Cross‐sectional analysis of germline BRCA1 and BRCA2 mutations in Japanese patients suspected to have hereditary breast/ovarian cancer

The prevalence of BRCA1/2 germline mutations in Japanese patients suspected to have hereditary breast/ovarian cancer was examined by a multi‐institutional study, aiming at the clinical application of total sequencing analysis and validation of assay sensitivity in Japanese people using a cross‐sectional approach based on genetic factors estimated from personal and family histories. One hundred and thirty‐five subjects were referred to the genetic counseling clinics and enrolled in the study. Full sequencing analysis of the BRCA1/2 gene showed 28 types of deleterious mutations in 36 subjects (26.7%), including 13 types of BRCA1 mutations in 17 subjects (12.6%) and 15 types of BRCA2 mutations in 19 subjects (14.1%). Subjects were classified into five groups and 22 subgroups according to their personal and family history of breast and/or ovarian cancer, and the prevalence of deleterious mutations was compared with previously reported data in non‐Ashkenazi individuals. Statistical analysis using the Mantel‐Haenszel test for groups I through IV revealed that the prevalence of Japanese subjects was significantly higher than that of non‐Ashkenazi individuals (P = 0.005, odds ratio 1.87, 95% confidence interval 1.22–2.88). Family history of the probands suffering from breast cancer indicated risk factors for the presence of deleterious mutations of BRCA1/2 as follows: (1) families with breast cancer before age 40 within second degree relatives (P = 0.0265, odds ratio 2.833, 95% confidence interval 1.165–7.136) and (2) families with bilateral breast cancer and/or ovarian cancer within second degree relatives (P = 0.0151, odds ratio 2.88, 95% confidence interval 1.25–6.64). (Cancer Sci 2008; 99: 1967–1976)     

Lack of influence of low blood cholesterol levels on pancreatic carcinogenesis after initiation with N-nitrosobis(2-oxopropyl)amine in Syrian golden hamsters

The effects of a cholesterol-free diet, a cholesterol-free dietsupplemented with sesamin, and a diet supplemented with sesaminon pancreatic carcinogenesis of N-nitrosobis(2-oxopropyl) amine(BOP) were investigated in 140 female Syrian golden hamsters.BOP (70 and 20 mg/kg body wt) was injected s.c. twice at aninterval of 2 weeks at the beginning of the experiment. Starting3 weeks thereafter, the animals were maintained on basal diet,cholesterol-free diet, basal diet plus sesamin, or cholesterol-freediet plus sesamin for a further 15 weeks. All surviving hamsterswere killed at week 18, and the pancreatic tissues examinedhistologically. The incidences of pancreatic neoplastic andpreneoplastic lesions in each group did not show any statisticallysignificant variation. The cholesterol-free diet significantlydecreased the cholesterol contents of the serum, pancreas andliver, and sesamin supplement significantly decreased the cholesterolcontents of the serum and liver. Both the cholesterol-free dietand sesamin decreased the serum lipoperoxide levels. The resultsthus indicated that low cholesterol per se and sesamin exertno significant influence on BOP-initiated pancreatic carcinogenesisin hamsters, at least within the 4 month period after carcinogentreatment.     

Mitogen-activated protein kinase inhibitor,PD98059, inhibits rat retinal pigment epithelial cell replication by cell cycle arrest

PURPOSE: To investigate the effect of PD98059, a mitogen-activated protein kinase (MAPK) inhibitor, on the replication of rat cultured retinal pigment epithelial (RPE) cells. METHODS: Growth-phase rat RPE cells were exposed to various concentrations of PD98059 in serum-free F12 medium containing 0.1% dimethyl sulfoxide. Cell proliferation was assessed by cell counts using a hemocytometer. Cell viability was tested by CellTiter 96 AQueous Non-Radioactive Cell Proliferation Assay at 24 hours after PD98059 application. Hoechst 33552 and propidium iodide staining were used to assess nuclear morphology. Immunostaining with Ki67 antibody was used for cell cycle analysis because the staining patterns produced on cells are characteristic depending on their position within the cell cycle. RESULTS: PD98059 inhibited cellular proliferation of cultured rat RPE cells in a dose-dependent manner but did not induce cell death. Twenty-four hours after the application of PD98059, cultured RPE cells were not immunopositive for Ki67, indicating that their cell cycle was arrested in the G0/G1 phase. CONCLUSION: These results demonstrated that MAPK inhibition arrested cell cycle progression of rat cultured RPE cells at the G0/G1 phase. The pharmacological induction of cell cycle arrest could be a new approach to inhibit cellular proliferation in such conditions as proliferative vitreoretinopathy.     

Effect of oral adsorbent (AST-120) on renal function,acquired renal cysts and aortic calcification in rats with adriamycin nephropathy

AIMS: The effect of oral adsorbent, AST-120, on the experimental renal disease induced by adriamycin, uninephrectomy and high protein diet proposed as a model of acquired cystic disease of the kidney was investigated. METHODS: 3 mg of adriamycin was injected into the tail vein of rats and 4 weeks later right-side nephrectomy was performed, 2 weeks thereafter 26 rats with urinary protein excretion between 100 and 358 mg/day were selected from 60 rats. Two groups, 13 rats in each group, namely the AST-120-treated group and control group, both of which had equal renal damage before the administration of AST-120 or placebo. AST-120 (0.4 g/100 g BW/day) was administered for 19 weeks. RESULTS: Serum creatinine and BUN in the AST-120-treated group were significantly lower (serum creatinine: 3.3 +/- 2.1 vs. 7.1 +/- 2.7 mg/dl, p < 0.003) and creatinine clearance was higher (0.62 +/- 0.49 vs. 0.29 +/- 0.30 ml/min, p < 0.05) at the final examination than in the control group. Survival rate which was examined using another set of 9 rats was higher in AST-120-treated rats than in AST-120-untreated rats. Serum indoxyl sulfate was significantly lower at all times after using AST-120 in the AST-120-treated group than in contrast to the control group. Histological examination revealed less severe interstitial and cystic changes in the AST-120-treated group. This suggests that AST-120 can prevent or retard the development of acquired renal cystic disease in this model. Aortic calcification tended to be less severe in the AST-120-treated group because of less serum Ca x P products. CONCLUSION: The AST-120-treated group significantly decreased serum creatinine and increased creatinine clearance with less severe renal cystic changes in this model during the later weeks of administration of AST-120 or at death, accompanied with the tendency of less severe aortic calcification.     

Tuberculous peritonitis defying diagnosis: Report of a case

(Received for publication on Feb. 10, 1999; accepted on Nov. 11, 1999)     

Multiple bile duct biopsies using a sheath with a side port: usefulness of intraductal sonography

OBJECTIVE: We clarified the number of biopsies required to determine malignancy of the biliary tract on the basis of the type of bile duct tumor. SUBJECTS AND METHODS: Patients with a biliary tract malignancy (n = 33) and a benign biliary stenosis (n = 3) underwent biopsy via the percutaneous transhepatic route. We performed intraductal sonography using a 20-MHz probe with a 2.0-mm diameter. The sonographic findings were prospectively classified as polypoid, circular, or semicircular. The tip of a long 9-French sheath with a side port was wedged into the stenosis, and six specimens were obtained with a 1.8-mm-diameter forceps with serrated cups. RESULTS: When cholangiography or intraductal sonography showed a polypoid lesion, the sensitivity of two biopsies was 100% (6/6). When cholangiography showed a stenotic lesion, the sensitivity of nine biopsies (96%, 26/27) was superior to that of two biopsies (74%, 20/27; p < 0.05). When intraductal sonography showed a circular lesion, the sensitivity of three biopsies (100%, 14/14) was superior to that of a single biopsy (64%, 9/14; p < 0.05). When it showed a semicircular lesion, the sensitivity of nine biopsies (92%, 12/13) was superior to that of two biopsies (54%, 7/13; p < 0.05). CONCLUSION: Bile duct biopsy using a sheath with a side port has a high sensitivity. However, the number of biopsies required depends on the cholangioscopic and intraductal sonographic appearance of the tumor.     

Analysis of survivorship after total hip arthroplasty using a ceramic head

To determine the clinical efficacy of an alumina ceramic head, 119 cemented total hip arthroplasties in 97 patients using an alumina head coupled with ethylene oxide gas sterilized polyethylene were reviewed. Eighty-two patients (101 hips) with greater than 10 years followup were evaluated clinically and radiographically (range, 10-17.6 years), and 97 patients (119 hips) were evaluated for survivorship analysis (range, 0.6-17.6 years). The average functional hip scores according to Merle d'Aubigné and Postel improved from 8.6 preoperatively to 15.0 at the final followup, and 57 patients (64 hips) had no pain. The average polyethylene wear rate was 0.15 mm/year (range, 0.04-0.34 mm/year). Patients with polyethylene wear greater than 3 mm showed significantly higher rates of acetabular loosening. Fifteen-year survival rates (with 95% confidence intervals) with radiographic evidence of aseptic loosening as the end point were 46.8% +/- 13.4% in acetabular components and 91.9% +/- 6.6% in femoral components. Fifteen-year survival rates of hip arthroplasties with revision because of aseptic loosening as the end point were 75.3% +/- 10.2% and 97.9% +/- 3.0%, respectively. Results of the current study suggest that using an alumina head instead of a metal head may not be beneficial when coupled with ethylene oxide gas sterilized polyethylene.     

Variation in K-ras Codon 12 Point Mutation Rate with Histological Atypia within Individual Colorectal Tumors

To elucidate genetic alteration in relation to morphology and also to confirm more directly the proposed adenoma-carcinoma sequence, we analyzed thirty-eight colorectal "cancer in adenoma" lesions exhibiting areas of different atypia, in terms of K- ras codon 12 point mutation. The mutation incidence was 26.3% (10/38) for all cancerous areas. Well-differentiated and very well-differentiated carcinoma exhibited values of 17.6% (3/17) and 30.4% (7/23), respectively (statistically not significant). Positive cases of adenoma with severe atypia and adenoma with moderate or slight atypia were 26.7% (8/30) and 8.3% (3/36) respectively (statistically significant). Thus, K- ras point mutation, as indicated previously, may play an important role in the early stages of colorectal tumorigenesis. As for the nature of the mutation, GGT(Gly) to GAT(Asp) was the most frequent (80%). Eight cases had mutations concurrently in different areas of the same tumor and in all of these the mutation was homogeneous (6 cases to GAT, 1 case to TGT and 1 case to GTT). This provides genetic support for the "adenoma-carcinoma sequence" theory proposed on the basis of morphological considerations. All lesions with a mutation were of polypoid type, and no mutation was found in the flat type.