Search

The aim of this study was to analyze the pharmacokinetics and pharmacodynamics (PK/PD) of 6- O-(3-ethoxypropionyl)-3',4'- O-exo-benzylidene-chartreusin (IST-622) and its metabolites, and to develop limited sampling models (LSM). Based on the data from 18 patients with breast cancer who were treated orally with 280 or 525 mg/m(2) of IST-622 once daily after breakfast for five consecutive days, we analyzed the relationship between the area under the plasma concentration versus time curve (AUC) and toxicities using a sigmoid E-max model and logistic regression. Plasma concentrations of IST-622 and its metabolites, 3',4'- O-exo-benzylidene-chartreusin (A-132) and 3"-demethyl-3',4'- O-exo-benzylidene-chartreusin (A-132M), were measured at 1, 2, 4, 8 and 24 h after administration on day 1. The AUC was calculated using the trapezoidal method. We also developed a LSM using stepwise linear regression analysis. IST-622 was detected in very few patients, and its concentration was very low and could be disregarded. It was suggested that meals promoted absorption of IST-622. AUCs of A-132 plus A-132M showed a better correlation with the rates of decrease and nadir counts of leukocytes, neutrophils and platelets than the AUC of each metabolite separately. Patients with the sum of AUCs more than 70 microg.h/ml showed severe myelotoxicities. Moreover, logistic regression analysis showed that grade 4 myelotoxicities would be seen in 30% of patients at an AUC of 65 microg.h/ml. We also developed an unbiased and precise LSM: AUCSUB0-24h/SUB=CSUB8h/SUBx17.6-0.95, where C(8h) denotes the sum of plasma concentrations of A-132 and A-132M. Myelotoxicities showed a good correlation with AUC(0-24h), and based on the results, it was decided that the target AUC was 65 microg.h/ml. The LSM was very convenient for estimating AUC(0-24h) and sufficiently accurate. These results show the possibility of predicting toxicities and dose adaptation for interpatient variability using LSM.

To study whether Japanese breast cancer patients obtain favourable results with breast-conserving surgery if the same selection criteria as those for Western patients are used, and, simultaneously, to assess the outcome of breast-conserving surgery alone versus breast-conserving surgery followed by either irradiation of the remaining breast or adjuvant chemotherapy with tamoxifen. A prospective, randomised study and a retrospective study of postoperative adjuvant therapy for breast cancer following breast-conserving surgery were performed at 21 centres in Japan during 1989 to 1991. In the prospective, randomised study, 112 patients with tumours 2cm or smaller in diameter who underwent lumpectomy received either adjuvant chemotherapy with tamoxifen 20 mg/day for 2 years (Group T, n = 53) or no therapy (Group C, n = 59) postoperatively. Median 5-year disease-free survival rates after 72 months were 78.5% and 86.0%, respectively, with no significant difference between the two groups [log-rank test: p = 0.308, hazard ratio 1.47 (95% confidence interval 0.59–3.66)]. In the retrospective study, a further 70 patients who underwent similar breast-conserving surgery during the same period as the prospective study followed by radiotherapy (Group R) were compared with the patients in Groups T and C combined (n = 112). Median 5-year disease-free survival rates after 71 months were 86.6% and 82.2%, respectively, with no statistically significant difference between the two groups [log-rank test: p = 0.352, hazard ratio 0.72 (95% confidence interval 0.33–1.59)]. These findings suggest that breast cancer patients may not always require radiotherapy after breast-conserving surgery.

The effectiveness of combining mitomycin C (MMC), tamoxifen (TAM), and 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) was evident in patients with estrogen receptor-positive (ER+) breast cancers. UFT, an oral preparation of tegafur and uracil at a molar ratio of 1:4, was reported to have higher antitumor effects than tegafur alone for patients with breast cancer. Therefore, the combined chemotherapy of MMC, TAM and UFT may possibly be effective for breast cancer.

A Phase II study of paclitaxel in patients with primary advanced or metastatic breast cancer was conducted by a cooperative study group consisting of 16 institutions in Japan. Paclitaxel at a dose of 210 mg/m2 was intravenously infused over 3 hours, along with premedication to prevent hypersensitivity reactions. The course was repeated at 21-day intervals. Of 62 eligible patients, 60 were evaluable for toxicity and 59 were evaluable for efficacy. Forty-five patients were previously treated with anthracyclines. Twenty-one of 59 patients (35.6%) had a major objective response including 2 CRs and 19 PRs (95% confidence interval, 23.6–49.1%). A response rate of 35.5% (CR1, PR10) was observed in 31 patients refractory to the anthracyclines containing prior metastatic chemotherapy. Median (range) time was 41 (6–100) days to onset of and median duration of response was 125 (36–305) days. Toxicities included leukopenia (grade 3, 4: 67%), anemia (grade 1–3: 80%), thrombocytopenia (grade 1: 8%), alopecia (grade 3: 43%), peripheral neuropathy (grade 1–3: 93%), arthralgia (59%), myalgia (46%), nausea and vomiting (40%), fever (33%), allergic reaction (grade 3: 2%) and hypotension (grade 3: 5%). All toxicities were tolerable and manageable. Paclitaxel intravenously infused over 3 hours demonstrated a significant antitumor activity for metastatic breast cancer. Furthermore, paclitaxel exhibited non-cross resistance to anthracycline. Paclitaxel administered as a convenient 3-hour infusion is effective for patients with metastatic breast cancer and has an acceptable toxicity profile.

Background: Multi-combination chemotherapy consisting of anthracyclines has been effective but has not invariably prolonged the survival period in advanced/recurrent breast cancer. The possibility hasbeendiscussed that chemoendocrine therapy combined with endocrine agents is more effective. Methods: In order to evaluate the toxicity and efficacy of a new endocrine therapy for advanced/recurrent breastcancer, we ran a pilot study during the period from July 1994to July 1996. Results: Twenty-two patients with advanced/recurrent breast cancer were treated with chemoendocrine therapy consisting of cyclophosphamide (100 mg/body) p.o. daily for 14 days, with adriamycin (40 mg/m 2) i.v. and 5-fluorouracil (500 mg/body) i.v, on day 1 (repeated every3 weeks for 9 weeks) (CAF therapy), and high-dose toremifene (120 mg/body) p.o. daily. Of 20 evaluable patients, two showed complete response (10 %), eight partial response (40%), six no change (30%) and four progressive disease (20%). The overall response ratewas 50%, and the median duration of response was 69.5 days (28-133+ days). The major toxicities were drug-induced alopecia, gastrointestinal toxicity andhematological toxicity, butthesewereclinically well tolerated. No serious cardiac, liver or renal symptom was seen. Conclusions: Based on these results, we consider the addition of high-dose toremifene to the CAFtherapy to be useful in the treatment of advanced and recurrent breast cancer.

To investigate the pathogenesis of porcine serum (PS)-induced liver fibrosis in rats, two experiments were carried out, taking into consideration of hypertension and vascular changes. In Experiment I, spontaneous hypertensive rats (SHRs), two-kidney, one clip hypertensive F344 rats (2K1C rats), and normotensive F344 rats were given an intraperitoneal injection of PS of 0.5 ml twice a week for 8 weeks. Histopathological, immunohistochemical, and electron microscopical examinations were performed on the liver from each rat. Histological features of liver fibrosis in hypertensive and normotensive rats were essentially identical. However, in the PS-treated SHRs, 2 of 5 animals showed the most severe fibrosis in all PS-treated groups. Electron microscopically, degranulated mast cells, eosinophils, and macrophages engulfing apoptotic cells were rarely observed in the late stage of fibrous septa (FS) in the PS-treated SHR liver. In Experiment II with normotensive F344 rats, histopathological features of early FS in the liver were compared with those of late FS observed in Experiment I using serial sections, and we found that FS developed along the wall of newly formed vessels to connect between neighboring central veins. However, the effect of hypertension on this fibrosis could not be clearly demonstrated in the present study using SHRs and 2K1C rats.

The second 5-year study of postoperative adjuvant therapy in patients with breast cancer between 1985 and 1988 was performed by the Study Group for Adjuvant Chemoendocrine Therapy for Breast Canecr (ACETBC). This report describes the results of a meta-analysis of the outcome. A total of 3012 patients with stage II, estrogen-receptor-positive primary breast cancer who underwent radical surgery (total mastectomy with at least axillary dissection) were eligible for the analyses. On the day of surgery, all patients received 13 mg/m(2) of mitomycin C (MMC) intravenously. Patients were then given one of two adjuvant chemoendocrine therapies for 2 years:regimen A, consisting of tamoxifen citrate (TAM) 30 mg/day, or regimen B, consisting of TAM 30 mg/day plus tegafur (Futraful, FT)600 mg/day. The results from all eligible patients were included in a meta-analysis according to the method of Peto et al. The odds reduction rate was 12 +/-13% (log-rank test, P= 0.35)for the 5-year survival rate and 16 +/- 10% (log-rank test, P=0.093)for the 5-year non-recurrence rate. In terms of the 5-year non-recurrence rate. regimen B(with FT)yielded slightly, but not significantly, better results than regimen A. In addition, stratified analyses were carried out with respect to the 5-year non-recurrence rate. Regimen B(with FT)yielded significantly better results than regimen A in patients with four or more positive axillary nodes (log-rank test, P= 0.039) and yielded slightly, but not significantly, better results than regimen A in premenopausal patients (log-rank test, P= 0.079).

Between 1985 and 1988, the effect of using ftorafur (FT) or PSK (an immunotherapy agent) in combination with the conventional postoperative adjuvant therapy using mitomycin (MMC) plus tamoxifen (TAM) was assessed in stage II, oestrogen receptor-positive (ER+) breast cancer patients. Furthermore, in ER- breast cancer stage II patients, the effects of postoperative adjuvant therapy using MMC plus FT were compared with the effects of postoperative adjuvant therapy using MMC plus PSK. Patients had primary stage II breast cancer and had undergone total mastectomy plus axillary dissection or more radical surgery. On the day of surgery, MMC (13 mg/m2) was administered intravenously. Then, ER+ patients received one of three regimens of drug therapy, starting 2 weeks after surgery: regimen A (daily oral treatment with 30 mg of TAM), regimen B (daily oral treatment with 30 mg of TAM and 600 mg of FT) or regimen C (daily oral treatment with 30 mg of TAM and 3 g of PSK) [corrected]. ER- patients received either regimen D (daily oral treatment with 600 mg of FT) or regimen E (daily oral treatment with 3 g of PSK), starting 2 weeks after surgery. Of the 540 ER+ patients registered, 525 were evaluated. The 5-year overall survival rate for ER+ patients was higher for patients who received regimen B (94.2%) than for those who received regimen A (86.9%) or regimen C (89.9%) (P = 0.063). The 5-year relapse-free survival rate was higher for regimen B (88.9%) than for regimen A (78.6%) and regimen C (77.2%) (P = 0.010). Stratified analysis revealed better results with the FT-combined therapy in patients positive for lymph node metastasis and premenopausal patients. These results indicate the effectiveness of using FT in combination with TAM. Of the 376 ER- patients registered, 364 were evaluated. The 5-year overall and relapse-free survival rate for ER- patients did not differ significantly between patients who received regimen D and those who received regimen E.

The effects of medroxyprogesterone acetate (MPA) therapy on advanced or recurrent breast cancer and its influence on blood coagulation and the fibrinolytic system were compared among three different therapy regimens consisting of cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) + MPA and CAF or MPA alone. A clinical response was observed in 42.9% (9/21) of the patients for CAF + MPA, 36.4% (8/22) for CAF and 23.8% (5/21) for MPA alone. No marked thrombosis or its prodromal condition was observed in any group. The effects on the test values for blood coagulation and the fibrinolytic system did not significantly change in the CAF group. However, both AT-III and protein C significantly increased above the normal ranges in the CAF+MPA and MPA groups. Increases in factor X, plasminogen, and alpha 2-plasmin inhibitor/plasmin complex (PIC) and decreases in fibrinogen, tissue plasminogen activator, and D-dimer, were all observed in the MPA and CAF + MPA groups, especially in the MPA group, although these changes remained within the normal ranges. The data indicated that MPA has various influences on blood coagulation and the fibrinolytic system, but these changes did not suggest activation of the blood coagulation system.

Although clinicians want to know how tumor response affects the survival of advanced cancer patients, the direct comparison of response with survival is severely discouraged because of biases essentially involved. In 159 patients with advanced breast cancer treated with adreno-oophorectomy, we analyzed the survival of the patients using the Kaplan and Meier method with the landmark method (landmark time of 3 months after treatment). A multivariate analysis with the Cox proportional hazard model for survival with explanatory variables including response of patients at the landmark time (3 months after therapy) was performed in order to find probable prognostic factors. By the Kaplan and Meier curves with the landmark method, response category showed a significant difference in the survival of the patients (log rank test; p0.0001). In the Cox model in the patients of landmark time of 3 months after therapy, we found that response was the most powerful factor for survival out of 10 variables (p = 0.0001), and the dominant site of metastasis significantly and independently modified the survival length (p = 0.001). ER status was indifferent in the analysis; however, when the response category was not included, ER was shown to be most influential. We propose that a combination of the Cox model with the landmark method would be a rational and useful approach to estimate probable prognostic factors including treatment outcome variables such as response for the survival analysis in advanced cancer patients.

Toremifene, a selective estrogen receptor modulator, is used as adjuvant therapy for postmenopausal patients with breast cancer in Japan. For Japanese patients, however, only limited data are available on the efficacy and safety profile of toremifene. To establish the long term efficacy and safety of toremifene for Japanese patients, we conducted a prospective, multicenter, randomized phase III trial comparing toremifene and tamoxifen.The subjects were postmenopausal Japanese patients who had undergone surgery for node-negative breast cancer. Toremifene or tamoxifen was administered for 2 years. The primary endpoint was demonstration of the non-inferiority of toremifene compared with tamoxifen in respect of 5-year survival. Secondary endpoints were cumulative overall survival, cumulative disease-free survival, effects on lipid profiles, and adverse events.A total of 253 patients were enrolled. The baseline characteristics of the two treatment groups were well-balanced. Median follow-up was 66.5 months. Five-year survival was similar for toremifene and tamoxifen (97.0 vs. 96.9 %; 90 % confidence interval -3.9 to 4.1), indicating that toremifene is not inferior to tamoxifen for postmenopausal Japanese patients with early breast cancer. Cumulative overall survival and cumulative disease-free survival were also very similar for toremifene and tamoxifen (97.5 vs. 97.3 %, log-rank test P = 0.9458; 88.4 vs. 90.6 %, log-rank test P = 0.3359, respectively). Adverse events in both groups were similar and mostly mild or moderate. Thus, both are equally effective and well tolerated.Our results suggest that the efficacy and safety of toremifene and tamoxifen are equivalent for postmenopausal Japanese patients with early breast cancer.

Background. A randomized adjuvant trial was conducted from October 1982 to January 1985 to evaluate the addition of tamoxifen (TAM) to combination chemotherapy with perioperative mitomycin C (MMC) and ftorafur (FT) for patients with estrogen receptor (ER)-positive tumors and the addition of PSK, a biologic response modifier, to MMC + FT chemotherapy for patients with ER-negative tumors in operable Stage IIA, IIB, and IIIA cancer. The doses used were 20 mg of oral TAM daily, 600 mg of oral FT daily, and 3 g of oral PSK daily for 2 years. Intravenous MMC (13 mg/m2) was given on the day of operation. Methods. A total of 967 patients were entered and randomized by stratification based on ER status and staging (1978 International Union Against Cancer [UICC] criteria at the time of trial execution). Of 967 patients, 914 (94.5%) were evaluable. At 5-year follow-up, significant prolonged overall survival (0s) and relapse-free survival (RFS) times were seen with the addition of TAM in patients with ER-positive and Stage IIIA T3NO cancer (1987 UICC-American Joint Committee on Cancer [AJCC] criteria); however, no significant survival benefit from TAM was seen in patients with ER-positive and Stage IIA T2N1 cancer. There was no significant difference between regimens, with or without PSK, in patients with ER-negative disease. Results. Results of subset analyses suggested a benefit from TAM in postmenopausal patients with ER-positive and Stage IIA T2N1 cancer and a benefit from PSK in patients with node-negative, ER-negative, and Stage IIA T2N1 cancer. Conclusions. The 5-year results of the current trial showed a survival advantage by the addition of TAM to chemotherapy in patients with ER-positive and Stage IIIA T3NO cancer.

In a retrospective multicenter study to investigate the correlation between estrogen (ER) and/or progesterone receptors (PgR) in primary breast cancer with patient Prognosis, 3118 patients with operable breast cancer (International Union Against Cancer Stages I, II, and III) were investigated from ten hospitals in Japan who underwent surgery from October 1972 to December 1982; 3089 were evaluable. The ER-positive and PgR-positive cancers were found in 56% and 34% of patients, respectively. The positivities decreased as the tumor size increased but were independent on lymph node metastasis. There were no significant differences in relapse-free survival (RFS) in relation to receptor status (median follow-up, 89 months [ER], 84 months [PgR]). However, in patients with four or more positive nodes, those with PgR-positive cancer had a longer RFS. The patients with ER-positive cancer survived significantly longer than ER- negative ones, with the greatest difference seen in those with four or more positive nodes. There was a significantly longer postrelapse survival (PRS) for patients with ER-positive cancer because of the different distribution of the major metastasis and better responses to first line and subsequent treatment. Cox's multivariate analysis showed that overall survival but not PRS was affected by ER (and more weakly by PgR) because of the longer PRS in patients with ER-positive cancer.

The relationship between the occurrence of breast cancer and dietary intake, in particular a high-fat diet, has attracted much attention in recent years. In addition, the prognosis of breast cancer patients on the basis of dietary intake is also an interesting subject. The present study utilized breast cancer patients whose dietary intake was carefully assessed about one decade previously in a case-control study to determine whether dietary intake was indeed related to the patients' prognosis. The study included 212 patients who underwent a surgical operation between 1975 and 1978. They were followed-up until 1987, and a total of 47 breast cancer deaths were certified. The 5- and 10-year relative survival rates were 78.5% and 75.3%, respectively. The older patients tended to ingest smaller amounts of all nutrients, except animal fat from fish. Height was significantly correlated with total animal protein intake, whereas there was no significant correlation between body mass index and intake of any nutrient. Although the age-adjusted mean values of the nutrient intakes, other than vegetable fat, decreased with advancing stage, the differences were statistically insignificant. The results of multivariate analyses, in which some confounding factors (e.g., clinical stage) were adjusted using a proportional hazards model, showed that all hazards ratios in each nutrient were close to unity, and no dose-response relationship was seen. The present investigation did not provide any support for the hypothesis that a high-fat diet is a survival determinant for breast cancer patients.(ABSTRACT TRUNCATED AT 250 WORDS)

To compare the cyclophosphamide, methotrexate, and fluorouracil (CMF) chemotherapy and the anthracycline-containing regimen cyclophosphamide, epirubicin, and fluorouracil (CEF) to evaluate the efficacy and safety of the latter.A total of 294 patients with axillary node-positive primary breast cancer of STAGE I-IIIa were randomly assigned to either CEF [cyclophosphamide (CPA) 500 mg/m(2) i.v. days 1 and 8; epirubicin (EPI) 60 mg/m(2) i.v. day 1; and 5-fluorouracil (5-FU) 500 mg/m(2) i.v. days 1 and 8] or CMF [CPA 500 mg/m(2) i.v. days 1 and 8; methotrexate (MTX) 40 mg/m(2) i.v. days 1 and 8; and 5-FU 500 mg/m(2) i.v. days 1 and 8]. Both treatment regimens were comprised of six cycles at 4-week intervals. Tamoxifen (TAM) 20 mg/day was concomitantly given to estrogen receptor (ER)-positive patients and those with undetermined ER status for 2 years.The overall 5-year survival was 77.1% for CEF and 71.4% for CMF [p = 0.24; hazard ratio 0.79 (95% CI 0.50-1.24)], and the 5-year disease-free survival was 55.7% for CEF and 48.9% for CMF [p = 0.15; hazard ratio 0.80 (95% CI 0.57-1.12)]. Although the log-rank test did not show a significant difference, both overall and disease-free survivals were higher for CEF according to the point estimates. Adverse drug reactions (ADRs) occurred more frequently in CEF.Whereas CEF had a good trend compare with CMF, it could not be proven statistically significant. The principal cause of the failure seems to be insufficient power, that is, the dose intensity (EPI: 60 mg/m(2)) set 10 years ago, when the trial began, was low, and the number of trial subjects was small because of the background of the times, which made the accumulation of cases extremely difficult. However, the trial should be considered to be meaningful, as it was the first, formally conducted controlled trial on chemotherapy in Japan.

The efficacy and toxicity of (2''R)-4'-O-tetrahydropyranyl adriamycin (THP) were assessed in the treatment of patients with advanced breast cancer by the Japan THP Study Group. Mean plasma levels of THP after single-dose administration revealed triexponential decay characterized by an initial half-life of 0.89 h. A higher concentration of THP was obtained in the metastatic lymph nodes than in the breast cancer tissue at 4 h after administration (4.01 vs. 1.17 micrograms/g). Whereas 1 complete (CR) and 12 partial response (PR) were observed in 56 evaluable patients after administration of THP alone (23.2%), 1 CR and 12 PR were observed in 37 evaluable patients who had combination therapy including THP (35.1%). Multivariate analysis of prognostic factor revealed that the site of metastases had the most valuable prognostic significance; second was irradiation in the previous treatment, and third was the disease-free interval. Life-table analysis adjusted with the Cox proportional hazard model revealed a similar survival curve of patients receiving THP-cyclophosphamide, adriamycin, and 5-fluorouracil (CAF) to that of those receiving CAF only in spite of the low incidence of toxicity in the THP therapy.

Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 ± 17% (p = 0.33) and 21 ± 11% (p = 0.060), respectively. Multivariate analysis using Cox’s proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 ± 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 ± 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I – IIIA breast cancer for the prolongation of the reccurence-free survival period.

A 10-month-old, female Holstein-Friesian cow with tetralogy of Fallot died during surgery for ameliorating pulmonary stenosis. Necropsy revealed no fracture of bones. Microscopically, fat emboli in the capillaries were detected in the brain, kidney, lung, adrenal gland and pituitary. In the kidney, many fat emboli were present in the glomeruli. No significant changes of the neurons were found throughout the brain, and perivascular hemorrhage and/or necrosis were rarely seen accompanying with fat emboli in the cerebral cortex. The trigger for fat embolism might be costectomy, and right-to-left shunt due to heart malformation might be attributed to crossed and systemic distribution of the fat emboli.

To assess the efficacy of 5'-DFUR, an intermediate of capecitabine, for adjuvant treatment of early breast cancer, we conducted an open-labeled multi-center randomized controlled trial to compare postoperative 5'-DFUR treatment with surgery alone. We enrolled 1217 primary breast cancer patients and randomly assigned them into two treatment groups; one received six-month postoperative 5'-DFUR treatment by consecutive or intermittent administration, and the other surgery alone. Follow-up surveys were conducted once a year for all subjects simultaneously and examined their outcome/presence or absence of the cancer recurrence. The central study committee reviewed all follow-up data and judged the recurrence data to be used for the analysis. Eight-year follow-up data showed no significant differences in relapse-free and overall survival between the two groups, and 5'-DFUR treatment regimen showed an extremely high tolerance. Possible explanations are discussed for the finding of no significant survival difference between adjuvant 6-month 5'-DFUR monotherapy and surgery alone in early breast cancer.

Summary Background: Women treated with tamoxifen for breast cancer are at increased risk of endometrial cancer. We conducted a retrospective cohort study to evaluate the risk of second primary cancers after adjuvant tamoxifen therapy for breast cancer in Japan. Patients and methods: The subjects of the study were 6148 women who had been diagnosed with stage I, II, or IIIA unilateral primary breast cancer and had received surgical treatment during the period from January 1982 through December 1990 at nine institutions in Japan. The information on each patient was obtained from medical records or a prospectively compiled computer database at each institution. Results: Of the 6148 women, 3588 (58.4%) were administered tamoxifen as an adjuvant treatment and 2560 (41.6%) were not administered. Median follow-up periods were 7.64 years for tamoxifen-treated patients and 8.10 years for non-tamoxifentreated patients, respectively. The duration of tamoxifen treatment was mostly two years or less (80.7%), and few patients received tamoxifen for more than five years. The cumulative incidence rates of all second cancers at 10 years were 4.61% and 4.09% among tamoxifen-treated and non-tamoxifen-treated patients (P = 0.62), respectively, and the incidence rate ratio (IRR) for all second cancers was 1.06 (95% confidence interval (CI): 0.77-1.47) after adjustment of several covariates. The numbers of endometrial cancers was 9 and 3 among tamoxifen-treated and non-tamoxifen-treated patients, respectively, and the IRR was 2.37 (95% CI: 0.64-8.77, P = 0.20). Of the 12 patients who developed endometrial cancer, 4 died of cancer (for 3 of them, the cause of death was breast cancer), and the other 8 patients were alive as of March 1996. Stomach cancer was the most frequent second cancer and the IRR was 1.34 (95% CI: 0.76-2.38, P = 0.31). There was no substantial increase in any other type of gastrointestinal cancer such as colorectal and liver cancers among tamoxifen-treated patients. Conclusions: The incidence and risk of second primary cancers associated with tamoxifen therapy is low. The potential benefit of adjuvant tamoxifen therapy in breast cancer patients outweighs the risk of second primary cancers for Japanese breast cancer patients.

A cat that was suspected some insulin resistance was diagnosed as pituitary dependent hyperadrenocorticism from an adrenocorticotropic hormone (ACTH) stimulation test, dexamethasone suppression test and measure of endogenous plasma ACTH concentration. Histopathological examination revealed chromophobe adenoma in pituitary gland and hyperplasia in adrenal cortex.

A randomized controlled comparative study of oral medroxyprogesterone acetate (MPA) 1,200 mg (arm I) and 600 mg (arm II) was conducted in 80 patients with advanced or recurrent breast cancer. There were no significant differences between arm I and arm II in terms of response rate, duration of response and survival, or in terms of incidence and severity of adverse reactions. The lowest serum MPA concentration in responders tended to be higher than that in nonresponders. In the cohort of this study, the lowest concentration in partial response was 17.4 ng/ml, suggesting that this level may be the required minimum serum concentration.

Based on estrogen receptor (ER) and menopausal status, operable breast cancer (UICC stage I, II, III-a) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the relapse-free survival (RFS) and overall survival (OS) were compared. Tamoxifen (TAM) 20 mg/day was administered orally for 2 years after mastectomy as an adjuvant endocrine therapy in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was performed before TAM administration. In the chemotherapy arm (CHEM), patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously, followed by an oral administration of cyclophosphamide (CPA) 100 mg/day in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated 4 times in 2 years. The chemoendocrine arm (CHEM + TAM) was composed of TAM with MMC + CPA chemotherapy. The patients were randomized according to ER and menopausal status. ER-positive patients were randomized to three arms: OVEX +/- TAM, CHEM, and CHEM + TAM. For ER-negative patients there were two arms: CHEM and CHEM + TAM. 1579 patients entered the trial between September 1978 and December 1991, with median follow-up of 8.2 years. In ER-positive, premenopausal patients, there were no significant differences in RFS or OS among OVEX + TAM, MMC + CPA, TAM + MMC + CPA arms. On the contrary, in ER-positive, postmenopausal patients, the chemoendocrine therapy showed a significantly higher RFS (p = 0.0400) and OS (p = 0.0187) as compared with TAM to chemotherapy alone. There were no significant differences in RFS or OS by addition of TAM on the chemotherapy, in both pre- and post-menopausal ER-negative patients. It was concluded that in ER-positive premenopausal breast cancer, endocrine therapy alone may be equivalent in prolonging RFS and OS to chemotherapy or chemoendocrine therapy, and that ER-positive postmenopausal breast cancer may be better controlled with the combination of TAM and chemotherapy, as compared to TAM or chemotherapy alone. The importance of stratification of operable breast cancer by ER and menopausal status, as well as the direct comparisons of different treatments, were stressed.

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located throughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage IIIa breast cancer. Patients with estrogen receptor-positive [ER( + )] breast cancer were treated with two types of regimens, ie, cyclophosphamide + adriamycin + fluorouracil (CAF; 2 cycles) + Futraful (FT) or CAF (2 cycles) + FT + tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER( + ) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation. The 5-year survival rate was 77.2% for the CAF + FT group and 74.6% for the CAF + FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF + FT + TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF + FT + TAM group was significantly higher than that for the corresponding patients in the CAF + FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF + FT+TAM group than in the CAF + FT group). Patients with estrogen receptor-negative [ER( -)] breast cancer were treated with two types of regimens, ie, CAF + FT or CAF + FT + adriamycin (ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478 (93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF + FT group and 63.0% for the CAF + FT + ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF + FT and CAF + FT + ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF + FT+ADR group than in the CAF + FT group.

Longer survival data are necessary to elucidate the prognostic factors for survival in advanced breast cancer patients. Univariate and multivariate analyses were performed in 159 patients treated with adreno-oophorectomy alone as the first-line treatment for advanced or recurrent breast cancer, between 1972 and 1983. Nine clinical factors included age, menopausal status, estrogen (ER)- and progesterone receptors (PgR) in recurrent tumors, disease-free interval (DFI), number of metastatic organs, performance status, and adjuvant therapy performed. Response was evaluated according to the UICC criteria. A 31% (50/159) response with 16 CR, 34 PR, 48 NC, and 61 PD was obtained. The logistic regression model of the factors showed that ER was the single affecting factor for the response. According to the Cox proportional hazard model, ER and the dominant site of metastasis were indicated to be significant for survival. According to the landmark method, the response significantly correlated to survival. Using the backward elimination procedure of the Cox proportional hazard model in the patient group defined by the landmark time of 3 months after therapy, the survival of the patients with advanced breast cancer was shown to be primarily influenced by the tumor response which was solely affected by ER status, and the dominant site, particularly the presence of liver metastasis, independently modified the survival length. These results may be useful in future studies of total estrogen blockade trials for breast cancer.

A double blind study to compare the efficacy of oral UFT (400 mg Tegafur (FT) plus 896 mg uracil/day) with that of oral FT (800 mg/day) on advanced breast cancer was performed between November, 1986, and November, 1989. Sixty patients were registered for the trial and fifty-six cases were evaluated (28 for UFT and 28 for FT). The primary end points in the study were response rate and time to relapse. There were no significant differences in patients' characteristics in either group. The objective response rates were 39% (11/28; 95% confidence interval (C.I.), 22-59%) in UFT and 21% (6/28; 95% C.I., 8-41%) in FT, without statistical significance (P = 0.25). For time to relapse, a trend was seen in favor of UFT, but this effect did not achieve statistical significance (P = 0.09). Both subjective and objective adverse effects were similar between the two treatments. The overall survivals were similar in both parts of the study. The size of the trial was too small for a definite conclusion to be drawn although, for both response rate and time to relapse, a trend was seen in favor of UFT. A large scale randomized study will be necessary to compare the drugs in the management of patients with advanced breast cancer.

Spontaneous hemangioendothelial cell hyperplasia of the heart was found in 12 of 3,910 female B6C3F 1(C57BL/6CrSlc x C3H/HeSlc) mice that were used in chronic toxicology and carcinogenicity studies at the An-Pyo Center (Shizuoka, Japan). Histologically, the lesions appeared diffusely in the heart as widened vascular spaces lined by a single layer of endothelial-like cells with enlarged nuclei between the muscle fibers. These proliferating cells were identified as hemangioendothelial cells by immunohistochemical techniques, lectin-binding patterns, and electron microscopic examination. Morphological differences were found between this spontaneous hemangioendothelial hyperplasia and that which has been reported as a preneoplastic lesion of hemangiosarcoma. Spontaneous hemangioendothelial cell hyperplasia of the heart occurs rarely; however, it was interesting that spontaneous hemangioendothelial cell hyperplasia was only seen in females with adenocarcinomas of the mammary gland.

A hospital-based retrospective cohort study of benign breast disease (BBD) as a risk factor of future breast cancer (BC) development was conducted. Four hundred and twenty-eight patients with biopsied BBD were followed-up for a median period of 8 years, together with age-matched women with normal breasts (normal control) and BC patients (cancer control), at the ratio of 1:2:2. Twenty-one breast cancers developed, 7 in the cases, 4 in the normal controls, and 10 in the BC controls, showing the relative risk (RR) with 95% confidence intervals (CI) to be 3.5 (1.03-11.9) in the cases with respect to the normal controls. The RR of the cases is not lower than that of contralateral breast cancer incidence. There were no significant differences in the risks of cancers in other organs among the groups. Pathological examination revealed that only atypical hyperplasia increased the RR of BC, as compared with the normal control breast group, or with non-proliferative disease. These results suggest that in a low-risk country, Japan, BBD is a definite risk factor for BC development as in high-risk countries.

Of 534 human primary breast cancers provided for clonogenic assay in vitro, 276 (51.7%) developed distinctive colony formation by the soft-agar method. Estrogen receptors (ERs) were assayed by dextran-coated charcoal methods. A total of 65 (23.7%) of 274 breast cancers responded to added 10 nM 17 beta-estradiol (E2) by an increase in the number of colonies per dish of 150% or more of that in the controls treated with dextran-coated charcoal. The ER-positive and ER-negative tumors differed significantly in their response to E2: 55 (29.9%) of 184 ER-positive tumors responded versus 10 (11.1%) of 90 ER-negative tumors. The cancers in which the number of colonies increased to 150% or more of that of the controls were considered to be estrogen dependent; those in which the number of colonies increased to less than 150% of the control values were considered to be estrogen independent. When 1 microM tamoxifen (TMX) was added to the medium, 48 (21.3%) of 225 cancers showed a decreased in the number of colonies to 50% or less of that of the controls. Thus, we could separate breast cancers that were TMX sensitive (No. of colonies less than or equal to 50% of that of controls) from those that were TMX resistant (No. of colonies greater than 50% of that of controls). The response to TMX of the ER-positive cancers was significantly higher than that of the ER-negative tumors: 39 (25.5%) of 153 ER-positive tumors responded versus nine (12.5%) of 72 ER-negative tumors. In 153 ER-positive and 71 ER-negative tumors, we evaluated the correlation between the response to E2 and the response to TMX. ER-positive and ER-negative tumors differed significantly in their sensitivities to the two drugs. The TMX sensitivity did not completely correlate with the E2 dependence.(ABSTRACT TRUNCATED AT 250 WORDS)

Out of the 365 young laboratory beagle dogs which were used in 17 toxicity bioassays, 15 cases (4.1%) were diagnosed as having congenital heterotopic gastric mucosa of the small intestine. Its incidence in the…male dogs (12 cases out of 187) was higher than in the female dogs (3 cases out of 178). Grossly, the lesions were seen as an ulcerous focus of the small intestine, 25 cm to 88 cm proximal to the ileocecal valve. All of the lesions were quite similar histologically and electron microscopically to the normal gastric mucosa, which are composed of the surface mucous cells, chief cells, parietal cells, mucous neck cells and basal granulated cells of the stomach. And consequently, they were considered to be that of a congenital heterotopic tissue in the small intestine. The only morphological characteristic of these lesions different from the regular gastric mucosa was an association with the tubular structure seen in the basal region of these mucosal layers. These cells were considered to be of mucous-secreting cell origin because of secreting type HI mucous evident from paradoxical concanavalin A or periodic acid Schiff stains. They seemed to be protecting the surrounding intestinal mucosa from gastric acid.

64 Japanese postmenopausal patients (pts) (median age 59: range 38–76) with advanced or recurrent breast cancer who had received more than 1 prior regimen (honnonotherapy and/or chemotherapy) were randomized between 2 oral regimen of letrozole for more than 8 weeks, 33 pts (ER+: 18, ER−: 3, unknown: 12) being given 0.5 mg of letrozole daily and 31 pts (ER+: 15, ER−: 3, unknown: 13), 1 mg daily. The tumor responses were peer reviewed and response rates (CR + PR in evaluable cases were 28% (3CR + 6PR/32, 95% C.I.: 14–47%) in 0.5 mg group and 39% (5CR + 6PR/28, 95% C.I.: 22–59%) in the 1 mg group, respectively. Stabilization of the disease for more than 6 months (long NC) was obtained in 19% for the 0.5 mg group and in 29% for the 1 mg group, respectively. Progressive disease was noted in 31% for the 0.5 mg group and in 21% for the 1 mg group, respectively. Clinical adverse experiences were observed in 6% of pts (2/33, 5 events) for the 0.5 mg group and in 6% of pts (2/31, 2 events) for the 1 mg group, all being only of mild severity (grade 1) except one event of grade 2 itching in the 1 mg group. Laboratory test abnonnalities were found in 9% of pts (3/33,6 events) for the 0.5 mg group and in 10% of pts (3/31, 6 events) for the 1 mg group, respectively. Except for one event of grade 2 GOT and GPT elevation noted in the 0.5 mg group, all other events were of either grade 0 or grade 1 severity. Estrone levels were maintained below the detection limit (2.5 pg/ml) and a sustained estradiol suppression was observed, with levels near the detection limit (1 pg/ml) during treatment. There was no clinically relevant changes in the other hormones (aldosterone, cortisol, FSH, LH, testostetone, androstenedione). These highly promising results support further extensive clinical evaluation.

For more precise prediction of response to endocrine therapy in patients with advanced breast cancer, we investigated the correlation between the presence of combination of estrogen (ER), progesterone (PgR) receptors, or combination of ER, PgR and androgen receptor (AR) and response to therapy. The patients with ER+, PgR+ tumors survived longer than those with ER+, PgR-, or ER-, PgR- tumors. A better response rate with longer survival time was obtained in patients with tumors that had three positive receptors or PgR+ and/or AR+ in addition to ER+ than in those with tumors of other combinations. According to the sequential assays of ER in tumors in several stages of breast cancer, it is likely that the positive rate of ER becomes lessened by the progression of cancer and by treatments. We stressed the significance of steroid hormone receptor assay in the mastectomy specimens for the prediction of response of therapy in case of the future recurrence of malignancy.

Rats deprived of blood, amounting to about one percent of body weight, via orbital venous plexus phlebotomy for 2 weeks developed severe anemia. Their mean hematocrit value was 19%, and centrolobular liver cell necrosis was observed in animals with hematocrit value of 20% or less at the end of the study. It is obvious that the animals must have been in a severe anemic condition to develop liver cell necrosis. Thus, anemia should be considered as a causative factor of liver cell necrosis in toxicity studies in which the animals are in severe anemia attributable to drug administration.

Based on estrogen receptor (ER) status and menopausal status, operable breast cancer (International Union Against Cancer [UICC] Stage I, II, and III) patients were randomized for adjuvant endocrine therapy, chemotherapy, and chemoendocrine therapy, and the effects on the disease-free survival (DFS) and overall survival (OS) were compared. Adjuvant endocrine therapy was composed of tamoxifen (TAM) 20 mg/day orally for 2 years in postmenopausal patients. In premenopausal patients, oophorectomy (OVEX) was done before TAM administration. In the chemotherapy arm, the patients were given 0.06 mg/kg of body weight of mitomycin C (MMC) intravenously (IV) and then an oral administration of cyclophosphamide (CPA) 100 mg/body orally in an administration of a 3-month period and a 3-month intermission. This 6-month schedule was repeated four times in 2 years. As the chemoendocrine therapy arm, TAM with MMC + CPA chemotherapy was added. The patients were randomized according to ER and menopausal status. Estrogen receptor-positive (ER+) cancer patients were randomized to three arms: TAM +/- OVEX, MMC + CPA, or MMC + CPA + TAM. For estrogen receptor-negative (ER-) patients, there were two arms: MMC + CPA, or MMC + TAM. The study started in September 1978, and 692 patients entered until the end of 1984 were evaluated. The median follow-up was about 46 months. Totally, a 9.8% rate (68/692) of recurrence was noted, a 7.5% rate (52/692) of mortality. There were no significant differences in DFS or OS among the treatment arms in ER+ or ER- patients. There was significant differences in adverse effects such as bone marrow suppression, gastrointestinal disturbances, cystitis, hair loss between endocrine therapy and chemotherapy or chemoendocrine therapy groups. In this preliminary study, it was concluded that because of less adverse effects of endocrine therapy, it seems rational to select the operable breast cancer patients by the presence or absence of ER, namely, endocrine therapy for ER+ and chemotherapy for ER- cancer patients.

In several sequences during the progression of cancer, the authors assayed estrogen receptors(ER) in 940 breast cancers and progesterone receptors(PgR) in 773 cancers. The percentages of ER+ and PgR+ cancers diminished according to the progression of malignancy. Sequential assays of ER and PgR were carried out in primary tumors and in the metastatic tumors at the first recurrence in 42 patients. During the disease-free interval, 10 (37%) of 27 ER+ tumors changed to ER- and all 15 ER- tumors remained negative. The hormone receptors were assayed before the treatments and after the tumor relapsed following regression or after the progression of cancer. The change of ER and PgR in 99 patients with advanced breast cancer were studied according to the type of systemic treatments. Through endocrine therapy, marked changes from ER+ to ER-, were noted (by antiestrogens, 47% [7/15]; by adreno-oophorectomy, 61% [11/18]). Almost no breast cancers changed from ER- to Er+ during the endocrine therapy (by antiestrogen, 1/6; by adreno-oophorectomy, 0/10). All of six PgR+ tumors changed to PgR- after therapy. By chemotherapy treatment, 44% (4/9) ER+ cancers became ER-, while 19% (3/16) ER- tumors changed to ER+. After the simultaneous combination of chemotherapy and endocrine therapy, 67% (10/15) of ER+ cancers changed to ER-, and 20% (2/10) of ER- tumors changed to ER+. Through the intervention of more than two kinds of chemotherapy and/or endocrine therapy between the first treatment and the last therapy, 79% (19/24) ER+ breast cancers changed to ER-. Thus, ER and PgR contents of breast cancer gradually became negative as the malignancy progressed, and with some kinds of treatments particularly including endocrine therapy. The significance of changes in hormone receptors after therapy was discussed.

The chemotherapeutic treatment of advanced and recurrent breast cancer was examined in a randomized controlled comparison test. Group A received (2″R)-4'-O-tetrahydropyranyladriamycin (THP) in combination with 5-fluorouracil (5-FU) and cyclophosphamide (CPA), while Group B was administered adriamycin (ADR) together with 5-FU and CPA. These combined chemotherapies were administered in a dosage regimen that was repeated in a 28-d cycle. On d l and d 8, THP and ADR were given at a dose of 30 mg m 2 IV and 5-FU was administered at a dose of 500 mg m 2 IV. CPA was administered at a dose of 100 mg body , PO on consecutive days from d 3 to d 16. Among 37 complete cases in Group A, a complete response (CR) was noted in one patient and a partial response (PR) in 12, to give a rate of 35.1 %. CR was noted in one patient and PR was observed in 7 out of 27 complete cases in Group B, giving a response rate of 29.6 %. The mean PR duration was 19 wk (range, 4+ −63) in Group A, and 14 wk (range, 4+−51+) in Group B. The 50% survival duration was 20.6 mo and 14.3 mo in Groups A and B, respectively, while mean survival duration was 17.9 mo and 16.6 mo in Groups A and B, respectively. No significant between-group differences were found for any of these measures. There were fewer side effects in Group A than in Group B, with Group A showing significantly less alopecia (P 0.1). Abnormal ECGs (myocardial disorder, lower voltage, and tachycardia) were observed in 3 patients in Group B, but were not found in Group A. It was suggested that THP was comparable in efficacy to ADR while inducing fewer side effects, and should be regarded as an effective new anthracycline agent for the treatment of breast cancer.

The relation between estrogen receptors (ER) in breast cancer and risk factors was studied in 456 Japanese patients. ER was shown to be positive in 55.3% (252/456) of patients. There was no difference in ER positivity between pre- and postmenopausal patients. In premenopausal patients, only the age at menarche and obesity showed some influence on the ER positivity of breast cancer. Among postmenopausal patients, on the contrary, ER(+) cancers were predominant in the patient groups that have been known to be higher in the risk of incidence of breast cancer. The factors included were the age at marriage, number of pregnancies, number of live children, and body weight. Of these, the body weight of patients was the strongest influence on the ER positivity in the postmenopausal patients. After excluding the effects of body weight, some of the reproductive factors such as number of pregnancies and number of live children were shown to be related to the ER status. These results may suggest the combination of lower incidence of breast cancer and lower percentage of ER(+) cancers in Japanese postmenopausal women as compared with the Western countries.

Although cancer chemotherapy or endocrine ablation therapy is effective by itself to some extent for advanced breast cancer, a synergistic effect would be expected if the both treatments were combined. It was demonstrated in the DMBA-induced rat mammary tumors that chemotherapy after oophorectomy was most effective to tumor regression with no mortality. Thus anticancer chemotherapy was suggested to be effective under suitable conditions caused by endocrine ablation therapy, and the “hormone conditioned cancer chemotherapy” for breast cancer was proposed.

Ten male rhesus monkeys, each weighing 3.5 kg, were divided into four groups of 3, 3, 2, and 2, and were fed daily with 100 g pelleted food containing 300, 30, 3, and 0 ppm cadmium, respectively. Urine samples were collected every 2 weeks and blood samples every 4 weeks. One monkey each of the 300 and 30 ppm groups was autopsied for pathological examination and tissue cadmium determination at the week 24 of the experiment; the remaining 8 animals were killed after 55 weeks. The lowest exposed group (3 ppm) did not show any specific biological response to cadmium over a period of 55 weeks. In the 30 ppm group, no significant changes were observed for up to 24 weeks, although cadmium concentration in the renal cortex and urine at 24 weeks were 300 mug/g wet weight and 18 mug/l., respectively. Plasma urea nitrogen and urine protein (quantitative determination) increased after 30 and 36 weeks. At 55 weeks of the experiment, qualitative tests were negative for low molecular weight proteinuria and glycosuria, and the results remained normal for renal and liver function tests and blood analysis, although cadmium concentrations in the renal cortex of two monkeys were 460 and 730 mug/g wet weight and those in the liver were 110 and 160 mug/g wet weight, respectively. In the highest exposure group (300 ppm), urine cadmium increased to 250 mug/l. by 11 weeks, and urine retinol-binding protein, plasma GOT, GPT, and LDH increased after 12 weeks. Proteinuria (quantitative determination), glycosuria, aminoaciduria (panaminoaciduria), and erythrocytopenia were observed after 16 weeks, when urine cadmium was 500-900 mug/l. Hypohemoglobinopathy and proteinuria (qualitative determination) were observed after 20 and 24 weeks, while cadmium concentrations in the renal cortex and the liver were 760 and 430 mug/g wet weight at 24 weeks, respectively. Slightly depressed tubular reabsorption of phosphate, increased urine beta(2)-microglobulin, increased plasma urea nitrogen, and increased plasma alpha(2)-globulin fraction (electrophoresis) were observed between 28 and 30 weeks of the experiment. Creatinine clearance and plasma cholinesterase decreased after 47 and 54 weeks, respectively. Cadmium concentrations in the renal cortex and the liver of two monkeys at 55 weeks were 350 and 580 mug/g wet weight and 410 and 630 mug/g wet weight, respectively. Pathological examinations revealed denaturation, destruction, and regeneration of the epithelial cells in renal proximal tubules, but no pathological changes in osseous tissues. Critical cadmium concentration in the renal cortex was estimated to be 380 mug/g wet weight for low molecular weight proteinuria and 470 mug/g wet weight for proteinuria, glycosuria, and aminoaciduria. Critical concentration in the liver was also estimated to be 210 mug/g wet weight. The apparent biological half-time of cadmium in monkeys at autopsied stage was calculated to be 0.66, 6.4, 5.2, and 22.4 years for the 300, 30, 3, and 0 ppm groups, respectively.