Phase II randomized clinical trial of lycopene supplementation before radical prostatectomy.

An inverse association has been observed between dietary intake of lycopene and the risk of prostate cancer. We investigated the effects of lycopene supplementation in patients with prostate cancer. Twenty-six men with newly diagnosed, clinically localized (14 T(1) and 12 T(2)) prostate cancer were randomly assigned to receive 15 mg of lycopene (n = 15) twice daily or no supplementation (n = 11) for 3 weeks before radical prostatectomy. Biomarkers of differentiation and apoptosis were assessed by Western blot analysis on benign and malignant parts of the prostate gland. Prostatectomy specimens were entirely embedded, step-sectioned, and evaluated for pathological stage, Gleason score, volume of cancer, and extent of high-grade prostatic intraepithelial neoplasia. Plasma levels of lycopene, insulin-like growth factor-1 (IGF-1), IGF binding protein-3, and prostate-specific antigen were measured at baseline and after 3 weeks of supplementation or observation. Eleven (73%) subjects in the intervention group and two (18%) subjects in the control group had no involvement of surgical margins and/or extra-prostatic tissues with cancer (P = 0.02). Twelve (84%) subjects in the lycopene group and five (45%) subjects in the control group had tumors <4 ml in size (P = 0.22). Diffuse involvement of the prostate by high-grade prostatic intraepithelial neoplasia was present in 10 (67%) subjects in the intervention group and in 11 (100%) subjects in the control group (P = 0.05). Plasma prostate-specific antigen levels decreased by 18% in the intervention group, whereas they increased by 14% in the control group (P = 0.25). Expression of connexin 43 in cancerous prostate tissue was 0.63 +/- 0.19 absorbance in the lycopene group compared with 0.25 +/- 0.08 in the control group (P = 0.13). Expression of bcl-2 and bax did not differ significantly between the two study groups. IGF-1 levels decreased in both groups (P = 0.0002 and P = 0.0003, respectively). The results suggest that lycopene supplementation may decrease the growth of prostate cancer. However, no firm conclusions can be drawn at this time because of the small sample size.

Rearrangement of chromosome 3 in renal cell carcinoma.

Rearrangements involving chromosome #3 were detected in 8 of 12 nonfamilial renal cell carcinomas. These results suggest that rearrangement of chromosome #3 is associated with the genesis and progression of a subclass of human renal cell carcinoma.

Predicting the need for adjuvant systemic therapy in patients receiving postprostatectomy irradiation.

OBJECTIVES: This study was initiated to determine if clinical, pathologic, or biochemical variables available in patients receiving postprostatectomy irradiation could be predictive of treatment outcomes, including the need for subsequent systemic therapy. METHODS: Between January 1992 and January 1995, 50 patients received external beam irradiation for a nonzero or rising postprostatectomy prostate-specific antigen (PSA) level. The median PSA values preoperatively and preradiation were 24 and 2.7 ng/mL, respectively. At the time of treatment, no patient had evidence of disseminated disease. The patients received a combination of axial and noncoplanar irradiation to an average total dose of 65 Gy at 1.8 Gy fractions. Univariate analysis and multivariate logistic regression were performed to identify factors predictive of outcome. RESULTS: Treatment was well tolerated with no grade 3 or higher gastrointestinal or genitourinary complications. A decline in the serum PSA during irradiation occurred in 82% of the patients. During radiation, 13 patients (26%) had a complete response (PSA less than 0.05 ng/mL), 56% had a partial response, and 18% had a rise in their PSA level. With a median follow-up of 16 months, 50% of all patients have an undetectable level of PSA. Twenty-six percent of patients have had evidence of biochemical progression. Seventeen percent of responding patients and 67% of nonresponders have evidence of progression (P= 0.002). On univariate analysis, other significant prognostic factors included clinical stage (P < 0.01), the preradiation PSA level (P < 0.05), and N stage (P < 0.01). On stepwise multivariate logistic analysis, a predictive model was generated from which treatment outcome could be predicted with 80% accuracy (percent correct classification) and an 85% sensitivity. CONCLUSIONS: The outcome of patients with an elevated postprostatectomy PSA level who receive irradiation can be accurately predicted using a combination of clinical stage, preradiation PSA value, Gleason score, and the response to treatment. In this way, patients who do not require additional treatment (that is, hormonal) will avoid the unnecessary cost and toxicity.

Percutaneous management of upper tract transitional cell carcinoma.

Conservative (nephron-sparing) surgery for transitional cell carcinoma of the upper tract generally has entailed variations of partial nephrectomy or open pyelotomy with excision and fulguration of tumor. We report on a patient in whom percutaneous technology was used successfully to manage transitional cell carcinoma of the lower infundibulum after other treatment options had been exhausted.

Studies of the growth of a murine renal cell carcinoma and its metastatic patterns.

Metastatic lung tumor cells from a murine renal cell adenocarcinoma were implanted in Blab/C mice for 12 transfer generations. Survival time of the implanted mice was observed to decrease from 48 days to 28 days. The incidence of lung metastases increased from 40% to 90%. These studies suggest a selection process under the terms of the experiment that has resulted in a change in the metastatic potential of the primary tumor and its serial passage of metastases. The results are compatible with current concepts regarding cell selection in this cancer state but do not, at the present time, precisely define how this is achieved. Appropriate and selective studies are ongoing to address this important issue.

Double-antibody immunoenzyme assay for human prostatic acid phosphatase.

We compare the double-antibody radioimmunoassay (RIA) and immunoenzyme assay (IEA) for measuring the concentration of prostatic acid phosphatase in human serum. Experimental details and assay performance of the two methods are outlined. Mean values for 385 normal persons were 1.02 (SD 1.32) microgram/L by IEA, 2.69 (SD 1.8) microgram/L by RIA. Results of the two methods was highly correlated [r = 0.9813, y(RIA) = 0.35 x (IEA) + 0.42, p < 0.001]. If we choose x- + 2 SD as the normal range, 3-10% false positives were seen.

Immunochemical studies of prostatic acid phosphatase.

Immunologic specificity of the prostatic acid phosphatase (PAP) and the kinetics of the PAP-anti-PAP antibody interactions were studied in detail. Antigenic identity of electrophoretic isozymes of PAP was established in this study. Counterimmunoelectrophoretic assay, radioimmunoassay, and immunofluorescence technique were developed to detect PAP and PAP-synthesizing cells. These techniques were applied to the determination of serum PAP levels and to the identification of metastatic prostate cancer cells in biopsies.

Human prostatic acid phosphatases: I. Isolation.

A new purification procedure is described for the human prostatic acid phosphatase. The procedure included carboxy-methyl-Sephadex and Concanavalin A affinity column chromatography. The purified enzyme has a high specific enzyme activity and is free from any extraneous proteins judging from immunochemical criteria and biochemical criteria such as SDS-polyacrylamide gel electrophoresis. The purified enyzme produced a monospecific anti-PAP antisera in animals and this anti-PAP antibody did not cross-react with other human acid phosphatases.

Human prostatic acid phosphatases: II. A double--antibody radioimmunoassay.

A double-antibody radioimmunoassay method for prostate-specific acid phosphatase (PAP) is presented. Experimental details are outlined to assess the reproducibility and reliability of the method under assay conditions. The upper limit of the serum PAP levels in the present assay was set at 2.4 ng/100 microliter by 162 determinations of normal serum samples. The serum PAP levels of patients with nonprostatic malignant tumors fell in the normal range, whereas the levels higher than 4.0 ng/100 microliter were found in patients with prostatic carcinoma.

Human prostatic acid phosphatases: III. Counterimmunoelectrophoresis for rapid identification.

When serial dilution of standard prostatic acid phosphatases (PAP) was reacted with constant amounts of anti-PAP serum by counterimmunoelectrophoresis (CIEP), the detection end point of enzyme concentration was 0.25 ng in a 10 microliter sample volume. The PAP concentrations in unknowns can be quantitated by comparing the dilution end points of reference PAP with the testing samples. Serum PAP levels were determined by a radioimmunoassay (RIA) and CIEP using normal male and female sera and serum samples from patients with prostatic cancer and nonprostatic tumors. An excellent correlation was observed between the two assay results. According to RIA data, the concentration of PAP higher than 0.4 ng per 10 microliter (or 4.0 ng per 100 microliter) signify the elevation of serum or bone marrow PAP level beyond normal range (normal value 1.6 +/- 0.8 ng/100 microliter). Thus, the CIEP assay will be a simple and reliable screening method for the serum PAP levels in the clinical diagnosis of prostatic cancer.

A micromethod for the measurement of estrogen receptors using high pressure liquid chromatography.

Adequate sample size has been one of the difficulties encountered in routine determination of estrogen receptors in prostatic disease. The recent commercial availability of protein analysis columns for use with high pressure liquid chromatography (HPLC) equipment has made the achievement of a considerable reduction in sample size feasible. We present a method for determination of ER which includes the use of 16 alpha-125-iodo-estradiol ( [125I]-E2) of 1600 Ci/mmol specific activity, the use of G-25 column chromatography, followed by fractionation by HPLC and finally relation of the fmol specifically bound to mg protein measured in the HPLC peak. Data obtained upon determination of ER in the immature rat uterine model system are given to show consistent recoveries, ligand specificity, saturability, inhibition, and commonly accepted KD and n values for this system. Also, in a pilot study on 13 samples from human prostatectomies, the utility of the HPLC technique for ER measurement in that tissue using single point analysis is demonstrated. For comparison, all receptor determinations reported were also made using conventional methods.

Purification and characterization of human prostatic acid phosphatase.

Human prostatic acid phosphatase (orthophosphoric monoester phosphohydrase, EC 3.1.3.2) is purified to homogeneity by standard procedures which include CM-Sephadex, Con A affinity chromatography and gel filtration. The purified enzyme is antigenically specific and has a M.W. of 100,000 with subunit M.W. of 48,000. However, the enzyme exhibited charge heterogeneity. Two major electrophoretic or chromatographic isozymic forms of PAP were separated by DEAE-Sephadex chromatography and their immunochemical identity was studied by immunodiffusion before and after the neuraminidase digestion. Quantitative precipitin and inhibition experiments showed immunological identity of the two chromatographic isozymes. Immunologic specificity of this enzyme resides on the protein moiety rather than the carbohydrate residue, although the latter group is mostly responsible for the charge group heterogeneity of the enzyme.

Expression of human prostatic acid phosphatase in a pancreatic islet cell carcinoma.

The immunologic specificity of human prostatic acidphosphatase has been established by several previous investigations as well as in this study. An apparent exception to this specificity was observed--a case of pancreatic islet cell carcinoma metastasized to the liver produced acid phosphatase that was immunologically indistinguishable from the prostatic acid phosphatase. In this case, the possibility of prostatic involvement was convincingly ruled out by clinical follow-ups and by postmortem pathologic studies. Highly purified prostatic acid phosphatase and this tumor acid phosphatase exhibited very similar Km values and identical molecular weights. Immunochemical analysis of the two enzymes using antiprostatic acid phosphatase sera showed that enzymes are antigenically identical. The implications of our observation are discussed in relation to clinical application of immunoassays for prostatic phosphatase in the future and to the molecular basis of human acid phosphatase polymorphism.

Correlation of estrogen and androgen receptor status in prostatic disease measured by high pressure liquid chromatography.

To further characterize human prostatic estrogen receptors (ER) determined by high pressure liquid chromatography (HPLC), we checked our procedure by which we nullify estrogen binders (including testosterone binding globulin, TeBG) other than ER by preincubation of cytosols with dihydrotestosterone (DHT). We also showed that the ER exhibited ligand specificity and that ER is present in BPH nuclear extract at 10-fold its concentration in the corresponding cytosols. Of seven prostates with localized cancer determined preoperatively, only 3 showed localization; ER concentration in the cancer parts was lower than in the corresponding surrounding BPH. A total of 22 specimens were evaluated for ER and androgen receptors (AR). Statistically, AR had higher values than ER but there was no correlation between the corresponding AR and ER for each tissue.

[Survival in stage T2-T3A bladder cancer treated with radical cystectomy]. / Supervivencia del cáncer de vejiga estadio T2-T3A tratado mediante cistectomía radical.

OBJECTIVE: The optimal treatment for patients with localized muscle-infiltrating urothelial carcinoma (Jewett stage B or T2-T3a of the TNM classification, UICC 1992) continues to be a controversy. The present study analyzed the survival rate in patients with stage T2-T3a bladder cancer who had been treated by radical cystectomy. METHODS: The records of 50 patients with T2-T3a NO tumor, submitted to pelvic lymphadenectomy and radical cystoprostatectomy, were reviewed to determine the prognosis in this group of patients. Seventeen patients (34%) received three courses of systemic chemotherapy (CMV) prior to cystectomy. RESULTS: The overall 5-year survival rate was 73%; 76% for those with T2 (n = 30) and 67% for those with T3a (n = 20) (log-rank, p = 0.27). No statistically significant differences were observed for age (less than or over 65 years), tumor growth pattern (papillary or flat), tumor size (less or greater than 5 cms) or treatment (with or without induction CMV). However, patients with G1-2 tumor had a better survival rate (94% at 5 years) than those with G3 tumor (51%), a difference with statistical significance (log-rank, p = 0.047). The Cox regression analysis showed no independent variable of prognostic significance. CONCLUSION: Muscle-infiltrating urothelial carcinoma is highly curable by radical surgery. Some authors believe it is unnecessary to distinguish T2-T3a lesions; therefore a critical review of the TNM classification appears to be warranted. We are unable to distinguish patients with a better prognosis that might benefit from less aggressive therapeutic options. Similarly, the therapeutic benefits of induction chemotherapy prior to cystectomy in patients with stage T2-T3a tumor could not be demonstrated.

A comparison of estrogen and androgen receptor levels in human prostatic tissue from patients with non-metastatic and metastatic carcinoma and benign prostatic hyperplasia.

Estrogen receptors (ER, N = 72) and androgen receptors (AR, N = 33) were determined by high pressure liquid chromatography (HPLC) in 72 human prostatic tissues obtained at prostatectomy, and exploratory statistical analyses of the resulting data were performed. To facilitate use of these data as well as other pertinent information from the patient charts, a program for a comparatively large data base was implemented on a Wang minicomputer. The median values of cytosolic AR in the four cancer stages examined were statistically different from each other (P = 0.01), with AR increasing from stages A through D. Even though ER differences between the four stages were not significant (P = 0.13), there was a trend, in the data examined, for median ER values to decrease with stages B through D. On the other hand, median BPH values for both ER and AR were found to lie mid-scale compared with the respective cancer stages, leading to the conclusion that receptor measurements probably cannot distinguish between CA and BPH in human prostatic tissue, at least as measured by competitive binding techniques.

[Prognosis prediction in patients with transitional cell carcinoma of the urinary bladder]. / La predicción de pronóstico en pacientes con carcinoma de células transicionales de la vejiga urinaria.

OBJECTIVES: Many attempts have been made during decades to identify factors predictive of prognosis in patients with transitional cell carcinoma (TCC) of the bladder. The present study attempts to determine the predictive factors in a large series of patients with long follow-up homogeneously treated at three institutions from 1983 to 1992. METHODS: The clinical and histological factors with presumed prognostic value were retrospectively evaluated in a series of 331 patients with a mean follow-up of 7.2 years, and a study of survival was performed. RESULTS: Univariate analysis showed tumor stage, growth pattern, grade, size, coexisting dysplasia, histologic type, topography of the lesion and patient age are useful parameters for the prediction of prognosis. The Cox analysis revealed tumor stage is the most important prognostic variable (Beta = 1.23, p < .001), followed by growth pattern as determined by the presence or absence of a papillary phenotype (Beta = 1.18, p < .001), tumor size (Beta = .98, p < .001), WHO modified histologic grading considering persistence or loss of cell polarity (Beta = .73, p < .01), tumor location (Beta = .48, p < .05), and histology (presence or absence of phenotypes other than pure TCC, Beta = .45, p < .05). Coexisting dysplasia, tumor multiplicity, age and sex did not independently influence survival. CONCLUSION: Despite the advancements in the field of molecular biology relative to prognostic markers in bladder cancer, the conventional morphological parameters and tumor stage continue to be the main source of prognostic information in clinical practice.