Effect of estrogen on tumor-associated immunity in patients with adenocarcinoma of the prostate.

Tumor-associated antigen-induced leukocyte adherence inhibition has been used as an in vitro criterion for evaluating the effect of estrogen on cell-mediated antitumor-associated immunity in patients with adenocarcinoma of the prostate. Significant (p less than 0.05) suppression from the reactivity obtained with untreated patients' leukocytes to allogeneic extracts of malignant prostatic tissue ranging from 19 to 80% was observed in all patients following preincubation of their leukocytes with diethylstilbesterol diphosphate. The observed suppression of tumor-associated immunity in the presence of exogenous estrogen provides further evidence to earlier studies that demonstrated estrogenic suppression of nonspecific cellular responsiveness as evaluated by phytohemagglutinin-induced lymphocytic blastogenesis of normal and prostatic cancer patients' lymphocytes and for the initially suggested concern over the efficacy of estrogenic therapy and its adverse effect on host cell-mediated immunological responsiveness.

Arming of normal leukocytes with sera from patients with adenocarcinoma of the prostate.

A tumor-associated antigen-induced leukocyte adherence inhibition assay was used to evaluate the effect of serum from patients with adenocarcinoma of the prostate on the antitumor reactivity of normal leukocytes. Peripheral blood leukocytes from 53 normal (control) subjects were armed with serum from 22 patients with localized (Stage A) and metastatic (Stage D) prostatic cancer and reacted with allogenic extract of malignant prostate as specific tumor-associated antigen. Leukocytes pre-treated with serum from patients with Stage A cancer show significantly stronger responses to malignant prostate than do those pretreated with serum from patients with Stage D cancer, which induced little or no response. This may be attributed to an "arming factor" present in the sera of patients with an initial stage of prostatic cancer which appears to be capable of sensitizing normal leukocytes and making them specifically reactive to tumor extract. The specificity of arming with individual and pooled patient's sera was delineated by the use of extracts from other genitourinary tumors.

Serum immunoglobulin E in pemphigus.

Immunoglobulin E levels in the sera of patients with pemphigus (12 with Brazilian pemphigus foliaceus (BPF) and 11 with pemphigus vulgaris (PV)) were determined by means of a solid phase radioimmunoassay. A significant increase in IgE level was observed in BPF patients compared to the level of IgE in PV patients and healthy adults. The implications of an elevated level of IgE with respect to other aberrations of immunologic responsiveness and the suggested infectious etiology of BPF are considered.

Fibrinolysis resistant fibrin deposits in lymph nodes with Hodgkin's disease.

Extravasal fibrin deposition is frequently observed within and around tumorous tissues and has been implicated in various aspects of tumor growth. However, no adequate information has been available on the mechanism how intratumoral interstitial fibrin deposits escape a prompt elimination by the fibrinolytic system. In this study we provide immunomorphological evidence showing that fibrin deposits in lymph nodes with Hodgkin's disease are stabilized and made resistant to fibrinolysis by factor XIII (FXIII) of blood coagulation. By double immunofluorescent labelling systems fibrin deposits were simultaneously stained for alpha 2-antiplasmin (alpha 2-AP), the main physiological inhibitor of fibrinolysis and in a number of nodular areas they were also labelled for plasmin(ogen). The detection of alpha 2-antiplasmin-plasmin complex-neoantigen (alpha 2-AP-P-Neo) revealed that alpha 2-AP reacted with plasmin, i.e., alpha 2-AP covalently linked to fibrin indeed inhibited intratumoral fibrinolysis. In addition to fibrin deposits FXIII was also found in cellular elements characterized earlier as tumor associated macrophages. These cells were attached to fibrin strands suggesting that they are involved in the intratumoral fibrin formation and might be a source of fibrin stabilizing factor in the tumor stroma.

Immunoquantitation of factor VIII-related antigen (von Willebrand factor antigen) in prostate cancer.

Metastasization may be associated with activation of haemostatic processes resulting in increased levels of circulating factor VIII-related antigen (FVIIIRAg) (von Willebrand factor antigen). To evaluate the relevancy of this in prostate cancer (PCa), the level of FVIIIRAg in the serum of patients with PCa, benign prostatic hypertrophy (BPH) and non-prostatic diseases was quantitated by a modified micro enzyme-linked immunosorbent assay. Significant (P less than 0.05) differences were noted between the level of FVIIIRAg in PCa and patients with BPH and other than prostatic disease. Noteworthy were elevated levels of FVIIIRAg in PCa patients with metastatic vs. localized disease. Consideration of the "unorthodox", but possibly more convenient use of routine serum specimens commonly available in the non-haematological laboratory vs. plasma for the quantitation of FVIIIRAg, in situations where an "absolute" level is not required, and of disseminated intravascular coagulation as contributory to the present observations, is given. Pending evaluation of a larger patient population these observations may be of prognostic value.

Effect of human seminal plasma on tumour-associated immunity in patients with adenocarcinoma of the prostate.

Tumour-associated antigen-induced leukocyte adherence inhibition has been used as an in vitro criterion for evaluating the effect of normal human seminal plasma (HuSePl) on cell-mediated anti-tumour-associated immunity in patients with adenocarcinoma of the prostate. Significant (P < 0.01) suppression from the reactivity obtained with unincubated patients' leukocytes to allogenic extracts of malignant prostatic tissue ranging from 16 to 80% was observed in 22 of 25 patients (88%) following preincubation of their leukocytes with HuSePl. The observed suppression of tumour-associated immunity in the presence of HuSePl provides further evidence for the suppressive activity of SePl on a range of in vitro immune response in normal murine and human hosts. It is suggested that these results, together with those demonstrating experimental prostatic cancer from sensitization by spermatozoa and the relationship of prostatic cancer to repression of sexual activity, provide preliminary evidence of the possible participation of SePl as contributory to the natural history of prostatic cancer.

A retrospective and prospective overview of prostate-specific antigen.

Since the identification of prostate-specific antigen (PSA), continued technological advances have provided highly sensitive assays for its quantification. Given its lack of disease specificity, and its recent detection at low levels in an increasing number of non-prostatic tissues, PSA is far from being the perfect "tumour" marker (biological marker). However, the positive predictive value of PSA for assessing cancer risk makes PSA the most useful "tumour" marker for monitoring progression and response to treatment among patients with prostate cancer. Earlier detection through screening for elevated levels of PSA, while controversial, has been proposed as a way to decrease prostate cancer mortality. Haematogenous identification of PSA mRNA may provide stage-related prognostic information, and the use of ultrasensitive assays for PSA may permit earlier identification of residual or recurrent cancer, following treatment and the initiation of adjuvant therapy. Various PSA-related concepts, including the ratio of "free" PSA and complexes of PSA with the protease inhibitor, alpha1-antichymotrypsin, to total PSA, have been proposed and placed within diagnostic and management algorithms. Elevations of PSA in other irregularities of the prostate, notably in benign prostatic hyperplasia, and the increasing frequency and number of non-prostatic tissues, including those in women, expressing PSA, have implications for future immunoassays for PSA and strategies for immunotherapy using PSA-based monoclonal antibodies or vaccines, as well as for the molecular basis for its anomalous expression and physiological function(s).

The female prostate and prostate-specific antigen. Immunohistochemical localization, implications of this prostate marker in women and reasons for using the term "prostate" in the human female.

Prostate-specific antigen (PSA) is currently the most frequently used marker for the identification of normal and pathologically altered prostatic tissue in the male and female. Immunohistochemically PSA is expressed in the highly specialized apically-superficial layer of female and male secretory cells of the prostate gland, and as well as in uroepithelial cells at other sites of the urogenital tract of both sexes. Unique active moieties of cells of the female and the male prostate gland and in other parts of the urogenital tract are indicative of secretory and protective function of specialized prostatic and uroepithelial cells with strong immunological properties given by the presence of PSA. In clinical practice, PSA is a valuable marker for the diagnosis and monitoring of diseases of the male and the female prostate, especially carcinoma. In the female, similarly as in the male, the prostate (Skene's gland) is the principal source of PSA. The value of PSA in women increases in the pathological female prostate, e.g., carcinoma. Nevertheless, the total amount of PSA in the female is the sum of normal or pathological female prostate and non-prostatic female tissues production, e.g., of diseased female breast tissue. The expression of an antigen specific for the male prostate, i.e., PSA in female Skene's glands and ducts, and structural and functional parameters and diseases similar to that of the male prostate, have provided convincing evidence of the existence of a prostate in women and definitive preference of the term "prostate" over that of Skene's glands and ducts. The use of the term Skene's glands incorrectly implies that some other structure rather than prostate is involved, promoting the vestigial position of this female organ.

Serum proteins in prostatic cancer. III. Relationship of levels of immunoglobulins and complement to clinical stage of disease.

The relationship between the level of the three major serum immunoglobulins, IgG, IgA, and IgM and of the third component of complement (C')C'3(B1A-globulin) and the clinical Stage of prostatic cancer was evaluated. While, statistically significant (P less than 0.05) differences in the levels of these proteins compared with their levels in patients with benign prostatic hypertrophy (applied only to the study of C'3) and healthy adults were observed, the levels of these proteins in each of the Stages evaluated were not significantly different from each other. The absence of a correlation between the Stage of disease and the levels of these humorally mediated effectors of immunologic responsiveness is in keeping with observations of cell-mediated effectors of immunologic responsiveness in prostatic cancer patients. Observation of the association of prostatic cancer with a deficiency of B-cell function and of C'3 is noted.

Carcinoembryonic antigen test in renal cell carcinoma.

CEA (carcinoembryonic antigen) determinations were performed on 203 blood and urine samples from 23 patients with renal cell carcinoma. Neither the blood nor the urine CEA test was able to confirm the diagnosis or predict the status of the disease in more than one half of these patients. As presently constituted, the CEA test is not accurate for the diagnosis or prognosis of renal cell carcinoma.

Serum proteins in prostatic cancer. II. Effect on in vitro cell-mediated immunologic responsiveness.

The sera from patients with prostatic cancer have been observed to posses an unidentified factor capable of inhibiting the migration of leukocytes and the proliferative response to the nonspecific mitogen, phytohemagglutinin. Observation of inhibition of these two suggested in vitro correlates fo cell-mediated immunologic responsiveness emphasizes (1) the importance to the adjunctive diagnosis and prognosis of patients with malignancy of identifying the presence of abnormal serum proteins, and (2) the role of humoral inhibitory or "immunoregulatory" factors as potential abrogators of mechanisms of host resistance, for example, immunologic surveillance, and thus the degree to whcih the host may respond to his tumor.

Effect of transurethral resection on coagulation in carcinoma of prostate.

Eleven patients with cancer of the prostate and 10 patients with benign prostatic hypertrophy (BPH) had thirteen parameters of coagulation evaluated before and after transurethral resection (TUR). Changes in fibrinogen and fibrin split products in both groups suggested potential incipient disseminated intravascular coagulation (DIC). It is concluded that prostatic cancer patients are no more susceptible to DIC than patients with BPH.

Inhibition of leukocyte migration by extracts of malignant prostatic tissue and correlation of degree of in vitro sensitization to clinical responsiveness in prostatic cancer patients.

In an attempt to evaluate the degree of in vitro cellular sensitization to tumor and its relationship to clinical responsiveness, direct leukocyte migration tests were carried out in patients with varying degrees of adenocarcinoma of the prostate employing pooled allogeneic extracts of normal, benign, and malignant prostatic tissue as a source of antigen. Cell-mediated immunity to presumably common prostatic tumor associated antigens was observed. The degree of sensitization of clinically significant specific reactivity of the patients' leukocytes to malignant prostatic tissue was greatest in patients with localized disease, low-grade tumor, and clinically inactive disease than in patients with advanced disease, high-grade tumor, and clinically active disease. Evaluation of the possible correlation of specific reactivity to malignant prostatic tissue as a prognostic index of clinical responsiveness revealed a positive correlation with the degree of sensitization in 3 (43 per cent) of 7 patients. Correlation in 4 patients was questionable because of observations of "stimulation" of migration rather than inhibition, suggested by some to be reflective of weak sensitization to tumor. Evaluation of a larger patient population as well as a prospective study of the relationship of the degree of sensitization and clinical responsiveness will be necessary before any definitive conclusions may be drawn regarding the present observations.

Immunostaging in carcinoma of prostate.

Immunostaging is a new method of assessing patients immunologically before and after immunotherapy. Twenty-eight patients with adenocarcinoma of the prostate were immunostaged independently by two investigators. There was a positive correlation between both immunostagings. There was also a positive correlation between the patient's immunostage and the clinical stage of his cancer.

Effect of hormone therapy on immune response in patients with prostatic cancer.

Thirty-one patients with adenocarcinoma of the prostate had laboratory studies done for total proteins, serum immunoglobulins, white blood cell counts, lymphocyte blastogenesis, skin tests, acid phosphatase, and CEA (carcinoembryonic antigen). The 16 patients receiving no hormones had depressed total proteins, lymphocyte and monocyte counts, skin tests, and CEA compared with the 15 patients receiving hromones who had depressed serum immunoglobulins, white blood cell counts, lymphocyte blastogenesis, and acid phosphatase.

Responsiveness of lymphocytes to soluble extracts of prostatic tumors and abrogation by serum-blocking factor(s).

Preliminary evidence is presented suggestive of antitumor immunity, cross reactive with allogeneic extracts from tumors of the same type, and serum-blocking factor(s), which appear to be specific to autologous tumor only, in patients with prostatic cancer employing the method of leukocyte adherence inhibition.

Cigarette smoking and its possible effects on sperm.

The possible effects of cigarette smoking on sperm were evaluated by comparison of the quality of sperm from 103 smokers and 135 nonsmokers in a blind study. Smokers were found to possess significantly (P less than 0.001) decreased density (number) and motility of their sperm than nonsmokers. Morphologic abnormalities, particularly bicephalia, although prevalent among individual smokers, did not differ significantly (P greater than 0.9) when a comparison of smokers versus nonsmokers was made as a whole. Based on these observations and those of others demonstrating the presence of the mutagenic properties of smoke condensates, we suggest that decreases in sperm density and motility in cigarette smokers may be reflective of smoke condensate-induced mutagenic spermatogenital alterations.

PIP: The possible effects of cigarette smoking on sperm were investigated in a blind study involving 103 smokers and 135 nonsmokers. The quality of sperm from study subjects was assessed on the basis of density (number), motility, and morphologic abnormalities. Spermatozoa from smokers possessed significantly decreased density and motility compared with nonsmokers (p 0.001). 75% of smokers versus 26% of nonsmokers had a sperm density under 40 x 10million sperm/ml. On the other hand, morphologic abnormalities were noted in 27% of men in both groups. These results differ from those of earlier studies that found no significant differences between sperm density and motility in smokers and nonsmokers yet noted a higher percentage of morphologically abnormal sperm in smokers. It is suggested that the decreases in sperm density and motility noted in the present study may reflect smoke condensate-induced mutagenic spermatogenital alterations. It is recommended that future studies consider 1) evaluation of the functional competency of spermatozoa from smokers, 2) whether smokers convey any genetic abnormality to their children, and 3) elimination of the possible contributory effect of the concomitant presence of a varicocele.

Antibodies to sperm in benign and malignant diseases of the prostate in man: incidence, disease-associated specificity, and implications.

Initial investigation demonstrated antibodies to sperm (ASA) in patients with benign prostatic hypertrophy (BPH) and prostate cancer (PCa). The occurrence of ASA under a variety of normal and pathological circumstances indicated the need for confirmation and extension, including delineation of their possible disease-associated specificity and implications. As countercurrent immunoelectrophoresis (CIEP) employing sonicated allogeneic sperm (Sp) extracts appeared most efficient from initial studies of ASA, CIEP was employed for the present further study of 200 serum specimens from patients with and without prostatic disease. While ubiquitous, the continuing presence of ASA in BPH and PCa, with a combined incidence in this study of 57 (52%) of 109 vs. 9 (10%) of 91 in the absence of prostatic disease remains provocative in view of the hypothesized role of Sp in the development of BPH and PCa. The presence, however, of ASA in patients with genitourinary neoplasms other than prostate, raises doubt as to their disease specificity. Implications of ASA, other than in their more commonly related role in infertility, including their cross-reactivity with foetal antigens and lymphocytes and higher incidence in association with tumours and the presence of tumour-associated immunity are considered. However, pending further investigation, the present data may most appropriately be viewed as being reflective of a host response (marker?) to aberrant genitourinary cellular alterations.

Immunobiology of the Dunning R-3327 rat prostate adenocarcinoma sublines: plasma and tumor effusion prostaglandins.

Enhanced production of prostaglandins (PGs) by experimentally-induced and naturally occurring tumors and their effect on tumor growth and immunosurveillance have been noted. Directed toward further evaluation of the relationship between prostatic tumor growth and its milieu, i.e., microenvironment, we investigated the possible correlation between levels of PGs, tumor size, and metastatic potential. For this purpose, the levels of PGE2 and PGF2 alpha in plasma and tumor effusions of three tumor sublines of the Dunning R-3327 rat prostate adenocarcinoma were measured: R-3327H, well-differentiated, slow-growing, and poorly metastatic; R-3327G, poorly differentiated, fast-growing, and poorly metastatic; and R-3327 Mat LyLu, anaplastic, fast-growing, and highly metastatic. The level of PGF2 alpha was highly variable with no significant differences being noted between the tumor sublines. The mean values of PGF2 alpha were, however, higher, although not significantly so, in the smaller tumors within each of the sublines. The levels of PGE2 were significantly higher in Mat LyLu effusions than those from the nonmetastasizing R-3327G and H sublines. Evaluation and comparison of the relationship between tumor burden, i.e., size versus levels of PGE2 and PGF2 alpha showed no significant differences. A vasodilator and regulator of immunological responsiveness, PGE2, may function as a modulator of tumor metastases. In consonance with studies by others elevated levels of PGE2 may possibly serve as a prognostic marker for the high metastatic potential of neoplastic cells.

Effect of transfer factor on tumor-associated immunity and tumor growth of the Dunning R-3327G rat prostate adenocarcinoma.

Of importance in the design and application of improved or new modalities of treatment are their evaluation on relevant animal models. In the case of prostate cancer (PCa) the Dunning R-3327 rat prostate adenocarcinoma (PCa), and its variant sublines, is one such experimental tumor model of its human counterpart. In a preliminary study, the effect of transfer factor (TF), one form of passive immunotherapy, on tumor-associated immunity (TAI) and tumour growth and histology of the G subline (a poorly differentiated, fast-growing, androgen sensitive, and poorly metastatic tumour of the Dunning R-3327 rat PCa) has been evaluated. TF prepared from the leukocytes of tumor-bearing animals and nontumor-bearing animals referred to as sensitized (STF) and unsensitized (UTF), respectively, had no significant effect on TAI or tumor size. The only noticeable effect of TF in this study was the presence of variable and moderate lymphocytic infiltrates, necrosis, and degenerative-type cells in tumors of animal recipients of STF. The failure to observe significant differences in TAI among tumor bearing and nontumor bearing animals raises doubt in part, of the immunogenicity of the G subline tumor and its appropriateness, at least for subsequent immunological studies. Further factors considered in this regard, are questions of tumor load, including the possible need for the use of adjuvant, and the parameters and sensitivity of immune responsiveness selected for evaluation and immunocompetency. Subsequent evaluation of the effect of TF on other more immunogenic variant sublines of the Dunning R-3327 rat tumor may yet provide further and more useful information.