Michio Maemura

Mitogen-Activated Protein Kinase Cascade in Breast Cancer

The mitogen-activated protein (MAP) kinase is considered to play a central role in diverse cellular events including carcinogenesis and tumor progression. Indeed, expression of MAP kinase, tyrosine-phosphorylated MAP kinase, and Raf-1 protein was greater in cancerous human tissues than in the surrounding noncancerous glands. In a 7,12-dimethylbenz[a]anthracene-induced rat mammary carcinoma model, estrogen promoted and ovariectomy and antiestrogen, tamoxifen (TAM) inhibited the tumor growth. Ovariectomy suppressed expression of MAP kinase, tyrosine-phosphorylated MAP kinase and Raf-1, whereas estrogen as well as TAM induced expression of MAP kinase and Raf-1 under castrated conditions. Since it was reported that MAP kinase was activated during the progression of breast carcinoma cells, such estrogenic actions of TAM toward the MAP kinase cascade might be responsible for malignant progression.

Serum concentration of hepatocyte growth factor in patients with metastatic breast cancer

The serum concentration of hepatocyte growth factor (HGF) was examined in 34 patients with metastatic breast cancer. Although no significant difference was observed between HGF concentration and the site of metastasis, serum HGF levels were slightly higher in patients with liver metastasis and in patients with multiple metastatic sites than in patients with other lesions. Significantly higher levels of serum HGF were observed in patients with progressive metastasis of breast cancer compared with those with stable metastasis. The patients with high HGF levels exhibited a significantly shorter survival rate than those with low HGF levels. Circulating HGF levels may be a useful indicator for the progression of metastatic lesions and the prognosis of patients with metastatic breast cancer.

The efficacy of technetium-99m-MIBI scan and intraoperative methylene blue staining for the localization of abnormal parathyroid glands.

The efficacy of the technetium-99m-2-methoxy-isobutylisonitrile (Tc-MIBI) scan and intraoperative methylene blue staining was analyzed in a consecutive series of 15 patients with primary hyperparathyroidism who underwent neck surgical exploration. A total of 17 abnormal parathyroid glands were removed, 7 of which were confirmed histologically as adenomas and 10 as hyperplasias. The Tc-MIBI scan and the thallium-201-technetium-99m subtraction (TI/Tc) scan preoperatively localized 11 (69%) of 16, and 6 (40%) of 15 abnormal parathyroid glands, respectively. The Tc-MIBI scan correctly localized two ectopic abnormal parathyroid glands which were not localized by the Tl/Tc scan or ultrasonography (US). However, it also demonstrated falsepositive accumulations caused by thyroid diseases in two patients. There were 4 abnormal parathyroid glands not detected by the preoperative imaging techniques, whereas all 17 abnormal parathyroid glands were stained with methylene blue, the infusion of which caused no adverse effects or toxicity. In conclusion, Tc-MIBI scanning and intraoperative methylene blue staining are effective techniques for the localization of abnormal parathyroid glands in patients with primary hyperparathyroidism.

1α-hydroxyvitamin D3, hypercalcemia, and growth suppression of 7,12-dimethylbenz[a]anthracene-induced rat mammary tumors

Summary1α-hydroxyvitamin D3 [1α(OH)D3] was administered to female Sprague-Dawley rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. 1α(OH)D3 suppressed the growth of the rat mammary tumors dose-dependently, and in the high dose groups treated with 0.5–1.0µg/kg of 1α(OH)D3, significant inhibition of tumor growth was observed. But daily oral administration of 1α(OH)D3 for four consecutive weeks caused side effects such as hypercalcemia and weight loss. We compared 0.5 µg/kg of 1α(OH)D3 three times weekly with the same dose six times weekly to discover whether or not the side effects can be reduced by treatment schedule. Both groups showed a significant oncostatic effect, compared with the control group, while the side effects were relieved in the three times weekly group. Regarding estrogen receptors (ER) in the tumors, there was no significant difference among the groups. These results suggested that the antitumor effect of 1α(OH)D3 on DMBA-induced mammary tumors was not related to ER status. Combined use of 1α(OH)D3 with 5-fluorouracil (5-FU) or medroxyprogesterone acetate (MPA) was also examined. No significant augmentation of the antitumor effect was seen in the two combinations, although the combined therapy with MPA showed a significant inhibition of weight loss in the rats.

Interferon potentiates antiproliferative activity of CPT-11 against human colon cancer xenografts

We studied the antiproliferative effect of recombinant human interferon-alpha/beta/gamma (rHuIFN-alpha/beta/gamma) and CPT-11 against human colon cancer xenografts in nude mice. CPT-11 (25 mg/kg) alone exhibited significant antiproliferative effects. Although rHuIFN-alpha/beta/gamma alone did not show antiproliferative activity, it markedly enhanced the antiproliferative activity of CPT-11. rHuIFN-alpha/beta/gamma significantly increased in the population of cells in the S-phase. rHuIFN-alpha/beta/gamma progressed cell cycle in the S-phase under the existence of CPT-11, which exhibited no effect on cell cycle progression. Because CPT-11 is known to exhibit antiproliferative effect on S-phase cells, IFNs, especially rHuIFN-alpha and beta, can enhance the antiproliferative effect of CPT-11 mediated by cell accumulation in the S-phase.

Effect of toremifene on the growth, hormone receptors and insulin-like growth factor-1 of hormone-dependent MCF-7 tumors in athymic mice

Toremifene given in different sizes of silastic capsules was used to treat MCF-7 tumors in athmic mice. Toremifene inhibited the estradiol-stimulated growth of MCF-7 tumors in athymic mice. Average serum concentrations of toremifene obtained using a sustained-release preparation of the drug (in 0.5-, 1.0-, and 2.0-cm silastic capsules) increased gradually in a capsule-size-dependent fashion. Much higher levels of toremifene orN-demethyltoremifene were detected in tumors(target tissues of estrogen) as compared with muscles (non-target tissues of estrogen). The concentration of toremifene in serum (i.e., 10–30 ng ml−1) was sufficient to inhibit the estrogen-stimulated growth of MCF-7 tumors at physiological (i.e., 200–400 pg ml−1) serum estradiol concentrations in premenopausal women. No significant difference in estrogen receptor (ER) levels was found between the estradiol-alone group and the toremifene-treated groups. However, the ER levels in the toremifene-alone group and the no-treatment group (no toremifene or estradiol) tended to increase as compared with the estradiol-alone group. Toremifene blocked the estradiol-induced increase in progesterone receptor levels in a dose-dependent fashion. Insulin-like growth factor-1 (IGF-1) levels in the MCF-7 tumors significantly decreased in the toremifene-alone group as compared with the estradiol-alone group. These results show the antiestrogenic action of toremifene on hormone-dependent MCF-7 tumors in athymic mice.

Highest microvessel count as a long-term prognostic factor in Japanese breast cancer patients.

The aim of this study was to determine whether microvessel density (MVD) could add useful information in predicting the prognosis of breast cancer patients. In our study, MVD was calculated by counting microvessels per x200 field in the highest neovascularized area of the tumor (highest microvessel count, HMC). HMC significantly increased according to the increased number of positive nodes. Higher HMC significantly correlated with worse relapse-free survival (RFS) of patients with negative node, one to three positive nodes in the axilla or with stage I and II tumors. HMC, however, was not predictive for RFS of patients with four or more positive nodes or with stage III tumors. Multivariate analysis revealed that HMC was second only to nodal status and tumor size as being predictive for RFS. These results suggest that HMC could be used in selection of patients with early-stage breast cancer who are at high risk for having occult metastasis.

Granular Cell Tumor of the Breast Diagnosed by Core Needle Biopsy: A Case Report

Granular cell tumor rarely occurs in the breast. We report a 69-year-old woman with a right breast mass that simulated carcinoma on palpation, mammography, and ultrasonography. Aspiration biopsy cytology showed no malignant atypical cells. Core needle biopsy was performed to obtain an accurate diagnosis. The lesion was histologically confirmed to be a granular cell tumor. Immunostaining was positive for S-100 protein and vimentin, and negative for keratin, carcinoembryonic antigen, estrogen receptor and gross cystic disease fluid protein-15. The tumor was treated by wide local excision. Surgeons should be aware that granular cell tumor can resemble breast cancer in order to avoid performing a needless radical mastectomy.

Tamoxifen-failed male breast cancer with a high level of circulating estrogen: report of a case.

Abstract We report herein the case of a 40-year-old man with grade II invasive ductal carcinoma of the breast (pT1, pN0, M0: stage I) in whom a recurrence developed shortly after completion of a 2-year course of tamoxifen and 5-fluorouracil therapy following a mastectomy. Although the metastatic tumor was estrogen receptor-positive, hormone therapy combined with chemotherapy had no significant effect on tumor growth, and the patient died from disseminated tumors 2 years 6 months after completion of the adjuvant therapy. It is noteworthy that the circulating estradiol level increased from 18.0 to 892.3 pg/ml during the period of tumor progression and dissemination. We interpret these findings as an indication of high aromatase activity in the metastatic tumors. We suggest that extending tamoxifen treatment to 5 years or longer be recommended for the standard adjuvant hormone therapy of male breast cancer to prevent the early recurrence of hormone-responsive disease.

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.