S.B. Malkowicz

Critical analysis of the ability of the endorectal coil magnetic resonance imaging scan to predict pathologic stage, margin status, and postoperative prostate-specific antigen failure in patients with clinically organ-confined prostate cancer.

PURPOSE To determine whether there is a role for endorectal coil magnetic resonance imaging (erMRI) in the prediction of pathologic stage, margin status, and/or postoperative prostate-specific antigen (PSA) failure in patients with clinically organ-confined prostate cancer. PATIENTS AND METHODS Using erMRI, the radiologic-pathologic correlation of extracapsular extension (ECE) and seminal vesicle invasion (SVI) was evaluated in 445 surgically managed patients. Logistic regression multivariable analysis was applied to the clinical stage, PSA, biopsy Gleason grade, and erMRI findings to assess the outcomes of ECE, SVI, positive surgical margins (PSM), and postoperative PSA failure. RESULTS The accuracy of erMRI to predict for ECE and SVI numerically decreased with both increasing PSA and biopsy Gleason score because of the increasing false-negative scans in cases of microscopic transcapsular or seminal vesicle disease. Of patients who could not be categorized into low or high risk for postoperative PSA failure on the basis of clinical stage, preoperative PSA, and biopsy Gleason score, a negative or positive erMRI for ECE or SVI stratified these patients into groups with a 78% versus 21% (P < .0001) 3-year rate of actuarial freedom from PSA failure. In this subgroup, the overall accuracy of the erMRI was 70% +/- 6% and 94% +/- 2% for ECE and SVI, respectively. The most significant predictor on multivariable analysis of PSM was the erMRI finding of ECE (P = .0001). CONCLUSION This initial report suggests that a preoperative erMRI can identify clinically organ-confined prostate cancer patients at high risk for having ECE, SVI, and PSM that otherwise would be missed on the basis of the clinical stage, preoperative PSA, and biopsy Gleason score. Confirmatory studies are needed.

Prostate-specific antigen failure despite pathologically organ-confined and margin-negative prostate cancer: the basis for an adjuvant therapy trial.

PURPOSE A multivariable analysis to evaluate the potential clinical and pathologic factors that predict for early biochemical failure in patients with pathologically organ-confined and margin-negative disease was performed to define patients who may benefit from adjuvant therapy. PATIENTS AND METHODS Three hundred forty-one prostate cancer patients treated with a radical retropubic prostatectomy between January 1989 and June 1995 and found to have pathologically organ-confined and margin-negative disease comprised the study population. A logistic regression multivariable analysis to evaluate the predictive value of the preoperative prostate-specific antigen (PSA) level, pathologic (prostatectomy) Gleason score, and pathologic stage on PSA failure occurring during the first postoperative year was performed. RESULTS Predictors of PSA failure during the first postoperative year in patients with pathologically organ-confined disease included pathologic Gleason score > or = 7 (P = .0007) and preoperative PSA level greater than 10 (P < .0001). Corresponding 3-year freedom-from-PSA-failure rates for these pathologic organ-confined patients with both, one, or neither of these factors were 60%, 75% to 84%, and 95%, respectively (P < .0001). CONCLUSION Prostate cancer patients with pathologically organ-confined and margin-negative disease and a preoperative PSA level greater than 10 ng/mL or a pathologic Gleason score > or = 7 have significant decrements in short-term PSA-failure-free survival. Therefore, these patients should be considered for adjuvant therapy in the setting of a phase III clinical trial.

Clinical characteristics of prostate cancer in African Americans, American whites, and Senegalese men☆

OBJECTIVES To describe the clinical features of prostate cancer in Senegalese men and compare these features with those found in African-American and white American men. METHODS We identified an unselected series of 121 patients with prostate cancer diagnosed at two hospitals in Dakar, Senegal between 1997 and 2002. Medical record abstractions were undertaken to evaluate the prostate tumor characteristics, patient age at diagnosis, prostate-specific antigen (PSA) levels, and reason for referral. In addition, these characteristics were compared with a sample of 455 U.S. white men and 60 African-American men with prostate cancer who were studied as part of a prostate cancer case-control study. RESULTS Senegalese men had a significantly worse tumor stage than Americans (41.3% versus 18.8%, P <0.001), a significantly worse mean PSA level at diagnosis (mean PSA 72.7 ng/mL versus 9.0 ng/mL in Americans; P <0.001), and were diagnosed at a significantly later age than U.S. men (69 years versus 61 years, P <0.001). U.S. men were most likely to be diagnosed with prostate cancer after an elevated PSA test, and Senegalese men were most often diagnosed after presenting for prostate-related symptoms. CONCLUSIONS These observations are not unexpected given the differences in the patterns of prostate cancer screening and health care in the United States compared with Senegal. However, our data provide descriptive information about the characteristics of prostate cancer diagnosed in Senegal and highlight differences in the characteristics and detection of these tumors across populations with very different healthcare systems.

Does Race Affect Postoperative Outcomes in Patients With Low-Risk Prostate Cancer Who Undergo Radical Prostatectomy?

OBJECTIVES To assess the magnitude of racial disparities in prostate cancer outcomes following radical prostatectomy for low-risk prostate cancer. METHODS We retrospectively reviewed our database of 2407 patients who under went radical prostatectomy and isolated 2 cohorts of patients with low-risk prostate cancer. Cohort 1 was defined using liberal criteria, and cohort 2 was isolated using more stringent criteria. We then studied pre- and postoperative parameters to discern any racial differences in these 2 groups. Statistical analyses, including log-rank, chi(2), and Fishers exact analyses, were used to ascertain the significance of such differences. RESULTS Preoperatively, no significant differences were found between the white and African-American patients with regard to age at diagnosis, mean prostate-specific antigen, median follow-up, or percentage of involved cores on prostate biopsy. African-American patients in cohort 1 had a greater mean body mass index than did white patients (26.9 vs 27.8, P = .026). The analysis of postoperative data demonstrated no significant difference between white and African-American patients in the risk of biochemical failure, extraprostatic extension, seminal vesicle involvement, positive surgical margins, tumor volume, or risk of disease upgrading. African-American patients in cohort 2 demonstrated greater all-cause mortality compared with their white counterparts (9.4% vs 3.1%, P = .027). CONCLUSIONS In patients with low-risk prostate cancer treated with radical prostatectomy, there exist no significant differences in surrogate measures of disease control, risk of disease upgrading, estimated tumor volume, or recurrence-free survival between whites and African-Americans.

Calculated prostate cancer volume greater than 4.0 cm3 identifies patients with localized prostate cancer who have a poor prognosis following radical prostatectomy or external-beam radiation therapy.

PURPOSE Patients with palpable extraprostatic disease (T3) have a poor prostate-specific antigen (PSA) failure-free (bNED) survival rate after radical prostatectomy (RP) or external-beam radiation therapy (RT). This study was performed to validate or refute the prognostic value of the previously defined calculated prostate cancer volume (cV(Ca)). PATIENTS AND METHODS For patients with clinically localized disease (T1c,2), a Cox regression multivariable analysis was used to assess the ability of the cV(Ca) value to predict time to posttherapy PSA failure following RP or RT. RESULTS The cV(Ca) value was a significant predictor (P < or = .0005) of time to posttherapy PSA failure in both an RP and RT data set independent of the one used to derive the cV(Ca)-based clinical staging system. In both RP- and RT-managed patients, estimates of 3-year bNED survival were not statistically different for patients with either T1c,2 disease and a cV(Ca) greater than 4.0 cm3 (RP, 27%; RT, 18%) or T3 disease (RP, 37%; RT, 34%). Despite pathologic T2 disease, the 3-year estimate of bNED survival was at most 51% in RP-managed patients with T1c,2 disease and cV(Ca) greater than 4.0 cm3. CONCLUSION A cV(Ca) greater than 4.0 cm3 identified patients with T1c.2 disease whose bNED survival was poor after RT or RP despite pathologic T2 disease that suggests the presence of occult micrometastatic disease in many of these patients. Prospective randomized trials to evaluate the impact on survival of adjuvant systemic therapy in these high-risk patients are justified.

Association of prostate cancer family history with histopathological and clinical characteristics of prostate tumors.

Genetic factors may be used not only to assess risk of prostate cancer development but also to evaluate prostate cancer outcomes including clinical prognosis, treatment methods, and treatment response. To assess the role of family history on prostate cancer outcomes, we evaluated tumor characteristics, diagnostic precursors and biochemical (prostate specific antigen) relapse‐free survival in men with and without a family history of prostate cancer. A total of 684 prostate cancer cases unselected for family history were identified from an ongoing hospital based prostate cancer case‐control study between 1995 and 2002. Self‐reported family history was grouped within the following categories: none, any, moderate (one affected first or second degree relative) and high (2 or more affected first or second degree relatives). We further considered groups defined by early (before age 60) and late (after age 60) age at diagnosis. Overall, tumor stage was not significantly associated with any (odds ratio [OR] = 1.43 95% confidence interval [CI] = 1.00–2.05) or moderate (OR = 1.48, 95% CI = 1.0‐2.19) family histories. Men diagnosed before age 60, however, had higher tumor stages if they had any (OR = 2.19, 95% CI = 1.28–3.75) or moderate (OR = 2.15, 95% CI = 1.2–3.9) family histories. Men diagnosed after age 60 with any family history were significantly more likely to experience biochemical (PSA) failure (Hazard ratio [HR] = 2.60, 95%CI = 1.08–6.25). Men with any and moderate family histories were at significantly increased risk of biochemical failure (HR = 2.49, 95%CI = 1.25–4.95 and HR = 2.46, 95% CI = 1.17–5.16, respectively). Moderate family history increased probability of seminal vesicle invasion (OR = 2.14, 95%CI = 1.06–4.34). Our results suggest that a family history of prostate cancer may be associated with predictors of clinical outcome in prostate cancer cases unselected for a family history of prostate cancer.

Ectopic expression of the TERE1 (UBIAD1) protein inhibits growth of renal clear cell carcinoma cells: Altered metabolic phenotype associated with reactive oxygen species, nitric oxide and SXR target genes involved in cholesterol and lipid metabolism

Current studies of the TERE1 (UBIAD1) protein emphasize its multifactorial influence on the cell, in part due to its broad sub-cellular distribution to mitochondria, endoplasmic reticulum and golgi. However, the profound effects of TERE1 relate to its prenyltransferase activity for synthesis of the bioactive quinones menaquinone and COQ10. Menaquinone (aka, vitamin K-2) serves multiple roles: as a carrier in mitochondrial electron transport, as a ligand for SXR nuclear hormone receptor activation, as a redox modulator, and as an alkylator of cellular targets. We initially described the TERE1 (UBIAD1) protein as a tumor suppressor based upon reduced expression in urological cancer specimens and the inhibition of growth of tumor cell lines/xenografts upon ectopic expression. To extend this potential tumor suppressor role for the TERE1 protein to renal cell carcinoma (RCC), we applied TERE1 immunohistochemistry to a TMA panel of 28 RCC lesions and determined that in 57% of RCC lesions, TERE1 expression was reduced (36%) or absent (21%). Ectopic TERE1 expression caused an 80% decrease in growth of Caki-1 and Caki-2 cell lines, a significantly decreased colony formation, and increased caspase 3/7 activity in a panel of RCC cell lines. Furthermore, TERE1 expression increased mitochondrial oxygen consumption and hydrogen production, oxidative stress and NO production. Based on the elevated cholesterol and altered metabolic phenotype of RCC, we also examined the effects of TERE1 and the interacting protein TBL2 on cellular cholesterol. Ectopic TERE1 or TBL2 expression in Caki-1, Caki-2 and HEK 293 cells reduced cholesterol by up to 40%. RT-PCR analysis determined that TERE1 activated several SXR targets known to regulate lipid metabolism, consistent with predictions based on its role in menaquinone synthesis. Loss of TERE1 may contribute to the altered lipid metabolic phenotype associated with progression in RCC via an uncoupling of ROS/RNS and SXR signaling from apoptosis by elevation of cholesterol.

KIAA1096, a gene on chromosome 1q, is amplified and overexpressed in bladder cancer.

Chromosomal gain on 1q23-24 is a cytogenetic finding found in approximately 30% of bladder tumors. Currently, no defined or candidate tumor-associated genes from this region have been identified. The objective of this study was to identify and quantitate the expression of putative cancer genes located at this chromosome locus in normal urothelium, superficial, and muscle invasive bladder tumors. We examined both normal and bladder cancer tissue specimens (N = 40-80 RNA, DNA, and protein) by semiquantitative RT/PCR, genomic PCR, and by Western blotting. The KIAA1096 gene is located at 1q23-24 with no overexpression or amplification in normal urothelium, but was significantly upregulated in 30% of tumors (P = 0.0001). There was a trend towards increased expression in invasive compared to superficial lesions (P = 0.06). A significant increase in gene copy was also found in a 38% of TCC of the bladder compared to normal bladder mucosa or peripheral blood lymphocytes. Immunohistochemistry (IHC) demonstrated KIAA1096 expression in nonmalignant bladder mucosa tissue but apparent upregulation in invasive transitional cell carcinoma. Two other genes, CH1 and RGS5, which are situated in the same region of chromosome 1q, demonstrated disparate patterns of expression. In summary, KIAA1096 is a gene situated at 1q23-24, which demonstrated a pattern of RNA and DNA expression consistent with the 38% expression of cytogenetic amplification noted on previous studies. This gene may, therefore, be a putative marker for this cytogenetic phenomenon and provide an opportunity to evaluate the clinical significance of previous cytogenetic findings.

Investigating the clinical utility of the percent of positive prostate biopsies in predicting PSA outcome following local therapy for patients with clinically localized prostate cancer

The clinical utility of the percent of positive prostate biopsies in predicting prostate-specific antigen (PSA) outcome following radical prostatectomy (RP), or external beam radiation therapy (RT), for men with PSA detected, or clinically palpable prostate cancer was investigated. After accounting for the established prognostic significance of the PSA level, biopsy Gleason score and the clinical T-stage, the percent of positive prostate biopsies added clinically significant information regarding time to PSA failure following RP. These findings were validated in the intermediate risk patients using an independent surgical and radiation data set.

Biochemical Outcome After Radical Prostatectomy, External Beam Radiation Therapy, or Interstitial Radiation Therapy for Clinically Localized Prostate Cancer

CONTEXT Interstitial radiation (implant) therapy is used to treat clinically localized adenocarcinoma of the prostate, but how it compares with other treatments is not known. OBJECTIVE To estimate control of prostate-specific antigen (PSA) after radical prostatectomy (RP), external beam radiation (RT), or implant with or without neoadjuvant androgen deprivation therapy in patients with clinically localized prostate cancer. DESIGN Retrospective cohort study of outcome data compared using Cox regression multivariable analyses. SETTING AND PATIENTS A total of 1872 men treated between January 1989 and October 1997 with an RP (n = 888) or implant with or without neoadjuvant androgen deprivation therapy (n = 218) at the Hospital of the University of Pennsylvania, Philadelphia, or RT (n = 766) at the Joint Center for Radiation Therapy, Boston, Mass, were enrolled. MAIN OUTCOME MEASURE Actuarial freedom from PSA failure (defined as PSA outcome). RESULTS The relative risk (RR) of PSA failure in low-risk patients (stage T1c, T2a and PSA level < or =10 ng/mL and Gleason score < or =6) treated using RT, implant plus androgen deprivation therapy, or implant therapy was 1.1 (95% confidence interval [CI], 0.5-2.7), 0.5 (95% CI, 0.1-1.9), and 1.1 (95% CI, 0.3-3.6), respectively, compared with those patients treated with RP. The RRs of PSA failure in the intermediate-risk patients (stage T2b or Gleason score of 7 or PSA level >10 and < or =20 ng/mL) and high-risk patients (stage T2c or PSA level >20 ng/mL or Gleason score > or =8) treated with implant compared with RP were 3.1 (95% CI, 1.5-6.1) and 3.0 (95% CI, 1.8-5.0), respectively. The addition of androgen deprivation to implant therapy did not improve PSA outcome in high-risk patients but resulted in a PSA outcome that was not statistically different compared with the results obtained using RP or RT in intermediate-risk patients. These results were unchanged when patients were stratified using the traditional rankings of biopsy Gleason scores of 2 through 4 vs 5 through 6 vs 7 vs 8 through 10. CONCLUSIONS Low-risk patients had estimates of 5-year PSA outcome after treatment with RP, RT, or implant with or without neoadjuvant androgen deprivation that were not statistically different, whereas intermediate- and high-risk patients treated with RP or RT did better then those treated by implant. Prospective randomized trials are needed to verify these findings.