Symposium on Uropathology. Introduction: Measurement of genitourinary diseases.
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Biomedical subjects
Publications and source records attributed to M Tannenbaum.
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Acid phosphatase was the first "tumor marker" to be measured in the blood, and over 40 years have passed since an elevation of the serum acid phosphatase level was observed in patients with prostatic carcinoma. However, significant elevations in the level of this enzyme have been observed in other diseases, as well as elevations of other tissue phosphatases. Many improvements in the colorimetric technique have been introduced, but none has been used successfully to detect the tissue origin of this ubiquitous enzyme. The finding that prostatic acid phosphatase is antigenically distinct from acid phosphatase of other tissues opened a new horizon in the measurement of acid phosphatase in prostatic cancer. On the basis of this immunochemical specificity, several immunoassays have been employed for determining the prostatic acid phosphatase level.
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Comparisons of the bone marrow and serum acid phosphatase values obtained by counterimmunoelectrophoresis and the Roy biochemical test were made in 72 patients with and in 13 patients without prostatic cancer. The counter-immunoelectrophoresis test, when positive at more than 1 international unit per liter, showed only 4.4% falsely positive results. The Roy biochemical test, which uses sodium thymolphthalein monophosphate as the substrate, had 65% falsely positive bone marrow acid phosphatase levels. Conflicting reports regarding the value of bone marrow acid phosphatase determinations in patients with prostatic cancer result from the use of non-specific substrates in biochemical methods for measurement and from the trauma incidental to bone marrow aspiration, which releases many non-prostatic acid phosphatase enzymes. The use of immunoassay such as counter-immunoelectrophoresis minimizes this source of error.
Dog prostates under defined hormonal influences were investigated by light microscopy (LM), transmission electron microscopy (TEM) and scanning electron microscopy (SEM). The normal acinar cell apices exhibited well-developed, densely packed microvilli. TEM demonstrated numerous secretory granules, indicating a high secretory activity. Following castration, the acinar cells of the dog prostate showed rounded apices. Most of the microvilli disappeared and only knob-like protrusions were seen. Castrated dogs following administration of 3 alpha-androstandiol showed fewer microvilli than the controls; however, a well-developed undulating surface could be observed. Castrated dogs given 3 alpha-androstandiol and cyproterone acetate showed almost completely atrophic glandular cells. Prostates of dogs with spontaneous benign prostatic hyperplasia (BPH) were characterized by pleomorphism of cell shapes and surfaces. The different hormonal influences induced changes of the prostatic surface structures and secretory activity.
Man, dog, rat and mouse prostatic glandular cells were compared by light microscopy (LM), transmission electron microscopy (TEM), and scanning electron microscopy (SEM). In rodents and dogs, a merocrine secretion exists, and in these species the undulating surface represented a confluence of secretory granules. The prominent secretory blebs observed in dog and human benign prostatic hyperplasia (BPH) corresponded to apocrine secretions. Also variations in the amount of secretory activity were seen. Androgenic hormones were responsible for the differentiation of the prostatic epithelial cells during development. Therefore, an absence of microvilli as well as the appearance of ruffles, microplicae, and bare cells were seen in the prepuberal and castrated rat. In the elderly rat and in human BPH, a pleomorphism of the apical cell surface was evident.
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An immunochemical method for detection of prostatic acid phosphatase is described. Acid phosphatase was obtained from benign human prostatic tissue. A specific antiserum to this enzyme was produced in rabbits. A counter immunoelectrophoretic method utilizing the specific antiserum with a chemical staining technique has been developed. Clinical trials have indicated the usefulness of this method for the specific determination of prostatic acid phosphatase.
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The possible activation of immunologic defenses against tumor by local ultrasonic irradiation was investigated. Sonication of one tumor of a dual implant destroyed that tumor only with no contralateral effect. Injection of tumor cells previously sonicated in vivo did not induced immunity to subsequent challenge with live cells. Immunofluorescent staining of host kidneys for antibody complexes was negative. It was concluded that sonication was only effective when directly applied to the tumor.
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Paired Wistar-Furth male rats were implanted subcutaneously with the Furth-Columbia rat Wilms' tumor. Seven days after implantation the tumors were either subjected to therapeutic ultrasound irradiation or were left as untreated controls. On the ninth day after implantation the animals were sacrificed, and suspensions of cells were made from the excised tumors by trypsinization. The cells were counted using trypan blue dye as an indicator of viability. New rats were then implanted with cells either from sonicated tumors or cells from controls. In half the recipient animals the suspensions were matched by total cell count. In the other half of the rats cell counts were matches for viability by the dye exclusion test. Tumors developed in a total of 8 of 11 rats receiving control cells and they died. A palpable tumor did not develop in any rat receiving cells fromsonicated tumors during the ninety-day study period. Surviving rats were challenged with Wilms' tumor by trocar implant. Tumor developed in all recipients, and they died.
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Local sonic irradiation was applied to subcutaneously implanted Furth-Columbia rat Wilms' tumor. The weight and the rate of tritiated thymidine uptake were measured in host organs distal to the application field. Kidney and spleen weights were inhibited by the Wilms' tumor, and sonication of the tumor removed all or part of this inhibition. Liver weight was increased after sonication of tumor-bearing rats but not in nontumor-bearing rats. This may have been a response to tumor-specific substances released into the circulation by sonic destruction of tumor tissue. The adrenals enlarged as a response to the stresses of both tumor-bearing and of sonication. Animals were implanted on both sides with the Wilms' tumor and on without any break in the growth curve while the sonicated right tumor was inhibited. These data suggest that the therapeutic effect of ultrasound is due solely to local factors and that systemic sequelae of some irradiation are unrelated to tumor inhibition.
The 24-hour urinary carcinoembryonic antigen determinations were performed on 61 patients with different stages of bladder carcinoma. Elevated titers were found in 81 per cent of the patients with active tumors and falsely positive studies were found in 7 per cent. High stage lesions were found to have high carcinoembryonic antigen levels. Plasma carcinoembryonic antigen determinations were elevated in only 45 per cent of the patients with active tumors but further study may be warranted in advanced bladder cancer cases. The 24-hour urinary carcinoembryonic antigen measurements yield the highest percentage elevations in bladder carcinoma and further investigation is required to better define its clinical application.
We studied the effect on tumor volumes and host survival of twenty-four chemotherapeutic and radiotherapeutic regimens in rats bearing the Furth/Columbia murine Wilms' tumor. After 5 years and some 100 transfers, this tumor retained its sensitivity to suitable combinations of actinomycin D, vincristine, and X-ray, regimens in current use in the treatment of human Wilms' tumor. Cytoxan alone was highly inhibitory; adriamycin was modestly inhibitory; and lethal doses of methotrexate followed by leucovorin "rescue" were slightly inhibitory to the growth of the rat tumor. No other chemotherapeutic agent tested was effective by our criteria. Cytoxan, with or without adriamycin, and X-irradiation, were the most useful combinations studied. The chemotherapeutic agents given 3 days before irradiation were significantly more carcinostatic than they were when given after radiotherapy.
Fluorescein-labeled antibodies (FA) to human immunoglobulins, complement, fetal proteins and other antigens were used to search for these immunologic reactants in malignant and benign neoplasia as well as in control tissues. The FA reacted with five or more target antigens in 42 of 59 (70%) malignant tumors and 21 of 23 (40%) benign tumors. The remaining neoplasia and normal tissues showed positive staining with fewer than five specific antibodies. IgM, IgA, B1C, fetal proteins and HSV were the antigens found most frequently. This indicates that neoplasia exhibits immunologic activity more frequently than normal tissue.