[Monoclonal antibodies to human breast epithelium].
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Animals↗
Biomedical subjects
B B Rasmussen
Publications and source records attributed to B B Rasmussen.
Detection of surface antigens defined by monoclonal antibodies in primary mucinous breast carcinomas. Relation to prognostic factors and recurrence-free survival.
Three monoclonal antibodies, 67D11, 115H10 and 115C2, raised against human milk fat globule membranes, have been applied to 207 primary mucinous breast carcinomas. The tumours reacted positively in 18% (67D11), 54% (115H10), and 20% (115C2) of the cases. The detected epitopes (MAM-3a (67D11), MAM-3b (115H10), and MAM-3c (115C2)) have formerly been shown to be markers of differentiation in infiltrating ductal carcinomas. In the present group of mucinous breast carcinomas, statistically significant correlation to high risk factors, such as occurrence of primary lymph node metastases, large tumour size, and local invasion of the tumour into overlying skin or deep fascie, were found. Furthermore, the antigen expression was less marked in pure mucinous carcinomas as compared to carcinomas also presenting with non-mucinous tumour areas. Thus, especially the antigen MAM-3b, is more frequently present in mixed tumours, in large tumours, in tumours with local invasion, and in tumours with primary lymph node metastases. However, no association could be demonstrated between expression of MAM-3b and recurrence-free survival. Mucinous carcinomas of the breast apparently differ from other carcinomas not only with respect to morphology, but also in their pattern of antigenic expression in relation to other prognostic factors.
Adenocarcinoma, Mucinous↗
Prognostic usefulness of estrogen receptor immunocytochemical assays for human breast cancer.
Breast cancers of postmenopausal patients at high risk for recurrence participating in an adjuvant therapy protocol were independently assayed for estrogen receptor by conventional dextran-coated charcoal steroid binding assays and by immunocytochemistry (ER-ICA) to compare the two assays and to assess the prognostic usefulness of ER-ICA. The ER-ICA was based on a monoclonal antibody to the estrogen receptor and was applied to lightly fixed, frozen sections of the cancers. Excellent agreement was found between the two estrogen receptor methods. It was found that a combination of the distribution of ER-ICA stained cells and the overall staining intensity gave a statistically significant correlation with the quantitative estrogen receptor dextran-coated charcoal steroid binding assay value. In addition, the overall appraisal of the lesion as ER-ICA positive or negative as well as the ER-ICA staining intensity and proportion of ER-ICA stained cancer cells related to patient disease-free interval and survival, independent of patient lymph node involvement. This relationship of ER-ICA status to prognosis appeared not to relate only to responses to adjuvant tamoxifen treatment since it also was observed with patients who did not receive the antiestrogen.
Breast Neoplasms↗
Steroid hormone receptors as prognostic indicators in primary breast cancer.
Recurrence-free survival (RFS) has been evaluated with regard to estrogen and progesterone receptor (ER and PgR) status for 145 postmenopausal women with primary breast cancer at high risk for recurrent disease. All patients received only local-regional therapy as an adjuvant therapy (DBCG protocol 77-c patients). ER+ patients had a significantly longer RFS than ER-patients. This difference was apparent using a cut-off level of 10 fmol/mg cytosol protein to distinguish between ER+ and ER-patients. There was no apparent difference in patients with high (greater than = 100 fmol/mg cytosol protein) ER levels vs. those with intermediate (10-99 fmol/mg cytosol protein) levels, indicating that the prognostic value of ER determinations in the natural course of the disease resides in a qualitative rather than a quantitative distinction among patients. No difference in RFS was found patients when patient were subdivided according to PgR status. The clinical applicability of the ER-ICA assay method for ER determinations is demonstrated in a subset of patients, some of whom received adjuvant endocrine therapy.
Actuarial Analysis↗
Beneficial effect of adjuvant tamoxifen therapy in primary breast cancer patients with high oestrogen receptor values.
Oestrogen receptor concentrations were measured in primary tumours of 291 postmenopausal breast cancer patients with high risk of recurrence. These patients were a subset of the 1650 patients participating in the Danish Breast Cancer Cooperative Group's trial of adjuvant treatment with tamoxifen (30 mg daily for one year). A cut-off point of 10 fmol/mg cytosol protein and the use of a Cox proportional hazards model distinguished between patients with long recurrence-free survivals and those with early recurrent disease. The use of this model also showed that patients with an oestrogen-receptor content below 100 fmol/mg did not benefit from the endocrine therapy, while those with concentrations above 100 fmol/mg had a significantly longer recurrence-free survival. This finding is consistent with the response of advanced breast cancer to endocrine treatment.
Aged↗
Ultrastructural characteristics and variations in human mucinous breast carcinomas.
Nineteen human mucinous breast carcinomas have been studied by electron microscopy in order to investigate the variations in the fine structure of this type of tumor. All the investigated tumors are characterized by a well-developed, rough endoplasmic reticulum and prominent Golgi complexes. The majority of tumor cells contain secretory granules. Approximately 50% (9/19) of the tumors have cytoplasmic dense core granules that are morphological identical to the neurosecretory granules found in APUD-cell derived tumors. Six out of the nine tumors react positively in a Grimelius staining for light microscopic argyrophilic granules. Two of the investigated breast carcinomas contain tonofilaments that are normally regarded as characteristic of squamous epithelium. It is concluded that mucinous breast carcinomas--that to this time have been regarded as a morphological homogenous group of tumors--are ultrastructurally characterized by heterogeneity.
Adenocarcinoma, Mucinous↗
Human mucinous breast carcinomas and their lymph node metastases. A histological review of 247 cases.
In a histologic reevaluation of 247 primary human mucinous breast carcinomas, 207 tumors fullfilled the criteria for further histopathological evaluation. The criteria for entrance in this survey are that at least 25% of the tumor consists of areas of extracellular mucin with small islands of solid epithelial tumor tissue floating in the mucin, and that the extracellular mucin should comprise at least 33% of the total tumor volume. The 247 carcinomas that have been further evaluated have been subclassified into two groups: "pure" mucinous breast carcinomas that consist solely of tumor tissue with extracellular mucin production (95 tumors), and "mixed" mucinous carcinomas that also contain infiltrating carcinoma without extracellular mucin (112 tumor). A significantly greater number of mixed carcinomas than pure carcinomas have an aggressive growth pattern--as defined by tumor size, adherence to overlying skin/bottom fascie, and primary axillary lymph node metastases. The histogenesis of the mucinous carcinomas is briefly discussed in relation to the present observations and the literature. The importance of clearly distinguishing between the mixed and the pure mucinous carcinomas in the diagnosis of these tumors is emphasized.
Adenocarcinoma, Mucinous↗
Argyrophilic cells in 202 human mucinous breast carcinomas. Relation to histopathologic and clinical factors.
Two hundred two human, mucinous breast carcinomas were investigated for the presence of argyrophilic granules, and these granules were found in 25% of the cases. The granules were located in the cytoplasm and were heterogeneously distributed within the tumors. Tumors with granules were otherwise morphologically indistinguishable from those tumors without granules. The recurrence-free survival was independent of the presence of granules, and no relation was found to other clinical or histopathologic factors. Tumors with granules were found to be estrogen-receptor positive, and they appear to have a slightly less aggressive growth pattern than tumors without granules, but the difference is far from being statistically significant. It is concluded that there is no convincing evidence that this group of primary breast carcinomas with argyrophilia originates from APUD cells.
APUD Cells↗
Prognostic value of surface antigens in primary human breast carcinomas, detected by monoclonal antibodies.
Three monoclonal antibodies, raised against human milk fat globule membranes, have been applied to 194 primary human breast carcinomas. The detected antigenic sites were found to be heterogeneously distributed. A statistical association with estrogen receptor content and grade of anaplasia was found for two of the antigens, Mam 3a and Mam 3b. The presence of all three antigens was independent of menopausal status, age, primary lymph node metastases, and progesterone receptor status. Life table analysis showed a better survival for patients with tumors positive for Mam 3b. The effect of these variables on recurrence-free survival has been analyzed using a Cox regression model. It is found that the most important prognostic factors are the number of positive lymph nodes, the estrogen receptor content, and the menopausal status of the high-risk patients. The ability of a model based on these factors to predict recurrence is not significantly improved by including any of the three surface antigens.
Antibodies, Monoclonal↗
Elastosis in relation to prognosis in primary breast carcinoma.
The content of elastic tissue has been evaluated in 171 primary breast carcinomas. Of the tumors, 35% had no or very little elastic tissue in the malignant areas, 42% presented with medium elastosis, and 22% had gross elastosis. The occurrence of elastin has been related to different prognostic factors. An increasing amount of elastin was found with increasing amounts of estrogen receptor (p = 0.0003), while there was only a slight correlation to the progesterone receptor content. Furthermore, the highly differentiated tumors contained more elastin in their tumor tissue than the poorly differentiated tumors (p = 0.003), and parous women had significantly more elastin than nonparous women (p = 0.02). The presence of elastin was not, however, of any demonstrable prognostic significance.
Breast Neoplasms↗
The influence of formalin and paraffin embedding on the immunohistochemical reaction of monoclonal antibodies applied to female breast tissue.
Monoclonal antibodies, raised against purified human milk fat globule membranes, were applied to human tissue and the corresponding antigenic determinants detected by an immunoperoxidase method. In human breast tissue, the presence of antigenic determinants was characterized by considerable heterogeneity although it is confined to epithelial cells and cannot be detected in non-epithelial areas. The effect of fixation and paraffin embedding on the reaction pattern was evaluated on tissue from 25 primary breast carcinomas. For each tumor, both frozen, acetone fixed and fixed, paraffin embedded tissue was available. Four of the eight applied antibodies could detect fewer positive cells in formalin-fixed tissue as compared to frozen, acetone-fixed tissue from the same tumor. The positive peroxidase reaction was better preserved after fixation in Lillie's solution. Treatment of formalin-fixed tissue with pronase did not give a better effect. Antibodies with preserved positive reaction in formalin-fixed breast tissue were applied to a range of epithelial and non-epithelial human malignant tumors of varying origin. A heterogeneous positive reaction could be detected in the majority of tumors derived from epithelial cells, but not in non-epithelial tumors.
Antibodies, Monoclonal↗
Estrogen and progesterone receptor profile patterns in primary breast cancer.
Estrogen (ER) and progesterone receptor (PgR) analyses have been performed in 884 primary, malignant human breast tumor biopsies. Receptor contents were evaluated with respect to age and menopausal status. The frequency of ER+ tumors was found to be significantly higher in postmenopausal than in pre/perimenopausal women. Age rather than menopausal status was found to be associated with this difference. The significant association with age was found in the post- but not the pre/perimenopausal women. The frequency of PgR+ tumors was found to be significantly lower in the postmenopausal than in the pre/perimenopausal women. Neither age nor menopausal status alone could account for this difference, which appears to be due to a compound effect of the two factors. The distribution of receptor profile patterns is described according to menopausal status. The patterns differ significantly in pre- and postmenopausal women. PgR dominates in the premenopausal tumor while ER dominates in the postmenopausal tumor. This difference is apparent within the subgroup of ER + PgR + patients as well. The current tenets for prediction of recurrent disease utilizing steroid hormone receptor determinations are discussed for the group of ER + PgR + patients.
Adult↗
DNA analysis by flow cytometry in lymphomatoid papulosis.
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Adult↗
Histopathological characteristics and oestrogen receptor content in primary breast carcinoma.
159 primary breast carcinomas were examined histologically with regard to grade of anaplasia, cellularity, amount of elastic tissue, and whether they were of ductal or lobular origin. Possible correlations between these variables and the oestrogen receptor (OR)-content were investigated. There was a marked tendency toward a greater number of OR-positive tumors in the group rich in elastosis. A significant correlation between the OR-content and the histological grade was found, whereas there was no correlation between either the OR-content or the grade of anaplasia and the cellularity. Furthermore, the group of tumors that were lobular in derivation had a significantly greater number of OER-positive tumors than the group ductally derived.
Breast Neoplasms↗
Teratogenic effect of maternal alcohol consumption on the mouse fetus. a histological study.
During pregnancy C3H mice were solely kept on a 10 or 20% liquid supply. They had free access to solids. All animals, including a group of controls, were chloroformed on the 19th day of pregnancy and the fetuses were examined for growth retardation, intrauterine death and microscopic malformations. Among the animals given alcohol, we found a significantly raised incidence of malformations as well as a raised number of intrauterine deaths and significant growth retardation as compared to the control animals. At the same time we found a clear dose-effect relation. The malformations were localize to the facial skeleton, the CNS, the eyes and lungs.
Animals↗
Teratogenicity of intrauterine copper wire in mice. A histopathological study.
Immediately after the implantation of the fertilized ovum, on the 6th day of pregnancy a copperwire was placed in the right hand uterine section on pregnant C3H mice. The left section was similarly surgically traumatized in order to serve as a control. The mice were killed with chloroform on the 19th day of pregnancy and by means of a special histological screening technique the fetuses were examined with special reference to growth reduction, intrauterine fetal death and microscopic malformations. Differences in intrauterine fetal death were shown not to exist, nor was there any significant growth retardation in the copperwire containing uterine section. Certain microscopic defects were found with slightly increased incidence in the copper containing section, but the differences were not statistically significant.
Animals↗
[Alcohol and fetal damage].
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Abnormalities, Drug-Induced↗
Fluvoxamine inhibits the CYP2C19-catalysed metabolism of proguanil in vitro.
OBJECTIVE: The potent CYP1A2 inhibitor fluvoxamine has recently been shown also to be an effective inhibitor of the CYP2C19-mediated metabolism of the antimalarial drug proguanil in vivo. The purpose of the present study was to confirm this interaction in vitro. METHODS: A high-performance liquid chromatography (HPLC) method was developed to assay 4-chlorophenylbiguanide (4-CPBG) and cycloguanil formed from proguanil by microsomes prepared from human liver. The limit of detection was 0.08 nmol mg-'. h-I. RESULTS: The formation of 4-CPBG and cycloguanil could be described by one-enzyme kinetics, indicating that the formation of the two metabolites is almost exclusively catalysed by a single enzyme, i.e. CYP2C19 within the concentration range used, or that the contribution of an alternative low-affinity enzyme, probably CYP3A4, is very low. This notion was confirmed by the lack of potent inhibition by four CYP3A4 inhibitors: ketoconazole, bromocriptine, midazolam and dihydroergotamine. Fluvoxamine was a very effective inhibitor of the oxidation of proguanil, displaying Ki values of 0.69 micromol x l(-1) for the inhibition of cycloguanil formation and 4.7 micromol x l(-1) for the inhibition of 4-CPBG formation. As expected, the CYP2C19 substrate omeprazole inhibited the formation of both metabolites with an IC50 of 10 micromol x l(-1). Norfluoxetine and sulfaphenazole inhibited proguanil oxidation with Ki values of 7.3-16 micromol x l(-1), suggesting that the two compounds are moderate inhibitors of CYP2C19. CONCLUSIONS: Fluvoxamine is a fairly potent inhibitor of CYP2C19 and it has the potential for causing drug-drug interactions with substrates for CYP2C19 such as imipramine, clomipramine, amitriptyline and diazepam. The combination of fluvoxamine and proguanil can not be recommended.
Algorithms↗