Bladder cancer clinical guidelines panel summary report on the management of nonmuscle invasive bladder cancer (stages Ta, T1 and TIS). The American Urological Association.

PURPOSE: The American Urological Association convened the Bladder Cancer Clinical Guidelines Panel to analyze the literature regarding available methods of treating nonmuscle invasive bladder cancer, and to make practice policy recommendations based primarily on treatment outcomes data. MATERIALS AND METHODS: The panel searched the MEDLINE database for all articles related to nonmuscle invasive bladder cancer published from 1966 to January 1998. Outcomes data were extracted from articles accepted after panel review and meta-analyzed to produce comparative probability estimates for alternative treatments. RESULTS: All of the intravesical agents (thiotepa, bacillus Calmette-Guerin, mitomycin C and doxorubicin) when used as adjuvant therapy after transurethral resection resulted in a lower probability of recurrence compared to resection alone. However, there is no evidence that intravesical therapy affects long-term progression. CONCLUSIONS: For patients with no prior intravesical therapy adjuvant intravesical chemotherapy or immunotherapy is a treatment option after endoscopic removal of low grade Ta bladder cancers. Intravesical instillation of bacillus Calmette-Guerin or mitomycin C is recommended for carcinoma in situ, and after endoscopic removal of T1 and high grade Ta tumors.

An assessment of fertility in male workers exposed to molinate.

Molinate is a thiocarbamate herbicide used for weed control in rice fields. Since the late 1970s, findings from reproductive toxicology studies of rats have led to concern that molinate might affect human male fertility. Semen samples were collected from 272 formulation and production workers at three US plants. The samples were collected at the end of four alternate monitoring periods of either high or low exposure to molinate. In addition, 222 married workers provided reproductive-history information. Workers' mean exposures to molinate during the monitoring periods ranged from 12.7 micrograms/m3 to 210.9 micrograms/m3. There was no evidence that sperm and serum hormone levels were related to exposure to molinate before the study or exposure during the four monitoring periods. There was also no evidence of a molinate exposure-related effect on the ratio of observed to expected births.

Receptors for BPH growth factors are located in some neuroendocrine cells.

BACKGROUND: Prostatic neuroendocrine (NE) cells play an important role in the growth and differentiation of the prostate. We are still unable to characterize the exact mechanisms which lead to interactions between the epithelial cell and the NE cell. We offer several interactions generated by the NE cells, and speculate on some actions of selected NE cells. METHODS: We used thin sections of prostatic tissue made from 20 radical prostatectomies. Our team used validated rabbit polyclonal antibodies which were raised against human EGFR and C-erb B-2, using the streptavidin-peroxidase conjugate method. RESULTS: A strong immunoreactivity was noted with both antibodies in the cytosol of some NE cells. These cells had a dendritic appearance, and they were located in the acini and ducts of small-to-moderate-sized prostatic glands. Double immunostaining revealed the colocalization of both antigens with chromogranin A (CgA), a polypeptide that is expressed by NE cells. Of interest was the finding that EGFR and C-erb B-2 were colocalized as well as independently expressed by separate populations of NE cells. CONCLUSIONS: We conclude that NE cells may be regulated by the HER protein family, probably in a ligand-specific fashion. This is a revised report which identifies a pathway regulating NE cells, and their interactions with epithelial cells.

Prognostic significance of neuroendocrine differentiation in clinically localized prostatic carcinoma.

Several recent studies have focused attention on neuroendocrine differentiation (NED) in prostatic carcinoma (PC). Clinical studies have shown PC with NED to behave aggressively and to be associated with poor prognosis. To evaluate NED as an independent prognostic factor, we conducted a retrospective study of 87 patients with clinically localized PC who underwent radical prostatectomy. The presence of neuroendocrine tumor cells was confirmed by positive immunostaining for serotonin, chromogranin A, and neuron-specific enolase. The correlation between NED and disease progression was assessed. Progression of cancer was demonstrated in 35 (40%) of the patients. The presence of NED was confirmed in 60 (69%) of cases, and of these patients 26 (43%) manifested evidence of disease progression. Disease progression was also manifest in nine (33%) of the 27 patients without evidence of NED. Thus, in the setting of clinically localized carcinoma of the prostate, NED does not appear to be a statistically significant independent prognostic factor.

DNA cytometry and chromosome 9 aberrations by fluorescence in situ hybridization of irrigation specimens from bladder cancer patients.

OBJECTIVES: To determine the sensitivity and specificity of combining fluorescence in situ hybridization (FISH) measurement of chromosome 9 and DNA cytometry of bladder irrigation specimens in the detection of bladder cancer. METHODS: Bladder irrigation specimens were obtained from 37 normal control patients and 317 bladder cancer patients during cystoscopic examinations. Bladder cancer patients were sampled in the absence of observable tumor (256 specimens) and concurrently with tumor (204 specimens). Chromosome 9 copy number was determined on a cellular basis by FISH, and cellular DNA content was determined by Feulgen DNA staining and image cytometry. RESULTS: Sensitivity of chromosome 9 FISH was 42% for all tumors and was not correlated to transitional cell carcinoma tumor grade, while the sensitivity of DNA cytometry was 55% and improved with increasing grade from 38% for grade 1 to 90% for grade 3 tumors. The results of FISH and DNA cytometry were combined, resulting in specificity of 92% and sensitivity of 69% for grade 1, 76% for grade 2, and 97% for grade 3 tumors. CONCLUSIONS: The lack of increase with grade in the percentage of positive specimens by FISH supports the hypothesis that chromosome 9 aberrations are critical events in bladder tumorigenesis for many patients. These data demonstrate the presence of cells in irrigation specimens with specific genomic lesions of chromosome 9 and DNA content. Combining FISH on chromosome 9 and DNA cytometry provides an increase in sensitivity to transitional cell carcinoma over either test alone.

Characterization of the cell-specific expression of parathyroid hormone-related protein in normal and neoplastic prostate tissue.

OBJECTIVES: Parathyroid hormone-related protein (PTHrP) is a primary factor in the pathogenesis of malignancy-associated hypercalcemia. By alternative splicing, the human PTHrP gene can generate three different species of mRNA that encode three initial translational isoforms of 139, 173, and 141 amino acids. We recently reported that PTHrP was present in normal prostatic neuroendocrine cells and was overexpressed in prostate cancer tissue as demonstrated by immunostaining. This study was undertaken to further clarify the complex expression of PTHrP gene in normal prostate tissue and prostate cancer. METHODS: PTHrP mRNA in samples prepared from normal prostate tissue, prostate cancer, and three prostate cancer cell lines, PC3, LNCaP, and DU145 was assessed using Northern hybridization. Expressed PTHrP isoforms were deduced from differential reverse transcription-polymerase chain reaction (RT-PCR) assays with exon-specific primers. Further localization of different species of PTHrP mRNA was performed using nonradioactive in situ hybridization with exon-specific probes on consecutive sections of normal and neoplastic prostate tissue. RESULTS: Northern hybridization showed that the PTHrP expression level was higher in prostate cancer than in normal prostate tissue. All three PTHrP isoforms could be detected in normal prostate tissues and prostate cancer with differential RT-PCR. Further analysis using in situ hybridization with exon-specific probes revealed that all three PTHrP isoforms were present in prostatic neuroendocrine cells and only PTHrP-1-139 isoform could be clearly detected in prostate cancer tissue. Two androgen-insensitive cell lines, PC3 and DU145, derived from a bone metastasis and a brain metastasis, respectively, expressed all three mRNA species encoding for the three isoforms, but DU145 cells expressed less than PC3 cells. Androgen-sensitive LNCaP cells exhibited a low level of expression of mRNA species encoding for PTHrP-1-139 and PTHrP-1-173, and no expression of PTHrP1-141 isoform. CONCLUSIONS: All three initial translational isoforms of PTHrP are produced by prostatic neuroendocrine cells. The mature products of PTHrP might exert their effects on other prostatic epithelial cells in a paracrine fashion and also participate in the homeostatic regulation of the ejaculate. In prostate cancer, differential expression of these three isoforms is evident and PTHrP-1-139 isoform is more abundant than the other two forms. These findings are valuable for designing future research studies to further elucidate the biological functions of PTHrP in normal prostatic glands and prostate cancer.

Schistosomiasis in Saudi Arabia, Egypt, and Iraq.

The incidence of schistosomiasis, a parasitic infestation caused by trematodes, or flukes, has decreased significantly in Egypt and other Middle Eastern countries. The education of people in the countryside is a primary reason. The water supply in these countries is now good, and, in most areas, women no longer use the stagnant river tributaries for washing clothes. Medications, which can be used to prevent the infection or kill the parasite include praziquante and metrifonate.

Pathophysiology of clinical varicoceles in infertile men.

In infertile men, clinical varicoceles most often occur bilaterally. In our experience with these patients, both testicles are smaller than normal. We find more than 25% to 35% immature and tapered sperm in in the ejaculum of these men, and the motility of the sperm is usually low. We have found serotonin in the plasma of the varicoceles, and believe this biogenic amine is responsible for the poor sperm motility. We now agree that a subset of neuroendocrine cells in the prostate secrete serotonin. Bilateral varicocele surgery can improve the patient's fertility potential, and we advocate surgical treatment.

Cloning and characterization of the alpha 1-antichymotrypsin produced by human prostate tissue.

BACKGROUND: alpha 1-antichymotrypsin (ACT) forms stable complexes with prostate-specific antigen (PSA), a serine protease, and this complex is the major form of PSA in the blood circulation. alpha 1-antichymotrypsin occurs in the blood in approximately 10(5) molar excess to PSA, mainly due to hepatic production, but local prostatic production of ACT has been demonstrated by immunohistochemistry and in situ hybridization. The present study was performed to further characterize this prostate-produced ACT. METHODS: The nucleotide structure of the prostatic transcript was determined from ACT coding clones isolated from prostatic cDNA. The occurrence of a prostatic ACT transcript was analyzed by Northern blot. RT-PCR was used to detect ACT transcripts in cultured prostatic cancer cells. RESULTS: Screening of two prostatic cDNA libraries showed the frequency of ACT transcripts to be about 1 clone in 40,000. The cDNA sequence of prostatic ACT is identical to that of the previously published hepatic ACT. Northern blot analysis of mRNA extracted from prostatic tissue showed a single transcript of approximately 1.5 kb. RT-PCR analysis demonstrated an ACT transcript in cultured prostatic cancer cells. CONCLUSIONS: In this study we provide further evidence for a local, prostatic production of ACT. The cDNA sequence data suggest that the peptide backbone of prostatic ACT is identical to the protein derived from the liver, and thus may be functional as a protease inhibitor.

Rapid exponential elimination of free prostate-specific antigen contrasts the slow, capacity-limited elimination of PSA complexed to alpha 1-antichymotrypsin from serum.

OBJECTIVES: To study the rates of elimination of total prostate-specific antigen (PSA-T), free PSA (PSA-F), and PSA complexed to alpha 1-antichymotrypsin (PSA-ACT) from blood after radical retropubic prostatectomy (RRP). METHODS: We obtained venous blood from 10 patients with prostate cancer who were undergoing RRP. We analyzed PSA-F and PSA-ACT and equimolar detection of both of these forms together (PSA-T) by using immunofluorometric assays. An attempt was made to fit the serum concentrations of PSA-F, PSA-ACT, and PSA-T for each patient to exponential curves by applying one- and two-compartment models for pharmacokinetic analysis. RESULTS: Manipulation of the prostate during RRP resulted in a 3- to 28-fold increase in PSA-F concentrations in serum. Removal of the prostate resulted in a rapid, biexponential elimination of PSA-F from serum, corresponding to a mean initial (alpha) half-life of 0.81 hours and a mean terminal (beta) half-life of 13.9 hours. Serum PSA-ACT concentrations decreased by 20% to 40% immediately after removal of the gland; the elimination after surgery was slow and nonexponential, corresponding to a mean rate of 0.8 ng/mL/day. The elimination of PSA-T reflects a combination of the elimination patterns for PSA-F and PSA-ACT. CONCLUSIONS: The main proportion of PSA-F is rapidly eliminated from serum, possibly by glomerular filtration. PSA-F released during surgery did not form complexes with ACT, as suggested by the lack of PSA-ACT elevation in serum. The size (approximately 90 kDa) and the extensive in vitro stability of the PSA-ACT complex prevents renal clearance. The nonexponential elimination of the PSA-ACT complex is evidence of a capacity-limited process (e.g., metabolic transformation).

Suppression of the growth and invasiveness of human prostate cancer cells in vitro by neuropeptide antagonist substance P analogues.

Neuropeptides may be essential to the growth and progress of prostate cancer, particularly during androgen-independent cell development. To determine whether neuropeptide antagonists substance P analogues can be used as therapeutic agents in the treatment of prostate cancer, their effects on the growth and invasiveness of established human prostate cancer cell lines were examined. The effects of [d-Arg(1), d-phe(5), d-Trp(7,9), Leu(11)]substance P and [Arg(6), d-Trp(7,9), MePhe(8)]substance P(6-11) on two androgen-independent cell lines (PC-3 and DU-145) and an androgen-dependent cell line (LNCaP) were studied. The cytotoxicity of substance P analogues was assessed based on their effects on DNA synthesis and cell proliferation by [(3)H]thymidine incorporation and cell growth assays, respectively. Inhibition of the invasiveness of prostate cancer cells was estimated based on the extent of cell penetration of reconstituted basement membrane. Substance P analogues inhibited DNA synthesis and cell proliferation of prostate cancer cells dose dependently but complete recovery was achieved by the addition of bombesin or substance P. [d-Arg(1), d-phe, d-Trp(7,9), Leu(11)]substance P inhibited the invasiveness of PC-3 cells. Neuropeptide antagonists substance P analogues have been found useful as therapeutic agents for prostate cancer. Their action occurs primarily through the inhibition of Ca(2+) mobilizing neuropeptides such as bombesin and substance P.

Alteration of the hormonal bioactivity of parathyroid hormone-related protein (PTHrP) as a result of limited proteolysis by prostate-specific antigen.

OBJECTIVES: To discover whether the proteolytic activity of prostate-specific antigen (PSA) affects the structure and function of parathyroid hormone-related protein (PTHrP), as both are abundant components of human seminal plasma. METHODS: The ability of PTHrP to act as a substrate was studied by incubating a synthetic polypeptide, consisting of 34 amino acid residues of the amino-terminal domain of PTHrP, with purified PSA. The incubate was then analyzed by sodium dodecyl sulfate-polyacrylamide gel electrophoresis, high-pressure liquid chromatography separation, amino-terminal peptide sequencing, and mass spectrometry. The physiologic effect of the proteolytic activity of PSA on PTHrP was studied by measuring any alteration in PTHrP (1-34)-induced elevation of cyclic adenosine monophosphate (cAMP) production by UMR-106 rat osteosarcoma cells in culture. All cell culture experiments were performed with PSA and PTHrP (1-34) at physiologic concentrations. RESULTS. Our data show that PSA proteolytically cleaves PTHrP (1-34) after either residue 22 or 23, generating three peptide fragments. Both cleavages occur carboxy terminally of a phenylalanine residue. The cAMP production in rat osteosarcoma cells, induced by the amino-terminal portion of PTHrP (1-34), as a result of its structural similarity with parathyroid hormone (PTH), was abated by PSA in a dose- and time-dependent fashion. In contrast, heat-inactivated PSA had no effect on cAMP production. CONCLUSIONS: Our study demonstrates that PTHrP is a substrate for PSA. The cleavage of the amino-terminal portion of PTHrP completely disrupts its ability to interact with the PTH/PTHrP receptor and thus inhibits its PTH-like activity. The proteolytic processing of PTHrP by PSA may play an important role in the post-translational/post-secretional regulation of prostatic PTHrP activities, which are believed to include regulation of prostate growth and differentiation.

Neuroendocrine differentiation in prostatic malignancy.

BACKGROUND: The prostatic neuroendocrine cell is a regulatory cell that produces serotonin and peptide hormones. This cell is part of a more widely dispersed diffuse neuroendocrine regulatory system known as the APUD system. Focal neuroendocrine differentiation is seen in virtually all prostate carcinomas to one degree or another. Specific malignancies that are purely neuroendocrine include small cell carcinoma and carcinoid/carcinoid-like tumors. A variety of studies suggest a possible prognostic significance of neuroendocrine differentiation in prostate carcinoma. METHODS: The literature on the prostatic neuroendocrine cell and neuroendocrine differentiation in prostate carcinoma is reviewed. RESULTS: Based on analogy with other better studied elements of the diffuse neuroendocrine regulatory system or APUD system, as well as the morphology and specific products produced by neuroendocrine cells, it is likely that they play an important regulatory role in the prostate. Neuroendocrine differentiation may be of prognostic significance in prostate carcinoma. Mechanisms are not well characterized at this point, but the known growth factor activity of the neuroendocrine cell products, an increase in proliferation in cells surrounding neuroendocrine cells, and a lack of androgen receptor expression in neuroendocrine cells, suggest mechanisms by which they may be of prognostic significance. CONCLUSIONS: Neuroendocrine differentiation in prostate carcinoma may be of prognostic significance, but better methods to define neuroendocrine, differentiation are necessary. The therapeutic implications of neuroendocrine differentiation in prostate carcinoma may be of significance and need to be explored further.