Change in prostate specific antigen following androgen stimulation is an independent predictor of prostate cancer diagnosis.

PURPOSE: We tested the hypothesis that a single exogenous androgen injection in men with low prostate specific antigen would provoke a differential prostate specific antigen response that would correlate with the presence and volume of cancer at biopsy. MATERIALS AND METHODS: Following institutional review board approval 40 men with prostate specific antigen between 2.5 and 4.0 ng/ml were given 1 intramuscular injection of 400 mg testosterone cypionate at the start of the study. Prostate specific antigen and early morning serum testosterone were measured at baseline, 48 hours, and weeks 1, 2 and 4. All men underwent 12-core transrectal ultrasound guided biopsy at week 4. RESULTS: Of the 40 men 18 (45%) were diagnosed with prostate cancer. The mean change in prostate specific antigen from baseline to 4 weeks was 3.1 to 3.4 ng/ml (9.7%) in men found to have benign findings on biopsy compared to a mean increase of 2.9 to 3.8 ng/ml (29%) in those with prostate cancer (p = 0.006). The change in prostate specific antigen following androgen stimulation was significantly associated with the percent of tissue involved with cancer and it was an independent predictor of cancer diagnosis on univariate and multivariate analysis. CONCLUSIONS: An increase in prostate specific antigen following androgen stimulation in men with prostate specific antigen between 2.5 and 4.0 ng/ml was highly predictive of the subsequent diagnosis of prostate cancer and it correlated with disease volume. If these findings are corroborated, prostate specific antigen provocation may become an important strategy to identify men at risk for harboring prostate cancer and minimize the number undergoing unnecessary biopsies.

The use of histone deacetylase inhibitor FK228 and DNA hypomethylation agent 5-azacytidine in human bladder cancer therapy.

The long-term disease-free survival in patients with metastatic transitional cell carcinoma (TCC) is still considerably low. Novel chemotherapeutic agents are needed to decrease the morbidity and mortality of TCC. In this study, we have evaluated several epigenetic modifiers for their therapeutic application in bladder cancer. Both histone deacetylase inhibitors (FK228, TSA) and DNA hypomethylating agent (5-Azacytidine) were tested using in vitro assays such as cell viability, cell cycle analysis and western blot to determine their mechanisms of action. Drug combination experiments were also designed to study any additive or synergistic effects of these agents. In addition, two bladder cancer xenograft models (one subcutaneous and one orthotopic) were employed to assess the therapeutic efficacy of these agents in vivo. Three agents exhibited various growth inhibitory effects on 5 different TCC cell lines in a dose- and time-dependent manner. In addition to G2/M cell cycle arrest, FK228 is more potent in inducting apoptosis than the two other single agents, and combination of both FK228 and 5-Aza further enhances this effect. p21 induction is closely associated with FK228 or TSA but not 5-Aza, which is mediated via p53-independent pathway. Consistent with in vitro results, FK228 exhibited a significant in vivo growth inhibition of TCC tumor in both subcutaneous and orthotopic xenograft models. FK228 is a potent chemotherapeutic agent for TCC in vivo with minimal undesirable side effects. The elevated p21 level mediated via p53 independent pathway is a hallmark of FK228 mechanism of action.

Contemporary techniques and safety of cardiovascular procedures in the surgical management of renal cell carcinoma with tumor thrombus.

OBJECTIVE: Renal cell carcinomas often form venous thrombi that extend into the vena cava. Frequently, cardiovascular consultation is necessary for complete surgical excision. We sought to investigate the risk factors, surgical techniques, and outcomes of patients treated for renal cell carcinoma with venous extension. METHODS: We reviewed the records of 46 consecutive patients who underwent surgical management of renal cell carcinoma with venous extension between 1991 and 2005. Data on patient history, staging, surgical techniques, morbidity, and survival were analyzed. RESULTS: There were 29 men and 17 women with a mean age of 60.2 +/- 12.0 years. Twenty-five (54%) procedures were completed with cardiovascular assistance. Nephrectomy was performed in 44 (96%) cases. Three (7%) patients underwent right heart venovenous bypass, and 2 (5%) patients underwent cardiopulmonary bypass with circulatory arrest. Fourteen (32%) patients had perioperative complications, including 1 (2%) perioperative death. Patients who required cardiovascular procedures (inferior vena cava clamping, right heart venovenous bypass, and cardiopulmonary bypass with circulatory arrest) had higher risks of perioperative complications (P < .02). The 1-, 2-, and 5-year overall survival rates were 78%, 69%, and 56%. CONCLUSIONS: This large series demonstrates that aggressive treatment of renal cell carcinoma with venous thrombus provides favorable outcomes. Our 5-year survival is among the highest of recent reviews, and our perioperative morbidity and mortality rates are comparable with those of other series. Tumors that require cardiovascular procedures are associated with increased complications when compared with radical nephrectomy and thrombectomy alone. Nevertheless, this aggressive treatment approach offers encouraging patient survival.

Prognostic model of event-free survival for patients with androgen-independent prostate carcinoma.

BACKGROUND: The current study was conducted to develop a prognostic model of event-free survival (EFS) in men with androgen-independent prostate carcinoma (AIPC). METHODS: Data from 160 patients diagnosed with AIPC between 1989-2002 were reviewed. No patient had received cytotoxic chemotherapy. A univariate Cox proportional hazards model identified significant predictors of EFS. Recursive partitioning analysis divided these significant variables into prognostic risk groups. The final prognostic model was tested with a Cox proportional hazards model. RESULTS: The final prognostic risk model included the presence of metastatic disease at the time of androgen-independent disease progression (P = 0.040), time to prostate-specific antigen (PSA) recurrence (P = 0.043), and PSA doubling time (P < 0.01). Three highly independent risk groups were identified. The observed median EFSs were 6.1 months (95% confidence interval [95= CI], 3.4-8.8 months), 33.6 months (95= CI, 25.3-41.9 months), and 96.1 months (95= CI, 57.9-134.3 months) for the low-risk, intermediate-risk, and high-risk groups, respectively. Each risk group was found to be independently predictive of EFS (P < 0.01). Patients who died of prostate carcinoma experienced significantly more clinical events than those who died of other causes (P < 0.01). CONCLUSIONS: The prognostic model in the current study stratified patients into three highly significant and independent risk groups for EFS. A detailed PSA history and knowledge of metastatic disease are sufficient to risk-stratify patients with AIPC. One very unique aspect of this model was that it was developed from a patient cohort that never received chemotherapy.

The natural history of androgen independent prostate cancer.

PURPOSE: We describe the natural history of androgen independent prostate cancer (AIPC) in the modern prostate specific antigen (PSA) era. MATERIALS AND METHODS: Data from 160 patients diagnosed with AIPC between 1989 and 2002 were reviewed. No patient had received cytotoxic chemotherapy. Univariate and multivariate proportional hazards models were constructed to identify significant risk factors for cancer specific survival. Recursive partitioning analysis stratified patients into prognostic risk groupings. The types and frequencies of cancer specific complications per risk grouping were compared. RESULTS: The final prognostic risk model included nadir PSA on androgen deprivation therapy (p = 0.023), time to PSA recurrence (p = 0.006) and prostate specific antigen doubling time (p <0.01). Three highly independent risk groupings were identified. The observed median cancer specific survivals were 14.0 months (95% CI, 8.3-19.8), 38.4 months (95% CI, 26.9-49.9) and 89.1 months (95% CI, 69.0-109.2) for low, intermediate and high risk groupings, respectively (p <0.001). Patients in the low risk grouping experienced significantly fewer cancer specific complications (p = 0.003). CONCLUSIONS: This prognostic model stratified patients into 3 highly significant and independent risk groupings. A detailed PSA history alone is sufficient to risk stratify patients with AIPC.

Prostate-specific antigen doubling time predicts response to deferred antiandrogen therapy in men with androgen-independent prostate cancer.

OBJECTIVES: To identify the pretreatment variables that are predictive of response and the duration of response to deferred antiandrogen therapy in men with androgen-independent prostate cancer (AIPC). METHODS: A total of 375 patients receiving androgen deprivation therapy for advanced prostate cancer between 1977 and 2002 had medical records available for retrospective review. Of these 375 patients, 163 were diagnosed with AIPC. The inclusion criteria included (1) diagnosis of AIPC and (2) treatment with deferred antiandrogen therapy. AIPC was biochemically defined as two consecutive rises in the prostate-specific antigen (PSA) level during androgen deprivation therapy. The treatment response to deferred antiandrogen therapy was defined as a 50% or greater decline in the pretreatment PSA level. The prognostic value of various pretreatment parameters was determined with the appropriate statistical methods and tested with a Cox proportional hazards model. RESULTS: Of the 163 patients with AIPC, 36 were treated with deferred antiandrogen therapy. Of these 36 patients, 12 (33.3%) experienced a PSA response. The median PSA failure-free survival was 9.0 months (95% confidence interval 5.2 to 12.9). The only pretreatment variable predictive of a PSA response was the PSA doubling time (PSADT). The mean PSADT in responders was 12.7 months versus 7.5 months in nonresponders (P = 0.037). Moreover, PSADT was the only statistically significant variable on univariate analysis of PSA failure-free survival in responders (hazard ratio 0.202, 95% confidence interval 0.041 to 0.990, P = 0.049). No statistically significant difference was found in cancer-specific survival between responders and nonresponders (P = 0.1501). CONCLUSIONS: The PSADT predicted both the response and the duration of the response to deferred antiandrogen therapy in patients diagnosed with AIPC.

Nadir prostate-specific antigen as a predictor of progression to androgen-independent prostate cancer.

OBJECTIVES: To determine the value of the before and after treatment level of prostate-specific antigen (PSA) to predict the time to androgen-independent progression (AIP) in patients with advanced prostate cancer who received androgen-deprivation therapy (ADT) at the time of recurrence or progression. METHODS: The records of 153 patients with advanced or metastatic prostate cancer who were treated with ADT were retrospectively reviewed. Fifty-six percent of the patients were initially treated with ADT. In the remainder, ADT was started at progression and/or failure. AIP was defined as two consecutive elevations of serum PSA above the nadir value by any threshold. Kaplan-Meier and multiple logistic regression analyses were used to determine the potential predictors of AIP. RESULTS: The median duration of the PSA response was 24 months. The most important predictors of the time to AIP were the initial Gleason grade and the nadir PSA level after the initiation of ADT. The odds ratio of having a response greater than 24 months was 15-times higher in patients achieving an undetectable serum PSA level versus those who did not. For each point increase in the Gleason sum, patients had a five times higher chance of progressing to AIP in 24 months or less. CONCLUSIONS: The ability to achieve an undetectable nadir PSA level and the initial Gleason grade are significant predictors of the time to AIP in men treated with ADT for metastatic and advanced prostate cancer.

Molecular imaging in prostate cancer.

Prostate cancer (PCa) is the most common non-cutaneous malignancy in men. New ways to diagnose this cancer in its early stages are needed. Unique genetic and biochemical changes in the cell pave the way for tumors to grow and metastasize. Novel imaging approaches attempt to detect pathological processes in cancer cells at the molecular level. This has led to the establishment and development of the field of molecular imaging. Positron emission tomography (PET), magnetic resonance spectroscopic imaging (MRSI), magnetic resonance imaging (MRI), and radiolabeled antibodies are a few of the modalities that can detect abnormal tumor metabolic processes in the clinical setting. Other imaging techniques are still in their early phase of development but hold promise for the future, including bioluminescence imaging (BLI), measurement of tumor oxygenation, and measurement of uptake of iodine by tumors. These techniques are non-invasive and can spare the patient undue morbidity, while potentially providing early diagnosis, accurate follow-up and, finally, valuable prognostic information.

The effect of combined androgen ablation on the expression of alpha1A-adrenergic receptor in the human prostate.

BACKGROUND: This study was designed to determine whether androgen ablation (AA) affects expression of alpha1A-adrenergic receptors (AR) in the human prostate. METHODS: Concentrations of alpha1A-AR mRNA were determined in benign prostatic tissue from patients undergoing surgery after a 3-month course of combined androgen ablation (CAD) therapy with leuprolide and flutamide, and a matched group of untreated patients with clinical BPH. RESULTS: Mean concentration of alpha1A-AR in the AA group was 0.53 +/- 0.53 SD (range 0.026-1.55) attomol/mg. Control mean was 0.29 +/- 0.22 SD (range 0.02-0.69; P = 0.3, two tailed t-test). Tissue composition did not statistically differ between the two groups. Expression of alpha1A-AR correlated with concentration of smooth muscle myosin heavy chain (SMMHC) (r = 0.84, P = 0.001). No significant differences were observed after adjusting for SMMHC content. CONCLUSIONS: A 3-month course of CAD does not appear to have a significant effect on alpha1A-AR mRNA expression in the human prostate.