Postmarketing Benefit-Risk Assessment for Erythropoiesis-Stimulating Agents Using a Health Care Database.

BACKGROUND: While benefit-risk (B-R) assessment in the real-world setting is an important challenge for pharmacovigilance, few studies have explored this approach. To investigate the utility and limitations of B-R assessment using a health care database by applying the Benefit Risk Action Team (BRAT) framework, we have conducted a case study with erythropoietin agents. METHODS: Postmarketing data from the Medical Data Vision health care database were used in a B-R comparison between methoxy polyethylene glycol-epoetin beta (continuous erythropoietin receptor activator; C.E.R.A.) and other erythropoiesis-stimulating agents (ESAs). Data were from patients with chronic kidney disease (CKD) treated with C.E.R.A. (n = 131: nondialysis, 109; hemodialysis, 22) or other ESAs (n = 542: nondialysis, 327; hemodialysis, 215) between July 2011 and March 2014. RESULTS: The B-R profile for C.E.R.A. appeared to be similar to that for other ESAs in both nondialysis and hemodialysis patients with CKD, when benefits and risks were mainly assessed in terms of odds ratios. Despite various point estimates and confidence intervals for each outcome, the results of subgroup analyses showed no notable differences from the overall analysis in B-R assessment. CONCLUSIONS: B-R assessment can be performed using the BRAT framework with a health care database, but limitations exist when using a single data source. Care should be taken when selecting data for extraction and defining outcomes of interest. Further research is necessary to facilitate practical application of this approach.

Sustained virological response of patients with hepatitis C virus genotype 2 depends on pegylated interferon compliance.

AIM: Patients infected with hepatitis C virus (HCV) genotype 2 are more sensitive to interferon (IFN) therapy than those infected with genotype 1, but 10-20% of patients do not achieve a sustained viral response (SVR) to combination therapy with pegylated (PEG) IFN and ribavirin (RBV). This study examines the prognostic factors associated with SVR in patients infected with HCV genotype 2 treated with PEG IFN and RBV. METHODS: We treated 149 patients with chronic hepatitis C caused by HCV genotype 2. The patients received s.c. PEG IFN-α-2b (1.5 µg/kg) and a weekly weight-adjusted dose of RBV (600, 800 and 1000 mg per <60, 60-80 and >80 kg, respectively) for 24 weeks and then prognostic factors associated with the SVR were examined. RESULTS: Among the 149 patients, 138 completed the combination therapy and a sustained viral response was achieved in 71.8% of them. Univariate analysis showed that age, as well as mean RBV and PEG IFN doses were factors affecting the SVR (P = 0.012, =0.021, =0.014). Multivariate analysis identified age and mean PEG IFN dose (P = 0.021, =0.018, respectively) as factors involved in the SVR, but not mean RBV dose. CONCLUSION: The SVR of patients infected with HCV genotype 2 depended on the dosage of PEG IFN, but not of RBV. Selecting sufficient doses of PEG IFN for combination with RBV is critical for treating such patients.

Aerobic exercise improves insulin resistance and decreases body fat and serum levels of leptin in patients with hepatitis C virus.

AIM: Hepatitis C virus infection often complicates glucose intolerance, which can be caused by insulin resistance. Aerobic exercise can improve insulin resistance and decrease body fat in patients with diabetes. The aim of the present study is to clarify whether aerobic exercise improves insulin resistance and decreases body fat in patients with chronic hepatitis C (CH-C). METHODS: Seventeen patients with CH-C received nutrition education at entry and every two months thereafter. The following were evaluated before and after 6 months of walking at least 8000 steps/day monitored using a pedometer that started 2 months after entry: body composition, fat and muscle weight, visceral and subcutaneous fat areas (VFA and SFA, respectively), liver function tests, the Homeostatic Model of Assessment of Insulin Resistance (HOMA-IR), serum tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, adiponectin, leptin and the Short Form-36. RESULTS: Fifteen of the 17 patients completed the study protocol. Bodyweight, body mass index, fat weight, VFA, SFA, alanine aminotransferase level and HOMA-IR were significantly decreased at the end of the study (P = 0.004, =0.004, =0.008, =0.041, =0.001, =0.023 and =0.002, respectively). Serum levels of TNF-α, IL-6 and adiponectin did not change, whereas those of leptin significantly decreased (P = 0.002). CONCLUSION: Patients with CH-C could safely walk as aerobic exercise. Furthermore, walking improved insulin resistance and decreased body fat while lowering serum levels of leptin.

Biochemical response to ursodeoxycholic acid predicts long-term outcome in Japanese patients with primary biliary cirrhosis.

AIM: There is an ongoing need for predictors of long-term outcomes for patients with primary biliary cirrhosis (PBC). Biochemical response to ursodeoxycholic acid (UDCA) has been introduced to predict development of symptoms by our group (Ehime criteria) and to predict long-term outcomes in Western countries (Paris, Barcelona and Rotterdam criteria). The aim of this study was to evaluate whether these criteria are also useful to predict long-term outcomes in Japanese patients with PBC. METHODS: A retrospective chart review was conducted for 227 Japanese patients with PBC. Patients taking UDCA with an observation period of more than 6 months were included in the study. Data collection included demographics, biochemical and serological markers, and histological stage. Four different criteria regarding biochemical response to UDCA were compared and evaluated. RESULTS: In total, 138 patients met the inclusion criteria and underwent analysis. Using the Ehime criteria, the transplant-free survival rate was significantly higher in responders than in non-responders (P = 0.010). The Paris criteria also predicted long-term outcomes in our population (P = 0.003), whereas the Barcelona and Rotterdam criteria showed no such association (P = 0.282 and P = 0.553, respectively). CONCLUSION: Good biochemical response to UDCA according to the Ehime and Paris criteria is associated with long-term outcome in Japanese patients with PBC and allows identification of non-responders who may benefit from further trials. Finally, Ehime criteria should be validated in a different patient cohort.

Liver fibrosis in patients with chronic hepatitis C: noninvasive diagnosis by means of real-time tissue elastography--establishment of the method for measurement.

PURPOSE: To prospectively measure liver stiffness with real-time tissue elastography in patients with chronic hepatitis C and to compare the results with those of clinical assessment of fibrosis by using histologic stage as the reference standard. MATERIALS AND METHODS: All subjects gave informed consent, and the study was approved by the institutional ethics committee. Seventy hospitalized patients (46 men, 24 women; mean age, 65.5 years ± 11.7 [standard deviation]; age range, 33-87 years) with chronic hepatitis C underwent real-time elastography between January 2009 and September 2009. Elastography was performed at four liver locations by two independent observers. The elastic ratio (ratio of the value in the intrahepatic venous small vessels divided by the value in the hepatic parenchyma) was calculated and was compared with histologic fibrosis stage at liver biopsy. The elastic ratio and clinical fibrosis markers were assessed by using receiver operating characteristic (ROC) analysis. The differences between body site and observers were assessed with κ statistics and intraclass correlation coefficients (ICCs). RESULTS: Real-time tissue elastography cutoff values were 2.73 for F of 2 or greater, 3.25 for F of 3 or greater, and 3.93 for F of 4. No site differences were observed (κ = 0.835, ICC = 0.966), and the elastic ratio measurement was correlated between the two examiners (r(2) = 0.869, P < .0001). The areas under the ROC curves for elastic ratio, hyaluronic acid, type IV collagen, aspartate aminotransferase-to-platelet ratio index, FibroIndex, Forns score, and Hepascore were 0.95, 0.32, 0.73, 0.76, 0.76, 0.87, and 0.70, respectively; the elastic ratio performed better than the serum fibrosis markers and other scores. CONCLUSION: Real-time tissue elastography is not invasive and could be used to evaluate liver fibrosis in patients with chronic hepatitis C. SUPPLEMENTAL MATERIAL: http://radiology.rsna.org/lookup/suppl/doi:10.1148/radiol.10100319/-/DC1.

Prospective study of chronic hepatitis C treated with reduced initial ribavirin dose.

BACKGROUND/AIMS: We prospectively examined the effects of a reduced initial dose of ribavirin (RBV) combined with pegylated interferon (Peg-IFN) to prevent RBV discontinuation due to adverse events in patients with chronic hepatitis C (CH-C) infection aged > 60y or with low hemoglobin values. METHODOLOGY: We enrolled 42 patients with hepatitis C virus (HCV) serotype 1. Twenty-one of them with hemoglobin values < 14g/dl or who were aged > 60y comprised group A. The other 21 patients (sex-and age-matched with group A) comprised group B, and received Peg-IFN (1.5 microg/ kg/week) and RBV (10-13 mg/kg/day) for 48 weeks. Group A initially received 200 mg less RBV than group B. RESULTS: Higher hemoglobin values persisted at 16, 20, 24 and 44 weeks, and the sustained viral response (SVR) ratio was lower in group A than in group B (17% vs. 57%). RBV therapy was discontinued due to severe anemia in group B, but not in group A. CONCLUSIONS: The reduced initial dose of ribavirin prevented discontinuation due to anemia. However, this protocol cannot be recommended even for patients with CH-C accompanied by low hemoglobin or advanced age, since a sufficient SVR ratio is not achievable.

Diabetes pattern on the 75 g oral glucose tolerance test is a risk factor for hepatocellular carcinoma in patients with hepatitis C virus.

BACKGROUND: Patients with hepatitis C virus (HCV) frequently show glucose intolerance. Diabetes mellitus (DM) has been proposed to be a risk factor for hepatocellular carcinoma (HCC). AIMS: The aim of this study is to clarify the influence of glucose intolerance as evaluated by the 75 g oral glucose tolerance test (OGTT) on hepatocarcinogenesis in patients with HCV. METHODS: This study was carried out in a cohort of 197 patients with HCV who had not been previously diagnosed as having DM. All patients underwent the 75 g OGTT at entry. They were also screened for HCC and, thereafter, the rate of hepatocarcinogenesis was compared between the patients with and without glucose intolerance. RESULTS: Based on the results of the 75 g OGTT, 125 (63%) had normal glucose tolerance (NGT), 49 (25%) had impaired glucose tolerance (IGT) and 23 (12%) had the DM pattern. HCC occurred more frequently in patients with the DM pattern than in patients with either NGT or IGT. Even in patients without advanced liver fibrosis, HCC was more frequently observed in patients with DM than in patients with NGT. A multiple logistic regression analysis showed advanced liver fibrosis, the DM pattern on the 75 g OGTT, an older age and gamma-glutamyltransferase to all be independent risk factors related to hepatocarcinogenesis. CONCLUSIONS: A DM pattern on the 75 g OGTT was thus found to be associated with hepatocarcinogenesis and the 75 g OGTT is considered to be useful for identifying this risk factor for HCC in patients with HCV.

Neuropsychiatric dysfunction in patients with chronic hepatitis and liver cirrhosis.

AIM: The aim of this study is to clarify the cerebral functions in patients with chronic hepatitis (CH) as well as those with liver cirrhosis (LC). METHODS: We studied 58 patients with CH (20 in fibrosis stage F1, 20 in F2, 18 in F3), 77 with LC (46 rated as Child-Pugh class A, 24 as B, 7 as C), and 20 healthy volunteers (HV). Computer-aided quantitative neuropsychiatric function test systems, including eight neuropsychiatric tests were performed. RESULTS: Subjects with results over the cut-off value for healthy subjects ranged from 11.1-28.6% in CH and 19.5-36.4% in LC. The percentages with abnormality in at least one test in CH and LC were 72.4% and 80.6%, respectively, which were significantly higher than that in the HV group (35.0%) (P = 0.003, P = 0.0003, respectively). Among CH subjects, those with three or more abnormal results in the F1, F2 and F3 subgroups were 15.0%, 20.0% and 38.9%, respectively. Among LC subjects, those with three or more abnormal results in the Child-Pugh class A, B and C subgroups comprised 30.4%, 50.0% and 57.1%, respectively. The rate in the CH F3 subgroup (P = 0.011) and in all three LC subgroups (P = 0.023, P = 0.001, P = 0.002, respectively) were significantly higher than that in the HV group. CONCLUSION: The percentage of patients with neuropsychiatric function impairment was high in both LC and CH, especially in stage F3. Neuropsychiatric dysfunction may initiate in CH in a considerable number of patients.

Hepatitis C virus replication is inhibited by 22beta-methoxyolean-12-ene-3beta, 24(4beta)-diol (ME3738) through enhancing interferon-beta.

UNLABELLED: A derivative of soyasapogenol, 22beta-methoxyolean-12-ene-3beta, 24(4beta)-diol (ME3738), ameliorates liver injury induced by Concanavalin A in mice. We examined whether ME3738 has independent antiviral effects against hepatitis C virus (HCV) using an established HCV replication model that expresses the full-length genotype 1a HCV complementary DNA plasmid (pT7-flHCV-Rz) under the control of a replication-defective adenoviral vector expressing T7 polymerase. Hepatocellular carcinoma (HepG2) cells, human hepatoma (Huh7) cells, or monkey kidney (CV-1) cells were transfected with pT7-flHCV-Rz, and infected with adenoviral vector expressing T7 polymerase. ME3738 or interferon-alpha (IFN-alpha) was added thereafter and then protein and RNA were harvested from the cells at 9 days after infection. HCV-positive and HCV-negative strands were measured by real-time reverse-transcription polymerase chain reaction and HCV core protein expression was measured using an enzyme-linked immunosorbent assay. The messenger RNA levels of innate antiviral response-related genes were assessed using real-time reverse-transcription polymerase chain reaction. ME3738 dose-dependently reduced HCV-RNA and core protein in hepatocyte-derived cell lines. The antiviral effect was more pronounced in HepG2 than in Huh7 cells. ME3738 increased messenger RNA levels of interferon-beta (IFN-beta) and of IFN-stimulated genes (2'-5' oligoadenylate synthetase, myxovirus resistance protein A [MxA]). Interferon-beta knockdown by small interfering RNA abrogated the anti-HCV effect of ME3738. Moreover, the anti-HCV effects were synergistic when ME3738 was combined with IFN-alpha. CONCLUSION: ME3738 has antiviral effects against HCV. The enhancement of autocrine IFN-beta suggests that ME3738 exerts antiviral action along the type I IFN pathway. This anti-HCV action by ME3738 was synergistically enhanced when combined with IFN-alpha. ME3738 might be a useful anti-HCV drug either with or without IFN-alpha.

Wilms' tumour 1 gene expression is increased in hepatocellular carcinoma and associated with poor prognosis.

BACKGROUND/AIMS: Wilms' tumour 1 gene (WT1) was originally isolated as a tumour-suppressor gene. We investigated the expression of WT1 in hepatocellular carcinoma (HCC; T) and in non-cancerous hepatic tissues (non-tumour: NT) from patients with chronic liver diseases, and then examined the role of WT1 in the carcinogenesis or prognosis of HCC. METHODS: The expression of WT1 in T and NT from 50 patients with HCC was investigated using Western blotting, immunohistochemistry and real-time reverse transcriptase-polymerase chain reaction (RT-PCR). We also examined whether WT1 expression was related to clinicopathological factors in individual patients in addition to prognostic factors in 50 patients with HCC and in 26 without HCC. RESULTS: Western blotting and immunohistochemical staining showed that WT1 was overexpressed in T compared with NT (P<0.001) and real-time reverse transcriptase-polymerase chain reaction (RT-PCR) showed that WT1 mRNA expression was similarly increased. Overexpressed WT1 in HCC was significantly associated with T factors at the TNM stage, and short doubling time of HCC. Univariate and multivariate analyses revealed that WT1 overexpression was an independent prognostic factor for HCC. The disease-free survival period in patients with overexpressed WT1 in NT tissues was significantly reduced. CONCLUSION: The expression of WT1 is increased more in HCC than in non-tumour tissues. Moreover, overexpressed WT1 was associated with tumour growth, and resulted in a worsening prognosis of HCC. Our findings from NT tissues revealed that WT1 overexpression might contribute to oncogenic potential.

Budd-Chiari syndrome associated with hypereosinophilic syndrome; a case report.

A 27-year-old man was admitted due to abdominal fullness. He had ascites and subcutaneous nodules on his head, with liver dysfunction and eosinophilia. Abdominal imaging revealed obstruction of the hepatic veins and stenosis of the inferior vena cava. Histological diagnosis of a subcutaneous nodule revealed obstructive thrombophlebitis with eosinophils. Tyrosine kinase created by fusion of the FIP1L1 and PDGFRA genes, which is characteristic of hypereosinophilic syndrome (HES), was detected. He was diagnosed with Budd-Chiari syndrome associated with HES. Liver function tests improved after interventional therapy followed by steroid therapy. It is important to diagnose the cause of Budd-Chiari syndrome.

[Drug-resistant bacteria isolated from pharyngeal swab cultures and urine in acutely or chronically febrile elderly nursing home inmates].

AIM: Patients in nursing homes are becoming more and more elderly and also prone to infectious diseases. It is important to select proper antimicrobial agents in treating such patients because of the increase in drug-resistant bacteria in recent years. METHODS: Pathogenic aerobic bacteria were isolated from cultures of the pharyngeal swab obtained from patients with acute febrile episodes and those with chronic febrile conditions with a repetition of fever or continuing low-grade fever. Isolation of pathogens was also carried out in patients with a urinary tract infection that was resistant to treatment. Isolated bacteria were tested for sensitivity to commonly used antimicrobial agents. RESULTS: Pathogenic bacteria were isolated from 33% of the patients with acute febrile episodes, while they were isolated from 75% of the patients with chronic febrile conditions. The number of major pathogenic bacteria from 85 isolates were methicillin-resistant staphylococcus aureus (MRSA) 13, methicillin-sensitive staphylococcus aureus (MSSA) 6, Streptococcus pneumoniae 8, beta-hemolytic streptococcus 5, Klebsiella pneumoniae 10, and Enterobacter cloacae 6. Only two isolates of Streptococcus pneumoniae were penicillin-sensitive (PSSP), while the others were penicillin-resistant (PRSP) (1) or penicillin-insensitive (PISP) (5). Among these 8 isolates, 5 were resistant to levofloxacin (LVFX). Escherichia coli was isolated from the pharyngeal swab of 2 patients, one of the 2 isolates being resistant to LVFX. Escherichia coli was isolated from 5 patients with urinary tract infection and 5 of the 6 isolates were resistant to LVFX; with one of them being extended spectrum beta-lactamases (ESBL). CONCLUSION: The frequency of isolation of antimicrobial-resistant pathogens was extremely high among elderly patients in our nursing home compared to values reported from a nation-wide survey recently carried out in Japan. In particular, attention should be focused on the resistance of bacteria to fluoroquinolones.

[Treatment of respiratory and urinary tract infections in elderly inmates at a nursing home by selective antimicrobial agents based on the sensitivity of the isolated bacteria].

OBJECTIVES: Elderly patients living in nursing homes can easily find themselves unable to carry out their daily activities, once they become ill, even with infectious diseases of a slight to mild degree, and rapid treatment is required to cure them of their malaise. However, treatment is often difficult due to the presence of drug-resistant bacteria. This study was designed to evaluate the efficacy of the selective use of antimicrobial agents based on a sensitivity test of isolated bacteria. METHODS: Possible pathogenic bacteria were isolated from cultures of pharyngeal swabs or urine obtained from patients with chronic febrile conditions or urinary tract infections, resistant to antimicrobial treatment. The efficacy of the treatment was evaluated based on release from febrile conditions and improvement of activities of daily living (ADL) accompanied by the disappearance of possible pathogenic bacteria following the use of selective antimicrobial agents. RESULTS: The outcome of 14 cases with sustaining febrile conditions and 3 cases with urinary tract infections was reviewed. Most of them showed a good response to treatment with remarkable improvement in ADL. In some cases, patients were switched from one antimicrobial agent to another each time new pathogenic bacteria were detected in the culture. A combination of rifampicin and sulfamethoxazole/trimethoprim (RFP/ST) was found to be the most convenient and effective treatment in patients with MRSA or drug-resistant Streptococcus pneumoniae. Levofloxacin (LVFX)-resistant Escherichia coli were detected together with MRSA in our 3 patients with urinary tract infections, corresponding to the frequent use of LVFX in our community. CONCLUSIONS: Identification of possible pathogenic bacteria and the use of proper antibiotic agents based on a sensitivity test are very effective in the treatment of elderly patients with chronic febrile conditions arising from the presence of drug-resistant bacteria. Careful use of fluoroquinolones is required in patients in whom MRSA is or had once been detected. This is beneficial not only for the elderly patients themselves but is also useful in preventing the spread of drug-resistant bacteria.

Characteristics of lamivudine-resistant hepatitis B virus (HBV) strains with and without breakthrough hepatitis in patients with chronic hepatitis B evaluated by serial HBV full-genome sequences.

Lamivudine therapy often causes breakthrough of hepatitis B virus (HBV) DNA and breakthrough hepatitis. The aim of this study was to determine the viral factors that relate to HBV-DNA breakthrough with and without breakthrough hepatitis. Among 82 patients with chronic hepatitis B (CHB) who received lamivudine at a dose of 100 mg daily for more than 24 months, 23 patients had HBV-DNA breakthrough induced by a lamivudine-resistant mutant. Of these 23 patients, 16 had breakthrough hepatitis and 7 had only HBV-DNA breakthrough. Serial HBV-DNA full-genome sequences during therapy were examined in 10 (7 had breakthrough hepatitis and 3 did not) of these 23 patients by direct sequencing. Mutations in the S region were examined by cloning in representative patients. There were no significant differences in the baseline clinical backgrounds and virus marker between patients with and without breakthrough hepatitis. The HBV amino acid substitutions at breakthrough hepatitis were identical to those at HBV-DNA breakthrough. Cloning analysis revealed that monoclonal mutational strain appeared at breakthrough and no such mutations existed at baseline. Regarding HBV amino acid substitutions in the polymerase region, S region, X region, and precore-core region with breakthrough compared to baseline, there was no significant differences of the numbers of amino acid substitution between breakthrough hepatitis and non-breakthrough hepatitis. There were no common amino acid changes in patients with breakthrough hepatitis. Although monoclonal lamivudine-resistant strain emerged at HBV-DNA breakthrough in patients with CHB, there were no common amino acid changes, suggesting viral factor may have insignificant role in breakthrough hepatitis.

Diabetes mellitus reduces the therapeutic effectiveness of interferon-alpha2b plus ribavirin therapy in patients with chronic hepatitis C.

AIM: Patients with chronic hepatitis C (CHC) often have diabetes mellitus (DM). However, it is unknown whether DM affects patient response to interferon (IFN) plus ribavirin therapy. Therefore, the aim of this study was to examine the influence of DM on the outcome of IFN-alpha2b plus ribavirin therapy. METHODS: In a cohort of 110 patients with CHC, the outcome of 6 months of IFN-alpha2b plus ribavirin therapy was evaluated by comparing the patients with and without DM. RESULTS: There were 46 sustained-responders; 64 patients did not become sustained responders. Higher age (P = 0.015), lower platelet counts (P = 0.036), hepatitis C virus (HCV) serotype 1 (P = 0.001), advanced liver fibrosis (P = 0.004), and the presence of DM (P = 0.007) were significantly associated with not becoming a sustained-responder. Seventeen CHC (15%) patients had DM. Sex ratio, age, body mass index, alanine aminotransferase levels, HCV-RNA titer, and HCV serotypes did not significantly differ between the patients with and without DM, while fasting plasma glucose, hemoglobin A1c and liver histological staging were significantly different. On multiple logistic regression analysis, HCV serotype 1 (odds ratio 8.743, 95% confidence interval 2.215-34.517; P = 0.002) and the presence of DM (odds ratio 8.657, 95% confidence interval 1.462-51.276; P = 0.014) were independently associated with not becoming a sustained-responder. CONCLUSIONS: The findings indicate that DM reduces the response to IFN-alpha2b plus ribavirin therapy in CHC patients.

Anti-HBs-positive liver failure due to hepatitis B virus reactivation induced by rituximab.

A 59-year-old man developed acute hepatitis with reactivated hepatitis B virus (HBV) following administration of rituximab (anti-CD20 monoclonal antibody). The patient was diagnosed with malignant lymphoma in 1998, and virus marker testing indicated HBV surface antigen (HBsAg)-negative and anti-HBs antibody (anti-HBs)-positive results when chemotherapy including rituximab was started. Levels of aminotransferases were elevated, and HBsAg results turned positive. Despite therapy for late-onset hepatic failure, the patient died. Rituximab appears likely to have induced HBV reactivation in this case. Anti-viral agents should be administered for both HBsAg-positive and anti-HBs-positive patients who are scheduled to receive rituximab.

Pleomorphic carcinoma of the lung associated with loss of heterozygosity of p53 gene.

We report a case with pleomorphic carcinoma of the lung in a 70-year-old man. Pleomorphic carcinoma is characterized by a heterogenous composition that includes epithelial and mesechymal malignancies. In the present case, the tumor was composed of a mixture of unequivocal squamous cell carcinoma and spindle cell components resembling sarcomatous overgrowth. The spindle component did not include a heterologous mesenchymal element characterized by overt differentiation for bone, cartilage, neuron or muscle tissue. To evaluate a state of differentiation of the spindle cell component, we immunohistochemically examined expression of the antigens including vimentin, cytokeratin, sarcomeric actin, alpha-smooth muscle actin, S-100 protein, CD34, Factor VIII, and CD68. The results showed sole expression of vimentin in the spindle cell component, suggesting an immature state of the mesenchymal lineage. Furthermore, the spindle cell component of this case was genetically characterized by loss of heterozygosity (LOH) at a codon 234 of exon 7 of the p53 gene. This mutation causes an amino-acid replacement (Tyr to Cys), which was previously proven to attenuate p53 function. The present case may suggest a relation between somatic alteration of the p53 gene and histogenesis of pleomorphic carcinoma.

Comparison of eight- versus 16-slice multidetector-row computed tomography for visibility and image quality of coronary segments.

Ten patients who underwent conventional coronary angiography (CA) were examined with both 8- and 16-slice multidetector-row computed tomography (MDCT) angiography within 6 months, and visibility and image quality of 16-slice MDCT-CA were compared with those of 8-slice MDCT-CA directly. In 136 segments determined by conventional CA, 101 (74.3%) and 126 (92.6%) segments were judged assessable by 8- and 16-slice MDCT-CA, respectively. Segment visibility in the right coronary and left circumflex arteries, as well as distal segments and small segments with diameters of <3.0 mm, was higher using 16-slice MDCT-CA than that of 8-slice MDCT-CA. As causes for invisibility in segments considered to be invisible, adjacent structures, as well as small diameters, were reduced by 16-slice MDCT-CA, suggesting that high spatial resolution contributes to higher visibility; however, nonassessable segments due to extensive calcium by 8-slice MDCT-CA were also judged nonassessable by 16-slice MDCT-CA.

Long-term survivors after resection of carcinoma of the head of the pancreas: significance of histologically curative resection.

BACKGROUND/PURPOSE: The prognosis of patients with pancreatic cancer is said to have not been improved markedly by any procedures in the past 20 years. Since 1973, we have gradually extended the area of dissection when performing curative resection for pancreatic cancer to improve the resection rate and prognosis. Nineteen patients have survived for 3 years or more, and the 5-year survival rates of patients with cancer of the head of the pancreas were 23.9% for macroscopically curative resection and 34.3% for histologically curative resection. METHODS: We histologically observed surgical specimens, cut into 3- to 5-mm sections and compared the histologic characteristics of the 19 patients who survived for 3 years or more with those of 41 patients who died of cancer within 3 years (excluding 6 operative and hospital deaths), in order to find the conditions required for long-term survival. RESULTS: The following conditions were associated with long-term survival: (1) tumor diameter 3 cm or less; (2) either absence of lymph node metastasis or metastasis limited to the n(1) group; (3) degree of invasion of the anterior pancreatic capsule of zero (s0); and (4) either no retropancreatic invasion (rp0) or exposed retropancreatic invasion (rpe) with no cancer invasion of dissected peripancreatic tissue ew(-). CONCLUSIONS: At present, because the rpe rate is more than 70%, resection of the pancreas, including the superior mesenteric vein and the retropancreatic fusion fascia, is essential for a curative resection, because the retropancreatic tissue between the back of the pancreas and this fascia is anatomically considered to be in the position of the subserosal tissue in the gallbladder or stomach. Combined resection of the superior mesenteric artery may further improve the results of resection for pancreatic cancer, from the anatomical viewpoint.

Renal transplant recipient with chronic hepatitis C who obtained sustained viral response after interferon-beta therapy.

A 44-year-old Japanese woman with a history of living-related renal transplantation was treated with interferon-beta (IFN-beta) for chronic infection with sero-group 2 hepatitis C virus (HCV). Serum HCV-RNA titer was 160 kilo-international units/ml. Treatment with intravenous IFN-beta daily was given for 6 weeks. Serum HCV-RNA was undetectable at 3 weeks after initiating therapy. Renal graft rejection did not occur. Six months after completing therapy, she obtained sustained viral response. This case demonstrates that IFN-beta therapy safely induced clearance of HCV in a renal transplant recipient with stable renal function, low viral load and/or HCV sero-group 2.