigeminal nerves were analyzed by 3D MR cisternogram and angiogram fusion imaging in relation to the cause of TN. MATERIALS AND METHODS: The inner view of the fusion MR imaging projected from inside the trigeminal nerve was used. The severity of the NVC was classified as none, simple, moderate, or severe, according to the nerve circumference in contact with the vessel. The NVC was analyzed in the affected nerves (n = 66) and the contralateral nerves (n = 66). Forty patients underwent microvascular decompression surgery, and 26 were treated medically. The NVC at the normal trigeminal nerves (n = 78) was studied in 39 control subjects without symptoms of TN. RESULTS: The NVC in the affected trigeminal nerve was observed more frequently and much more severely than that at the contralateral and normal trigeminal nerves in controls (P < .01). Additionally, the NVC in the surgical patients was more severe than that in the medically treated patients (P < .01). CONCLUSIONS: Severity analysis of the NVC with the inner view of the fusion MR imaging may provide useful information in the diagnosis of TN and can be a helpful adjunct in treatment planning for patients with TN.

Identification of novel defective HCV clones in liver transplant recipients with recurrent HCV infection.

Patients with recurrent hepatitis C after liver transplantation usually have a high viral load and are generally resistant to interferon (IFN)-alpha2b plus ribavirin (RBV) therapy. However, it remains unclear whether pretreatment viral titre determines the effectiveness of combination therapy, especially in patients with a high viral load. The aim of this study was to identify the viral factors associated with a sustained virological response (SVR) to antiviral therapy in patients with recurrent hepatitis C after living-donor liver transplantation. Twenty-three patients with recurrent hepatitis C received combination therapy of IFN-alpha2b plus RBV. SVR was achieved in 7 of the 23 patients (30.4%). Predictive factors for SVR included a 2 log10 decline in Hepatitis C virus (HCV) RNA at 2 weeks after the start of therapy and disappearance of HCV RNA at 4 or 24 weeks after the start of therapy. As the pretreatment high viral load showed no association with SVR, we asked whether other viral factor was associated with the response to the combination therapy in transplant recipients. We found the several novel defective HCV clones in 4 of 12 recipients' sera. All defective HCV clones had deletions in the envelope region. Interestingly, no patients with defective clones showed a prompt decrease in HCV RNA after the start of IFN-alpha2b plus RBV therapy. Thus, early decline in serum HCV RNA after treatment was closely associated with SVR. The circulating defective HCV clones are present and might be associated with the response to the combination therapy in patients with recurrent hepatitis after liver transplantation.

Prevention of hepatitis B virus recurrence after living donor liver transplantation.

The emergence of lamivudine-resistant hepatitis B mutations is a major complication during pretransplantation treatment. The proper time to begin Lamivudine before transplantation is not yet known. Twenty-six patients received preoperative lamivudine treatment followed by combined lamivudine and hepatitis B immunoglobulin after transplantation up to December 2002. The length of preoperative lamivudine treatment ranged from 13 to 200 days (mean, 52 +/- 37 days). Hepatitis B virus-DNA was positive in 22 of 26 (84.6%) patients before preoperative lamivudine prophylaxis and persistently positive among only 4 of 22 patients (18%) who at transplantation did not show a viral mutation. In all patients, hepatitis B virus-DNA became negative immediately after transplantation. At a median follow-up of 34 months, neither a hepatitis B recurrence nor a mutation had occurred in any patient. The ability to schedule the proper time for preoperative lamivudine prophylaxis is an advantage of living donor liver transplantation.

Serological and immunohistochemical detection of human herpesvirus 8 in Kaposi's sarcoma after immunosuppressive therapy for bullous pemphigoid.

Kaposi's sarcoma (KS) developed in an 87-year-old human immunodeficiency virus-negative woman from Hokkaido island 4 months after oral administration of prednisolone for the treatment of bullous pemphigoid (BP), and rapidly disseminated to almost the entire body within 2 months. The open reading frame (ORF) 59 and ORF73 proteins encoded by human herpesvirus 8 (HHV-8) were detected immunohistochemically in the nuclei of the tumour cells of KS. The protein coded by ORF73, latent protein, was detected in most of the nuclei of the tumour cells, but only a few tumour nuclei were positive for the ORF59 protein, a lytic protein expressed during active infection. The antibodies against both lytic and latent proteins of HHV-8 were detected retrospectively in the serum 4 months before the appearance of KS and before prednisolone therapy had been started. Immunosuppression associated with the treatment for BP possibly activated latent HHV-8 infection and induced the development of KS.

[Comparison of therapeutic effects of SMANCS (+TAE) and Non-SMANCS/LpTAE].

Therapeutic effects of SMANCS and LpTAE were evaluated for hepatocellular carcinoma (HCC). Since June 1995, SMANCS has been used in 59 patients for their first treatment. LpTAE had been performed for HCC before introduction of SMANCS in our hospital, and 71 patients treated after 1992 were chosen for comparison with the therapeutic effect of SMANCS. Among the patients treated with SMANCS, complete and partial responses (CR and PR) were obtained in 24 cases (41%) and 17 cases (33%), respectively. SMANCS accompanied by TAE was more effective than SMANCS alone. The effects did not depend on the level of the hepatic arterial branch at which SMANCS was administered. In patients treated with LpTAE, CR and PR were obtained in 12 cases (17%) and 18 cases (25%), respectively. SMANCS was significantly more effective than LpTAE. Because of our short experience with SMANCS, we could only show a two year survival rate. The one- and two-year survival rates for SMANCS were 71% and 57%, respectively. They were not significantly different from those for LpTAE, at 80% and 60%. Despite good results of treatment for HCC, a better prognosis could not be expected by SMANCS in this study. These results may be explained as follows. The evaluating the cause of death within two years after first treatment, hepatic failure was more common in patients treated with SMANCS. After treatment by SMANCS, 11 patients (55%) died from hepatic failure. On the other hand, 4 patients (15%) died from hepatic failure after LpTAE. Although there is no significant difference of Child Pugh score, this may indicate that SMANCS has been used for patients with lesser hepatic reserve and this leads to early deaths in patients treated with SMANCS. However, because of the short experience in this study, further observation is necessary for precise evaluation of clinical efficacy of SMANCS.

Evaluation of protective effects of prostaglandin E1 on ischemic liver damage with in vivo 31P-MR spectroscopy.

The cytoprotective effect of prostaglandins (PG) was evaluated by in vivo 31P MR spectroscopy. Twenty rabbits were divided into two groups; the control group given physiological saline, and the PG group given prostaglandin E1 (0.5 microgram/kg/min). Each solution was infused for 8 min, after which complete hepatic ischemia was induced for 20 min, followed by reperfusion for 40 min. During ischemia, beta-ATP decreased to 23.6% and 42.3%, phosphomonoester increased to 260% and 200% of their initial values in the control and the PG groups, respectively. Inorganic phosphate also increased. After reperfusion, beta-ATP recovered to 65.2% and 96.5%, phosphomonoester to 130% and 110%, inorganic phosphate to 140% and 120% in the control and PG groups, respectively. The changes during ischemia were significantly smaller and the recoveries during reperfusion were more complete in the PG group. These results may confirm the cytoprotective effect of prostaglandins by in vivo 31P-MR spectroscopy.

Correlation of Tc-99m GSA hepatic studies with biopsies in patients with chronic active hepatitis.

To determine whether scintigraphic findings of Tc-99m DTPA-galactosyl-HSA (GSA) correspond to histopathologic findings, Tc-99m GSA hepatic scintigraphy and biopsy were compared in 65 patients with chronic active hepatitis. After injecting 185 MBq of Tc-99m GSA, anterior images were obtained at 5 minutes and 15 minutes. Scintigrams were classified into three grades according to the extent of visualization of the cardiac blood pool on 5 minute and 15 minute images. Biopsies were subjectively graded for findings of necrosis and fibrosis. Scintigraphic grades on 5 minute images were correlated with hepatic necrosis and fibrosis and those on 15-minute images with hepatic fibrosis. Scintigraphic abnormalities of Tc-99m GSA correlated well with histopathologic abnormalities, especially with hepatic fibrosis and necrosis in patients with chronic active hepatitis.

Vascular complications in living related liver transplantation detected with intraoperative and postoperative Doppler US.

BACKGROUND/AIMS: The purpose of this study was to clarify changes in the graft hemodynamics induced by vascular complications in living related liver transplantation. METHODS: This study included 46 pediatric recipients who underwent partial liver transplantation from living related donors. The blood flow was evaluated in the portal system, the hepatic artery and the hepatic vein with serial intra- and post-operative Doppler ultrasound (US). RESULTS: In 12 patients, intraoperative Doppler US showed a decrease in portal venous inflow (< 9 ml.min-1.kg-1) toward the liver graft and could act as a guide for ligation of collaterals in seven patients, portal re-construction in two, thrombectomy in one and relief of hepatic venous outflow obstruction in two for increasing the portal venous inflow. In five patients, intraoperative Doppler US showed poor arterial inflow, i.e. dampened arterial waveforms which involved both low pulsatility index (< 0.90) and low peak-systolic velocity (< 31 cm/s). In three of them, the waveform was more pulsatile after re-anastomosis or relief from stretching of the hepatic artery. The remaining two patients developed hepatic artery thrombosis. Most of the hepatic venous outflow obstruction (four of five patients) had flat waveforms, low flow velocity (< 10 cm/s) of the hepatic vein, and poor portal inflow (flow velocity < 14 cm/s). Postoperative Doppler US showed hepatic venous outflow obstruction in three patients, hepatic artery thrombosis in three (twice in one patient), portal vein stenosis in two and portal vein thrombosis in one. These complications were successfully managed with surgical procedures in three patients, transhepatic angioplasty in three and conservative treatments in four. Six patients died of non-vascular complications. CONCLUSIONS: Serial intra- and post-operative Doppler US was a useful technique for making an early diagnosis of abnormal hemodynamics of the graft circulation. Furthermore, intraoperative Doppler US could assess reconstructed vessels objectively and would reduce the incidence of vascular complications following transplantation.

Azygos venous blood flow: measurement with direct bolus imaging.

PURPOSE: To evaluate a magnetic resonance (MR) imaging technique for measurement of azygos blood flow volume, which is an important indicator of superior collateral circulation in patients with portal hypertension. MATERIALS AND METHODS: Azygos blood flow was measured by means of direct bolus (DB) imaging, an MR flow measurement technique. A presaturation pulse was applied in combination with electrocardiographic gating. RESULTS: The measured flow volume was 320 mL/min +/- 30 (mean +/- standard error of mean) in the control subjects, 550 mL/min +/- 130 in patients with cirrhosis of the liver and without varices, and 660 mL/min +/- 60 in patients with cirrhosis of the liver and with varices. The flow volume was significantly higher in each of the groups with cirrhosis of the liver than in the control group (P < .01). Furthermore, a significant correlation was shown between DB imaging and continuous thermodilution measurements (r = .707, P < .01). CONCLUSION: DB imaging, which is noninvasive, was useful in the monitoring of the effect of treatment and in determination of the prognosis in patients with portal hypertension.

Nephrotoxicity induced by adenine and its analogs: relationship between structure and renal injury.

Twenty-four adenine analogs were administered to mice and the relationship between the structure of analogs and the occurrence of renal injury was examined. Plasma urea nitrogen (UN) and creatinine levels were measured 24 h after oral administration of analogs. Both levels increased in the adenine-, 8-azaadenine-, isoguanine-, or 6-dimethyl aminopurine (6-DMAP)-administered group, but did not increase in the other analog groups. From light microscopy, the damages of tubuli, mainly of proximal tubuli, were observed in the kidneys of these four groups. The common property of these compounds is the strong basicity of nitrogen which binds the 6-position of the purine ring. Furthermore, UN and creatinine increased time-dependently with intravenous administration of isoguanine. When adenine was intravenously administered, UN slightly increased at 1 h, but creatinine was unchanged. No changes were observed in the 6-DMAP- or 8-azaadenine-administered group. The basicity of nitrogen which binds to the 6-position of the purine ring is thus considered to be related to the occurrence of renal injury with oral administration, and isoguanine has high affinity with the kidney.

[CT findings of pulmonary sarcoidosis].

A retrospective review was performed on CT findings in 46 patients of pulmonary sarcoidosis proven by histology. Pulmonary lesions were detected in 26 patients (56.5%). Frequent CT findings were peribronchial markings (69.2%), diffuse small nodules (65.4%), pleural lesions (38.5%), lymphangitis carcinomatosa like changes (30.8%), and large irregular nodules (30.8%). Follow up CTs were obtained in 18 patients. Peribronchial markings and diffuse small nodules had tendency to improve, although atelectasis, pleural thickening, and bullae were irreversible and progressive. CT plays an important role in the diagnosis and have a prognostic value in pulmonary sarcoidosis.

Embryonal rhabdomyosarcoma arising in the buccal mucosa: a case report with immunohistochemical and electronmicroscopic findings.

Rhabdomyosarcoma is one of the most common soft-tissue neoplasms in children. We report a case of a 9-year-old female with embryonal rhabdomyosarcoma arising in the buccal region with immunohistochemical and electronmicroscopic findings. Under a light microscope, it was observed that the tumor was composed of small round or spindle-shaped cells with pleomorphic and hyperchromatic nuclei. They were immunoreactive for actin, myoglobin and desmin. With an electron microscope, it was found that most tumor cells contained filamentous structures and free ribosomes. Some of them showed typical myofilaments, M-bands and Z-lines. These findings were specific evidence of rhabdomyosarcoma. Twenty courses of VAC (vincristine, D-actinomycin and cyclophosphamide) chemotherapy were administered, followed by surgical resection of the tumor.

Selective MR angiography of the liver.

OBJECTIVE: Two-dimensional time-of-flight MR angiography was done with a 1.0 T whole-body imaging system. METHODS: The 10 mm thick presaturation slab was positioned between two sagittal imaging slices of the liver. Images were obtained through the right lobe of the liver by moving the slab and slices together. Each image was acquired during a breath-holding interval of 16 s. RESULTS: Since the directions of the portal and hepatic venous flows are opposite to each other in the right lobe, these two venous systems could be visualized on separate images by the interleaved presaturation slab. On the reconstructed angiograms, separation between the two venous systems was complete and even the fourth and fifth branches were demonstrated clearly. These images facilitate clear understanding of the structure of the intrahepatic blood vessels. CONCLUSION: Although this technique is limited to volunteer studies and works only on the right lobe of the liver, it will provide valuable information for evaluating the location and vascular involvement in various liver diseases.

Distribution of mesenteric and splenic blood flow in cirrhosis of the liver as estimated by radionuclide angiography.

We used radionuclide angiography following an injection of 185 MBq Tc-99m tin colloid as a non-invasive method for measuring the mesenteric and portal components of the total hepatic circulation, according to the method of Fleming et al (J Nucl Med 24; 1983). Fifty-seven patients with cirrhosis and 33 controls were examined. The relative mesenteric flow (MF) and the relative portal flow (PF) were 68.6 +/- 8.5% and 78.6 +/- 5.9%, respectively, in the control group. These values were 42.0 +/- 16.4% and 70.9 +/- 8.9%, respectively in the cirrhosis group, and were significantly lower than in the controls. In the cirrhosis group, the reduction in PF was small, while that in MF was large. Consequently, we found that portal blood flow was relatively well maintained in the cirrhosis patients, while the contribution of splanchnic blood flow to the portal flow was relatively reduced.