A history of urology at Cook County Hospital: a focus for Chicago, the midwest and the United States.
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Biomedical subjects
Publications and source records attributed to P D Guinan.
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In an attempt to define the relationship among tumor size, stage and survival, the Cancer Incidence and End Results Committee of the American Cancer Society, Illinois Division, Inc. reviewed the records of 2,473 patients with a histological diagnosis of renal cell carcinoma. Tumor size was related to stage and survival. Larger tumors were generally associated with an increased stage (p < or = 0.0005) as well as poorer survival (p < or = 0.005). For Robson stages II, III and IV, tumor size may contribute additional prognostic information for patient survival.
Results in the literature are inconsistent regarding the value of tumor size in predicting survival from renal cell carcinoma, and its use as a staging variable in the current tumors, nodes and metastases system has been questioned. In this study tumor size had no prognostic significance in Kaplan-Meier or Cox regression models examining survival differences between 93 patients with stage T1N0M0 and T2N0M0 renal cell carcinoma dichotomized by tumor size cutoffs at 2.5, 5, 7.5 or 10 cm. In multivariate Cox regression models for 122 patients with stage T1NallMall or T2MallMall renal cell carcinoma, metastatic disease was the strongest predictor of survival, and patients with smaller tumors had significantly longer survival than those with larger tumors at all cutoffs except 2.5 cm., for which differences were insignificant. A 5 cm. cutoff maximized the value of tumor size in predicting survival. If tumor size is to remain the variable by which tumors, nodes and metastases stages T1 and T2 disease are differentiated, a 5 cm. cutoff should replace the current 2.5 cm. definition.
BACKGROUND: Primary renal sarcomas in adults are rare and unusual neoplasms. This study was performed to better define the natural history and current management of these sarcomas in a typical medical setting in the United States. METHODS: The hospital records of 4018 adult patients with renal neoplasms treated in the state of Illinois from 1975 to 1985 were examined by American Cancer Society professional volunteers. RESULTS: A primary renal sarcoma occurred in 34 patients (0.8% incidence). Eleven adult patients had Wilms tumor, 21 had primary renal sarcoma (47% leiomyosarcoma), and 2 were not found to have sarcoma on review. The median age of the patients with Wilms tumor was 30 years, whereas that of the patients with non-Wilms sarcoma was 65 years. Four of the patients with Wilms tumor (36%) are long-term survivors and all received adjuvant chemotherapy after radical nephrectomy. Six of the patients with non-Wilms sarcoma (29%) are long-term survivors after radical nephrectomy alone. CONCLUSIONS: Primary renal sarcomas, when treated with radical nephrectomy and, in the case of Wilms tumor, adjuvant chemotherapy, appear to be curable in 29-36% of cases. Histologic review of patients younger than 40 years of age with renal neoplasia is recommended.
Hormonal manipulation of prostate cancer is an effective therapy for metastatic disease. Unfortunately, following an initial response tumors reestablish themselves as hormone independent variants and progress. This study was designed to assess the interrelationship of cytokeratin P (Cyto P), vimentin, epidermal growth factor receptor (rEGF) and tissue testosterone following androgen deprivation therapy. Animals bearing the hormone dependent Dunning R3327 G subline prostatic adenocarcinoma were surgically castrated and progressing tumors from both hormone intact and castrated groups were quantitatively assayed for immunohistologic reactivity against the described markers. The results demonstrate a significant (p < 0.05) decrease in cytokeratin (Cyto P), rEGF and testosterone levels following castration. When the expression of both rEGF and Cyto P are related to the tissue testosterone content, it is observed that the ratio between rEGF and testosterone remains essentially unchanged (0.65 +/- 0.21 to 0.65 +/- 0.41), suggesting that in the Dunning R3327 G subline, rEGF expression is coordinately under androgen control. At least some cytokeratin expression also appears to be particularly sensitive to androgen levels, since the ratio between Cyto P and testosterone decreased from 0.92 +/- 0.39 to 0.35 +/- 0.41 following castration. In contrast, following castration, the expression of vimentin was unaffected.
In an effort to determine the effect of cytoreductive surgery on the metastatic process, MAT-LyLu flank tumors were excised from Copenhagen x Fischer rats and the effects of this surgery on metastatic lung lesions were observed. Cytoreduction resulted in a decrease in lung lesions (P less than 0.05). Adjuvant cyclophosphamide (CTX) further enhanced this beneficial effect. A concurrent increase in the helper/suppressor ratios suggested that this beneficial response might be mediated by the host's immune response.
Copenhagen X Fischer rats bearing single and bilateral Dunning R3327 AT-3 tumors were either treated or not treated at a single site with bacillus Calmette Guerin (BCG). One week later tumors were removed, tumor infiltrating lymphocytes (TIL's) isolated, and then characterized for total-T, helper-T and suppressor-T cell subsets utilizing monoclonal antibodies. The purpose was to determine the effect of BCG on TIL's in treated as well as untreated tumors. In summary: 1) BCG treatment significantly alters TIL distributions at both injected and noninjected sites; 2) a noninjected contralateral tumor compromises the effectiveness of BCG therapy at the suppressor T cell level; 3) contralateral tumors, whether inoculated or not, have similar TIL distributions.
Rats bearing (or not bearing) the Dunning R3327 MAT-LyLu prostatic adenocarcinoma were treated with Bacillus Calmette-Guérin (BCG) and evaluated for immune competence using functional and phenotypic markers. Tumor presence significantly depressed total T and helper T cell representation along with the helper/suppressor T cell ratio. Functional immunity, measured by phytohemmagglutinin (PHA) induced blastogenesis, was also significantly depressed. When BCG was administered to non-tumor bearing animals, it had no effect upon T cell subset distributions but significantly reduced PHA induced blastogenesis. BCG similarly administered to tumor bearing animals did not alter the depressed helper/suppressor T cell ratio found in tumor bearing rats, but did significantly elevate PHA induced blastogenesis. However, these elevated levels of functional immunity in BCG treated tumor-bearing rats remained significantly below normal. These data demonstrate a poor correlation between functional and phenotypic assessments of immune capability.
Acid phosphatase is a secretory product frequently utilized as a tumor marker for disseminated, late stage (D2) prostatic cancer. In the 40 years since this association has been recognized, this enzyme has been subjected to extensive biochemical and immunological characterizations. These techniques have also been adapted for rapid and specific determinations of the prostatic isoenzyme levels using a variety of techniques. Since acid phosphatase levels do not become significantly elevated until late stage cancer, newer markers such as prostate-specific antigen have been sought which appear earlier and may be more useful for the screening and monitoring of high risk populations. At this time it is appropriate to review the current and future status of acid phosphatase as a diagnostic aid.
The Dunning R3327 tumor represents a system for studying prostate cancer in Copenhagen X Fischer rats. Animals bearing variant sublines (H, G, and MAT-LyLu) differing in growth rate, differentiation, hormone responsiveness, and metastatic ability were assayed for three immunological markers. Spleens were passed through a tissue sieve, and mononuclear cells were obtained by Ficoll-Hypaque centrifugation. These were assayed for leukocytic subsets using monoclonal antibodies. An adherent population was isolated and evaluated using thin-layer chromatography for conversion of radiolabeled arachidonic acid to E series prostaglandins. Finally, sera from these animals were assayed for levels of circulating immune complexes using polyethylene glycol precipitation. Data from 52 rats bearing the various tumors were obtained, correlated with subline aggressiveness, and compared to 15 controls. Each tumor group demonstrated significantly lower helper/suppressor T-cell ratios than controls, probably due to general tumor presence. In addition, the most aggressive R3327 MAT-LyLu variant had significantly increased prostaglandin E synthesis by adherent spleen cells compared to the H or G sublines and significantly increased levels of circulating immune complexes relative to the H subline. G subline values for both prostaglandin E and circulating immune complexes levels were intermediate, suggesting that these markers correlate better with tumor aggressiveness than helper/suppressor T-cell ratios.
Prostate cells of human and rat origin produce polyamines in high content, whose apparent functions relate to cellular proliferation and secretory activities. Formation is dependent on the enzyme ornithine decarboxylase (ODC) which is irreversibly inhibited by alpha-difluoromethylornithine (DFMO). It has been postulated that pretreatment with DFMO may render cells more susceptible to subsequent chemotherapy. Copenhagen X Fischer F1 rats bearing the Dunning R3327 MAT-LyLu prostatic adenocarcinoma were given DFMO or adriamycin (ADR), alone or in combination. Those receiving DFMO were continuously provided the drug ad libitum, in water (2.5%), for the duration of the experiment, beginning 2 days prior to ADR administration. At intervals, tumor sizes were measured, animal survivals noted and comparisons made to nontreated, tumor-bearing controls. The results indicate that ADR alone or in combination with DFMO significantly reduced tumor progression, but that only combination therapy significantly prolonged survivals. Decreased tumor progression produced by DFMO alone was not statistically significant. Differences produced with combined use were additive and suggest that DFMO may augment ADR chemotherapy.
The Dunning R3327 adenocarcinoma represents a model for studying prostate cancer in rats; early studies have indicated its utility for studying relationships between tumor growth, immunologic markers, and chemotherapy. Normal animals and those bearing the metastatic Dunning R3327 MAT-LyLu tumor were treated with 10, 30, and 100 mg/kg doses of cyclophosphamide (CTX) and their spleens assayed for leukocytic subset distributions using monoclonal antibodies. Tumor-bearing animals had significant reductions in helper T cell content as well as reduced helper/suppressor T cell ratios, compared to controls. These effects occurred rapidly following implantation and were not reversed by chemotherapy. When administered to both tumor- and non-tumor-bearing animals, CTX also depleted T cell populations. Despite reductions produced in all subsets, two administrations of CTX (30 mg/kg) were capable of retaining (in non-tumor-bearing animals) or restoring (in tumor-bearing) normal helper/suppressor T cell ratios. Such studies aid in identifying therapeutically effective dosages of cytotoxic drugs that minimize their deleterious effects on the immune system.
Copenhagen X Fischer F1 rats bearing palpable Dunning R3327 MAT-LyLu prostatic adenocarcinomas were treated by intraperitoneal (i.p.) or intratumor (i.t.) injection with either human serum albumin alone or in combination with recombinant tumor necrosis factor (rTNF). At intervals tumors were measured and survivals noted. A maximum tolerable dose and least toxic route of administration was then determined. Those treated i.t. with rTNF survived significantly longer and ultimately developed significantly smaller tumors than untreated controls. Those administered rTNF by the i.p. route had less significant increases in survival with intermediate final tumor sizes.
Employing monoclonal antibodies, the relative frequencies of mononuclear cell types found in spleen cell populations were compared between rats bearing variants of the Dunning prostate adenocarcinoma and a series of non-tumor bearing control animals. The identification and quantitation of such subsets greatly expands our knowledge of immune status and function. The results indicate that the spleen cell populations from animals bearing either the Dunning R3327-H, G or MAT-LyLu sublines have significant decreases in their helper T cell/suppressor T cell ratios when comparisons are made to cells obtained from non-tumor bearing animals. In addition decreases in total T cell content and increases in splenic monocytes were noted. It appears that most of these deviations are the result of general Dunning tumor presence, rather than due to any particular subline characteristic. These changes may be analogous to similar alterations reported in the peripheral blood of humans bearing Stage D prostatic cancer, suggesting that the Dunning tumor may provide an appropriate model for evaluating interactions between the immune response, the tumor and therapy.
Prostaglandins of the E series (PGE) have been implicated in many facets of immunoregulation, as well as having a possible role in metastatic dissemination. Variant sublines of the Dunning R3327 rat prostatic adenocarcinoma, differing in growth rate, hormonal responsiveness and in propensity for metastasis, were carried in Fisher X Copenhagen F1 animals. Adherent spleen cells were assayed in vitro for their ability to convert arachidonic acid to prostaglandins of the E series. These glass adherent cells presumably include the monocytic and T cell populations which have been implicated as being immunoregulatory. The results indicated that those spleen cells obtained from animals carrying the metastatic R3327-MAT-LyLu subline tumor converted more arachidonic acid to PGE's than cells derived from animals bearing non-metastatic sublines. Cyclophosphamide therapy did not alter such conversion. Multiple regulatory mechanisms for prostaglandin metabolism are suggested.
Utilizing the Dunning rat prostate adenocarcinoma, a low dose of cyclophosphamide (CY), 30 mg/kg, administered either alone or following diethylstilbestrol (DES) therapy, was as effective as higher levels of CY (100 mg/kg) in ability to initiate tumor regression. A lower dose (10 mg/kg) of CY was initially ineffective. Animals which had been injected with tumor an additional 10 days prior to initiation of CY treatment were apparently more responsive to this mode of chemotherapy. The effect of this additional 10 days of immunologic exposure supports the belief that the activity of CY is augmented by the presence of immunologic competence. All animals which responded favorably toward therapy utilizing CY, alone or in combination with DES, were similarly able to reject subsequent tumor challenges. It is thought that low-dose CY may reduce the immunosuppressive effects observed with higher levels and presumably preserve the helper T cell population necessary to mount secondary immune responses.
The distribution of mononuclear cell types found in the peripheral blood of patients bearing carcinoma of the prostate were compared by stage and to a control group using monoclonal antibody techniques. Patients with lower stage disease (A, B) had no significant alteration in subset distribution when compared to a control group, while those with higher stage disease (D) had significant deviations. Stage D patients had a decreased representation of helper-inducer T cells and an increased representation of suppressor-cytotoxic T cells, with an overall reduction in the total T cell content. In addition elevated levels of monocytic, granulocytic and null cells were recognized by the polyspecific OKM1 antibody. These differences were in part reversible following hormonal therapy. Such alterations in the ratios between the various T cell populations could be useful in patient staging and treatment selection.