MR urography versus retrograde pyelography/ureteroscopy for the exclusion of upper urinary tract malignancy.

AIM: To evaluate the diagnostic performance of magnetic resonance urography (MRU) versus retrograde pyelography and/or ureteroscopy (RPU) in the detection of upper urinary tract neoplasms. MATERIALS AND METHODS: This retrospective study included 35 patients with suspected upper urinary tract malignancy who underwent MRU and RPU within 6-months in our institution during the study period (February 2002 to January 2007). MRU and RPU reports were reviewed and results recorded. For each patient, the urinary tract was sub-divided into four regions for analysis: left kidney/renal pelvis, left ureter, right kidney/renal pelvis, and right ureter. MRU and RPU results for each patient were compared to a reference standard and the diagnostic performance of both techniques was compared. RESULTS: A total of 113 regions were analysed on MRU and 90 regions on RPU. Nineteen neoplasms were identified. Sensitivity, specificity, positive predictive value, and negative predictive value for the detection of urinary tract neoplasms were 63, 91, 60, and 92% for MRU, respectively, and 53, 97, 83, and 88% for RPU, respectively. These differences were not statistically significant (p>0.05). CONCLUSION: The high negative predictive value of MRU in the present series supports its use as a non-invasive screening examination for excluding the presence of upper urinary tract malignancy.

Preoperative serum acid phosphatase and alkaline phosphatase are not predictors of pathological stage and prostate-specific antigen failure after radical prostatectomy.

OBJECTIVE: To examine the utility and prognostic significance of enzymatic serum acid phosphatase (total acid phosphatase, TAP, and prostatic fraction of acid phosphatase, PFAP) and alkaline phosphatase (ALP) for staging, grading and outcome of patients who underwent radical retropubic prostatectomy (RRP) after the introduction of prostate-specific antigen (PSA) testing. PATIENTS AND METHODS: In all, 180 consecutive patients with clinically localized prostate cancer who underwent RRP with standard obturator lymph-node dissection between 1 January 1990 and 31 December 1995 were evaluated. Levels of TAP of > 5.4 IU/L, PFAP of > 1.2 IU/L and ALP of > 120 IU/L were classified as abnormally high. The relationship between abnormally high values and prostate cancer stage, grade and time to recurrence after RRP were calculated. The median follow-up was 86 months (approximately 7 years). RESULTS: Of the 180 patients, information about preoperative TAP, PFAP and ALP were available in 164, 163 and 154, respectively; TAP was abnormal in seven (4%), PFAP in 33 (20%) and ALP in only 13 (8%). None of the markers examined was associated with any variables of disease severity, as measured by pathological stage, Gleason score, perineural invasion, capsular penetration, positive margins, seminal vesicle involvement, and lymph node involvement. Abnormal TAP, PFAP or ALP were not associated with recurrence (P = 0.96, 0.45 and 0.41, respectively). In contrast, a PSA level of > 4 ng/mL was predictive of recurrence after RRP (P < 0.001). In the sample overall, 25 (14%) of the patients had recurrence and only one died from prostate cancer. CONCLUSIONS: Preoperative enzymatic serum TAP, PFAP and ALP levels are not predictors of the severity of disease or PSA disease-free recurrence after RRP.

Clinical management of prostatic intraepithelial neoplasia as diagnosed by extended needle biopsies.

OBJECTIVE: To examine the results of the clinical management of patients with high-grade prostatic intraepithelial neoplasia (PIN), as diagnosed by extended needle biopsies. PATIENTS AND METHODS: The clinical data were reviewed from a cohort of 387 men who underwent > or = 10 core prostate needle biopsies between 1 January 1996 and 31 December 1997 by one urologist (W.C.D.). Two study groups were identified; the first comprised 47 patients with only high-grade PIN and the second was a control group of 137 patients with only benign findings on their biopsies. Those patients with cancer, atypia or a prostatic biopsy with fewer than 10 cores were excluded. The clinical and histological data were evaluated. The criteria for re-biopsy were two successive increases in prostate specific antigen (PSA) level or any change in the findings on digital rectal examination (DRE). All patients were monitored at 6-12 month intervals. RESULTS: Of the 387 patients, 46% had normal findings, 5.2% had atypia, 12.6% had PIN alone, 15 (3.9%) had PIN plus atypia, 6.7% had PIN plus cancer and 32.3% had cancer. There was no significant difference between the PIN and control groups in age, DRE, PSA level, prostate size (by ultrasonography), free testosterone level, number of the cores and time of follow-up (median 34.8 and 36.6 months for the PIN and control groups, respectively). Of the PIN and control groups, 21 (45%) and 43 (31%) respectively had at least one re-biopsy. Five patients (24%) in the PIN and one (2.3%) in the control group developed cancer (P = 0.0124). All these patients had organ-confined disease and were found to have either Gleason scores 3 + 3 or 3 + 4 on surgical specimens. There was no correlation between the original location of PIN and the location of subsequent malignancy. CONCLUSIONS: Patients with one set of extended needle biopsies with high-grade PIN should be followed clinically every 6-12 months, and it may be safe to reserve repeat biopsy for those with changes in PSA level and/or in the DRE.

Long-term remission in a patient with metastatic collecting duct carcinoma treated with taxol/carboplatin and surgery.

Collecting duct carcinoma of the kidney is a rare and aggressive neoplasm of the distal collecting tubules for which there is no established therapy. We describe a young woman with metastatic collecting duct carcinoma who responded to Taxol/carboplatin chemotherapy with an 80% reduction in her tumor burden, including complete regression of lymph node metastases and significant shrinkage of a renal mass. She was rendered free of disease through nephrectomy and has been without a recurrence for 20 months. This suggests that Taxol/carboplatin chemotherapy and surgery should be considered for the treatment of metastatic collecting duct carcinoma.

Salvage intravesical therapy with interferon-alpha 2b plus low dose bacillus Calmette-Guerin is effective in patients with superficial bladder cancer in whom bacillus Calmette-Guerin alone previously failed.

PURPOSE: We determined whether combining low dose bacillus Calmette-Guerin (BCG) interferon-alpha 2B would be effective for patients in whom previous BCG failed. MATERIALS AND METHODS: A total of 40 patients in whom 1 (19) or more (21) previous induction courses of BCG failed received 6 to 8 weekly treatments of 1/3 dose (27 mg.) BCG plus 50 million units interferon-alpha 2B. Additional 3 week miniseries of further decreased BCG (1/10, 1/30 or 1/100) titrated to symptoms without changing the interferon-alpha 2B dose were given at 5, 11 and 17 months. In 12 patients a second induction course was given with 1/10 BCG plus 100 million units interferon-alpha 2B. There was multifocal disease in 39 patients, previous BCG had failed within 6 months in 34, disease was aggressive (stage T1, grade 3 or carcinoma in situ in 31, there had been 2 or more previous recurrences in 25 and disease history was greater than 4 years in 13. RESULTS: At a median followup of 30 months 63% and 53% of patients were disease-free at 12 and 24 months, respectively. Patients in whom 2 or more previous BCG courses had failed fared as well as those with 1 failure. Of the 18 failures 14 occurred at the initial cystoscopy evaluation. Of 22 patients initially counseled to undergo cystectomy 12 (55%) are disease-free with a functioning bladder. Combination therapy was well tolerated. CONCLUSIONS: While longer followup and larger multicenter studies are required to validate these encouraging findings, intravesical low dose BCG plus interferon-alpha 2B appears to be effective in many cases of high risk disease previously deemed BCG refractory. However, early failure while on this regimen should be aggressively pursued with more radical treatment options.

Early catheter removal in 100 consecutive patients undergoing radical retropubic prostatectomy.

OBJECTIVES: To investigate the outcome of 100 consecutive patients selected for early catheter removal after radical retropubic prostatectomy (RRP), where urethral catheter drainage is used routinely for 2-3 weeks. PATIENTS AND METHODS: The study included 129 consecutive patients with clinically localized prostate cancer who underwent RRP. Catheters were removed in the clinic (with no radiographic studies) 8-9 days after RRP provided there was no evidence of urine leak, pelvic haematoma, rectal injury or severe obesity. The follow-up (mean 21 months) results were available for 118 patients, 100 of whom were candidates for early catheter withdrawal. Their records were reviewed for evidence of complications, including urinary retention, anastomotic stricture formation and urinary incontinence. RESULTS: Urinary retention developed in two of the 100 patients, requiring simple catheter replacement. Nine patients developed bladder neck contracture requiring dilatation or incision. No patients developed anastomotic disruption, urinary tract infection or pelvic abscess. At the mean follow-up of 21 months, 76% of patients were continent and did not require pads; 19% of patients had mild stress urinary incontinence requiring the use of 4 pads/day. CONCLUSION: With appropriate patient selection as described, catheters can be removed in the clinic (with no radiographic studies) 8-9 days after RRP, with no increased incidence of complications, including anastomotic stricture, retention or incontinence.

Clinical and pathological characteristics of micropapillary transitional cell carcinoma: a highly aggressive variant.

PURPOSE: We present preliminary clinical, histochemical and molecular findings for 5 patients with micropapillary transitional cell carcinoma of the bladder, a rare histological variant not widely recognized in the urological literature. MATERIALS AND METHODS: The 5 patients were prospectively identified. In 3 cases immunohistochemical staining for expression of CD31, p53, E-cadherin, and alpha, beta and gamma-catenin was performed on paraffin embedded tissue. Sequencing was used to identify point mutations in exons 5 to 9 of p53, and exons 1 and 2 of H-ras. RESULTS: Of the patients 2 died within 1 year of presentation to our institution with rapid local extension along the bladder serosal surface and ureteral sheaths. Another patient had progression to invasive disease within 22 months. In the 3 cases with immunohistochemical staining p53 was negative, despite positive staining of nonmicropapillary transitional cell carcinoma within the same specimen. Stains for the angiotrophic marker CD31 were negative. In all 3 cases normal membrane associated alpha, beta and gamma-catenin expression was present. Examination of p53 sequences revealed a single point mutation in exon 8 of 1 case. In 2 cases different mutations in exon 1 of H-ras were noted. CONCLUSIONS: Micropapillary transitional cell carcinoma is a rare and highly aggressive variant. Paradoxically, our study demonstrated no significant p53 abnormalities. The lacunar histological pattern did not appear to represent invasion of vascular spaces. Rather, these tumors seemed to have the ability to disrupt and replace the normal stromal matrix to achieve rapid nonendothelial extension. Thus, micropapillary histology may predict a lesser likelihood of surgical cure.

Is low serum free testosterone a marker for high grade prostate cancer?

PURPOSE: The association of free and total testosterone with prostate cancer is incompletely understood. We investigated the relationship of serum free and total testosterone to the clinical and pathological characteristics of prostate cancer. MATERIALS AND METHODS: We retrospectively reviewed the clinical records of 117 consecutive patients treated by 1 physician and diagnosed with prostate cancer at our medical center between 1994 and 1997. Low free and total testosterone levels were defined as 1.5 or less and 300 ng./dl., respectively. RESULTS: After evaluating all 117 patients we noted no correlation of free and total testosterone with prostate specific antigen, patient age, prostatic volume, percent of positive biopsies, biopsy Gleason score or clinical stage. However, in patients with low versus normal free testosterone there were an increased mean percent of biopsies that showed cancer (43% versus 22%, p = 0.013) and an increased incidence of a biopsy Gleason score of 8 or greater (7 of 64 versus 0 of 48, p = 0.025). Of the 117 patients 57 underwent radical retropubic prostatectomy. In those with low versus normal free testosterone an increased mean percent of biopsies demonstrated cancer (47% versus 28%, p = 0.018). Pathological evaluation revealed stage pT2ab, pT2c, pT3 and pT4 disease, respectively, in 31%, 64%, 8% and 0% of patients with low and in 40%, 40.6%, 12.5% and 6.2% in those with normal free testosterone (p>0.05). CONCLUSIONS: In our study patients with prostate cancer and low free testosterone had more extensive disease. In addition, all men with a biopsy Gleason score of 8 or greater had low serum free testosterone. This finding suggests that low serum free testosterone may be a marker for more aggressive disease.

Mutated ras p21 as a target for cancer therapy in mouse transitional cell carcinoma.

PURPOSE: To establish an experimental mouse model for bladder cancer immunotherapy using mutated ras as a target. MATERIALS AND METHODS: A tumorigenic mouse bladder transitional cell carcinoma (TCC) line MB49 (C57BL/6 origin) was analyzed for its c-ras gene status by DNA cloning and sequencing. Aberrant expression of the ras gene was measured with Western blotting. 13-mer peptides corresponding to residues 5 to 17 of the ras protein were synthesized and tested for immunogenicity in syngeneic C57BL/6 mice. Induction of specific immune responses was evaluated by analyzing splenocyte activity in vitro and tumor suppression in vivo. RESULTS: MB49 cells were found to contain a single amino acid substitution of serine for glycine at codon 12 in K-ras loci and an abundant amount of cellular mutated ras p21 protein. C57BL/6 mice immunized with the 13-mer serine-containing ras peptide exhibited mutation-specific immune responses in splenocyte proliferation, cytokine production and cytotoxicity. Specific antitumor immunity in the form of tumor growth delay in vivo was observed in mice immunized with the same mutant peptide followed by subcutaneous MB49 tumor challenge and was enhanced by the addition of low dose interleukin-12. CONCLUSIONS: The mouse bladder TCC line MB49 contains a serine mutation at codon 12 of its K-ras gene that is sufficient to induce mutation-specific immune responses in vitro and specific protective immunity to MB49 tumor in vivo. Mutated oncoproteins may be ideal targets for the development of specific immunotherapy regimens for bladder cancer immunotherapy.

IFN-alpha 2B enhances Th1 cytokine responses in bladder cancer patients receiving Mycobacterium bovis bacillus Calmette-Guérin immunotherapy.

Combination therapy with intravesical bacillus Calmette-Guérin (BCG) plus IFN-alpha for superficial bladder cancer has been demonstrated to be more effective than either single agent alone in animal studies and of suggested greater efficacy in clinical studies. However, the mechanism by which IFN-alpha enhances BCG-mediated antitumor activity is poorly understood. Using PBMCs from bladder cancer patients, IFN-alpha was found to substantially enhance the efficacy of BCG to induce IFN-gamma production. Among 34 patients tested, 80% showed >4-fold increase. This effect of IFN-alpha was observed in both initial and memory responses to BCG. In addition, IFN-alpha up-regulated BCG-induced IL-12 and TNF-alpha and down-regulated BCG-induced IL-10. Neutralizing endogenous IL-10 or adding exogenous IL-12 provided further synergy for IFN-gamma production. In clinical practice, intravesical IFN-alpha 2B (50 million units (MU)/dose) was observed to accelerate urinary IFN-gamma production to low-dose BCG (one-tenth or one-third of a full dose) in patients treated with combination therapy compared with BCG alone. These results suggest that IFN-alpha is a potent BCG enhancer that polarizes the BCG-induced immune response toward the cellular immune pathway by promoting Th1 cytokine expression and reducing Th2 cytokine expression. This study provides an immunological basis for future rational use of IFN-alpha in conjunction with intravesical BCG for bladder cancer immunotherapy.

Metastatic merkel cell tumor to bladder presenting as an encroachment tumor with gross hematuria.

Merkel cell carcinoma is an uncommon and aggressive tumor of neuroendocrine and epithelial origin. A case of metastatic Merkel cell tumor with hematuria secondary to invasion into the bladder is presented. This is the second reported case of metastatic Merkel cell tumor to the bladder and the first published cystoscopic image of such a lesion.

p53-mediated germ cell quality control in spermatogenesis.

Spontaneous germ cell death is a common cellular process in the mammalian testis, although the function of this process during spermatogenesis is unclear. An investigation was undertaken to determine whether p53 serves as a mechanism in germ cell quality control by causing spontaneous germ cell death. Using an annexin V assay, lower levels of spontaneous apoptosis were found in the testes of p53-/- mice compared to p53+/+ mice. Propidium iodine staining revealed that the greatest reduction in apoptosis and the largest increase in cell numbers occurred in the tetraploid germ cell population of p53-/- mice. Microscopic examination of sperm morphology showed an increased percentage of abnormal forms in p53-/- mice. Furthermore, p53-/- mice sired fewer offspring than p53+/+ mice did when both groups were mated with p53+/+ females. These results suggest that p53 mediates spontaneous testicular germ cell apoptosis and failure to remove defective germ cells by this mechanism results in increased percentages of abnormal sperm and reduced fertility. p53-mediated apoptosis may be an effector of cellular proofreading that acts to maintain the cellular integrity of germ cells during spermatogenesis.

Experimental cryptorchidism induces testicular germ cell apoptosis by p53-dependent and -independent pathways in mice.

Cryptorchidism is associated with male infertility: germ cell loss occurs by apoptosis in response to elevated temperature. Since the tumor suppressor p53 is highly expressed in the testis and is known to induce apoptosis, an investigation was undertaken to establish whether heat stress causes p53-mediated germ cell apoptosis. Using a mouse model of experimental unilateral cryptorchidism, it was observed that testicular weight reduction, germ cell loss, and DNA fragmentation all began in the cryptorchid testes on Day 6-7 in wild-type mice. In contrast, these changes were delayed by 3 days in p53-/- mice. These results suggest that abdominal heat stress induces germ cell loss through two apoptotic pathways: a p53-dependent pathway responsible for the initial phase of germ cell apoptosis, and a p53-independent pathway that accounts for subsequent apoptosis.

Heat-induced testicular apoptosis occurs independently of hormonal depletion.

Previous studies have demonstrated that testicular germ cell apoptosis can be induced both by heat stress and by withdrawal of androgens and gonadotrophins. To investigate whether heat-induced germ cell apoptosis occurs independently of the altered levels of hormones that occur with heat exposure, mouse testicular apoptosis was studied using an in vitro system with controlled levels of testosterone, FSH and LH. It was observed that cells underwent apoptosis sooner in the absence of hormones at the same temperature. Apoptosis also occurred earlier at abdominal temperature compared to scrotal temperature with the same hormonal levels. No somatic tissues studied underwent apoptosis at 37 degrees C under the same culture conditions. These results suggest that heat stress may independently activate an apoptotic pathway in the testis, and that hormone deprivation may induce apoptosis via a separate mechanism.

Immediate sexual rehabilitation by simultaneous placement of penile prosthesis in patients undergoing radical prostatectomy: initial results in 50 patients.

OBJECTIVES: To evaluate the results of simultaneous placement of a penile prosthesis with radical prostatectomy. METHODS: From June 1993 to June 1996, 50 men underwent a combination procedure of non-nerve sparing radical retropubic prostatectomy and placement of a penile prosthesis. We performed a retrospective chart review of these patients, examining patient age, preoperative prostate-specific antigen level, Gleason score, operative time, estimated blood loss, analgesic use, length of hospital stay, time until intercourse, and complications. This group was compared with a group of 72 men undergoing radical prostatectomy alone during the same time interval. RESULTS: No significant differences were noted in preoperative patient variables. The mean operative time for prosthesis insertion was 82 minutes, and the mean time to sexual intercourse was 12.7 weeks. No prosthesis infections have occurred, with a mean follow-up of 1.7 years. Four men (8%) have required revision of their inflatable penile prosthesis. There were no significant differences between the combination procedure and radical prostatectomy alone with regard to estimated blood loss, length of hospital stay, or analgesic use. CONCLUSIONS: Simultaneous placement of a penile prosthesis during radical prostatectomy provides early return to sexual function, with no apparent increase in morbidity. Further study will be required to determine the impact of combination surgery on psychosocial adjustment and quality of life.

p53 is associated with the nuclear envelope in mouse testis.

p53 has been postulated to play a role in meiosis as well as in the regulation of germ cell numbers by apoptosis. This study investigated the subcellular localization of p53 in the testis, including conditions known to induce germ cell apoptosis. Western blot analysis showed that p53 was enriched in the nuclear envelope fraction, and confocal microscopy confirmed that p53 was associated with the nuclear envelope of germ cells. Exposure of the testis to heat stress induced translocation of p53 into the nucleus. Nuclear envelope binding provides an optimal site for rapid entry of p53 into the nucleus, where it may act as a DNA-binding protein to induce apoptosis or cell cycle arrest in response to appropriate stimuli. The nuclear envelope sequestration of p53 also provides a framework to understand how mitosis and meiosis in the testis may proceed despite high intracellular concentration of p53.

Temperature-mediated germ cell loss in the testis is associated with altered expression of the cell-cycle regulator p53.

The dependence of spermatogenesis on the relatively cool environment of the scrotum is well known, and recent work has shown that germ cells undergo apoptosis upon exposure to abdominal temperature. p53 is a potent inducer of apoptosis and regulator of cell growth, and is found in high concentrations in the testis. The purpose of this study was to determine whether exposure of the testes to suprascrotal temperature was associated with alterations in testicular p53 expression. Male adult CD-1 mice were rendered unilaterally cryptorchid by surgically fixing one testis to the anterior abdominal wall while leaving the contralateral tests in the scrotum to serve as the euthermic control. p53 expression was evaluated in the cytoplasmic, soluble nuclear, and insoluble fractions by Western blot analysis with the monoclonal p53 antibody pAb240. The weights of the scrotal testes were unchanged over the 15 day study period. The weights of the cryptorchid testes remained stable for 7 days and then decreased by approximately 40% over the next two days. Histological evidence of germ cell loss was evident only after day 7. Altered expression of p53 protein in the cryptorchid testis was noted beginning on day 7, and consisted of the expression of a new 47 kD isoform of p53 in the cytosolic form and a 30 kD isoform in the soluble nuclear fraction. Scrotal testes showed no changes at any time point. These results demonstrate altered expression of the regulatory protein p53 beginning 1-2 days prior to the onset of germ cell loss following experimental unilateral cryptorchidism. Given the known function of p53 as an inducer of apoptotic cell death, these observations suggest a significant role for p53 in temperature-mediated germ cell loss.

Heat stress causes testicular germ cell apoptosis in adult mice.

An investigation was undertaken to determine whether the germ-cell loss associated with exposure of the testis to abdominal temperature occurs by apoptosis. Using an adult-mouse model of experimental unilateral cryptorchidism, it was observed that DNA fragmentation, consistent with apoptosis, was observed on day 6 in the cryptorchid testis, with subsequent loss of testicular weight, histologic evidence of germ-cell loss, and histochemical staining of apoptotic germ cells observed on day 7. Vacuolization of the germinal epithelium and the appearance of multinucleated giant cells was noted synchronously with the onset of germ-cell loss. Histochemical staining for apoptosis was noted most frequently among the primary spermatocytes and round spermatids. These results indicate that the testicular germ-cell loss observed with exposure to abdominal heat stress occurs by apoptosis. Further investigation of the biochemical mechanisms involved in testicular apoptosis may provide strategies to address a variety of male reproductive issues such as contraception and infertility.

Primary lymphoma of the bladder: a unique cystoscopic appearance.

Primary lymphoma of the bladder is a rare disorder that occurs in the fifth to seventh decades, with a female preponderance. Although computed tomographic scanning is the best diagnostic imaging study, cystoscopic biopsy and immunoperoxidase staining are needed to make the diagnosis. Primary lymphoma of the bladder has a good prognosis and responds to a variety of therapeutic modalities. Throughout the literature, authors have described primary lymphoma of the bladder as a submucosal tumor, smooth, nonulcerative, edematous, friable, or even hemorrhagic. We present what we believe to be the first photographic image of the cystoscopic appearance of primary lymphoma of the bladder.

Occult prostate cancer in men with low serum testosterone levels.

OBJECTIVE: To determine the prevalence of occult prostate cancer in men with low serum total testosterone or free testosterone levels. DESIGN: Retrospective analysis of a consecutive series of men. SETTING: Academic teaching hospital. PATIENTS: Seventy-seven men with low total testosterone or free testosterone levels, with normal results of digital rectal examination and prostate-specific antigen (PSA) levels of 4.0 ng/mL or less. The mean age was 58 years. INTERVENTIONS: Sextant prostate needle biopsies with ultrasound guidance. MAIN OUTCOME MEASURES: Results of prostate needle biopsies, transrectal ultrasound, prostate volume, PSA level, PSA density, total and free testosterone levels. RESULTS: Prostate cancer was identified in 14% (11/77) of the entire group and in 10 men (29%) aged 60 years or older. The median age for men with cancer was 64 years. Histologic examination showed Gleason scores of 6 or 7 for all cancers. No significant differences were noted between the cancer and benign groups with regard to PSA level, PSA density, prostate volume, total testosterone level, or free testosterone level. CONCLUSIONS: A high prevalence of biopsy-detectable prostate cancer was identified in men with low total or free testosterone levels despite normal PSA levels and results of digital rectal examination. These data suggest that (1) digital rectal examination and PSA levels are insensitive indicators of prostate cancer in men with low total or free testosterone levels, and (2) PSA levels may be altered by naturally occurring reductions in serum androgen levels.