Effect of the number of core biopsies of the prostate on predicting Gleason score of prostate cancer.

PURPOSE: We determined the effect of the number of core biopsies of the prostate on predicting the Gleason score of the prostatectomy specimen. MATERIALS AND METHODS: The Gleason scores from 124 radical prostatectomy specimens were compared to those from preoperative core needle biopsies of the prostate. The number of cores obtained and tumor stage were compared regarding agreement in prostate cancer score. RESULTS: Four to 6 core biopsies yielded the best results, with agreement within 1 Gleason score in 75% of the cases. Further increases in the number of core biopsies did not improve results. Additionally, 37% of the well differentiated tumors on core biopsy were stage C. CONCLUSIONS: Gleason score from the core biopsy has limitations in respect to predicting prostatectomy tumor score and stage and, therefore, it is problematic for use in therapeutic decision making.

Differentiation of murine embryonal carcinoma in vitro and in vivo with N,N-dimethyl acetamide.

Polar solvents such as N,N-dimethyl acetamide (DMA) are known inducers of tumor cell differentiation in vitro. Nothing is known about their ability to induce differentiation in vivo. Using PCC4 AZArL murine embryonal carcinoma (EC) cells we examined the time course and dose response relationship of DMA induced EC differentiation in vitro. The effective continuous dose range of 0.1% to 0.15% gave a linear increase in differentiation index with the probability of attaining complete differentiation. EC tumors were raised subcutaneously in the flanks of strain 129 mice and DMA injected intraperitoneally at a dose calculated to attain tissue levels of between 0.1% and 0.15%. DMA induced significant differentiation primarily into neuroepithelium when compared to negative controls, but DMA was not as effective as retinoic acid. The extent of differentiation was dosage dependent, but the maximal dose of DMA was limited by toxicity mainly to the liver and lymphoid tissues. A graduated dosage schedule of DMA treatment reduced toxicity. These preliminary studies suggest that "differentiation therapy" with polar solvents such as DMA may be an effective adjunct to standard therapies.

Arterial dissections associated with pregnancy.

Two cases of spontaneous arterial dissection occurring in young, multiparous women shortly after delivery of uncomplicated pregnancies are described. Histologic analysis of arterial tissue samples obtained in both cases at points near and remote from the dissection sites shows evidence of significant arterial degeneration and loss of integrity, with changes similar to those observed in pregnant women, women using oral contraceptives, and animals given female sex hormones. The types of arterial lesions associated with pregnancy and their sites of predilection and the etiologic roles of the hemodynamic stresses of pregnancy and hormones are discussed.

Immunocytochemical localization of progesterone receptors in breast cancer with anti-human receptor monoclonal antibodies.

Monoclonal antibodies (MAbs), recently produced against human progesterone receptors (PR), were used for immunocytochemical localization of PR. The specificity of the immunocytochemical assay for PR was demonstrated by incubation with control MAbs, preabsorption of MAbs with highly purified human PR, and by the cell and tissue distribution of the immunostaining reaction. With human breast cancer cell lines, immunoreactivity was confined to cells that contain PR by steroid-binding assay. Moreover, immunostaining was induced by estradiol in estrogen-responsive cells, MCF-7 and ZR-75-1. In a preliminary study with 33 breast carcinomas, a good correspondence was obtained between immunocytochemical staining and PR content assessed by conventional steroid-binding assay. Immunoperoxidase localization was also obtained with other human target tissues. In normal breast and benign breast disease, immunoreactivity was observed with nuclei of ductal epithelial cells and hyperplastic epithelium. In uterus, immunostaining of endometrium was localized to nuclei of stromal and glandular epithelial cells and in myometrium to nuclei of smooth muscle cells. The effect of the progestin agonist, R5020, and antagonist, RU 486, on PR localization was investigated with the PR-rich T47D human breast cancer cell line. In the absence of hormone, immunostaining was exclusively nuclear. This was true under a number of cell culture conditions designed to eliminate endogenous progestins from the culture medium. Exclusive nuclear localization of PR was not due to a failure of the MAbs to recognize unoccupied PR, since each MAb bound equally well in vitro with different receptor forms. These included liganded and unliganded cytosol PR, molybdate stabilized PR, and nuclear-transformed receptors. Nor was failure to detect cytoplasmic staining due to a selective destruction or loss of unoccupied PR from the cytoplasmic compartment as a result of cell fixation. This was assessed by dot blot immunoassay of PR antigen distribution in subcellular fractions of fixed and unfixed cells. Continuous exposure of cells to R5020 resulted in a transient (30-60 min) increase in nuclear staining intensity (without change in cytoplasmic reactivity), followed by a progressive decline in immunoreactivity. By 24 h of R5020 treatment, the vast majority of cells displayed no immunostaining reaction. These immunocytochemical data are consistent with progestins down regulating their own receptors due to a loss in cellular PR content and not to inactivation of receptors.(ABSTRACT TRUNCATED AT 400 WORDS)

Malignant fibrous histiocytoma in a bonnet macaque (Macaca radiata).

Spontaneous sarcomas, not associated with an underlying disease, appear to be relatively rare in nonhuman primates. Since 1970, there have been few reported cases of naturally-occurring sarcomas of any kind in these species. A malignant histiocytoma and malignant fibrous histiocytoma have been described in a rhesus macaque and baboon, respectively. A malignant fibrous histiocytoma is defined as a sarcoma of varied pattern consisting of a mixture of histiocytic and fibroblastic elements. It is thought that the two cells types arise from a common precursor or that the fibroblastic elements are derived from the histiocytes. These tumors are relatively common in humans. Here we report a case of spontaneously-occurring malignant fibrous histiocytoma in an adult bonnet macaque.

Tumors as caricatures of the process of tissue renewal: prospects for therapy by directing differentiation.

A concept of neoplasms, based upon developmental and oncological principles, states that carcinomas are caricatures of tissue renewal, in that they are composed of a mixture of malignant stem cells, which have a marked capacity for proliferation and a limited capacity for differentiation under normal homeostatic conditions, and of the differentiated, possibly benign, progeny of these malignant cells. The concept brings order to the facts about carcinoma, has predictive value for embryogenesis, and indicates possibilities for differentiation therapy. One such possibility assumes on the basis of experimentation in vitro that malignant stem cells can be induced to differentiate into postmitotic cells by application of chemicals. Another suggests study of naturally occurring substances which regulate cell proliferation and differentiation in adult tissues. The other possibility, based upon experiments in vivo and in vitro, indicates that embryonic fields are capable of converting their closely corresponding malignant lineages into apparently normal lineages responsive to homeostatic control. Induced differentiation of embryonal carcinoma has been achieved in vivo with improvement in longevity of the host and in some cases with apparent cure. However, ultimate success of treatment based upon turning malignant cells into benign cells will depend upon the nature of the benign cells. Will they remain benign?

Induction of differentiation of murine embryonal carcinoma cells by ouabain.

Murine embryonal carcinoma cells (EC) can be induced to differentiate by a variety of chemical agents, including retinoid acid (RA) and dimethyl acetamide (DMA). However, it is not known how these agents exert their effects. In this study we demonstrate that murine EC cells can also be induced to differentiate by ouabain at concentrations which inhibit Na+, K+-ATPase activity as measured by inhibition of 86Rb+ uptake. Since the pharmacologic action of ouabain is thought to be specific, we investigated the role of Na+, K+-ATPase inhibition and specific metabolic consequences of this inhibition in the induction of EC differentiation, and explored whether this might be a common mode of action for a variety of structurally diverse inducers. Although the Na+, K+-ATPase maintains ion gradients in cells, our studies failed to demonstrate a consistent role for alterations of ion flux or ion concentration on the differentiation process. Ouabain inhibited cell growth, but a direct correlation between the degree of growth inhibition and the extent of differentiation could not be demonstrated. There was also no evidence that RA or DMA induces differentiation by inhibiting the Na+, K+-ATPase. The mechanism of ouabain induction may be mediated by some alternative consequence of Na+, K+-ATPase inhibition, but it appears to be specific for that inducer and cannot be generalized to that of other inducers of EC differentiation.

Ionic channels in a line of embryonal carcinoma cells induced to undergo neuronal differentiation.

The gigaseal patch clamp technique was used to investigate the electrophysiological properties of a line of embryonal carcinoma cells (PCC4) that were induced to undergo neuronal differentiation. A large increase in number of voltage-dependent potassium and sodium channels was observed during differentiation. The pharmacology and kinetics of the macroscopic sodium and potassium currents in the differentiated cells closely resembled those of the rapid inward sodium current and the delayed rectifier, respectively. The kinetic behavior of single-channel potassium currents was consistent with the properties of the macroscopic delayed rectifier current.

Malignant neoplasms of differentiated cells occurring after retinoic acid treatment of murine embryonal carcinomas in vivo.

Murine embryonal carcinoma tumors were induced to differentiate in vivo using retinoic acid. Six mice bearing seven tumors survived more than 100 days after treatment. Histological samples of these tumors showed no residual embryonal carcinoma cells, and, for the most part, they were benign cystic teratomas. Three tumors, in addition to the benign tissue, had solid, mitotically active areas. Two of these tumors upon transplantation gave rise to progressively growing, potentially lethal tumors which have proven to be permanently transplantable cell lines. Using techniques of light and electron microscopy, immunohistochemistry, flow microfluorometry, and cytogenetics, we have characterized these lines. One is a chondrosarcoma, and one is a glioma:chondrosarcoma mixture. Both are chromosomally different from the parent embryonal carcinoma stem cell line, but both were clearly derived from it.

Chemically induced differentiation of murine embryonal carcinoma in vivo: transplantation of differentiated tumors.

Murine embryonal carcinoma tumors were induced to differentiate in vivo by administration of retinoic acid. Six long-term surviving animals had seven slowly growing tumors which were transplanted s.c. into strain 129 mice. Untreated embryonal carcinomas were transplanted as controls. All of the 16 control transplants grew rapidly and killed their hosts within 25 days. All of the 24 transplants of retinoic acid-differentiated tumor survived. Sixteen experimental transplants originating from five original tumors showed no or slow growth for up to 16 weeks and were found to be histologically benign cystic teratomas. Two original tumors gave rise to eight relatively rapidly growing transplants. One tumor resulted in four histologically similar solid tumors which resembled chondrosarcomas, and the second tumor gave rise to four histologically similar solid tumors which proved to be a mixture of glioma and chondrosarcoma. Examination of the tumor sources of these latter transplants showed benign cystic teratomas with focal solid, mitotically active cellular areas which were histologically similar to the transplants. These data confirm that retinoic acid-induced differentiation of murine embryonal carcinoma cells results in altered biological potential of these cells and usually the formation of a benign teratoma. Rarely (about 1 per 2 X 10(8], the resulting differentiated cells will give rise to rapidly growing, histologically malignant tumors. One can predict such biological propensity when solid, mitotically active areas in the original tumor are found.

Malignant struma ovarii. A case report and literature review.

A woman developed papillary adenocarcinoma in a struma ovarii. The focus of malignancy was within a benign struma found at laparotomy for a pelvic mass. The patient had a previous history of bilateral cystic teratomas. The tumor was composed of papillae of crowded, pleomorphic cells with minimal cytoplasm but a wide range of chromatin patterns. Immunoperoxidase staining for thyroglobulin revealed positive regions in both the benign and malignant areas of tumor. A 15-year review of cystic teratomas in the state of Colorado revealed a frequency of 0.3% for malignant struma ovarii.

Immunohistochemical localization of carcinoembryonic antigen in microglandular hyperplasia and adenocarcinoma of the endocervix.

Immunoperoxidase localization of carcinoembryonic antigen (CEA) was performed on tissue sections of microglandular hyperplasia and adenocarcinoma of endocervical origin to see if CEA would be a marker of malignancy in this context. Twenty (95%) of 21 of the benign lesions were negative and one was focally positive. Nine (64%) of 14 adenocarcinomas were widely positive, four were focally positive, and one was negative. These results suggest that extensive immunohistochemical positivity for CEA in endocervical glandular lesions is indicative of malignancy.

Conversion of malignant murine embryonal carcinomas to benign teratomas by chemical induction of differentiation in vivo.

PCC4azal embryonal carcinoma tumors were grown in strain 129 mice by s.c. transplantation. When palpable, the tumors were treated with a combination of retinoic acid and dimethylacetamide. In vitro, this embryonal carcinoma cell line shows minimal spontaneous differentiation and is exquisitely sensitive to retinoic acid and/or dimethylacetamide induction of differentiation. Ten daily 20-microliter intratumor injections of a solution of 10 mg retinoic acid per ml of dimethylacetamide resulted in nearly complete induction of morphological differentiation mainly into neuroepithelial and glandular derivatives. Control tumors showed minor spontaneous differentiation. Differentiation was associated with decreased tumor growth rate, decreased mitotic index, decreased extent of necrosis, and increased survival time of the hosts. In 4 of 18 cases, long-term survival of the hosts was effected by a complete differentiation of the malignant embryonal carcinoma tumors into benign teratomas. Retinoic acid:dimethylacetamide was also effective in inducing differentiation with the same dosage and schedule when administered systemically, i.e., i.p. or s.c.

Evidence for the presence of receptors for C3 and IgG Fc on human synovial cells.

The presence of receptors for IgG Fc and fragments of C3 on primary cultures and cryostat sections of normal and rheumatoid synovial tissues was assessed. Significant proportions of large rounded cells with asteroid projections found in such cultures had receptors for both IgG Fc and fragments of C3. Moreover, Gram negative bacteria that had fixed complement, but not EAC, bound in a linear fashion on the superficial layers of synovial cryostat sections. On the basis of morphologic and histochemical criteria, the cultured cells bearing these receptors were tentatively determined to represent a subset of synovial lining cells. The possible role of such receptors on synovial lining cells in the pathogenesis of rheumatoid arthritis is discussed.

Chemically induced bidirectional differentiation of embryonal carcinoma cells in vitro.

N,N-dimethylacetamide, hexamethylene bisacetamide, and Polybrene induced rapid and extensive differentiation in vitro in an otherwise slowly differentiating subline of embryonal carcinoma cells. The type of differentiated cell induced was dependent on the spatial organization of the stem cells during drug treatment. In monalayer culture "epithelial" cells were produced exclusively. However, treatment of aggregated suspension cultures yielded predominantly "fibroblast-like" cells. The undifferentiated embryonal carcinoma cells and the two differentiated cell types were morphologically distinct when examined by light microscopy, scanning electron microscopy, and transmission electron microscopy; and they had differences in cell surface antigens. Both differential cell types produced large amounts of fibronectin, whereas the embryonal carcinoma cells produced only minimal amounts. This system provides a convenient way to induce relatively synchronous differentiation of embryonal carcinoma cells into specific differentiated cell types.