Graham F. Greene

Association of SULT1A1 phenotype and genotype with prostate cancer risk in African-Americans and Caucasians

Exposure to heterocyclic amines may increase prostate cancer risk. Human sulfotransferase 1A1 (SULT1A1) is involved in the bioactivation of some dietary procarcinogens, including the N-hydroxy metabolite of the food-borne heterocyclic amine, 2-amino-1-methyl-6-phenylimidazo(4,5-b) pyridine. This study compares a polymorphism in the SULT1A1 gene, SULT1A1 enzyme activity, meat consumption, and the risk of prostate cancer in a population based case-control study. Prostate cancer patients (n = 464) and control individuals (n = 459), frequency matched on age and ethnicity, provided informed consent, answered a survey, and provided a blood sample. Platelets were isolated for phenotype analysis, and DNA was isolated from lymphocytes for genotype determination. Meat consumption was assessed using a dietary questionnaire. Caucasians homozygous for the SULT1A1*1 high activity allele were at increased risk for prostate cancer [odds ratio (OR), 1.68; 95% confidence interval (CI), 1.05–2.68] compared with individuals homozygous for the low-activity allele. The association between SULT1A1 genotype and prostate cancer risk in African-Americans did not reach significance (OR, 1.60; 95% CI, 0.46–5.62). When SULT1A1 activity was considered, there was a strong association between increased SULT1A1 activity and prostate cancer risk in Caucasians (OR, 3.04; 95% CI, 1.8–5.1 and OR, 4.96; 95% CI, 3.0–8.3, for the second and third tertiles of SULT1A1 activity, respectively) compared with individuals in the low enzyme activity tertile. A similar association was also found in African-American patients, with ORs of 6.7 and 9.6 for the second and third tertiles of SULT1A1 activity (95% CI, 2.1–21.3 and 2.9–31.3, respectively). When consumption of well-done meat was considered, there was increased risk of prostate cancer (OR, 1.42; 95% CI, 1.01–1.99 and OR, 1.68; 95% CI, 1.20–2.36 for the second and third tertiles, respectively). When SULT1A1 activity was stratified by tertiles of meat consumption, there was greater risk of prostate cancer in the highest tertile of meat consumption. These results indicate that variations in SULT1A1 activity contributes to prostate cancer risk and the magnitude of the association may differ by ethnicity and be modified by meat consumption.

Patient Selection for Salvage Cryotherapy for Locally Recurrent Prostate Cancer After Radiation Therapy

PURPOSE Our objective was to identify clinical pretreatment factors associated with early treatment failure after salvage cryotherapy. PATIENTS AND METHODS Between 1992 and 1995, 145 patients underwent salvage cryotherapy for locally recurrent adenocarcinoma of the prostate. Treatment failure was defined as an increasing postcryotherapy serial prostate-specific antigen (PSA) level of more than or equal to 2 ng/mL above the postcryotherapy nadir or as a positive posttreatment biopsy. We evaluated the following factors as predictors of treatment failure: tumor stage and grade at initial diagnosis, type of prior therapy, stage and grade of locally recurrent tumor, number of positive biopsy cores at recurrence, and precryotherapy PSA level. RESULTS Among patients with a prior history of radiation therapy only, the 2-year actuarial disease-free survival (DFS) rates were 74% for patients with a precryotherapy PSA less than 10 ng/mL and 28% for patients with a precryotherapy PSA more than 10 ng/mL, P <.00001. The DFS rates were 58% for patients with a Gleason score of less than or equal to 8 recurrence and 29% for patients with a Gleason score greater than or equal to 9 recurrence, P <.004. Among patients with a precryotherapy PSA less than 10 ng/mL, DFS rates were 74% for patients with a prior history of radiation therapy only and 19% for patients with a history of prior hormonal therapy plus radiation therapy, P <.002. CONCLUSION Patients failing initial radiation therapy with a PSA more than 10 ng/mL and Gleason score of the recurrent cancer more than or equal to 9 are unlikely to be successfully salvaged. Patients failing initial hormonal therapy and radiation therapy are less likely to be successfully salvaged than patients failing radiation therapy only.

Polymorphisms in hOGG1 and XRCC1 and Risk of Prostate Cancer: Effects Modified by Plasma Antioxidants

OBJECTIVES To investigate whether polymorphisms in genes involved in the repair of oxidative DNA damage, modulate, and/or interact with antioxidants to influence prostate cancer risk in a population-based case-control study in Central Arkansas. Accumulating evidence indicates that oxidative stress plays a role in prostate carcinogenesis. METHODS Cases (n = 193) included men aged 40-80 years, diagnosed with prostate cancer in 3 major hospitals in 1998-2003, and controls (n = 197) were matched to cases by age, race, and county of residence. RESULTS After adjustment for confounders, subjects who were heterozygous or homozygous for the variant allele of the hOGG1 Ser326Cys polymorphism appeared to experience a lower risk of prostate cancer than those who were homozygous for the wild-type allele (odds ratio [OR] (95% confidence interval [CI]): 0.72 (0.46-1.10)]. Conversely, a significant increased risk was observed for individuals who carried 1 or 2 copies of the variant allele of the XRCC1 Arg399Gln polymorphism, compared with those who only harbored the wild-type allele (OR [95% CI]: 1.56 [1.01-2.45]). The above-mentioned associations were generally more pronounced among subjects with low plasma carotenoids or alpha-tocopherol (<median). Among subjects who had low plasma levels of beta-cryptoxanthin (<73 microg/L), possession of at least 1 copy of the XRCC1 399Gln allele conferred a greater than 2-fold elevated risk (OR [95% CI]: 2.64 [1.40-5.07]). CONCLUSIONS Our study offers preliminary but intriguing data suggesting that variability in the capacity of repairing oxidative DNA damage influences susceptibility to prostate cancer and that these effects are modified by antioxidants.

LOCAL TUMOR CONTROL WITH SALVAGE CRYOTHERAPY FOR LOCALLY RECURRENT PROSTATE CANCER AFTER EXTERNAL BEAM RADIOTHERAPY

PURPOSE We identified variables associated with a positive prostate biopsy after salvage cryotherapy in patients in whom initial external beam radiotherapy for prostate cancer failed to improve our cryotherapy technique, optimize local control and improve our patient selection criteria for salvage cryotherapy. MATERIALS AND METHODS Between July 1992 and January 1995, 145 patients underwent salvage cryotherapy. Post-cryotherapy sextant prostate biopsies were performed in 107 cases. We evaluated certain variables on univariate and multivariate analysis as predictors of a positive biopsy after cryotherapy, including the type of previous therapy, tumor stage and grade at initial diagnosis, prostate volume, pre-cryotherapy prostate specific antigen (PSA), number of positive biopsy cores before cryotherapy, PSA nadir after cryotherapy, stage and grade of local recurrence, number of cryoprobes, number of freeze-thaw cycles and use of a urethral warming catheter during cryotherapy. RESULTS Biopsies were positive in 23 cases (21%) after salvage cryotherapy. Variables associated with a positive biopsy on univariate analysis were initial stage, precryotherapy PSA, PSA nadir after cryotherapy, number of cryoprobes, number of freeze-thaw cycles and a history of chemotherapy (p = 0.005, 0.027, 0.001, 0.009, 0.018 and 0.008, respectively). Variables that remained associated with a positive biopsy on multivariate analysis were the number of probes used and post-cryotherapy PSA nadir (p = 0.013 and 0.019, respectively). CONCLUSIONS Patients with initial clinical stage T1-2N0M0 disease and PSA no more than 10 ng./ml. have a higher rate of negative biopsies after salvage cryotherapy. Therefore, they are better candidates for salvage cryotherapy for locally recurrent prostate adenocarcinoma after external beam radiotherapy. To optimize the potential for local control the technique of salvage cryotherapy should include 2 freeze-thaw cycles and a minimum of 5 cryoprobes. Detectable PSA after salvage cryotherapy is a strong predictor of local failure.

Plasma carotenoids and prostate cancer: a population-based case-control study in Arkansas.

Abstract Carotenoids possess antioxidant properties and thus may protect against prostate cancer. Epidemiological studies of dietary carotenoids and this malignancy were inconsistent, partially due to dietary assessment error. In this study, we aimed to investigate the relation between plasma concentrations of carotenoids and the risk of prostate cancer in a population-based case-control study in Arkansas. Cases (n = 193) were men with prostate cancer diagnosed in 3 major hospitals, and controls (n = 197) were matched to cases by age, race, and county of residence. After adjustment for confounders, plasma levels of lycopene, lutein/zeaxanthin, and β -cryptoxanthin were inversely associated with prostate cancer risk. Subjects in the highest quartile of plasma lycopene (513.7 μ g/l) had a 55% lower risk of prostate cancer than those in the lowest quartile (140.5 μ g/l; P trend = 0.042). No apparent association was observed for plasma α -carotene and β -carotene. Further adjustment for the other 4 carotenoids did not materially alter the risk estimates for plasma lycopene, lutein/zeaxanthin, and β -cryptoxanthin but appeared to result in an elevated risk with high levels of plasma α -carotene and β -carotene. The results of all analyses did not vary substantially by age, race, and smoking status. This study added to the emerging evidence that high circulating levels of lycopene, lutein/zeaxanthin, and β -cryptoxanthin are associated with a low risk of prostate cancer.

CYP3A43 Pro340Ala Polymorphism and Prostate Cancer Risk in African Americans and Caucasians

The human cytochrome P450 3A subfamily of enzymes is involved in the metabolism of steroid hormones, carcinogens, and many drugs. A cytosine-to-guanine polymorphism in CYP3A43 results in a proline-to-alanine substitution at codon 340. Although the functional significance of this polymorphism is unknown, we postulate that the substitution of proline, an α-imino acid, with alanine, an amino acid, could be of biochemical significance. In a case-control study with 490 incident prostate cancer cases (124 African Americans and 358 Caucasians) and 494 controls (167 African Americans and 319 Caucasians), we examined the association between CYP3A43 Pro340Ala polymorphism and prostate cancer risk. When all subjects were considered, there was a 3-fold increase in risk of prostate cancer among individuals with the CYP3A43-Ala/Ala genotype (odds ratio, 3.0; 95% confidence interval, 1.2-7.2) compared with those with the CYP3A43-Pro/Pro genotype after adjusting for age, race, and smoking. The prevalence of the polymorphism was significantly higher in African Americans than Caucasians (45% versus 13%). In African Americans, there was a 2.6-fold increase in prostate cancer risk among individuals with the CYP3A43-Ala/Ala genotype (odds ratio, 2.6; 95% confidence interval, 1.0-7.0) compared with those with the CYP3A43-Pro/Pro genotype. Among Caucasians, the small number of homozygotes precluded computing risk estimates; there were only three individuals with the CYP3A43-Ala/Ala genotype. Our results suggest that the CYP3A43-Pro340Ala polymorphism contributes to prostate cancer risk.

PREDICTIVE VALUE OF PROSTATE SPECIFIC ANTIGEN NADIR AFTER SALVAGE CRYOTHERAPY

PURPOSE We determined nadir prostate specific antigen (PSA) after salvage cryotherapy to distinguish patients who are potentially cured from those at risk for subsequent biochemical and biopsy proved failure. MATERIALS AND METHODS A total of 146 patients who underwent salvage cryotherapy were followed a median of 21 months (range 3 to 47) with regular serum PSA analysis and digital rectal examination. Sextant biopsies were performed at 6 months or earlier when PSA increased greater than 2 ng./ml. from the nadir value (biochemical failure) or there was a palpable local recurrence. We compared the incidence of biochemical failure and biopsy specimens positive for cancer to pretreatment PSA and posttreatment nadir PSA. RESULTS In 59 of the 146 patients (40%) PSA decreased to an undetectable level within a median of 3 months. In 85 of the 109 patients (78%) who underwent biopsy the specimens were negative for cancer. Low serum PSA nadir values were associated with low pretreatment PSA and a low incidence of biochemical failure. In 6 of 60 patients (10%) in whom PSA nadir was 0.5 ng./ml. or less and in 18 of 49 (37%) with a higher PSA nadir biopsy was positive for cancer. CONCLUSIONS A PSA nadir of 0.5 ng./ml. or less should be achieved after salvage cryotherapy. Higher nadirs are more likely to be associated with increasing posttreatment PSA and positive biopsies. PSA nadir is a better prognostic indicator of biochemical and biopsy proved failure after salvage cryotherapy than pretreatment PSA.

Concurrent Robotic Renal and Prostatic Surgery: Initial Case Series and Safety Data of a New Surgical Technique

INTRODUCTION In the era of prostate-specific antigen screening and frequent cross-sectional abdominal imaging, concurrent prostate cancer and renal masses are being identified and treated. Minimizing patient morbidity and cost by avoiding separate surgical procedures is advantageous, provided technical feasibility, and safety data. Our goal was to assess the feasibility and safety of single-setting robotic renal surgery and prostatectomy. We present our initial experience. PURPOSE To assess the feasibility and safety of single-setting concurrent robot-assisted renal surgery and radical prostatectomy utilizing the same port access scheme. PATIENTS AND METHODS From February 2009 to June 2009, we performed single-setting concurrent robot-assisted radical nephrectomy/partial nephrectomy and radical prostatectomy on two patients with synchronous kidney tumors and prostate cancer. Identical port sites were used during both aspects of the procedure with the exception of one additional port during prostatectomy. Prostate cancer clinical stage and Gleason scores were T1c and 6 and T2a and 7, respectively. Corresponding renal tumors were 5 cm, respectively. RESULTS Both operations were performed, with no conversion to open surgery. There were no intraoperative complications and the postoperative course was uneventful in both patients. Discharge was on postoperative day 2 and 3, respectively. Patient 2 had an episode of delayed bleeding on postoperative day 9, treated by selective angio-embolization. Mean operative time for nephrectomy and prostatectomy (135 and 139 minutes, respectively) and estimated blood loss (75 and 100 mL, respectively) were reasonable. We began with the renal portion utilizing a lateral decubitus position before re-positioning into the lithotomy position for the prostatic portion. Clamping time was 34 minutes during partial nephrectomy. CONCLUSION Single-setting robotic radical/partial nephrectomy and radical prostatectomy is technically feasible and safe in properly selected patients who present with synchronous primary renal and prostate malignancies.

Should hilar lymph nodes be expected in radical nephrectomy specimens

Lymph node (LN) status is essential in staging both renal cell carcinoma (RCC) and pelvic urothelial carcinoma (PUC). The rate of regional LN involvement is influenced by pathologic tumor stage, extent of the surgical resection, and accuracy of pathologic gross examination. In this study, we assess the presence of hilar LNs in radical nephrectomies (RN) by entirely submitting the hilar fat region (HFR) for microscopic evaluation (ME). Fifty consecutive RNs from 2006 to 2008 were evaluated by a standard gross examination protocol (SGEP) which consisted of palpation and sectioning of the HFR with submission of grossly identified LNs. Subsequently, the entire HFR was re-evaluated and submitted as studys total submission protocol (TSP). The number and disease status of hilar LNs identified by the SGEP and TSP were compared. Fifty RNs (37 clear cell RCC, 6 papillary RCC, 7 PUC) were studied prospectively. Ten of the 50 RNs had LNs identified (20%) with both protocols. Four of the 50 RNs had nodal metastases (8%) with the LN sizes ranging between 1.3 and 2.5 cm (mean 1.8 cm). All nodal metastases were identified by the SGEP. In three RNs (6%), additional minute (mean 0.12 cm) negative LNs not seen by the SGEP were identified by the TSP. LNs are present in only 20% of RNs, even after complete ME of the HFR. The SGEP for identifying hilar LNs in RNs is sufficient for staging and did not lead to underreporting of LN metastases.

Abstract B123: Sequence variants in inflammatory genes, plasma antioxidants, and prostate cancer risk

Background: Presence of xenotropic murine leukemia virus‐related virus and chronic inflammation in prostate tumor tissue suggests that inflammation plays a role in prostate cancer etiology. This study thus investigated whether variants in genes involved in inflammation influence alone or interact with plasma antioxidants to influence prostate cancer risk in a population‐based case‐control study in Central Arkansas. Methods: Cases (n=193) were men, ages 40–80 years, diagnosed with prostate cancer in three major hospitals in 1998–2003, and controls (n=197) were matched to cases by age, race, and county of residence. Results: After adjustment for confounders, polymorphisms in COX2 (rs689466) and IL‐8 (rs4073) were not significantly associated with prostate cancer risk. However, significant interactions were observed between these genetic variants and plasma antioxidants on the risk of this malignancy. The protective effect of the mutant allele of the COX polymorphism was more pronounced among subjects with high plasma levels of β‐cryptoxanthin, lycopene, β‐carotene, or selenium (≥median) [e.g., OR (95% CI): 0.37 (0.15–0.86) (AG/GG vs. AA) for β‐cryptoxanthin]. Conversely, the promoting effect of the variant allele of the IL‐8 polymorphism was more remarkable in subjects with low plasma levels of Lutein/zeaxanthin, β‐cryptoxanthin, and β‐carotene ( Conclusions: We found that genetic variants in inflammatory genes interact with plasma antioxidants to modulate the risk of prostate cancer. The results obtained from our study need to be replicated in large epidemiologic studies. Citation Information: Cancer Prev Res 2010;3(1 Suppl):B123.