The evolution of chemotherapy for the treatment of prostate cancer.

Chemotherapy has been explored as a treatment option for metastatic prostate cancer since the early 1980s. Docetaxel, a taxane chemotherapeutic, was approved for the treatment of men with metastatic castration-resistant prostate cancer in 2004, and is now standard of care for late stage disease. Recent clinical studies demonstrated that patients with metastatic castration-sensitive disease, and possibly those with high-risk localized prostate cancer also benefit from docetaxel administration, expanding the role of chemotherapy in the prostate cancer treatment landscape. Another taxane, cabazitaxel, is approved for post-docetaxel metastatic castration-resistant prostate cancer. Taxanes and other chemotherapeutics, such as carboplatin, are now being tested in combination regimens. This review presents an outline of recent and ongoing clinical studies assessing docetaxel and its derivative cabazitaxel at different stages of the disease, and in various combinations with other agents. We summarize current knowledge on biomarkers predictive of response to chemotherapy, which may in future be used to guide individualized treatment decisions.

Updated postoperative nomogram incorporating the number of positive lymph nodes to predict disease recurrence following radical prostatectomy.

BACKGROUND: A significant number of patients with minimal lymph node disease at radical prostatectomy (RP) and pelvic lymph node dissection (PLND) have better than expected long-term outcomes. We explored whether stratification by number of positive nodes enhances our institutional prediction model for biochemical recurrence after RP. METHODS: A total of 7789 patients underwent RP and pelvic lymph node dissection from 1995 to 2012 at a tertiary referral center. We compared two recurrence prediction models: one incorporated lymph node invasion and the other tracked the number of positive nodes. Existing and updated models' discrimination was assessed using Harrell's c-index and calibration. The 10-fold cross-validation was performed to correct for model overfitting. RESULTS: Of the 491 patients (6.3%) harboring nodal disease, 387 (5.0%) had 1-2 positive nodes and 104 (1.3%) had ⩾3 positive nodes. Data on number of positive nodes did not improve the c-index for the cohort as a whole. When we assessed discrimination for node-positive patients only, c-index for the model with number of positive nodes was 0.01 (95% confidence interval 0.001-0.024) higher than the model with lymph node invasion. Illustrative examples were provided by reclassification tables using number of positive lymph nodes. For instance, 40 of 7789 patients would be reclassified with a cutoff point of 50% for biochemical recurrence at 1 year, and 36 of 7789 patients would be reclassified with a cutoff point of 40% for biochemical recurrence at 10 years. CONCLUSIONS: Stratification by number of positive lymph nodes provided additional discriminative ability for evaluating risk in node-positive patients. Pending external validation, this model could be used for patient counseling and clinical trial stratification in this subpopulation.

Periprostatic adipose inflammation is associated with high-grade prostate cancer.

BACKGROUND: Obesity, a cause of subclinical inflammation, is associated with increased risk of high-grade prostate cancer (PC) and poor outcomes. Whether inflammation occurs in periprostatic white adipose tissue (WAT), and contributes to the negative impact of obesity on PC aggressiveness, is unknown. METHODS: In a single-center, cross-sectional design, men with newly diagnosed PC undergoing radical prostatectomy were eligible for study participation. The primary objective was to examine the prevalence of periprostatic WAT inflammation defined by the presence of crown-like structures (CLS-P) as detected by CD68 immunohistochemistry. Secondary objectives were to explore the clinical and systemic correlates of periprostatic WAT inflammation. Tumor characteristics and host factors including BMI, adipocyte diameter, and circulating levels of lipids, adipokines, and other metabolic factors were measured. Wilcoxon rank-sum, Chi-square, or Fisher's exact tests, and generalized linear regression were used to examine the association between WAT inflammation and tumor and host characteristics. RESULTS: Periprostatic fat was collected from 169 men (median age 62 years; median BMI 28.3). Periprostatic WAT inflammation was identified in 49.7% of patients and associated with higher BMI (P=0.02), larger adipocyte size (P=0.004) and Gleason grade groups IV/V tumors (P=0.02). The relationship between WAT inflammation and high Gleason grade remained significant after adjusting for BMI (P=0.04). WAT inflammation correlated with higher circulating levels of insulin, triglycerides, and leptin/adiponectin ratio, and lower high density lipoprotein cholesterol, compared to those without WAT inflammation (P's <0.05). CONCLUSION: Periprostatic WAT inflammation is common in this cohort of men with PC and is associated with high-grade PC.

Clinical characteristics and biopsy specimen features in African-American and white men without prostate cancer.

BACKGROUND: The reported incidence of prostate cancer is higher among African-American men than among white men. We conducted a study of African-American and white men without prostate cancer to determine whether clinical and histologic findings might be associated with racial differences in serum prostate-specific antigen (PSA) levels. METHODS: From January 1990 through March 1997, 493 (59.5%) of 829 African-American men and 736 (74.1%) of 993 white men who had elevated serum PSA levels (> or = 4.0 ng/mL) and/or abnormal digital rectal examinations and who underwent transrectal ultrasound-guided prostate biopsies were found to be without prostate cancer. Also reviewed were patients' age and race, indication for biopsy, histologic features of the prostate biopsy specimen, ultrasound-measured prostate volume, PSA density (i.e., the PSA level divided by the prostate volume), and (in some cases) serum testosterone levels. RESULTS: Among these men without prostate cancer, there were no statistically significant differences by race in the ages of the patients, their prostate volumes, or their serum testosterone levels; however, the mean serum PSA levels and PSA densities were significantly higher in African-American men than in white men (two-sided P values of .00003 and .000009, respectively). A higher proportion of African-American men than white men had inflammation in their prostate biopsy specimen, and men of both races with prostate inflammation had higher PSA values than those without inflammation. African-American men without inflammation had higher PSA values than white men without inflammation. CONCLUSIONS: In this study, African-American men without histologic evidence of prostate cancer had significantly higher PSA levels and PSA densities than similarly aged white men. This finding was not accounted for by racial differences in patients' age, serum testosterone level, or prostate volume.

A preoperative nomogram for disease recurrence following radical prostatectomy for prostate cancer.

BACKGROUND: Few published studies have combined clinical prognostic factors into risk profiles that can be used to predict the likelihood of recurrence or metastatic progression in patients following treatment of prostate cancer. We developed a nomogram that allows prediction of disease recurrence through use of preoperative clinical factors for patients with clinically localized prostate cancer who are candidates for treatment with a radical prostatectomy. METHODS: By use of Cox proportional hazards regression analysis, we modeled the clinical data and disease follow-up for 983 men with clinically localized prostate cancer whom we intended to treat with a radical prostatectomy. Clinical data included pretreatment serum prostate-specific antigen levels, biopsy Gleason scores, and clinical stage. Treatment failure was recorded when there was clinical evidence of disease recurrence, a rising serum prostate-specific antigen level (two measurements of 0.4 ng/mL or greater and rising), or initiation of adjuvant therapy. Validation was performed on a separate sample of 168 men, also from our institution. RESULTS: Treatment failure (i.e., cancer recurrence) was noted in 196 of the 983 men, and the patients without failure had a median follow-up of 30 months (range, 1-146 months). The 5-year probability of freedom from failure for the cohort was 73% (95% confidence interval = 69%-76%). The predictions from the nomogram appeared accurate and discriminating, with a validation sample area under the receiver operating characteristic curve (i.e., comparison of the predicted probability with the actual outcome) of 0.79. CONCLUSIONS: A nomogram has been developed that can be used to predict the 5-year probability of treatment failure among men with clinically localized prostate cancer treated with radical prostatectomy.

Prostate-specific antigen (PSA) and PSA density: racial differences in men without prostate cancer.

BACKGROUND: Many physicians now use serum prostate-specific antigen (PSA) to screen for prostate cancer in asymptomatic men. Whether or not a prostate biopsy should also be performed depends on an accurate definition of what constitutes a normal PSA value. Until recently, studies conducted to establish normal serum PSA values have involved study populations that have included few African-American men. PURPOSE: We sought to compare serum PSA levels and PSA density (i.e., serum PSA level/prostate volume ratio) in African-American and white men without histologic evidence of prostate cancer. METHODS: We reviewed the medical records of 826 consecutive men who underwent one or more prostate biopsies at the Veterans Affairs Medical Center in Shreveport, LA, from January 1993 through December 1995. In this retrospective review, we recorded patient's age, race, serum PSA level, digital rectal examination result, ultrasound-determined prostate volume, indications for biopsy, and biopsy results. Data from a total of 752 consecutive men who were either white or African-American and whose indication for biopsy included a serum PSA of greater than 4.0 ng/mL and/or an abnormal digital rectal examination were analyzed. To examine possible differences in serum PSA level, PSA density, prostate volume, and patient age, the two-sided Student's t test was employed. Multivariate linear regression analysis was used to determine if serum PSA levels were associated with the patient's age, race, or prostate volume in men without prostate cancer. RESULTS: Of the 752 men included in this analysis, 254 had histologic evidence of prostate cancer and 498 did not. Of the 498 men without prostate cancer, 367 (74%) men were white and 131 (26%) were black. There were no racial differences in age or calculated prostate volume. Serum PSA levels and calculated PSA density, however, were significantly (both P < .0001) higher in African-American men that in white men. A multivariate linear regression analysis indicated that race and prostate volume were independent variables associated with serum PSA level. For African-American and white men, serum PSA values of greater than 4 ng/mL were associated with prostate cancer with sensitivities of 89.5% and 81.9%, respectively, and specificities of 38.2% and 52.3%, respectively. CONCLUSION: Among biopsied men without histologic evidence of prostate cancer, African-Americans have a significantly higher PSA level and PSA density than similarly aged white men. IMPLICATIONS: Published criteria for normal PSA level and density have been derived primarily from white men and may not be directly applicable to other populations. Race-specific data are needed to fully optimize PSA as a tumor marker in racial populations that are at high risk for prostate cancer death.

In vivo gene therapy with p53 or p21 adenovirus for prostate cancer.

We introduced the gene for wild-type human p53 or p21, a critical downstream mediator of p53-induced growth suppression, into a p53-deficient mouse prostate cancer cell line using a recombinant adenoviral vector (Ad5CMV-p53 or Ad5CMV-p21). Elevated levels of endogenous mouse p21 mRNA provided evidence for the functional activity of virally transduced p53. Functional activity of viral-transduced p21 was demonstrated through immunoprecipitation of cellular protein extracts, which showed that the viral-transduced p21 associates with cyclin-dependent kinase 2 and was sufficient to down-regulate the activity of the cyclin-dependent kinase by approximately 65%. In vitro growth assays revealed significantly higher growth suppression after Ad5CMV-p21 infection compared to Ad5CMV-p53. In vivo studies in syngeneic male mice with established s.c. prostate tumors demonstrated that the rate of growth and final tumor volume were reduced to a much greater extent in mice that received intratumor injection of Ad5CMV-p21 compared to Ad5CMV-p53. In addition, the survival of host animals bearing tumors that were infected with Ad5CMV-p21, but not Ad5CMV-p53, was significantly extended. These data suggest that Ad5CMV-p21 may be effective as a therapeutic agent for prostate cancer.

Number of metastatic lymph nodes as determinant of outcome after salvage radical prostatectomy for radiation-recurrent prostate cancer. / Número de ganglios linfáticos metastásicos como determinante de los resultados de la prostatectomía radical de rescate en el cáncer de próstata de recidivante tras radioterapia.

BACKGROUND: Presence of lymph node metástasis (LNM) at salvage radical prostatectomy (sRP) is associated with poor outcome. Predictors of outcome in this context remain undetermined. ThE objective was to assess the role of number of positive lymph node on outcome of patients with LNM after sRP and for radio-recurrent prostate cancer. MATERIAL AND METHODS: We analyzed data from a consecutive cohort of 215 men treated with sRP at a single institution. We used univariate Cox proportional hazard regression models for biochemical recurrence (BCR) and metastatic outcomes, with prostate-specific antigen, Gleason score, extraprostatic extension, seminal vesicle invasion, time between radiation therapy and sRP, and number of positive nodes as predictors. RESULTS: Of the 47 patients with LNM, 37 developed BCR, 11 developed distant metastasis and 4 died with a median follow-up of 2.3 years for survivors. The risk of metastases increased with higher pre-operative PSA levels (HR 1.19 per 1ng/ml; 95% CI: 1.06-1.34; P=.003). The remaining predictors did not reach conventional levels of significance. However, removal of 3 or more positive lymph nodes demonstrated a positive association, as expected, with metastatic disease (HR 3.44; 95% CI: 0.91-13.05; P=.069) compared to one or 2 positive nodes. Similarly, the presence of extraprostatic extension, seminal vesicle invasion and Gleason grade greater than 7 also demonstrated a positive association with higher risk of metástasis, with hazard ratios of 3.97 (95% CI: 0.50, 31.4; P=.2), 3.72 (95% CI: 0.80-17.26; P=.1), and 1.45 (95% CI: 0.44-4.76; P=.5), respectively. CONCLUSIONS: In patients with LNM after sRP for radio-recurrent prostate cancer, the risk of distant metástasis is likely to be influenced by the number of positive nodes (3 or more), high preoperative PSA, Gleason grade and advanced pathologic stage. These results are consistent with the findings of number of nodes (1 to 2 vs. 3 or more nodes positive) as a prognostic indicator after primary radical prostatectomy and strengthen the plea for a revision of the nodal staging for prostate cancer.

Loss of p53 function leads to metastasis in ras+myc-initiated mouse prostate cancer.

To study the interactions between dominantly acting oncogenes and tumor suppressor genes we used p53 'knockout' mouse urogenital sinus tissue for retroviral transduction of ras and myc in the mouse prostate reconstitution (MPR) model system. Epithelial hyperplasia was observed in all wild-type p53 MPRs with one small focal cancer and no evidence of metastasis. Prostatic cancer was found in 100% of the heterozygous and homozygous p53 mutant MPRs with metastatic deposits in 95% of the mice. The pattern of metastasis was remarkably similar to that in human prostate cancer with gross metastatic deposits in the lung, lymph nodes, bone and liver of many animals. Progression of carcinomas in the ras+myc-initiated heterozygous p53 mutant MPRs was invariably associated with either complete loss, partial deletion or loss of expression of the wild-type p53 allele. Southern blotting analysis of proviral-cellular DNA junction fragments in primary carcinomas and cell lines derived from metastatic deposits revealed that metastases do not necessarily seed out from the most abundant clone in the primary carcinoma.

Fifteen-year survival and recurrence rates after radiotherapy for localized prostate cancer.

PURPOSE: To determine 15-year survival and recurrence rates after radiotherapy for localized prostate cancer. METHODS: One hundred thirty-six patients with clinically localized prostate cancer treated from 1966 to 1974 with interstitial gold seed and external-beam irradiation were evaluated to determine the probability of recurrence and survival > or = 15 years after therapy. All patients were surgically staged with pelvic lymphadenectomy and none received hormonal therapy before relapse. RESULTS: Overall, 60 patients (44%) have never recurred, although 57% (34 of 60) of these same patients have died of causes other than prostate cancer. Local progression developed in 39% of patients and distant metastases in 42%. At 15 years, the probability of dying of prostate cancer was 33%+/-8% (% +/- 2SE) and of all causes was 72%+/-8%. In clinical stage A2 and B, 29%+/-9% of patients died of their cancer within 15 years, compared with 57%+/-21% in stage C1, while only 18%+/-8% with clinical stage A2 and B and negative lymph nodes died of cancer within this period. In contrast, the prostate cancer mortality rate at 15 years was high for patients with positive nodes regardless of the stage of the primary tumor (73% for A2 and B; 71% for C1). Patients with nodal metastases, poorly differentiated tumors, and advanced local disease all had a significantly (P < .0001) increased risk of cancer death. CONCLUSION: The cancer-specific mortality rate for patients with stage A2 and B tumors and negative nodes compares favorably with other series of patients treated with radiation therapy and > or = 15 years' follow-up evaluation. While local progression rates are high and associated with a substantial risk of prostate cancer death, many patients live with the disease and ultimately die of causes other than prostate cancer.

Southwest Oncology Group Study of paclitaxel and carboplatin for advanced transitional-cell carcinoma: the importance of survival as a clinical trial end point.

PURPOSE: The combination of paclitaxel and carboplatin for the treatment of advanced transitional-cell carcinoma (TCC) of the urothelium has promising activity and acceptable toxicity. The purpose of this trial was to evaluate the efficacy of this regimen in a cooperative group setting. PATIENTS AND METHODS: Twenty-nine patients with advanced TCC were treated every 21 days with paclitaxel 200 mg/m(2), administered as a 3-hour infusion, followed by carboplatin dosed to an area under the curve of 5. Prior systemic adjuvant or neoadjuvant platinum-based therapy was not permitted unless completed at least 1 year before enrollment. Patients were evaluated for response every three cycles, and follow-up was conducted to determine survival. RESULTS: Twenty-nine patients were enrolled and were assessable. Four (14%) had received prior adjuvant or neoadjuvant therapy. Node-only disease was present in 24%, and 76% of patients had extranodal disease. The median number of cycles received was five. Grade 4 toxicity consisted primarily of neutropenia (38% of patients). Neurologic toxicity was noted in 16 patients (grade 1 in four patients, grade 2 in five patients, grade 3 in six patients, and grade 4 in one patient). Six partial responses and no complete responses were noted, for a response proportion of 20.7% (95% confidence interval, 8% to 40%). Median progression-free survival time was 4 months, and overall survival time was 9 months. CONCLUSION: The combination of paclitaxel and carboplatin for the treatment of advanced TCC is reasonably well tolerated. However, a response proportion considerably lower than that previously reported was noted. In addition, the median survival time of 9 months was less than the survival time previously reported for patients treated with the combination of methotrexate, vinblastine, doxorubicin, and cisplatin. Although our results may reflect enrollment of patients with poor prognostic features, they also call into question the utility of this regimen.

Association of p53 mutations with metastatic prostate cancer.

In prostate cancer, mutation of the p53 tumor suppressor gene has been associated with locally advanced disease and hormone-resistant disease that is predominantly localized to bone. However, little is known regarding the status of the p53 gene in metastatic prostate cancer that has not been treated with hormonal manipulation. We evaluated formalin-fixed, paraffin-embedded malignant tissues from 86 patients with various stages of prostate cancer, including pathologically confined, locally advanced, and metastatic disease, to detect abnormal p53 nuclear protein accumulation using immunohistochemistry. No abnormal p53 immunostaining was detected in 18 patients with prostate cancer confined to the gland. Two tumors from 21 patients with locally advanced disease (extracapsular extension and/or seminal vesicle invasion) had abnormal nuclear p53 accumulation, and a mutation in exon 7 of the p53 gene was detected in tumor DNA from one patient using single-strand conformation polymorphism-direct sequencing analysis. Of the remaining 47 patients studied in whom tissues from the prostate gland and a metastatic site (44 lymph node, 2 bone, and 1 lung) were available, only 3 had received hormonal therapy prior to obtaining metastatic tissue. In four patients both primary and metastatic tumors demonstrated accumulation of p53 protein, whereas seven additional patients exhibited p53 accumulation only at the metastatic site. In three patients the metastatic tumors harbored missense single-base substitutions in exon 5, as detected using single-strand conformation polymorphism-direct sequencing. These results indicate that p53 abnormalities are associated with lymph node metastases derived from prostate cancer patients that had not undergone hormonal therapy.

The diffusion of minimally invasive radical prostatectomy in the United States: a case study of the introduction of new surgical devices.

BACKGROUND: The diffusion of minimally invasive radical prostatectomy (MIRP) in the United States may have led to adverse patient outcomes due to rapid surgeon adoption and collective inexperience. We hypothesized that throughout the early period of minimally invasive surgery, MIRP patients had inferior outcomes as compared with those who had open radical prostatectomy (ORP). METHODS: We used the Surveillance, Epidemiology and End RESULTS-Medicare dataset and identified men who had ORP and MIRP for prostate cancer from 2003-2009. Study endpoints were receipt of subsequent cancer treatment, and evidence of postoperative voiding dysfunction, erectile dysfunction (ED) and bladder outlet obstruction. We used proportional hazards regression to estimate the impact of surgical approach on each endpoint, and included an interaction term to test for modification of the effect of surgical approach by year of surgery. RESULTS: ORP (n=5362) and MIRP (n=1852) patients differed in their clinical and demographic characteristics. Controlling for patient characteristics and surgeon volume, there was no difference in subsequent cancer treatments (hazard ratio (HR) 0.89, 95% confidence interval (CI) 0.76-1.05), although MIRP was associated with a higher risk of voiding dysfunction (HR 1.31, 95% CI 1.20-1.43) and ED (HR 1.43, 95% CI 1.31-1.56), but a lower risk of bladder outlet obstruction (HR 0.86, 95% CI 0.75-0.97). There was no interaction between approach and year for any outcome. When stratifying the analysis by year, MIRP consistently had higher rates of ED and voiding dysfunction with no substantial improvement over time. CONCLUSIONS: MIRP patients had adverse urinary and sexual outcomes throughout the diffusion of minimally invasive surgery. This may have been a result of the rapid adoption of robotic surgery with inadequate surgeon preparedness.

Prostate cancer gene therapy: herpes simplex virus thymidine kinase gene transduction followed by ganciclovir in mouse and human prostate cancer models.

Prostate cancer is the most common internal malignancy in men in the United States. Most cancers are diagnosed when they are locally advanced or metastatic and there is no effective treatment. In this study we evaluated the effectiveness of cytotoxic gene therapy in human PC-3 and DU145 prostate cancer cell lines and in a rodent cell line, RM-1, derived from the mouse prostate reconstitution model system. The cell lines were efficiently transduced in vitro by a replicative-defective recombinant adenovirus (ADV) carrying the herpes simplex virus thymidine kinase gene (HSV-tk). A virus titer-dependent sensitivity to ganciclovir (GCV) was observed. To determine a target therapeutic viral dose in vivo, subcutaneous tumors were generated by injection of RM-1 cells in syngeneic male hosts and injected with escalating doses of HSV-tk virus (5 x 10(7) to 1 x 10(9) pfu). The mice received GCV twice daily for 6 days and were sacrificed when tumor volumes exceeded 2.5 cm3 or when they appeared to be in distress. Because the two highest doses were equally as effective, further controlled studies were performed with the lower dose of 5 x 10(8) pfu with ADV/RSV-tk or a control virus containing the beta-galactosidase gene (ADV/RSV-beta-Gal) and treated with GCV or saline (PBS). The mean tumor volume in the treated animals was 16% that of control animals at 13 days. Histologically, treated tumors demonstrated necrosis and had a significantly higher apoptotic index. Survival data indicated that the treatment animals lived 7 days (21 in total) longer than the control animals, with 1 treatment animal being totally free of tumor. These results demonstrate that HSV-tk + GCV cytotoxic gene therapy can inhibit the growth of mouse and human prostate cancer cells in vitro and interrupt tumor growth of an aggressive mouse prostate cancer cell line in vivo.

Amphiregulin is coordinately expressed with heparin-binding epidermal growth factor-like growth factor in the interstitial smooth muscle of the human prostate.

Peptide growth factors have been proposed as mediators of smooth muscle-epithelial cell interactions in the human prostate; however, the identity of these molecules has not been established. In this study, we compared expression levels of messenger RNAs (mRNAs) encoding the epidermal growth factor (EGF) receptor-related receptor tyrosine kinases (ErbB1 through 4), the six EGF receptor ligands, EGF, transforming growth factor (TGF)-alpha, amphiregulin (ARG), HB-EGF, betacellulin, and epiregulin, and the related molecule heregulin-alpha, in a series of 10 prostate tissue specimens. Only EGF showed a disease-specific association, with increased mRNA levels in four of five PCa specimens in comparison to matched normal tissue from the same subject. In contrast, ARG and HB-EGF mRNAs showed a coordinate pattern of expression in 7/10 specimens that was distinct from all other growth factor or receptor genes examined and from mRNAs for prostate specific antigen, the androgen receptor and GAPDH, a house-keeping enzyme. Analysis of an additional series of benign prostatic hyperplasia and prostate cancer specimens from 60 individuals confirmed that ARG and HB-EGF mRNA levels varied in a highly coordinate manner (r = 0.93; P < 0.0001) but showed no association with disease. ARG was immunolocalized largely to interstitial smooth muscle cells (SMC), previously identified as the site of synthesis of HB-EGF in the prostate, while the cognate ARG and HB-EGF receptor, ErbB1, was localized exclusively to ductal epithelial cells and carcinoma cells. Although ARG was a relatively poor mitogen for Balb/c3T3 cells in comparison to HB-EGF, it was similar in potency to HB-EGF in stimulating human prostate epithelial cell growth, suggesting that prostate epithelia may be a physiologic target for ARG in vivo. Expression of both ARG and HB-EGF mRNAs was induced in cultured prostate SMC by fibroblast growth factor-2, a human prostate SMC mitogen linked to prostate disease. These findings indicate that ARG and HB-EGF are likely to be key mediators of directional signaling between SMC and epithelial cells in the human prostate and appear to be coordinately regulated.

The incidence and implications of renal cell carcinoma in cadaveric renal transplants at the time of organ recovery.

BACKGROUND: With the exception of primary central nervous system tumors, organ recovery is no longer considered from donors with known malignancy. Because intrathoracic and intraabdominal organs are usually recovered before the kidneys, we examined the incidence of renal cell carcinoma in cadaveric donor kidneys at the time of organ recovery. This would establish the theoretical risk of transplanting donor organs from a patient with a known renal malignancy. METHODS: In cooperation with the Louisiana Organ Procurement Agency, we reviewed the records of all patients who were cadaveric kidney donors in the state of Louisiana between September 1991 and October 1997. Information was reviewed and analyzed on donor age, sex, race, past medical/surgical history, cause of death, and the findings at the time of organ recovery. RESULTS: A total of 553 consecutive cadaveric donors were identified, with 1106 kidneys recovered. Of the 553 cadaveric donors, 5 (0.9%) were noted to have an incidental renal cell carcinoma. All tumors were identified in separate donors; that is, none of the tumors were bilateral. None of the five donors had documented symptoms referable to their urinary tract. All tumors were either T1 or T2 by the tumor, node, metastasis classification system, and no evidence of nodal or distant metastatic disease was present. In one case, the contralateral kidney, heart, and liver were transplanted before the tumor was identified. In the remaining four cases, all organs (renal and nonrenal) were discarded. CONCLUSIONS: Renal cell carcinoma is rarely found during renal recovery from a cadaveric donor. However, because the kidneys are usually recovered after the intrathoracic and intraabdominal organs, careful palpation of the kidneys and exploration of any abnormalities is mandated to avoid transplanting any organs from a donor with a known renal malignancy.

Renal cell carcinoma detected in a cadaveric donor after orthotopic liver and contralateral renal transplantation in two recipients: four-year follow-up.

BACKGROUND: Although rare, renal cell carcinoma has been found during renal recovery for cadaveric organ transplantation. Previously, we reported this incidence to be 0.9%. In one cadaveric donor, the liver and left kidney had been transplanted before the discovery of renal cell carcinoma (T1) in the right kidney. METHODS: We retrospectively reviewed the medical records of two patients who had received cadaveric allografts from a donor with a known renal cell carcinoma. RESULTS: Both patients have been followed for 4 years with blood chemistries and chest x-ray every 3 months for year 1, every 4 months for years 2 and 3, and every 6 months thereafter. They also underwent allograft ultrasound every 6 months and an annual CT scan of the abdomen. Both patients have shown no evidence of metastatic disease throughout their follow-up. DISCUSSION: In the rare instance that a patient receives an organ from a cadaveric donor with a known renal cell carcinoma, it is mandatory to follow these patients closely observing for both allograft recurrence and metastatic disease.

Androgen receptor gene CAG repeat length varies in a race-specific fashion in men without prostate cancer.

OBJECTIVES: Preliminary studies suggest that black men have shorter androgen receptor CAG repeat length compared with non-Hispanic whites. Because decreased CAG repeat length (in particular less than 20 repeats) may be associated with increased prostate cancer risk, these findings are potentially important in providing a hypothesis to explain the increased risk of prostate cancer in black men. METHODS: CAG repeat length in the androgen receptor (exon one) was determined by a polymerase chain reaction method in 130 non-Hispanic white and 65 black men. All men had prostate-specific antigen levels less than 4 ng/mL and normal digital rectal examinations. Men self-classified themselves into racial categories by a standardized questionnaire. RESULTS: For whites, the mean +/- SD, median, and range of CAG repeat length were 21.0+/-3.0, 21, and 9 to 28, respectively. For blacks, the mean +/- SD, median, and range of CAG repeat length were 19.0+/-3.0, 19, and 13 to 26, respectively. The mean and median CAG repeat length in blacks were statistically significantly shorter than in whites. Black men were twice as likely as whites to have fewer than 20 CAG repeats (56.9% versus 28.5%, P = 0.0001). CONCLUSIONS: These data unequivocally demonstrate that androgen receptor gene CAG repeat length varies in a race-specific manner in men without evidence of prostate cancer.

Testicular microlithiasis as a predictor of intratubular germ cell neoplasia.

Sonographically detected testicular microlithiasis is an uncommon condition, which in recent years has been demonstrated with increased prevalence in patients with testicular tumors. We report a case of a 31-year-old man with left testicular carcinoma and right intratubular germ cell neoplasia diagnosed by biopsy of the right testis at the time of left radical orchiectomy. In this case, preoperative ultrasound revealed right testicular microlithiasis, signaling the presence of intratubular germ cell neoplasia. We propose ultrasound as a noninvasive tool for selecting patients for testicular biopsy.

Race is not independently associated with a positive prostate biopsy in men suspected of having prostate cancer.

OBJECTIVES: To examine whether race is associated with the prostate biopsy result after controlling for other clinical factors in men undergoing ultrasound-guided prostate biopsy to evaluate an elevated serum prostate-specific antigen (PSA) or an abnormal digital rectal examination (DRE), or both. METHODS: We reviewed the records of all men undergoing transrectal ultrasound-guided prostate biopsy at our facilities from January 1990 through March 1998. This included 1056 white men and 874 black men. Patient age, serum PSA, indication for prostate biopsy, and race were examined for association with the biopsy result. RESULTS: Of the 1 930 black and white men who underwent prostate biopsy, 639 (33%) had cancer, including 355 (41%) of 874 black men and 284 (27%) of 1056 white men. Serum PSA, abnormal DRE, and age were independent predictors of a prostate biopsy being positive for cancer. Race was not an independent predictor of cancer being identified in the prostate biopsy. CONCLUSIONS: After controlling for PSA, DRE, and age, black men were not at an increased risk of a positive prostate biopsy relative to white men. Our data do not support the need to consider race when estimating the probability that a man has prostate cancer.