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Purpose: The contribution of 11-oxygenated androgens to the progression of lethal prostate cancer (PCa) remains unresolved. We hypothesized that evaluating circulating levels of 11-oxygenated androgens, such as the androgen receptor agonist 11-ketotestosterone (11KT), could serve as a potential predictor of the onset of castration-resistant PCa (CRPC)., Methods: We used mass spectrometry to quantify 11-oxygenated androgens in postoperative plasma samples acquired from 145 patients who subsequently received androgen deprivation therapy for biochemical recurrence and achieved castrated testosterone levels. Kaplan-Meier survival analyses and multivariable Cox models were used to investigate relationships between steroids and CRPC., Results: Of 145 patients, 31 developed CRPC with a median time to CRPC of 57 months. 11-oxygenated androgens levels were unaffected by androgen deprivation therapy, which stands in contrast to the observed changes in testosterone and other steroids. 11KT was the most abundant androgen but was not linked to clinical features. Kaplan-Meier analysis revealed that 11KT levels above the median of 273 pg/mL were associated with a shorter time to CRPC ( P = .03). In multivariable analyses, this was supported with an adjusted HR of 2.17 (95% CI, 0.99-4.71; P = .05)., Conclusions: 11KT is a key component of the hormonal profile predictive of earlier onset of CRPC. Enhancing our understanding of the specific role of 11KT in the progression to CRPC could help optimize hormonal therapy for castration-sensitive patients with PCa and CRPC.

Purpose: Adrenal 11-oxygenated androgens may support cancer progression in men with prostate cancer owing to their abundance and androgenic potential. We hypothesized that preoperative circulating levels of 11-oxygenated androgens influence clinical outcomes in men with newly diagnosed localized prostate cancer., Materials and Methods: We studied 1,793 treatment-naïve patients and 155 patients who received preoperative treatment with 5α-reductase inhibitors in the prospective PROCURE cohort, for which preoperative plasma samples were obtained prior to radical prostatectomy. Adrenal 11-oxygenated precursors, potent 11-oxygenated androgens and their metabolites (n=7), were quantified using liquid chromatography-tandem mass spectrometry. Circulating levels were evaluated in relation to prognostic factors, disease-free survival, and metastasis-free survival using multivariable Cox proportional hazards models., Results: At a median follow-up of 93.8 months after surgery, 583 patients experienced biochemical recurrence, 104 developed metastatic disease, and 168 deceased. Higher levels of 11-hydroxytestosterone and 11-ketotestosterone were observed in men with PSA >20 ng/mL and positive nodal status ( P < .05). In multivariable analyses, no significant association between 11-oxygenated androgens and disease-free survival was observed. Adrenal 11β-hydroxyandrostenedione, the predominant androgenic 11-ketotestosterone, and its metabolite 11-ketoandrosterone, modeled as quartiles, were associated with metastasis-free survival ( P = .06, P = .03, and P = .008, respectively). Significant accumulation of 11-oxygenated androgen precursors and bioactive androgens, but reduced metabolite levels, was observed in patients on 5α-reductase inhibitors ( P < .001)., Conclusions: Preoperative circulating 11-oxygenated androgen levels are associated with metastasis-free survival in men with localized prostate cancer undergoing radical prostatectomy and are affected by 5α-reductase inhibitor treatment.

Purpose: Dihydrotestosterone and testosterone are thought to be major contributors of prostate cancer progression and resistance. We studied the modulation of 15 circulating steroids by castration and their association with dihydrotestosterone and testosterone levels., Materials Methods: A total of 116 serum samples were collected from 99 prostate cancer patients and categorized as eugonadal, castration-sensitive prostate cancer, castration-resistant prostate cancer, or castration-resistant prostate cancer under abiraterone acetate. Serum levels of 15 steroids were measured using mass spectrometry and compared between groups using analysis of variance. Intrapatient association of steroid levels and the androgens testosterone and dihydrotestosterone were assessed using Pearson correlation and linear regression., Results: Testosterone, dihydrotestosterone, androstenedione, dehydroepiandrosterone, dehydroepiandrosterone-sulfate, androsterone, androstenediol, estrone, estrone-sulfate, estradiol, and androsterone/3α-diol-3/3α-diol-17-glucuronide levels were significantly decreased in castration-sensitive prostate cancer (castrated) compared to eugonadal patients. Testosterone levels were strongly associated with multiple steroids under eugonadal conditions, whereas they were weakly affected by precursor steroids in castrated patients. By contrast, dihydrotestosterone levels under androgen deprivation therapy were associated with testosterone and the backdoor pathway metabolite androsterone. In castration-resistant prostate cancer patients, levels of androstenedione were significantly associated with testosterone level, while testosterone was the only steroid associated with dihydrotestosterone levels., Conclusions: Androgen deprivation therapy significantly reduces the levels of 13 circulating steroids. Upon androgen deprivation therapy initiation, the backdoor pathway metabolite androsterone are strongly associated with dihydrotestosterone levels. Under castration-resistant prostate cancer conditions, androstenedione was significantly associated with testosterone levels, suggesting the presence of tumor-related circulating androgens in these patients. These results provide further rationale to intensify treatments with androgen receptor axis signaling pathway inhibitors in patients with prostate cancer.

Purpose: Beyond testosterone, several steroids contribute to the activation of the androgen receptor pathway, but their relative contributions to the activation of the androgen receptor signaling axis in patients with castrated prostate cancer remain unknown., Materials and Methods: Serum levels of 9 steroids were measured by mass spectrometry from continuously castrated patients of the PR.7 study (219) and from the PCA24 cohort (116). For each steroid standard curves for dose dependent prostate specific antigen promoter activation were built in castration sensitive (LAPC4) and resistant (VCaP) prostate cancer models. Standard curves were used to determine the androgen receptor activation potency for each steroid measurement from patients in these trials., Results: In LAPC4 and VCaP cells testosterone, dihydrotestosterone and androstenedione induced androgen receptor transcriptional activity, while dehydroepiandrosterone, 5alpha-androstan-3beta,17beta-diol, androstenediol and androsterone stimulated androgen receptor only in VCaP cells. Extragonadal steroids were responsible for 34% (LAPC4) and 88% (VCaP) of the serum total androgen receptor transcriptional activity found in castrated cases. The total androgen receptor transcriptional activity secondary to testosterone, dihydrotestosterone and androstenedione was associated with time to castration resistance in patients from the PR.7 study (HR 2.17, 95% CI 1.12-4.23, p=0.02) in multivariate analysis using the castration sensitive model (LAPC4). Androgen receptor transcriptional activity of extragonadal androstenedione was the only steroid statistically associated with time to castration resistance in univariate analysis (HR 1.89, 95% CI 1.04-3.44, p=0.036)., Conclusions: Extragonadal steroids contribute significantly to the androgen receptor axis activation at castration levels of testosterone in recurrent nonmetastatic prostate cancer and these sustain the development of castration resistance after primary local treatment.

Purpose: Superficial bladder tumors have a high recurrence rate and 10% to 20% of recurrences progress to invasive cancer. Recurrence and progression can best be prevented by nonspecific immunotherapy using intravesical BCG instillations. The NRAMP1 gene has been implicated in susceptibility to infectious and autoimmune diseases, and in response to BCG in murine models. We evaluated the association of 5 NRAMP1 gene polymorphisms with the risk of superficial bladder cancer recurrence and response to immunotherapy., Materials and Methods: The (GT)n, 274 C/T, 469 + 14 G/C, 1465-85 G/A and D534N polymorphisms were tested on peripheral blood DNA of individuals from three cohorts: 37 bladder tumor patients treated by transurethral resection and without recurrence after up to eight years, 67 patients at high risk of recurrence of their bladder tumors and treated with BCG and 109 controls, using restriction fragment length polymorphisms or microsatellite analysis following PCR amplification., Results: The D543N G:A genotype was found more frequently in patients at high risk of recurrence (8 of 67 or 12%) than in controls (2 of 109 or 2%) (p = 0.007). Patients with nonrecurrent tumors showed no difference with controls (1 of 37 or 3%) (p = 1.0). Moreover, in multivariate and survival analyses, both D543N and (GT)n polymorphisms showed association with recurrence-free survival in the cohort of patients at high risk of recurrence, following BCG treatment., Conclusions: These data suggest the implication of the NRAMP1 gene in bladder cancer recurrence and response to BCG immunotherapy.

Purpose: Postoperative nasogastric tube (NGT) use has been shown to increase postoperative morbidity in patients undergoing nonurological abdominal surgery. We examine the omission of NGTs as a method of decreasing postoperative gastrointestinal complications and hospital stay in patients undergoing cystectomy with urinary diversion., Materials and Methods: Between January 1983 and December 2001, 430 patients underwent cystectomy with urinary diversion at our institution. We retrospectively compared patients who received postoperative NGTs with those who did not with regard to gastrointestinal recovery time, gastrointestinal complications and hospital stay., Results: After correcting for confounding factors using ANCOVA the time to first bowel sounds, time to first flatus and the duration of hospitalization were shorter in patients not receiving NGTs (p = 0.006, 0.001 and 0.032, respectively). Omitting NGTs did not increase the risk of ileus, bowel obstruction, wound dehiscence, anastomotic leakage or aspiration pneumonia and it did not result in more frequent postoperative NGT placement., Conclusions: The results of the current study suggest that gastric decompression with NGTs following cystectomy with urinary diversion may prolong gastrointestinal recovery, which may be a factor leading to increased duration of hospitalization. We propose that postoperative NGTs should not be used routinely in the management of cystectomy cases.

Purpose: We retrospectively evaluated the benefit of neoadjuvant androgen deprivation therapy administered before salvage external beam radiation treatment in patients with biochemical failure following retropubic radical prostatectomy (RRP)., Materials and Methods: A total of 81 patients were treated with neoadjuvant androgen deprivation therapy before salvage external beam radiation treatment because of an increased prostate specific antigen (PSA) level following RRP. Preoperative, pathological, postoperative, and pre-salvage treatment parameters and radiation therapy dosage were examined for influence on outcome. Biochemical failures after RRP or salvage external beam radiation treatment were defined as a PSA greater than 0.3 ng/ml on 2 consecutive measurements. Median radiation dose delivered was 60 Gy. Neoadjuvant androgen deprivation therapy consisted of a 3 month injection of a luteinizing hormone releasing hormone analogue. Median followup was 38 months (range 12 to 102) after completion of external beam radiation treatment and 91 months (range 20 to 163) after radical prostatectomy., Results: The actuarial free biochemical failure rates at 3 and 5 years were 75% and 50%, respectively. Two patients (2%) died of prostate cancer. Significant predictors of response to salvage external beam radiation treatment on a univariate analysis were a pre-radiation serum PSA less than 1 ng/ml and a pathological Gleason score less than 7. However, only pre-radiation PSA remained statistically significant on a multivariable analysis., Conclusions: External beam radiation with neoadjuvant androgen deprivation therapy is a viable option for patients with an increasing post-prostatectomy serum PSA. The most powerful predictor of biochemical failure was pre-radiation serum PSA.

Purpose: We establish the relationship among symptom duration, cystometric and cystoscopic findings and potassium stimulation test in patients with interstitial cystitis., Materials and Methods: A retrospective chart review was performed of 189 patients treated at an ambulatory clinic between 1992 and 1998. Urodynamic parameters, potassium stimulation test results and subjective response to treatment were evaluated. Fisher's exact test was used for statistical analysis., Results: Of the 189 patients diagnosed with interstitial cystitis 173 (92%) were female and 16 (8%) were male. The potassium stimulation test was positive in 105 (83%) patients, negative in 16 (13%) and equivocal in 6 (4%). A cystometrogram and potassium stimulation test were done in 118 patients. Bladder capacity averaged 259 ml. in patients with tests potassium positive and negative, while average bladder volume at first sensation to void was 85 ml. and 148 ml. in those with negative and positive tests, respectively. Among the 102 patients with a positive potassium stimulation test 52 had normal cystoscopic findings., Conclusions: The potassium stimulation test is not correlated with either bladder capacity or cystoscopic findings.

Purpose: To date there is little information on the long-term effect of neoadjuvant hormonal therapy on prostate cancer progression. We performed a prospective study to determine whether patients with prostate cancer receiving neoadjuvant hormonal therapy before radical prostatectomy (hormonal therapy group) have a lower risk of prostate specific antigen (PSA) failure than those treated with radical prostatectomy alone (prostatectomy group). We also evaluated whether type of neoadjuvant hormonal therapy and duration were associated with the risk of PSA failure., Materials and Methods: We followed 680 men initially treated for prostate cancer with radical prostatectomy between January 1988 and December 1997 at our university hospital. Of the patients 292 received neoadjuvant hormonal therapy. Median followup was 38 months. Cox regression analysis was used to assess the association between neoadjuvant hormonal therapy and PSA failure (greater than 0.3 ng./ml.) controlling for age, clinical stage, grade, initial PSA and adjuvant therapies., Results: Surgical margins were positive less often in the hormonal therapy (25%) than the prostatectomy (47%) group (p = 0.0001). PSA failure was observed in 163 patients and the 5-year failure rate was 33%. No difference in risk of PSA failure was observed overall between the hormonal therapy and prostatectomy groups (hazards ratio 0.94, 95% confidence interval 0.68 to 1.30). Treatments with antiandrogen alone for any duration, and those combining antiandrogen and luteinizing hormone-releasing hormone analogue for 3 months or less were not associated with improved survival. However, patients receiving combined therapy for more than 3 months had a significantly lower risk of PSA failure than those treated with radical prostatectomy alone (hazards ratio 0.52, 95% confidence interval 0.29 to 0.93)., Conclusions: Prolonged neoadjuvant hormonal therapy combining antiandrogen and luteinizing hormone-releasing hormone analogue may improve disease-free survival after radical prostatectomy.