This study was carried out to assess the influence of site of biopsy and tumor heterogeneity upon the value of progesterone receptor (PR) measurements for prediction of response of patients with advanced carcinoma of the breast to tamoxifen or ovarian ablation. One hundred eighty-one assessable patients were studied. Sixty-nine % of responders and 31% of nonresponders were PR positive. The times to progression and survival were not significantly different for responders whether they were receptor positive or receptor negative. PR was measured on operable primary tumors (97), inoperable primary tumors (59), and secondary deposits (69). The proportion of responders who had PR-positive biopsies from these sites was 59%, 88%, and 61%, respectively, and the proportion of PR-positive nonresponders was 30%, 27%, and 42%, respectively. Ten to 12 separate PR measurements were made on seven tumors, and in four of them, there were PR-positive and PR-negative areas which could account for false positive and false negative results. We conclude that the optimum prediction of response was seen when the biopsy was performed on inoperable primary tumors. Errors in prediction of response at this site were, in part, explained by within-tumor heterogeneity of PR; the greater errors in prediction when measurements were made on operable primary tumors or on secondary deposits are presumed to be related to the additional effects of change in receptor status with time and between-tumor-site heterogeneity, respectively.

Biopsy↗

PubMed1987

Endocrine therapy for advanced carcinoma of the breast: relationship between the effect of tamoxifen upon concentrations of progesterone receptor and subsequent response to treatment.

In some cell lines and tumors of mammary origin, tamoxifen causes an increase of progesterone receptor (PR) as a result of its partial estrogen agonist activity. In this study we have assessed the effect of tamoxifen on PR in patients with advanced carcinoma of the breast in order to test if those with a rise in PR are more likely to respond to endocrine therapy. PR was measured before and a median of 13 days after treatment with tamoxifen in a group of 52 patients with either locally advanced (n = 28) or recurrent (n = 24) carcinoma of the breast. Controls were a group of patients with operable disease who had two biopsies with no intervening tamoxifen (n = 51) or with intervening tamoxifen (n = 58). In the test group PR was higher in the second biopsy than the first in 21 patients, and 19 of these responded to continued endocrine therapy (90%). In the remaining 31 patients PR was either lower in the second biopsy (n = 19) or was negative in both biopsies (n = 12), and 11 of the total of 31 patients (35%) responded to continued endocrine therapy. The prediction of response and time to progression was better when both biopsies were taken into account than either the first or the second alone. The prediction of survival was similar for the group selected by an increase in the second biopsy and the group with PR present in the second biopsy. The controls without tamoxifen showed a marked variation in the level of PR in the first and second biopsies, suggesting heterogeneity of PR across the tumors studied. However, the PR level was significantly higher in the second biopsy in the controls given tamoxifen and in the test group compared with those with no intervening treatment (p = 0.031). This study indicates that some effect of tamoxifen upon PR can be demonstrated in human mammary tumors in vivo and that, by taking a second biopsy for PR estimation during treatment with tamoxifen, a more precise indication of subsequent response is obtained. The value of a single estimation of PR before treatment on secondary deposits is limited, and if one biopsy only is performed, it is of greater predictive value if taken after a few days treatment with tamoxifen.

Aged↗

PubMed1987

DNA analysis by flow cytometry, response to endocrine treatment and prognosis in advanced carcinoma of the breast.

The relationship between DNA content of mammary cancer and subsequent response to endocrine therapy was studied in 136 patients with advanced disease. All were treated with tamoxifen or ovarian ablation as first-line systemic therapy after relapse and were evaluable for response according to UICC criteria. DNA characterisation by flow cytometry was used on formalin fixed paraffin-embedded samples of tumour. Tumours were grouped according to DNA index into diploid (n = 52, 38%), 'tetraploid' (n = 46, 34%) and 'other DNA-aneuploid' (n = 38, 28%). The highest proportion of oestrogen receptor positive tumours (ER + ve) was found in the 'tetraploid' tumours (38/46, 85%, Chi-square = 8.53, P less than 0.02), and response rates, (SD + PR + CR), were 26/52 (50%), 34/46 (74%), and 15/38 (39%) respectively (Chi-square = 10.88, P less than 0.005). Patients with diploid or 'tetraploid' tumours survived longer and stayed in remission longer than those with 'other DNA-aneuploid' tumours. We suggest that 'tetraploid' or 'near tetraploid' human mammary tumours may comprise a distinct group of endocrine responsive tumours within the overall group of aneuploid tumours. The conventional interpretation of DNA histograms, grouping into diploid and aneuploid, may be masking important features of some tumour groups.

Adult↗

PubMed1987

Effect of tamoxifen upon cell DNA analysis by flow cytometry in primary carcinoma of the breast.

The effect of tamoxifen upon cellular DNA ploidy in carcinoma of the breast was assessed by flow cytometry (FCM), in a prospective group of 77 patients with primary operable disease. Each had a needle biopsy at the outpatient visit for diagnosis and FCM analysis, and definitive surgery was performed a median of 8 days later. Forty received tamoxifen during this period - 40 mg qds loading dose for 24 h, followed by 20 mg daily until the day of operation: 37 patients received no therapy. The DNA histogram from the needle biopsy was compared with that obtained from the resected tumour for each individual. There was little change between the pair of histograms from tumours from the untreated patients. In those who had received tamoxifen the most consistent effect was a marked reduction in the magnitude of the 'tetraploid' peak in tetraploid or near-tetraploid tumours with DNA indices 1.8-2.0. There was little change in diploid or 'other DNA-aneuploid' tumours. In tetraploid tumours (DNA index of 2.0) the percentage of nuclei in the diploid S phase was significantly related to the percentage of nuclei in the diploid G2 + M/tetraploid G1 peak (P less than 0.003, unpaired t test). These data suggest that an effect of tamoxifen can be demonstrated by FCM upon tumours exhibiting a tetraploid or near-tetraploid DNA content. It is possible that tetraploid or near-tetraploid human mammary tumours may be a distinct group of endocrine responsive tumours within the overall group of aneuploid tumours, and that the majority are probably derived from the diploid population rather than being a true aneuploid population.

Adult↗

PubMed1987

Delayed excretion of 3-methylhistidine in goats.

The purpose of this study was to evaluate the use of 3-methylhistidine (3MH) as an index of muscle protein degradation in dairy goats. The criterion for validation was the rapid and quantitative excretion of radiolabeled 3MH. Three adult dry does and four bucks were confined to metabolism cages and injected with 5 ml of L-3-[14C]methylhistidine dihydrochloride (4 microCi/mL) diluted in normal saline. The does' urine was collected from catheters and the bucks' urine from stainless steel separators protected with fecal collection bags. The daily urine samples were analyzed for labeled amino acid. Urinary recovery of radioactivity from all does was less than 33% after 3 d and was proceeding at less than 5% d. After 9 d, total recovery was less than 50% of total dose for the does. Elimination rates were slightly higher and more variable for the yearling bucks (25-63% after 4 d). On the basis of these data, 3MH does not appear to be a valid index of muscle protein degradation in either male or female dairy goats.

Animals↗

PubMed1987

Clinical, virologic, and histopathologic observations of induced porcine parvovirus infection in boars.

Twelve 8- to 12-month-old crossbred boars were inoculated with a virulent strain (NADL-8) of porcine parvovirus (PPV). Hemicastrations were performed on 6 boars 3, 7, 10, 14, 21, and 28 days after an IM injection of 10(8) median cell culture infectious dose (CCID50) of PPV (n = 3) or injection of 10(7.4) CCID50 given intratesticularly (IT, n = 3). Noninfected cell culture medium (0.25 ml) was injected into each testicle of a 7th boar (IT inoculated control). Virus or viral antigen was detected in testicular and epididymal tissues up to 14 days after inoculation. Direct immunofluorescence indicated that viral antigen was mainly associated with the vasculature of the interstitium. Microscopic lesions were not evident in the testicles and epididymides of IM inoculated boars. Acute-to-chronic testicular degeneration was evident in the IT inoculated boars, as well as in the IT inoculated control boar. Six boars were inoculated IM or orally/nasally with 10(7.9) CCID50 of PPV. Semen was collected twice weekly for 8 weeks after inoculation. Virus was not detected in any ejaculates. Semen also was collected from 4 boars for 5 weeks before inoculation, and preinoculation and post-inoculation semen quality was compared. Pronounced changes in sperm output, ejaculate volume, motility, or morphologic defects were not observed. The reproductive consequences of experimental PPV infection in boars were minimal because reproductive function was unaffected and venereal transmission of PPV was not detected.

Animals↗