Steven A. Bigler

PREDICTORS OF FIRST REPEAT BIOPSY CANCER DETECTION WITH SUSPECTED LOCAL STAGE PROSTATE CANCER

PURPOSE We determine demographic and tumor related predictors of repeat biopsy cancer detection in men with suspected stage T1c-2 prostate cancer. MATERIALS AND METHODS The study population included 298 consecutive men with suspected stage T1c-2 prostate cancer who had a benign prostate biopsy at 1 institution between January 1, 1992 and April 1, 1999 and underwent 1 repeat biopsy. Mean age plus or minus standard deviation was 66.8+/-6.7 years for 133 black (55%) and 165 white (45%) patients. Clinical measures included determination of high grade prostatic intraepithelial neoplasia in benign biopsy specimens, Gleason score of malignant biopsy specimens, prostate specific antigen (PSA), PSA density, annualized interbiopsy PSA change, percent free PSA (201 cases) and PSA velocity (171). RESULTS Cancer was detected on repeat biopsy in 80 cases (27%). Significant differences between patients with benign and malignant repeat biopsies included age (p = 0.001), PSA density (p = 0.0001), percent free PSA (p = 0.0001) and PSA velocity (p = 0.009). High grade prostatic intraepithelial neoplasia in an initial benign biopsy was not predictive of cancer in repeat biopsy (p = 0.12). Multiple logistic regression analysis of all cases showed that age (p = 0.002) and PSA density (p = 0.0002) were independent predictors of cancer. Subset multiple logistic regression analysis modeled with age, PSA density and percent free PSA demonstrated that age (p = 0.002) and percent free PSA (p = 0.0001) were significant independent predictors of malignancy. Subset multiple logistic regression analysis modeled with age, PSA density, percent free PSA and PSA velocity revealed that age (p = 0.02) and percent free PSA (p = 0.0003) were significant independent predictors of cancer. There were no significant differences between the Gleason scores of cancers detected on repeat biopsy compared to 587 stage T1c-2 cancers detected on initial biopsy during the study period (p = 0.09). PSA, PSA density, percent free PSA and PSA velocity were not significantly different among men without a cancer diagnosis who had high grade neoplasia in 1 or 2 benign biopsies. CONCLUSIONS Greater than 25% of this population of select patients with suspected stage T1c-2 prostate cancer had malignancy detected on repeat biopsy. Percent free PSA was the most powerful predictor of cancer. High grade prostatic intraepithelial neoplasia was not a predictor of repeat biopsy cancer detection and PSA functions were similar among men without cancer who did and did not have high grade neoplasia in 1 or more benign biopsies. This finding suggests that high grade prostatic intraepithelial neoplasia may not be a reliable indicator of clinically significant existing prostate cancer.

RACE AND CAUSE SPECIFIC SURVIVAL WITH PROSTATE CANCER: INFLUENCE OF CLINICAL STAGE, GLEASON SCORE, AGE AND TREATMENT

PURPOSE We assess the influence of race on stage stratified cause specific survival of men with prostate cancer, and Gleason score, age at diagnosis and treatment on potential racial differences in survival. MATERIALS AND METHODS A total of 524 black and 396 white men were diagnosed with prostate cancer at a Veterans Affairs Medical Center between January 1982 and December 1992. Clinical stage was determined by retrospective review of the medical records and Gleason score of biopsy material as assigned by a single uropathologist. Of 611 patients who died the cause of death was determined by retrospective or prospective review of hospital records in 493 and by review of the death certificates in 102. In 16 cases the cause of death was indeterminate. Median potential followup was 112 months (range 60 to 182) and median period of observation was 61 months (range 1 to 182). RESULTS Cause specific survival with stage T1b-2 cancer was lower in 231 black than in 264 white men of all ages (p = 0.02) and lower in 110 black than in 170 white men younger than in 70 years at diagnosis (p = 0.04). Gleason 7 to 10 cancer, which was associated with a less favorable cause specific survival compared to Gleason 2 to 6 cancer (p <0.0001), was more common in black than in white men with stage T1b-2 cancer of all ages (p = 0.01) and younger than 70 years at diagnosis (p = 0.04). No or unknown treatment status, which was associated with a less favorable cause specific survival compared to treatment (p = 0.05), was more common in black than in white men with stage T1b-2 cancer of all ages (p = 0.0005) but not significantly different when stratified by age. In men of all ages racial differences in cause specific survival were not significant when adjusted for age and Gleason score (p = 0.14) or age, Gleason score and treatment status (p = 0.17). In men younger than 70 years racial differences in cause specific survival were not significant when adjusted for age and Gleason score (p = 0.22). There were no significant racial differences in overall or age stratified all cause survival of men with stage T1b-2 cancer. There were no significant differences in overall or age stratified cause specific or all cause survival of 112 black and 58 white men with stage T3-4 cancer, or 181 and 74, respectively, with metastatic cancer. CONCLUSIONS Our data indicate that local stage prostate cancer is more lethal in black than in white men and the difference is most pronounced in men younger than 70 years. The survival disadvantage of black men with local stage cancer is due in part to a propensity for development of less differentiated and more aggressive malignancies.

Renal Cell Carcinoma and End Stage Renal Disease

PURPOSE Patients with ESRD secondary to acquired renal cystic disease have been reported to have a higher incidence of RCC than the general population. We examined the clinical and pathological significance of incidental renal masses in patients with ESRD. MATERIALS AND METHODS From January 1994 to July 2000, 852 consecutive patients with ESRD who were being considered for renal transplantation at University of Mississippi Medical Center were evaluated with renal ultrasound as part of assessment for possible kidney transplantation. Those patients with ultrasound suspicious for a malignant renal lesion were further evaluated with CT of the abdomen with and without intravenous contrast medium. Any patient with CT findings suspicious for RCC was recommended to undergo radical nephrectomy before kidney transplantation. RESULTS A total of 19 patients had CT criteria for a possible malignant renal lesion. Seven patients had Bosniak class 3 renal cysts and 12 patients had solid, enhancing renal masses. Of the patients 17 underwent radical nephrectomy. On pathological examination 14 patients had RCC with a 1.64% prevalence in the population screened. Mean Fuhrman nuclear grade in our patients was 2.45. CONCLUSIONS RCC in patients with ESRD are of clinical significance, considering the size, grade, histology and pathological stage of these tumors. The higher prevalence of clinically significant RCC in patients with ESRD as well as the risk of cancer progression while patients are on immunosuppressive medications justifies screening for RCC in patients with ESRD who are awaiting renal transplantation.

Hormone Therapy for Locally Advanced Prostate Cancer

PURPOSE We assessed cause specific and all cause survival in men with locally advanced prostate cancer after hormone therapy. MATERIALS AND METHODS Between February 1991 and November 2000, 208 men with locally advanced prostate cancer were treated with gonadal androgen ablation or gonadal androgen ablation and an antiandrogen at a single medical center. Median PSA was 46 ng./ml. (range 2 to 748). Median potential followup was 78 months (range 4 to 122) and the median observation period was 46 months (range 3 to 122). RESULTS Of the patients 14 (7%) died of causes related to cancer and 71 (34%) died of competing co-morbid disease. Actuarial cause specific survival at 5 and 8 years was 92% and 80%, respectively. The only demographic or tumor related variable that influenced cause specific survival was Gleason score less than 8 versus 8 or greater (p = 0.02). Actuarial all cause survival at 5 and 8 years was 59% and 41%, respectively. The only variable that influenced all cause survival was a Charlson weighted co-morbidity score of less than 2 versus 2 or greater (p <0.0001). Major morbidity from the primary tumor, including bothersome obstructive voiding symptoms requiring transurethral prostate resection, ureteral obstruction or persistent hematuria, developed in 13 patients (6%), while major treatment related morbidity, including flutamide hepatotoxicity and hip fracture, developed in 4. CONCLUSIONS Hormone therapy for locally advanced prostate cancer is associated with minimal morbidity from the primary tumor and from treatment. All cause survival parallels that reported for integrated hormone and radiation therapy.

Relationships between prostate-specific antigen and prostate volume in black and white men with benign prostate biopsies

OBJECTIVES To determine whether the higher age-adjusted serum prostate-specific antigen (PSA) levels in black compared with white men with no clinical evidence of prostate cancer reflect racial differences in relationships between PSA and prostate volume. METHODS The age, PSA, findings on digital rectal examination (DRE), prostate volume, and PSA density were assessed prospectively in 810 consecutive, evaluable men who underwent prostate biopsy for suspected cancer but who had benign histologic findings. RESULTS Among the black and white patients, there were significant differences in age (mean 67.2 +/- 8.1 and 65.9 +/- 7.7 years, respectively, P = 0.02), PSA (median 4.7 and 3.9 ng/mL, respectively, P <0.0001), prostate volume (median 41 and 36 mL, respectively, P = 0.004), and PSA density (median 0.11 and 0.08 ng/mL/mL, respectively, P = 0.005). Multiple linear regression analyses showed that black race was significantly associated with increased prostate volume when controlled for age (P = 0.02), with increased PSA when controlled for prostate volume and age (P = 0.002), and with increased PSA density when controlled for age (P = 0.007). When controlled for prostate volume, PSA was not significantly different in black and white men 50 to 59 years old but was significantly greater in black men 60 to 69 and 70 to 79 years old (P = 0.02 and 0.002, respectively). CONCLUSIONS On a volume/volume basis, the benign prostatic tissue of black men appears to contribute more PSA to the circulating blood than does the benign prostatic tissue of white men, and the difference increases with advancing age. These phenomena provide a reasonable explanation for the age-adjusted racial differences in the PSA of men with no clinical evidence of cancer.

PERCENT FREE PROSTATE SPECIFIC ANTIGEN AND CANCER DETECTION IN BLACK AND WHITE MEN WITH TOTAL PROSTATE SPECIFIC ANTIGEN 2.5 TO 9.9 NG./ML.

PURPOSE The ratio of free-to-total prostate specific antigen (PSA), or percent free PSA, is a useful adjunct to total PSA for estimating the risk of prostate cancer when total PSA is 2.5 to 9.9 ng./ml. Relationships between cancer detection and total PSA are influenced by race but to our knowledge relationships between cancer detection and percent free PSA have not been studied. MATERIALS AND METHODS A total of 222 black and 298 white consecutive and evaluable men with total PSA 2.5 to 9.9 ng./ml. underwent prostate biopsy for suspected cancer at a Veterans Affairs Medical Center. Clinical measurements included digital rectal examination, total and free serum PSA, prostate volume, PSA density and Gleason score of malignant biopsy specimens. RESULTS Median percent free PSA was 14.1 (range 3.6 to 49.2) in 201 men with prostate cancer and 21.9 (range 5.7 to 83.3) in 319 without detectable cancer (p <0.0001). Significant racial differences in demographic characteristics and clinical measurements were limited to total PSA, which was higher in black men (p = 0.03). Cancer was detected in 156 black (47%) and 206 white (33%) men (p = 0.001). Areas under receiver operating characteristics curves for percent free PSA and total PSA were 0.66 and 0.58, respectively, for black men (p = 0.15), and 0.76 and 0.58, respectively, for white men (p <0.00001). Percent free PSA was 35.2 in black men and 29.2 in white men, and specificity was 9.1% and 28.7%, respectively, when sensitivity for percent free PSA was set at 95%. Of 156 black and 206 white men with percent free PSA less than 25, 83 (53%) and 85 (41%), respectively, had detectable cancer (p = 0.03). Of 66 black and 92 white men with percent free PSA 25 or greater 21 (32%) and 12 (13%), respectively, had detectable cancer (p = 0.005). CONCLUSIONS Our study demonstrates racial differences in relationships between percent free PSA and cancer detection in men with suspected prostatic carcinoma and total PSA 2.5 to 9.9 ng./ml. Clinical application of the commonly used percent free PSA cutoff of less than 25 to determine the advisability of prostate biopsy may lead to under diagnosis of early stage prostate cancer in black men, who are at greater risk of morbidity and mortality from disease than white men.

Antioxidant lazaroid U-74006F improves renal function and reduces the expression of cytokines, inducible nitric oxide synthase, and mhc antigens in a syngeneic renal transplant model. Partial support for the response-to-injury hypothesis

In a recent study, antioxidant therapy at the time of renal transplantation in humans was associated with fewer rejection episodes and extended graft survival. A hypothesis generated by such studies and based on the response-to-injury model is that reducing the oxidative injury during transplantation may dampen certain cellular responses to injury that are important in triggering allograft rejection. To test whether ablation of oxidative injury would limit such responses, kidneys were transplanted between Wistar-Furth rats, with and without antioxidant 21-aminosteroid. 21-Aminosteroid was administered before kidney harvest and, again, before transplant reperfusion. The recipients left kidneys, removed to accommodate the donor kidneys, were used as normal control. The removal of the right kidneys contralateral to the transplant were delayed to day 4 to provide interim renal support. The transplanted kidneys were harvested on day 7. Administration of 21-aminosteroid was associated with better graft function and reduced lipid peroxidation. Compared with the normal control kidneys, the kidneys transplanted with vehicle had higher cytokine mRNA levels (measured by reverse transcriptase-polymerase chain reaction) for interleukin 2, interleukin 6, tumor necrosis factor-alpha, and interferon-gamma. The levels for these cytokines were reduced in kidneys transplanted with 21-aminosteroid. An increase in inducible nitric oxide synthase mRNA in the transplanted kidney was inhibited by 21-aminosteroid, as were the increase in class I and II MHC antigens. The new finding, that a reduction in transplantation-related oxidative injury in a syngeneic model is accompanied by a reduction in the expression of cytokines, MHC antigens, and inducible nitric oxide synthase, provides partial support for the response-to-injury hypothesis in the setting of renal transplantation. The data also demonstrate for the first time the efficacy of 21-aminosteroid to reduce lipid peroxidation and renal injury in kidneys transplanted after cold preservation.

Prostate cancer detection in black and white men with abnormal digital rectal examination and prostate specific antigen less than 4 NG./ML.

PURPOSE Prostate cancer is more common in black than in white American men. Experience in a longitudinal prostate cancer screening program implies that cancer detection is greater in black than in white men with an abnormal digital rectal examination and prostate specific antigen (PSA) less than 4 ng./ml. We investigated potential racial differences in cancer detection in men treated in clinical practice who had an abnormal digital rectal examination and PSA less than 4 ng./ml. MATERIALS AND METHODS Between January 1992 and December 1999 prostate biopsy was done at a Veterans Affairs Medical Center in 179 black and 357 white men with an abnormal digital rectal examination, PSA less than 4 ng./ml. and no history of prostate surgery. Significant racial differences in demographic and clinical parameters were limited to PSA, which was higher in black men (p = 0.01). RESULTS Cancer was detected in 38 black (21%) and 65 white (18%) men (p = 0.42). There were no significant racial differences in the PSA adjusted cancer detection rate or in the Gleason score of detected disease. In men with PSA less than 1.0, 1.0 to 1.9, 2.0 to 2.9 and 3.0 to 3.9 ng./ml. the detection rate was 4%, 15%, 27% and 29%, respectively. CONCLUSIONS In clinical practice prostate cancer detection appears to be equivalent in black and white men when an abnormal digital rectal examination is the only indication of malignancy.

TRENDS IN DIAGNOSIS OF STAGE T1A-B PROSTATE CANCER

PURPOSE Stage T1a-b prostate cancer comprised about 44% of newly diagnosed local prostate cancer cases in the United States before the advent of medical and minimally invasive treatments for symptomatic benign prostatic hyperplasia (BPH) and before the widespread use of prostate specific antigen (PSA) testing in men with BPH. Information about the impact of these advances on detection of T1a-b cancer is not available. MATERIALS AND METHODS Prevalence of T1a-b prostate cancer was determined in 1,554 consecutive men who underwent surgical prostatectomy for suspected BPH at a Veterans Affairs Medical Center from 1985 through 1996. Since 1991 a PSA blood test was obtained routinely before surgery and patients with PSA greater than 4.0 ng./ml. usually underwent ultrasound guided prostate biopsy. RESULTS The number of T1a-b cancer cases was relatively stable during 1985 to 1990 but declined from 36 in 1990 to 9 in 1996. There were no temporal trends in proportion of prostatectomy patients with T1a-b cancer and the decline in cancer detection paralleled less frequent use of surgical prostatectomy for treatment of BPH. The proportion of prostatectomy patients with T1a-b cancer was similar in 1985 to 1990 and in 1991 to 1996 but the percentage of Gleason 7 to 10 cancers declined from 26 in 1985 to 1990 to 10 in 1991 to 1996 (p < 0.0001). PSA and PSA density of evaluable patients with cancer were significantly greater than in evaluable patients with BPH. Of 105 patients with PSA greater than 4.0 ng./ml. who underwent preoperative prostate biopsy 16 (15%) had T1a-b cancer. CONCLUSIONS The less frequent use of surgical prostatectomy at our institution has produced marked decline in detection of T1a-b cancer. If representative of national trends this experience suggests that many men with obstructive voiding symptoms and T1a-b cancer will remain undiagnosed and that periodic monitoring to identify unsuspected cancer is important in men who are treated with medical or minimally invasive therapies for BPH. Decline in detection of T1a-b cancer may also confound the accuracy of projected incidence rates of local prostate cancer in the United States.

Role of Cytochrome P450 2B1 in Puromycin Aminonucleoside-Induced Cytotoxicity to Glomerular Epithelial Cells

Puromycin aminonucleoside (PAN)-induced glomerular injury in rats mimics minimal-change nephrotic syndrome (NS) in humans. We have demonstrated an important role of cytochrome P450 (CYP) as a significant source of catalytic iron in this model of NS. The current study was designed to identify CYP isozyme(s) present in the rat glomerular epithelial cells (GEC) and to explore the role of the specific CYP isozyme in PAN-induced cytotoxicity. CYP2B1 was identified in GEC by immunocytochemistry and Western blot. Treatment of GEC with PAN resulted in a marked generation of hydrogen peroxide (H2O2) and reduction of CYP2B1 content associated with significant increase in catalytic iron and hydroxyl radical formation. Preincubating GEC with CYP2B1 inhibitors (piperine and cimetidine) and H2O2 scavenger (pyruvate) significantly reduced H2O2 generation, preserved CYP2B1 content, prevented the increase in catalytic iron and hydroxyl radical formation including PAN-induced cytotoxicity. We also observed the induction of heme oxygenase (HO-1) in PAN-treated GEC, and this up-regulation was reduced by pretreatment of the CYP inhibitors and pyruvate. Our data thus indicate an important role of CYP2B1 in PAN-induced cytotoxicity by serving as a site of reactive oxygen metabolite generation and a significant source of catalytic iron.