Quantitative study of mitochondria in rat liver. Dry mass, wet mass, volume, and concentration of solids.

The dry mass, wet mass, and volume of mitochondria of normal rat liver were determined, as well as nitrogen content and concentration. A scheme of multiple approaches to these quantities was devised, permitting comparison of values obtained by independent methods. The following basic values are considered highly accurate: Mean dry mass, 13.6 x 10(-14) g; mean wet mass, 51.8 x 10(-14) g; mean volume, 0.43 micro(3); nitrogen content, 1.75 x 10(-14) g The work emphasizes the fact that in mitochondria the quantities, mass, and volume occur in logarithmic-normal distributions.

Contralateral primary tumors in breast cancer patients in a randomized trial of adjuvant tamoxifen therapy.

Prophylactic treatment with the anti-estrogen tamoxifen may reduce the risk of breast cancer because estrogens are thought to act as promoters in the pathogenesis of the disease. This article presents results on the incidence of contralateral new primary tumors among 1846 postmenopausal breast cancer patients included in a randomized trial of adjuvant tamoxifen therapy for 2 or 5 years after surgery versus no adjuvant endocrine therapy. The median follow-up was 7 years (range, 3-13 years). There was a significant reduction of contralateral breast cancer in the 931 patients in the tamoxifen group versus that in the 915 control patients (29 versus 47 cases, respectively; P = .03). The cumulative incidence at 10 years in the tamoxifen group and the control group was 5% and 8%, respectively. Analysis of the relative hazard of contralateral tumor over time showed that the benefit with tamoxifen therapy was greatest during the first 1-2 years, but there was a continued risk reduction during the entire follow-up period, i.e., more than 10 years after cessation of treatment. There was no significant difference in the number of contralateral cancers in the patients randomly assigned to 2 or 5 years of treatment, but the 95% confidence interval of the relative hazard was wide. The proportion of estrogen receptor-negative contralateral breast cancers was higher in the tamoxifen group than in the control group. There was no difference, however, between the two groups in recurrence-free survival time from the diagnosis of the contralateral cancer.(ABSTRACT TRUNCATED AT 250 WORDS)

Long-term adjuvant tamoxifen in early breast cancer: effect on bone mineral density in postmenopausal women.

The decrease in sex steroid hormone levels after the onset of menopause is associated with bone loss and subsequent osteoporosis. Tamoxifen has antiestrogenic properties and may thus theoretically decrease bone mineral density, particularly after long-term treatment. Bone mineral density (BMD) was assessed in 75 recurrence-free postmenopausal breast cancer patients included in a randomized trial of adjuvant tamoxifen (40 mg daily) for 2 or 5 years versus no adjuvant endocrine therapy. The measurements were done about 7 years after the initial randomization. BMD was measured with single-photon absorptiometry (SPA) at two levels of the distal forearm representing cortical and trabecular bone. The BMD was found to be similar among tamoxifen patients compared with the controls. For cortical bone, the BMD was 1.03 g/cm2 (95% confidence interval [Cl], 0.97 to 1.09) among tamoxifen patients and 1.03 g/cm2 (95% Cl, 0.96 to 1.11) in controls. For trabecular bone, the values were 0.74 g/cm2 (95% Cl, 0.70 to 0.79) and 0.73 g/cm2 (95% Cl, 0.68 to 0.79), respectively. The results thus did not indicate an accelerated postmenopausal bone loss with long-term adjuvant tamoxifen.

Adjuvant tamoxifen in early-stage breast cancer: effects on intercurrent morbidity and mortality.

Intercurrent mortality and the pattern of inpatient hospital care was studied among 1,846 postmenopausal patients included in the Stockholm randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no adjuvant endocrine therapy. The median follow-up time was 54 months (range, 2 to 123 months). The patients were matched to the Swedish National Registry of Causes of Death and a computerized register covering about 95% of all hospital admissions in Stockholm County. There was no significant difference in the pattern of intercurrent mortality among the tamoxifen and control patients. The total number of hospital admissions was similar in both groups, but the tamoxifen patients were admitted significantly less frequently because of immunologic diseases (relative risk [RR] = 0.4; 95% confidence interval [CI], 0.2 to 0.9). Admissions because of thrombotic diseases were slightly, but not significantly, more frequent among the tamoxifen patients (RR = 1.2; 95% [CI], 0.6 to 2.3). The risk of hospital stay for benign gynecologic diseases other than prolapse or uterine bleeding was increased in the tamoxifen group (RR = 3.2; 95% CI, 1.2 to 8.6). No significant differences were found for diseases related to arteriosclerosis or osteoporosis. The study confirms and extends previous reports, which have shown that tamoxifen has few and usually mild side effects. However, the current results should be judged cautiously because of the relatively short median follow-up time (4.5 years) and the limitation of data in detecting morbidity that does not necessarily result in hospitalization.

The relationship between hormone receptor content and the effect of adjuvant tamoxifen in operable breast cancer.

The relationship between hormone receptor status and the effect of adjuvant tamoxifen in early breast cancer remains controversial. This article presents the results of a randomized trial of adjuvant tamoxifen (40 mg daily for 2 years) versus no adjuvant endocrine therapy in postmenopausal patients. During 1976 to 1984, 1,407 patients were included in the study. Of these, 427 (30%) had high-risk tumors (pN + or pT greater than 30 mm) and were included in a concurrent randomized comparison of postoperative radiotherapy versus adjuvant polychemotherapy. The mean follow-up time was 61/2 years. Tamoxifen improved the recurrence-free survival (RFS) (P less than .01), but the overall survival difference in favor of the tamoxifen-allocated patients was not significant. Data on estrogen (ER) and progesterone receptor (PgR) content were available in 750 patients. Their mean follow-up time was 41/2 years. The effect of tamoxifen was significantly related to ER level (P less than .01). No benefit with tamoxifen was observed among ER-negative patients. The relation to PgR level was of borderline significance (P = .06). Multivariate analysis indicated that most of the interaction between treatment and receptor content was explained by the interaction with ER (P less than .01). The PgR status appeared to modify the effect of tamoxifen among the ER-positive patients and the greatest effect was observed among patients who were positive for both receptors. However, the additional predictive information provided by the PgR assay did not help to identify an unresponsive subgroup of patients.

Intravenous clodronate for the treatment of hypercalcaemia in breast cancer patients with bone metastases--a prospective randomised placebo-controlled multicentre study.

In a double blind randomised multicentre study the effect of intravenous clodronate plus hydration was compared with placebo plus hydration in the treatment of hypercalcaemia in breast cancer patients with bone metastases. The patients were treated either with hydration plus clodronate 300 mg/day or hydration plus placebo, up to 7 days or until serum ionised calcium was below 1.4 mmol/l. 25 patients received clodronate and 19 placebo. A significant difference in favour of clodronate was observed in the time to reach normocalcaemia (P = 0.004) and in the number of patients achieving normocalcaemia (P = 0.0003). 17 patients of 21 evaluable patients on clodronate achieved normocalcaemia compared with 4 of 19 patients on placebo. The only adverse event clearly associated with clodronate was symptomatic hypocalcaemia in 1 patient. Thus, clodronate seems to be a safe and highly efficacious drug for the treatment of hypercalcaemia in breast cancer patients.

Myocardial damage in breast cancer patients treated with adjuvant radiotherapy: a prospective study.

PURPOSE: To look for early and late signs of cardiac side effects of postoperative radiotherapy in patients with left-sided breast cancer. METHODS AND MATERIALS: Seventeen left-sided primary (Stage I-III) breast cancer patients considered eligible were recruited. Their computer tomography-based dose planning showed a part of the heart's left ventricle irradiated with at least 85-95% of the total dose. Twelve patients were examined both before treatment and an average of 13 months later, at a first follow-up. In partially mastectomized patients tangential opposed photon fields were used to the breast tissue, while in patients with modified radical mastectomy electrons were given to the thorax. Echocardiography and a bicycle ergometry stress test with myocardial perfusion scintigraphy were carried out before and after radiotherapy to assess if any myocardial damage could be detected. RESULTS: Six of the 12 patients exhibited new fixed scintigraphic defects after radiotherapy indicating regional hypoperfusion. Four of them received treatment only to the breast after breast-conserving surgery. The localization of the defects corresponded well with the irradiated volume of the left ventricle. No deterioration in left ventricular systolic or diastolic function could be detected by echocardiography. CONCLUSIONS: In this study half of the patients exhibited new scintigraphic defects that indicate radiation-induced myocardial damage, probably affecting the microcirculation. There were no changes on electrocardiography or any deterioration of the left ventricular function at this stage. Long-term follow-up is necessary to assess whether this finding is a prognostic sign for developing radiation-induced coronary artery disease.

Radiotherapy, chemotherapy, and tamoxifen as adjuncts to surgery in early breast cancer: a summary of three randomized trials.

The paper summarizes up-dated results of three randomized adjuvant trials from the Stockholm Breast Cancer Group. The objective of all studies included an evaluation of the role of megavoltage radiation in the primary management of patients with early breast cancer. The first trial was started in 1971 and included 960 pre- and postmenopausal patients with operable disease. The study compared adjuvant radiotherapy with surgery alone. All patients were treated with a modified radical mastectomy. There was a sustained improvement of the recurrence-free survival with radiotherapy (p less than 0.001). Among node positive cases radiation reduced the frequency of both loco-regional recurrence (p less than 0.001) and distant metastasis (p less than 0.01). This observation indicates that distant dissemination in subgroups of patients can originate from uncontrolled local deposits of tumor cells, for instance in the regional lymph nodes. No adverse effect from radiation on long-term survival was observed. The second study was started in 1976 and compared postmastectomy radiation with adjuvant chemotherapy in pre- and postmenopausal high-risk patients. At a mean follow-up of 6 1/2 years there was no significant difference in recurrence-free survival between the two treatments. However, postmenopausal patients fared better with radiotherapy (p less than 0.01). In this subgroup, radiation was more effective than adjuvant chemotherapy in reducing both distant metastases (p less than 0.01) and loco-regional recurrences (p less than 0.001). In the third trial--which only included postmenopausal patients--2 years of adjuvant tamoxifen was compared with no adjuvant endocrine treatment. The number of treatment failures was significantly reduced with tamoxifen (p less than 0.01) but there was no significant overall survival benefit. Subset analysis indicated that tamoxifen improved the recurrence-free survival among patients treated with adjuvant chemotherapy (p less than 0.01) but only to a level close to that achieved with radiotherapy alone. Addition of tamoxifen to radiotherapy failed to further increase the recurrence-free survival.

Changes of blood T cell subsets following radiation therapy for breast cancer.

The changes of the size of various T cell subsets in the blood, as defined by monoclonal antibodies and Fc-receptors for IgG and IgM, were examined in 11 women after postoperative radiation therapy (45 Gy) for breast cancer. All subsets of T cells were significantly reduced at completion of irradiation. The most extensive depletion was noted in a subset with receptors for IgG, which may exert suppression. Approximately 1 year later this subset had recovered significantly in parallel with another subset, also rich in suppressor T cells, which was detected by monoclonal antibodies. On the contrary, T cell subsets rich in cells with helper activity did not exhibit any significant recovery.

Pulmonary function following adjuvant chemotherapy and radiotherapy for breast cancer and the issue of three-dimensional treatment planning.

BACKGROUND AND PURPOSE: The frequency and grade of pulmonary complications following adjuvant radiotherapy for breast cancer are still debated. This study focuses on loss of pulmonary function. MATERIALS AND METHODS: We have measured the reduction of pulmonary function 5 months following radiotherapy in 144 node-positive stage II breast cancer patients by using pulmonary function tests. RESULTS: No deterioration of pulmonary function was detected among the patients who were treated with local radiotherapy. On the contrary, there was a mean increase in diffusion capacity by 7% (P = 0.004) following radiotherapy, which most likely was explained by the adjuvant chemotherapy administered prior to the baseline pulmonary function tests. Patients undergoing loco-regional radiotherapy showed a mean reduction in diffusion capacity by 5% (P < 0.001) and in vital capacity by 3% (P = 0.001). The subset of patients (9%) who were diagnosed with severe pulmonary complications needing cortisone treatment had significantly larger mean paired differences in vital capacity (-0.446 L, -15% (equivalent to 15 years of normal ageing or the loss of 3/4 of a lung lobe)) compared to the patients who were asymptomatic (-0.084 L) (P < 0.05). When the effects of potential confounding factors and different radiotherapy techniques were tested on the reduction of pulmonary function by stepwise multiple regression analysis, a significant correlation was found only to locoregional radiotherapy including the lower internal mammary lymph nodes. CONCLUSIONS: We conclude that a clinically important reduction of pulmonary function is seen in the subset of patients who are diagnosed with severe pulmonary complication following loco-regional radiotherapy for breast cancer. The results of this study warrant further studies based on individual lung dose volume histograms.