Prostaglandin in human breast cancer: Evidence suggesting that an elevated prostaglandin production is a marker of high metastatic potential for neoplastic cells.

Prostaglandin (PG) production by human breast cancers was investigated in 91 lesions selected so that the distribution of histologic type was similar to that of the general population of mammary carcinomas. With regard to the shape characteristics of the tumors, PG production was higher in lesions classified T1 and T2 than in lesions classified T3 and T4 (T-classification is based on extent of tumor as graded by the International Union Against Cancer), higher in tumors exhibiting a high cellularity than in lesions with a low tumor cell density and higher in tumors in which the cells were still adherent to each other. A high PG production was associated with the presence of neoplastic cells in tumor lymphatic and blood vessels and in axillary lymph nodes. PG production by node metastases was always higher than that by the primary tumor sites. The analysis of the stroma reaction and the presence of edema and necrosis suggest that an active PG synthesis occurred in lesions in which the tumor cell-surrounding stroma presented characteristics of low resistance to invasive growth of cancer cells. With regard to histologic differentiation and histoprognostic grade of lesions, PG production was elevated in carcinomas that retained a minute part of the acinoductal differentiation and in tumors with a moderate or high degree of cancer. A lesion containing a steroid receptor (SR) tended to produce less PG than did an SR-negative tumor. PG production increased slightly according to ages and times of menopause of the patients. PG production occurred early in the natural course of breast cancer and was elevated in tumors at a time when active tumor invasion proceeded. By contrast, PG production decreased later in the course of tumor development. These results indicated that elevated PG production can be used as a marker of high metastatic potential for neoplastic cells in breast cancer.

Multiparametric evaluation (SAMBA) of growth fraction (monoclonal Ki67) in breast carcinoma tissue sections.

Breast tissue samples, including normal breast, nonmalignant disorders, and breast carcinomas (n = 257), were tested with monoclonal antibody Ki67 to define the growth fraction in each tissue subgroup. Immunocytochemical assays using anti-Ki67 and avidin-biotin-peroxidase complex and/or alkaline phosphatase anti-alkaline phosphatase were applied in frozen sections. The immunoreactions were analyzed with a computerized system of image analysis referred to as SAMBA (Systeme d'Analyse Microphotometrique à Balayage Automatique). This system permitted a multiparametric and automatized analysis of colored images. The results obtained were: (a) the SAMBA analysis of Ki67-positive staining was accurate, reliable, and reproducible; (b) the anti-Ki67 immunostaining was significantly (P less than 0.01) increased in malignancies and was related to the tumors' degree of differentiation, the vascular invasion, and the presence of axillary lymph node metastases; (c) anti-Ki67 immunostaining is increased (P less than 0.01) in tumors in which estrogen receptor and progesterone receptor antigenic sites are not detected. It is concluded that the SAMBA analysis of the anti-Ki67 immunocytochemical assay provides relevant information in selecting subgroups of patients with higher risk for relapse.

Estrogen receptor immunocytochemical assay (ER-ICA): computerized image analysis system, immunoelectron microscopy, and comparisons with estradiol binding assays in 115 breast carcinomas.

An estrogen receptor (ER) immunocytochemical assay (ER-ICA) was applied to 115 malignant breast carcinomas and the results were compared to those of steroid binding assays performed on cytosol extracts of the same tumors. Immunoperoxidase (peroxidase-antiperoxidase) staining was performed on frozen sections using rat monoclonal antibody to estrogen receptor H222SP gamma. A preembedding method was used for the immunoelectron microscopy study. A semiquantitative analysis and a computerized image analysis system (SAMBA 200 TITN) were used to evaluate the positive ER immunostaining. Positive immunostaining (81 of 115) was always located in the nucleus of tumor cells and of normal cells in adjacent breast tissue. The immunostaining pattern differed from one tumor to another, due to variations in either the intensity or the percentage of positive cells. When immunohistochemical staining was correlated to biochemical assay, there was an 88% correlation, and staining intensity and percentage of positive cells significantly increased (P less than 0.01) with cytosolic ER levels and were independent of cellularity. These results indicated that ER-ICA is to date the most reliable histochemical method for ER detection and correlated in 88% of the cases with ER biochemical assay; ER-ICA constitutes a method particularly valuable to screen ER negative tumors on condition that tumor fragment quality (sampling and storage) is perfectly controlled; ER-ICA provides additional information for heterogeneous ER distribution within tumors; ER-ICA as a qualitative method is unable to replace the quantitative ER determination obtained with biochemical assay although the computerized system (SAMBA 200) for image analysis of microscopic preparations constitutes a valuable improvement of immunostaining analysis; and ER-ICA based on ER antigenic site detection is complementary to biochemical assay based on ER functional site determination.

Multiparametric study (SAMBA 200) of estrogen receptor immunocytochemical assay in 400 human breast carcinomas: analysis of estrogen receptor distribution heterogeneity in tissues and correlations with dextran coated charcoal assays and morphological data.

Estrogen receptor (ER) immunocytochemical assay (ER-ICA) was assessed in 400 human breast carcinomas. In all cases, patient's age, tumor size, histological type and Scarff-Bloom-Richardson grade, and presence or absence of axillary lymph node metastases and of vessel invasion in tumor borders were recorded. In 310 cases estrogen and progesterone receptors were concomitantly evaluated (dextran coated charcoal method). In 60 of these cases the ER immunoenzymatic assay (ER-IEA) was also assessed. Monoclonal H222sp gamma and peroxidase antiperoxidase procedures (Abbott kit) were applied in frozen sections, tumor imprints, and fine-needle aspirates. A computerized system of image analysis referred to as SAMBA (TITN), permitted a multiparametric quantitative analysis of ER-positive surfaces. With this system, in each tumor, the cellularity, percentage of ER surface versus the total cell surface and versus the epithelial (keratin-positive) surface, integrated optical density, mean optical density, index of the concentration of labeled objects, and integrated optical density histograms, were obtained and correlated to histological and biochemical data. It was shown that (a) ER antigenic sites were heterogeneously distributed in ER-positive tumors, with a specific nuclear localization in epithelial cells; (b) SAMBA 200 multiparametric analysis of the ER sites distribution in tissue was appropriate, accurate, reproducible, and therefore more reliable than the semiquantitative analysis; (c) standardization and complete automation of this method of immunoprecipitates evaluation on tissue section permits daily and routine analysis of a large number of preparations; (d) there was a correlation between ER binding sites evaluation (dextran coated charcoal) and ER antigenic sites immunodetection (ER-ICA and ER-IEA); (e) there was a correlation between the SAMBA evaluation of ER-ICA and other histological prognostic factors such as small tumor size, low Scarff-Bloom-Richardson grade; (f) the preliminary SAMBA analysis of ER-ICA in tissue sections, imprints, and fine needle aspirates suggest that fine needle aspirates may not reflect accurately the tumor cell heterogeneity.

Bromocriptine effects on cultured human prolactin-producing pituitary adenomas: in vitro ultrastructural, morphometric, and immunoelectron microscopic studies.

In an effort to better characterize the ultrastructural, morphometric, and immunocytochemical changes induced by 10(-8) M bromocriptine (BR), tumor cells from three surgically removed PRL-producing pituitary adenomas were cultured on an extracellular matrix in serum-free medium. In each instance, the treated cultures were compared to control cells at the end of 24 h and 16 days. PRL RIAs were performed on culture medium. A decrease in cell and nucleus surface area was found on day 16 in two cultures. This supports the well known shrinkage of BR-treated PRL-producing adenomas. BR induced no change in these parameters in the tumor from a third patient who was partly resistant to the drug. Changes in the secretory process were discernible as of day 1 in all three tumors, with a dramatic reduction of exocytosis and intracellular accumulation of PRL-immunoreactive granules. This induced delayed inhibition of protein synthesis, demonstrated by preembedding immunocytochemistry on day 16. These results, obtained for the first time in human PRL-producing adenomas, are informative as to the subcellular events subsequent to short term BR treatment and illustrate that secretory inhibition and tumor shrinkage are not necessarily linked.

Role of the blood-brain barrier in the establishment of the immune response against polyoma virus-induced cerebral tumours in hamsters.

The existence of an immunological blood-brain barrier (BBB) is well established but its role in cerebral tumour immunology is less well defined. Attempting to clarify this problem we tested the graft rejection of polyoma virus-induced central nervous (CNS) tumours in hamsters after systemic or intracerebral immunization with polyoma virus. Animals were immunized by intracerebral or subcutaneous inoculations of polyoma virus before tumours were induced by intracerebral or intramuscular graft of polyoma-transformed hamster neuroglial cells. The growth of cerebral and muscular tumours was significantly inhibited in animals immunized subcutaneously. In animals immunized intracerebrally the inhibition of growth was highly significant for cerebral tumours and only very slight for intramuscular tumours. These results suggest that the blood-brain barrier allowed immunocompetent effector cells to penetrate inside the CNS but prevented the locally elicited cell-mediated immune response from diffusing outside the CNS. The ability of the brain to develop a local immune response and the partial lack of circulation of immunocompetent cells to cross the BBB could be mainly responsible for the special immune status of the CNS and may greatly interfere with the establishment of an efficient immune response toward brain tumours.

Prostaglandins and steroidogenesis in isolated bovine adrenal cells. Effects of ACTH, prostaglandin-synthesis inhibitors, prostaglandins and prostaglandin analogs.

In bovine adrenal cortex cells, dispersed without preferential loss of cells, we investigated (1) whether endogenous prostaglandins (PGs) are involved in ACTH-induced adrenal steroidogenesis, and (2) the steroidogenic effects of PGs and PG analogs. Free cells produced considerable amounts of PGE2, whereas only minute quantities of PGF2 alpha and PGA1 were synthesized. PGE2 synthesis, however, was not significantly increased when ACTH elicited a steroidogenic response in free cells. High concentrations of PG-synthesis inhibitors such as indomethacin affected both PG synthesis and steroidogenesis, whereas intermediate concentrations (10(-6) M) inhibited production of both PGE2 and aldosterone even after cAMP and cortisol response to ACTH had returned to normal values. It is concluded that endogenous PGE2 is not a link in the acute mechanism of action of trophic hormones in which cAMP is involved. Of the prostanoid structures, PGs of the E series were the most potent stimulating agents of cortisol production, although less active than ACTH. On the other hand, PGA1 induced an ACTH-like aldosterone synthesis. PGE2 was less active, and other prostanoid structures were without effect on aldosterone production. It is suggested that in pathological circumstances, PGA1 regulates aldosterone production and PGE2 increases both aldosterone and cortisol production.

Macrophagic activity in intracerebral germinoma: ultrastructural study of a case.

This report presents the ultrastructural study of a germinoma of the third ventricle occurring in a 13 year old boy. The electron microscopic data showed similarities linking this tumor to gonadal and mediastinal germinomas and emphasized the exceptional glycogenic storage in tumor and stroma cells. Another morphological analogy was the intense macrophagic activity that led to tumor cell phagocytosis. The authors discuss the meaning of such an immune response, which is usually not observed in cerebral tumors.

Immunohistochemical detection of laminin in 98 human breast carcinomas: a light and electron microscopic study.

The distribution of laminin was studied in 98 breast carcinomas with antilaminin and the avidin-biotin-peroxidase complex method. Laminin was observed within vascular and epithelial basement membranes. Laminin displayed a continuous linear pattern in intraductal carcinomas, and it was heterogeneously distributed, with a discontinuous linear pattern, in invasive carcinomas. No intracellular laminin staining was detected. Electron microscopic study showed laminin immunostaining in the lamina densa of basement membranes in nonneoplastic breast tissue. In tumors, laminin immunostaining frequently revealed multilayered basement membranes and abnormal multilayered basement membranes in blood vessels in the tumor stroma. These data suggest that laminin immunostaining, as a new approach to the heterogeneous basement membrane changes occurring in carcinomas, should permit better understanding of cell diffusion processes and of stroma-tumor cell interactions. The consistent extracellular distribution of laminin in contact with the stroma indicates that the latter plays an important role in the assembly of basement membrane components.

Multiple steroid receptors in human breast cancer. III. Relationships between steroid receptors and the state of differentiation and the activity of carcinomas throughout the pathologic features.

Histopathologic features (tumor cell density, histological type, and histoprognostic grade) were analyzed in 314 breast cancers investigated for estrogen (E) and progestin (P) receptors (R). The presence of PR is associated with the presence of ER. A relationship was found between the acinoductal differentiation of the lesions and the presence of SR: the more differentiated the carcinoma, the higher the frequency of ER. HPG III carcinomas have the lowest frequency of positive ER and HPG I tumors the opposite: the likelihood of the presence of SRs is inversely correlated with HPG. No statistically significant relationship existed between tumor cell density (TCD) and the presence of ER or ER content. Similar findings were observed for the stromal reaction. The results are discussed with respect to the biological significance of SR and histopathologic features: SR presence could be correlated with (1) a differentiated state of the tumors and (2) a slow rate of cellular replication.

Changes in the nigrostriatal system following microinjection of an unconventional agent.

The effect of apomorphine, a direct dopamine receptor agonist, was studied in golden hamsters after unilateral injection of scrapie agent (strain 263K) into the nigrostriatal system. Twenty-five received an injection into the left striatum and 24 into the left substantia nigra. Varying volumes (5, 1 and 0.5 microliterss) and dilutions of the homogenate (10(-2), 10(-3), 10(-4)) were used. The duration of the incubation period (delay of appearance of clinical signs of the disease) was dependent on the dose of the agent used: it varied within a range of 72 +/- 5 days (5 microliter 10(-4) and 123 +/- 8 days (0.5 microliter 10(-4)). Apomorphine-induced circling behavior appeared after an average of 84 +/- 15 days post-injection and this delay was closely related to the dose of agent. The direction of the rotation dependent on the site of injection: most of the animals circled towards the inoculated side after striatal injection and away from it after inoculation in the substantia nigra. In the group of animals inoculated in the substantia nigra with 0.5 X 10(-4) microliters, 6 presented the clinical phase of the disease and showed circling behavior but no clinical signs when they were killed 200 days post-injection. However, neuropathological studies revealed characteristic foci of vacuolation in the brain stem. Apomorphine-induced circling behavior can only be contained by replication of scrapie agent into the nigrostriatal neurons and the subsequent imbalance between the two sides which it reveals. Circling behavior and clinical signs of the disease can be temporally dissociated: low doses of agent slightly extended the circling behavior latency, whereas the incubation period was considerably increased. Circling behavior and neuropathological lesions in nigrostriatal system were not closely related.

[Ultrastructural study of a chordoma]. / Etude ultrastructurale d'un chordome

An ultrastructural study of a case of sacral chordoma is reported. The cell type was monomorphic. The epithelial nature and the secretory function of the tumour cells was obvious in view of their content of desmosomes and the presence of mucopolysaccharide in the ergastoplasm and in the extracellular space. Because of the lack of intracytoplasmic vacuoles in the case reported, the authors doubt the individuality of the so-called "giant physaliphorous cell". The authors consider that the vacuolar appearance of the tumour cells is due to cytoplasmic invaginations caused by the enlarged extracellular space containing acid mucopolysaccharides or by processes of histiocytes containing the same material.

Peripheral neuropathy induced by amiodarone chlorhydrate. A clinicopathological study.

Four cases of amiodarone neuropathy are reported. Patients presented a sensorimotor neuropathy with distal predominance. Improvement occurred after drug discontinuation. Nerve conduction velocities were significantly decreased. Other secondary effects of amiodarone were noted in two cases. In one case serum levels of amiodarone and N-monodesethylamiodarone were evaluated during and after treatment. Pathological study of nerve with morphometric evaluation was performed. Axonal degeneration changes were predominant in 3 cases. Aspects of segmental demyelination and remyelination were noted in one case and related to secondary demyelination. Numerous lysosomal inclusions were present in Schwann cells, fibroblasts, capillary endothelial and perithelial cells and in perineural cells. Similar inclusions have been observed in other drug-induced lipidosis. The factors responsible for this neuropathy are unknown. In one case, amiodarone-induced hepatic failure might explain the persisting high serum levels of the drug.

[Cerebral hemangiopericytoma. Ultrastructural study of one case]. / Hémangiopéricytome cérébral. Etude ultrastructurale d'un cas

The authors report electron-microscopic observations upon a primitive cerebral haemangiopericytoma. The vascular appearance of the tumour is due to the presence of abundant extracellular material which has a structure like that of vascular basement membranes. The fact that the tumour cells are pericytes is confirmed by the existence of intracytoplasmic microfilaments of 60-80 A in diameter, sometimes gathered into osmiophilic aggregations and forming simple cellular junctions (zonulae adherentes). Stress is laid upon the importance of differentiating this rare tumour from an angioblastic meningioma; the haemangiopericytoma is more rapidly growing and carries a more serious prognosis.

[Atypical juvenile neurolipidosis. Ultrastructural study of a cerebral biopsy]. / Neurolipidose juvénile atypique. Etude ultrastructurale d'une biopsie cérébrale

Electron-microscopic findings on a brain biopsy in a 9-year-old male affected by juvenile lipidosis are reported. Two types of neuronal cytosomes were discribed: lamellar concentric bodies, resembling membranous cytoplasmic bodies, and polymorphous complex bodies, unit membrane bound including various material, mostly resembling lipofuscin. The same storage was found in glial and endothelial cells. Neurochemical data failed to pin-point any specific abnormalities. The present case cannot be classified in the category of neuronal ceroid-lipofuscinosis but seems similar to certain reported cases of atypicalneurolipidosis.

Biochemical characterization of 17 beta-hydroxysteroid dehydrogenase in human meningioma.

17 beta-Hydroxysteroid dehydrogenase (E2-DH) activity was characterized on a semipurified microsomal preparation of human meningioma tissue (mean Km of 2 microM and Vmax of 500 pmol/mg protein/10 min) and then assayed in 49 meningioma specimens with high progesterone receptor and low estrogen receptor levels. Of these 49 tumors, 36% contained an E2-DH activity greater than 1,000 pmol/mg protein/10 min and similar to that of uterine myometrium. In this limited series of tumors, no correlation between E2-DH activity and progesterone receptor levels was noted.

Immune complex vasculitis associated with mediterranean spotted fever.

We report a case of mediterranean spotted fever complicated by leucocytoclastic vasculitis. Rickettsia conorii, IgA, complement and fibrin deposits were found in a skin biopsy. Treatment with tetracycline was successful.

Corticolipotropin immunoreactivity in silent chromophobe adenomas: a light and electron microscopic study.

Twenty silent human pituitary adenomas were morphologically studied. Immunoperoxidase methods showed numerous adrenocorticotropic hormone-immunoreactive tumor cells in 14 cases by light microscopy and in one additional case by electron microscopy. Three of these cases were positive for beta-endorphin and one for beta-lipotropin by electron microscopy. These immunoreactions were found in undifferentiated tumors as well as in oncocytic adenomas, and could not be related to the presence of basophils by light microscopy. The peptides so detected in silent adenomas may have no biological activity and may correspond to common precursor molecule subunits.

[Ultrastructural study of a Masson's "humid meningioma"]. / Etude ultrastructurale d'un "méningiome humide" de Masson

The authors report the ultrastructural analysis of a Masson's humic meningioma. The tumor presents at the electronic microscopic examination every sign of secretive hyperactivity and does not show any degenerative characteristics. The existence of an important extracellular material rich in pre-collagenic fibres accounts for lacunar texture of this neoplasia at optic microscopic investigation; the role played by tumoral cells in the elaboration of the material is taken into account and seems to corroborate histogenic ecto-mesenchymatous theory of arachnoidal cells.

[Human mammary carcinoma: relationship between steroid hormone receptors and histopathology. An hypothesis, the prognostic value of hormone receptors (author's transl)]. / Tumeurs mammaires humaines: corrélations entre les récepteurs hormonaux stéroïdiens et l'anatomie pathologique. Une hypothèse: valeur pronostique des récepteurs hormonaux.

In 318 cases of human primary breast carcinoma, the presence and content of estrogen receptor (ER) have been correlated to histopathological features of these carcinomas. We have evidenced that: a) there is a relationship between the ER presence, the histoprognostic grade and the histological type; b) there is no correlation between the frequency of ER presence, the neoplasic cellularity and the stromal reaction. The presence of ER appears to be related to a differentiated state of the carcinoma and to a moderate neoplasic activity. These data show that ER, correlated with histopathological features, could be used as an estimation's factor of the cellular activity of a human mammary carcinoma, thus as a factor of better prognostic value for the evolution of this tumor.