Y Iino

High proportion of missense mutations of the BRCA1 and BRCA2 genes in Japanese breast cancer families

AbstractMutations in either of two recently identified genes, BRCA1 and BRCA2, are thought to be responsible for approximately two-thirds of all cases of autosomal-dominantly inherited breast cancer. To examine the nature and frequency of BRCA1 and BRCA2 mutations in Japanese families exhibiting a high incidence of breast cancer, we screened 78 unrelated families in this category for mutations of these two genes. Examining the entire coding sequences as well as exon–intron boundaries of both genes by polymerase chain reaction (PCR) single-strand conformation polymorphism (SSCP) and multiplex-SSCP analysis, we identified possible disease-causing alterations in BRCA1 among affected members of 15 families and in BRCA2 in another 14 families. In 15 of those 29 families, the affected individuals carried missense mutations, although most germline mutations reported worldwide have been deletions or nonsense mutations. Our results, indicating that missense mutations of BRCA1 and BRCA2 tend to predominate over frameshifts or nonsense mutations in Japanese breast cancer families, will contribute signifi-cantly to an understanding of mammary tumorigenesis in Japan, and will be of vital importance for future genetic testing.

Percutaneous ethanol injection therapy for patients with inoperable thyroid papillary cancer: a report of two cases

Abstract Percutaneous ethanol injection therapy (PEIT) has been proposed for the treatment of autonomously functioning thyroid nodules and cysts. We report two patients with inoperable thyroid papillary cancer treated with PEIT, which has not, to date, been used frequently for this purpose. One patient, who had a large thyroid papillary cancer, had had liver cirrhosis for more than 5 years. The other patient was elderly and had diabetes mellitus and chronic hepatitis. In both patients, there was massive adhesion between the tumor and the trachea. Because a complete resection would have been both difficult and risky for either patient, we elected to use the PEIT procedure. The tumors regressed markedly in size as a result of the repetition of PEIT. There were no severe complications in either patient, except for slight pain and transient mild dysphagia. PEIT may be a useful treatment for patients with advanced thyroid papillary cancer and/or for those patients at high risk for surgical remedies; it is a viable option for patients with inoperable disease.

Histochemical demonstration of endogenous estrogen in breast carcinomas: biochemical and clinical correlation *

In a study of 277 patients with breast carcinomas, the PAP immunoperoxidase method for demonstrating endogenous estrogen was correlated with the sucrose density gradient (SDG) assay and with histologic and clinical features. The results from the PAP method and SDG assay agreed in 59 of 84 patients (82.1%) on whom both methods were performed. Histologically, the PAP method was positive in 7 of 7 patients with non-invasive carcinomas, in 164 of 233 patients (70.4%) with common invasive ductal carcinoma, and in 21 of 22 of those with special histological types of invasive carcinomas not including Pagets disease, medullary or apocrine carcinoma, where only 5 of 14 were positive. Clinically, 15 of 18 patients with positive endogenous estrogen showed a response to endocrine therapy as opposed to 1 of 9 patients with a negative endogenous estrogen. The mean survival was 31.2 and 15.6 months, respectively for patients with positive and negative endogenous estrogen. Remission for longer than 2 years was seen more often in patients with positive endogenous estrogen. These results suggest a clinical utility of the present PAP method which, therefore, deserves a further trial as an alternative to histochemical methods aiming at the estrogen receptors.

Platelet-derived endothelial cell growth factor/thymidine phosphorylase expression in macrophages correlates with tumor angiogenesis and prognosis in breast cancer

Expression of platelet-derived endothelial cell growth factor/thymidine phosphorylase (PD-ECGF/TP), an angiogenic factor, was immunohistochemically analyzed in 117 specimens of invasive breast carcinoma (IBC). PD-ECGF/TP expression was observed in cancer cells and/or stromal cells; most of these stromal cells were activated macrophages. Therefore, we assessed the PD-ECGF/TP expression separately in cancer cells and stromal cells. Sixty-one (52.1%) cases were classified as PD-ECGF/TP-positive in cancer cells and 44 (37.6%) were classified as positive in stromal cells. The PD-ECGF/TP expression in cancer cells did not correlate with any prognostic factors. However, its expression in stromal cells positively correlated with both tumor size and microvessel count, and inversely correlated with estrogen receptor status. Relapse-free survival and overall survival (OS) were significantly worse in patients with PD-ECGF/TP-positive stromal cells than in patients with negative cells. A multivariate analysis using the Cox proportional hazards model showed that the PD-ECGF/TP expression in stromal cells independently predicted OS as well as nodal status and tumor size. In conclusion, PD-ECGF/TP expression in stromal cells correlates with tumor angiogenesis and can be used to predict the prognosis of patients with IBC.

Antitumor effect of medroxyprogesterone acetate (mpa) on 7,12-dimethylbenz(a)anthracene-induced rat mammary-carcinoma depends upon the mpa concentration in tumors of rats.

Medroxyprogesterone acetate (MPA) in doses of 1 mg, 5 mg or 10 mg, was orally administered daily for four weeks to rats with 7,12-dimethylbenz(a)anthrace (DMBA)-induced mammary carcinoma. All rats were sacrificed after four weeks and MPA concentration was determined in serum, tumor and muscle. MPA concentration in the tumor was much higher compared with that in the serum or in the muscle in each treatment group. There was no difference between responder group and non-responder group in MPA concentration in the serum, however, MPA concentration in the responder group was significantly higher than that in the non-responder group in all the tumors of the treatment groups. These results suggest that antitumor effect of MPA on DMBA-induced rat mammary tumors depends upon the MPA concentration in the tumor of the rat.