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The anti-ischemic heart effect of (+/-)-(E)-4-ethyl-2-[(E)-hydroxyimino]- 5-nitro-3-hexenamide (FK409), a novel nitric oxide donor, was studied in dog and rat preparations in vivo and in vitro. In anesthetized dogs with partially occluded coronary artery that were subjected to atrial pacing at a constant blood pressure, FK409 (1-100 micrograms/kg, i.v.) suppressed the ST-segment elevation on epicardial electrocardiograms. Glyceryl trinitrate (GTN; 10, 32 micrograms/kg) or dipyridamole (1000 micrograms/kg) failed to suppress the ST-segment elevation, although continuous i.v. infusion of GTN (32, 100 micrograms/kg/min) was effective. FK409 also suppressed the ST-segment elevation induced by methacholine in anesthetized rats by both i.v. (10, 100 micrograms/kg) and intraduodenal (i.d., 100, 1000 micrograms/kg) injections, while GTN (100 micrograms/kg, i.v.; 1000 micrograms/kg, i.d.) was effective only by the i.v. route. FK409 (0.32 microgram/kg/min, i.v.) and GTN (10 micrograms/kg/min) increased the blood flows of the endomyocardium (ENDO) and the epicardium (EPI) and the flow ratio of ENDO/EPI in the ischemic zone in anesthetized dogs with occluded coronary artery. Furthermore, in isolated dog vascular preparations, FK409 (4.6 x 10(-10)-4.6 x 10(-7) M) had a greater vasorelaxing effect on the large coronary artery [2.0-2.5-mm outer diameter (od)] than on the small coronary artery (0.3-0.5-mm od) or the saphenous artery. The results suggest that FK409 protects against acute experimental myocardial ischemia through relaxation of the large conductive coronary artery, and may be a useful oral drug for the treatment of angina pectoris.

The purpose of this study was to compare the results of 133 cases (131 patients) of subcutaneous mastectomy with axillary dissection between 1983 and 1999 and 910 cases of radical mastectomy during the same period. The median follow-up period of the subcutaneous mastectomy group and the radical mastectomy group were 66 months and 81 months, respectively. The age at operation was significantly (p0.01) younger in the subcutaneous mastectomy group than in the radical mastectomy group and the clinical stage was significantly (p0.01) earlier. Lymph node metastasis was significantly (p0.01) higher in the radical mastectomy than in the subcutaneous mastectomy group. There was no difference in ER status between the two groups. There was local recurrence in 5 (3.8%) members of the subcutaneous mastectomy group and in 12 (1.3%) members of the radical mastectomy group. There was no difference in disease-free survival and overall survival between the two groups. Divided into two subgroups by lymph node status, there was no difference in disease-free survival and overall survival between the two groups. Local recurrence occurred more frequently (p0.05) in the subcutaneous mastectomy group, however, than in the radical mastectomy group when no lymph node metastasis was found. Multivariate analysis using the Cox hazard model showed that operation method and lymph node status were independent prognostic factors for local recurrence, whereas, lymph node status and ER status were independent prognostic factors of disease-free survival. In conclusion, subcutaneous mastectomy presents a risk factor for local recurrence, but the survival rate of the subcutaneous mastectomy group is as favourable as the radical mastectomy group.

The effect of a combined therapy of medroxyprogesterone acetate (MPA) and 5-fluorouracil (5-FU) on tumor size, pyrimidine nucleoside phosphorylase (PyNPase) activity, and thymidylate synthetase (TS) activity was examined in Sprague-Dawley (SD) rats with 7,12-dimethylbenz[a]anthracene (DMBA)-induced mammary tumors. MPA augmented the antitumor activity of 5-FU and protected against body weight-loss due to 5-FU administration. PyNPase activity of both the MPA group and the MPA+5-FU group tended to increase compared with that of the 5-FU alone group. TS inhibition levels in the MPA+5-FU group tended to increase compared with those in the 5-FU alone group. These results indicate that MPA tended to augment antitumor activity of 5-FU and to reduce the side effects caused by 5-FU.

Screening mammography (MMG) for women aged 50 years and older has been widely accepted all over the world. However, the efficacy of screening mammography for women aged under 50 years has not been established. We compared mammographic findings of the patients under age 50 (the younger group) and those of patients 50 and older (the older group). From 1992 to 1997, 107 patients with early breast cancer (non-invasive and Stage I) were treated in our hospital. There was no difference between the groups in background. Of 53 patients in the younger group, 40 (75.5%) were diagnosed as having cancer using mammography, while 44 of 54 (81.5%) of the older group were diagnosed as having cancer. A total of 46 (86.8%) patients in the younger group were diagnosed using MMG and physical examination (PE), and 50 (92.6%) in the older group were diagnosed as cancer using MMG and PE. There was no difference in the successful diagnosis rate using mammography in the two groups. Breast cancer screening using MMG may also be useful for women aged under 50.

A consecutive series of 128 breast cancer patients detected by breast screening were enrolled in this study to analyze their age-dependent characteristics. They were classified into three groups; 40 years or less (young): 26 patients, 41-55 years (middle-aged): 67 patients and 56 years or over (old): 35 patients. The percentage of patients who had noticed breast abnormality by self-examination at the time of the breast screening increased from the young patients to the old without statistical significance. Nonpalpable breast cancer was more frequently (p0.05) observed in the young patients or the middle-aged rather than the old patients. The incidence of noninvasive carcinoma decreased from the young patients to the old without statistical significance. Decreased survival was seen in older patients rather than younger patients, without statistical significance. As a result, prognostic features were more favorable in patients aged 40 years or less than the other. Women aged 35-40 years should be recommended to attend breast screening.

A 13-year-old girl and her older sister were referred to our hospital because her father and another older sister and been suffering from medullary thyroid carcinoma (MTC). Physical examinations revealed no thyroid mass. Ultrasonography (US) detected a small hypoechoic lesion in the right thyroid lobe, 3 mm in size. The serum calcitonin level was slightly elevated for their age. One and half year later, US finding showed a slightly larger mass, 7 mm in size, which was not palpable. Genetic testing for ret protooncogene mutation revealed a point mutation at codon 634 (Cys--Arg) in exon 11. Surgical treatment was recommended, however, the patient wanted to receive it only after the admission to senior high school. Her sister had no mutation in ret protooncogene. The patient underwent total thyroidectomy with modified neck dissection at 16 years of age. At that time, a new mass emerged in the left thyroid lobe and the serum calcitonin level increased to 171 pg/ml. MTC was found in each lobe with positive staining of CEA and carcitonin. No lymph node metasis was found. Her postoperative course was uneventful. Genetic testing for ret mutation is effective for early diagnosis and treatment of patient with FMTC, and is recommended as standard management for hereditary MTC in affected families.

We demonstrated that the prognosis of breast cancer patients who received adjuvant immunochemotherapy with Krestin (PSK) showed a tendency to be better than that of breast cancer patients receiving chemotherapy only. We retrospectively investigated the usefulness of HLA typing for selecting patients to receive adjuvant immuno-chemotherapy with PSK. One hundred and thirty-four patients with operable breast cancer were typed as HLA-A, -B, -C by a lymphocytotoxicity test. Patients without vascular invasion had no adjuvant therapy (NA group). Patients with vascular invasion in the tumor and/or in the metastatic lymph node were randomized into two groups. In group 1 (FEMP only), a combination chemotherapy of 100 mg of 5-fluorouracil (F), 50 mg of cyclophosphamide (E), 2 mg of mitomycin C (M), and 5 mg of predonisolone (P) was orally administered daily for 28 days (one course). In group 2 (FEMP+PSK), FEMP and 3.0 g of PSK were orally administered for 28 days (one course). Two courses a year of these agents were given for five years in both groups. Each group (NA, FEMP, FEMP+PSK) was stratified by the presence of HLA B40 type (B40(+)) or not (B40(-)). Five- and 10-year disease-free survival (DFS) rates (93%, 80%, respectively) of patients with B40(+) seemed to be better than those (83% and 51%) of patients with B40(-). In the NA group, 5- and 10-year DFS were 100% and 71% in patients with B40(+), 92% and 76% in those with B40(-), respectively. In the FEMP group (chemotherapy only), 5- and 10-year DFS of patients with B40(+) were both 84%. These were not statistically significant compared with those (82% and 33%) of patients with B40(-). On the other hand, in the FEMP+PSK group, 5- and 10-year DFS of patients with B40(+) were both 100%, and those of patients with B40(-) were 76% and 55%, respectively. DFS of patients with B40(+) was significantly better than that of patients with B40(-). It is concluded that HLA typing may be a predictive index in determining the use of immunochemotherapy combined with PSK for patients with operable breast cancer.

The hypothyroid state or nonthyroidal illness is often observed in patients with recurrent cancer. High levels of cytokines are frequently observed in critically ill patients. Recent studies have shown that interleukin (IL)-6 may be a cause of nonthyroidal illness. We reported the relationship between thyroid function and the prognosis of the patients with recurrent breast cancer. In this study, we measured the serum level of cytokines (IL-2, IL-6, IL-8) and thyroid function (free T3, free T4, and thyrotropin (TSH)) in 38 patients with recurrent breast cancer. All patients had received three or more different courses of therapy before they were entered the study. The patients were divided into three groups according to their response to therapy. There were 16 partial response (PR), 10 no change (NC) and 11 progressive disease (PD) patients. They did not receive any medication that influenced the thyroid hormone level other than medication for cancer. The IL-2 level was under the detectable limit in all groups. No abnormal levels of cytokines were observed in the PR group. IL-6 and IL-8 levels in the PD group were significantly higher than that in the NC group (p0.05). Significant negative correlation was observed between IL-6 and thyroid hormones (free T3, free T4). Patients whose IL-6 level was 20 pg/ml or more died within four months after the beginning of the treatment. We concluded that IL-6 may lead to a hypothyroid state in patients with recurrent breast cancer. A high level of IL-6 and IL-8 means the confusion of the defense system in hosts. Therefore, these cytokines will be predictive indicators of the therapeutic response and the prognosis of the patients with recurrent breast cancer.

Breast conserving surgery with nipple resection was carried out on 4 patients with early breast cancer because location of each tumor was very close to nipple. These consisted of 3 patients with state I invasive ductal carcinoma and 1 patient with stage II invasive ductal carcinoma. Cancer cells were not recognized histopathologically in the resection margins of each case and all cases underwent a curative resection with axillary dissection (up to level III). The rested areola in each case was made to be round-shaped by skin suture and the edge of the wound located in the center of areola looked like a small nipple. The cosmetic result of this operation were excellent in all patients. This operation may be effective both for these patients with early breast cancer locating under the nipple or areola and for those whose tumor was very close to nipple.

Twenty-two patients with inflammatory breast cancer treated between 1962 and 1994 were analyzed. Before the introduction of multidisciplinary treatment with anthracycline agents between 1962 and 1981, 11 patients out of 14 were resected, however, a curative operation was performed for only 3 of these patients (29.3%). Ablative endocrine therapy, intraarterial infusion of anticancer drugs (mitomycin C or 5-fluorouracil), and radiation were carried out as the preoperative induction therapy for inflammatory breast cancer. All 14 patients died within 36 months. After the introduction of multi-disciplinary treatment with anthracycline agents between 1981 and 1994, preoperative induction chemotherapy or chemoendocrine therapy using anthracyclines was carried out on 7 out of 8 patients and the remaining patient received radiation. Of the former 7 patients, 6 (85.7%) underwent a curative operation. There was approximately a 35 percent cumulative survival rate observed 60 months after operation, and 3 patients out of the 7 lived for more than 5 years. To conclude, multidisciplinary treatment including systemic induction chemotherapy with anthracyclines was an effective treatment for inflammatory breast cancer.

In this study, thyroid (T3, T4, free T3, free T4) and pituitary function (thyrotropin (TSH), growth hormone (GH), prolactin (PRL)) in 38 patients with recurrent breast cancer were examined. The patients were divided into three groups according to their response to the therapy. There were 16 partial response (PR), 10 no change (NC) and 11 progressive disease (PD) patients. The maximum and the minimum value for each hormone throughout the course of treatment were compared between three groups. The PD group showed significantly lower minimum T3 levels than the other two groups (p0.05). The maximum TSH level in the PD group was significantly higher than that of the other groups. The minimum TSH level in the PD group was significantly lower than that in the PR group (p0.05). The minimum TSH level in the NC group was also lower than that in the PR group. The maximum PRL level in the NC and the PD group was higher than that in the PR group (p0.05, p0.01, respectively). The tumors of the patients with temporal increase of TSH level were resistant to all subsequent therapies. These five patients died within four months followed by decreasing of the TSH level. It is concluded that thyroid and pituitary function, especially free T4, TSH and PRL, are predictive indicators of therapeutic response and the prognosis of the patients with recurrent breast cancer.

A 66-year-old woman developed a malignant rhabdoid tumor of the breast, with a tumor doubling time of 10 days. One month after radical mastectomy, there was local recurrence, followed by multiple pulmonary metastases, and the patient died of respiratory failure 5 months after surgery. The gray-white-colored tumor measured 13 x 12 x 10 cm, and its border was well defined. The tumor was composed of diffusely growing round or polygonal cells with vesicular nuclei, prominent nucleoli, and ample cytoplasm containing eosinophilic inclusions. Lymph node involvement was widespread. Both vimentin and keratin were clearly demonstrated by immunohistochemical staining. Ultrastructural studies revealed that the MRT cells contained cytoplasmic whorls of intermediate filaments.

We describe a case of Pneumocystis carinii pneumonia (PCP) in a woman with recurrent breast cancer without human immunodeficiency virus (HIV) infection. The PCP was associated with severe lymphocytopenia due to treatment with anticancer agents in combination with granulocyte colony-stimulating factor (G-CSF). Despite the severe lymphocytopenia, the total leucocyte count never fell below 3000/mm3 during the treatment. It was difficult to determine whether the patient's respiratory failure was caused by severe infectious pneumonia, hypersensitivity pneumonia or pneumonitis carcinomatosis. She was treated with steroid for suspected drug-induced hypersensitivity pneumonia. However, as her condition did not improve, PCP was suspected, and sulfamethoxazole-trimethoprim was administered. At the same time, anticancer drugs were administered to half the progression of the cancer, since lymphangitis carcinomatosa was also suspected. The severe respiratory failure did not improve, and the patient died on day 23 after admission. At autopsy, the cause of death was confirmed to respiratory failure due to PCP.

Oral high-dose medroxyprogesterone acetate (MPA) treatment (600, 800, 1200 mg/day or changed dosage) was given to 49 patients with recurrent breast cancer from January 1979 to December 1992. The overall response rate to MPA was 38.8% (19/49). The response rate in the soft tissue was significantly higher compared with that in bone metastases or in visceral metastases. MPA was effective on patients both with or without previous treatment. Several side effects were recognized, but they were mild and tolerable. These results demonstrate that MPA is effective when used as first line or second line treatment.

Two patients with surgical intervention for pulmonary arteriovenous fistula were presented. Lobectomy was performed in a cyanotic patient and fistula excision in another. To prevent the unsatisfactory prognosis of pulmonary arteriovenous fistula, surgical treatment is preferable to drug therapy when the diagnosis of this disease is established. The operative method should be selected according to the size, shape and localization of pulmonary arteriovenous fistula.

The effects of 5-isopropyl 3-methyl 2-cyano-1,4-dihydro-6-methyl-4-(m-nitrophenyl)-3,5-pyridinedicarboxylate (nilvadipine, FR 34235, FK 235) on the cardiovascular system were investigated in isolated organs and whole animals. 1. Nilvadipine inhibited Ca2+-induced contractions of isolated dog coronary artery in high-K+, Ca2+-free medium, and the pA2 value was 10.64. In this effect, nilvadipine was 18 times more potent than nifedipine and 525 times more potent than diltiazem. In contrast, its inhibitory effect on Ca2+-induced contractions of isolated guinea pig atria was weaker (pA2:8.2): only twice that of nifedipine and 25 times that of diltiazem. 2. Nilvadipine also inhibited K+-induced 45Ca2+ uptake in isolated dog coronary arteries and isolated guinea pig atria. In the coronary arteries, the IC50 value of nilvadipine was 2.7 x 10(-10) mol/l, which was, respectively 17, 8, and 589 times lower than that of nifedipine, nicardipine and diltiazem. In the atria, on the other hand, the IC50 value of nilvadipine was 4.4 x 10(-9) mol/l, almost the same as that of nifedipine or nicardipine, and 47 times lower than that of diltiazem. These 45Ca2+ uptake inhibitory effects of the drugs were consistent with their effects on mechanical response in both tissues. 3. Nilvadipine (2.6 x 10(-10) mol/l and higher) dose-dependently inhibited ergometrine (ergonovine)-, serotonin-, and norepinephrine-induced contractions of isolated dog coronary artery, and its effects were 2 to 450 times more potent than those of nifedipine, nicardipine and diltiazem. 4. Nilvadipine (2.6 x 10(-8) mol/l or more, 32 micrograms/heart or more), like nifedipine, produced negative inotropic and chronotropic effects in isolated guinea pig atria and in dog heart-lung preparation, and was more potent than nifedipine in the negative chronotropic effect. 5. Nilvadipine in intravenous doses of 1-32 micrograms/kg decreased total peripheral resistance and systemic blood pressure, and slightly increased cardiac output, pulmonary arterial blood flow and stroke volume, but had no significant effects on pulmonary vascular resistance or pulmonary arterial blood pressure. Heart rate decreased at doses of 32 micrograms/kg or more. Nifedipine had almost the same effects as nilvadipine on total peripheral resistance and blood pressure, but was more potent than nilvadipine in increasing effects on cardiac output, stroke volume and pulmonary arterial blood flow.(ABSTRACT TRUNCATED AT 400 WORDS)