Prostatic Neoplasms: Clark PE

Montie JE, Clark PE, Eisenberger MA, El-Galley R, Greenberg RE, Herr HW, Hudes GR, Kuban DA, Kuzel TM, Lange PH, Lele SM, Michalski J, Patterson A, Pohar KS, Richie JP, Sexton WJ, Shipley WU, Small EJ, Trump DL, Walther PJ, Wilson TG, Anonymous00046. · University of Michigan Comprehensive Cancer Center. · J Natl Compr Canc Netw. · Pubmed #19176203 No free full text.

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Rackley JD, Clark PE, Hall MC. · Department of Urology, Wake Forest University School of Medicine, Comprehensive Cancer Center, Winston-Salem, NC 27157-1094, USA. · Urol Clin North Am. · Pubmed #16631462 No free full text.

Abstract: Complimentary and alternative medicines (CAM) have increased drastically in popularity in the past decade. These are largely in the form of nutritional supplements. Despite a wealth of information sources on the subject, the fundamental problem with CAM therapies is a dearth of evidence-based medicine. Advanced prostate cancer has significant long-term morbidity, and there is a growing interest in alternative and complimentary forms of therapy that will improve the outcomes of patients who have recurrent or advanced prostate cancer while obviating the need for more toxic forms of therapy. In this article we summarize the use of some of the more common CAM nutritional supplements and review the scientific data that are available to support their use.

Clark PE, Hall MC. · Department of Urology, Wake Forest University Health Sciences, Medical Center Boulevard, Winston-Salem, NC 27104, USA. · Urol Clin North Am. · Pubmed #15862617 No free full text.

Abstract: The incidence of urethral TCC after radical cystectomy is approximately 8% overall. The most important risk factor for urethral TCC after radical cystectomy and urinary diversion is prostatic involvement by TCC, particularly stromal invasion. The safety of using the urethra for orthotopic urinary diversion seems to be best when intra-operative frozen section analysis of the urethral margin is performed at the time of radical cystectomy. There is provocative but unconfirmed evidence that orthotopic urinary diversion may be protective against the development of urethral TCC. Although most urethral "recurrences" occur within 5 years, delayed recurrences have been documented, mandating life-long follow-up of the retained urethra. Follow-up should include urinary cytology, either voided or urethral wash cytology as appropriate, with evaluation by endoscopy of any urethral related symptoms or change in voiding symptoms. The management of urethral TCC after cystectomy remains a total urethrectomy including excision of the meatus; however, in carefully selected patients with superficial disease and an orthotopic urinary diversion, urethra sparing may be attempted after a careful discussion with the patient. Survival after urethral TCC has generally been disappointing. The relative value of urethral versus original cystectomy pathologic stage and symptomatic versus nonsymptomatic recurrence in predicting survival remains controversial and awaits further studies that will most likely require the pooling of data from several large series.

Clark PE, Torti FM. · Wake Forest University Baptist Medical Center, Winston-Salem, NC 27157, USA. · Clin Orthop Relat Res. · Pubmed #14600605 No free full text.

Abstract: Prostate cancer is the most common malignancy in men in the United States. With the long natural history of the disease, management of skeletal morbidity related to advanced prostate cancer becomes a major public health issue. The standard of care in advanced prostate cancer is androgen deprivation therapy. This may accelerate the development of osteoporosis and further exacerbate the risks of having adverse skeletal-related events develop. Recently, the use of bisphosphonates in men who have not responded to androgen deprivation therapy has been shown to reduce the incidence of skeletal-related events with time. Questions remain as to whether bisphosphonates should be broadly applied to earlier stages of the disease or tailored to men at higher risk of having bone-related morbidity. Work is ongoing to improve other approaches to the medical treatment of bone metastases in patients with advanced prostate cancer including the use of radiopharmaceuticals and combined chemotherapy.

Clark PE, Irvine RA, Coetzee GA. · Department of Urology, Wake Forest University School of Medicine, Winston-Salem, NC, USA. · Methods Mol Med. · Pubmed #12725125 No free full text.

This publication has no abstract.

Borden LS, Clark PE, Lovato J, Hall MC, Stindt D, Harmon M, M Mohler R, Torti FM. · Department of Urology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157, USA. · Cancer. · Pubmed #16888761 links to  free full text

Abstract: BACKGROUND: Ultimately, patients with metastatic prostate cancer progress on androgen ablation therapy. The investigation of new chemotherapeutic regimens for the treatment of androgen-independent prostate cancer (AIPC) is essential. The authors conducted a Phase II trial with vinorelbine, doxorubicin, and daily prednisone (NAP) to investigate the antitumor activity and palliative response of this regimen in patients with AIPC. METHODS: Forty-six patients entered this Phase II combination chemotherapy trial. Patients were treated with both vinorelbine and doxorubicin at doses of 20 mg/m2 on Days 1, 8, and 15 every 28 days and prednisone 5 mg twice daily. Endpoints included prostate-specific antigen (PSA) response and palliation, as measured by the Functional Assessment of Cancer Therapy-Prostate (FACT-P) instrument, the Brief Pain Inventory Scale, and a narcotic analgesic log. RESULTS: The median follow-up for all 46 patients was 13.4 months. Fifty-two percent of patients had impaired performance status at baseline. One responding patient remained on NAP and was progression-free at 11.5 months. Thirty-nine patients progressed, 3 patients died prior to response assessment, and 3 patients refused therapy. The median overall survival was 57 weeks (95% confidence interval [95% CI], 36-76 weeks), and the median time to disease progression was 17 weeks (range, 11-24 weeks). The PSA response among the 36 patients who completed 3 cycles of NAP was 42% (95% CI, 26-59%). There was a statistically significant improvement in quality of life measured both by the FACT-General instrument (P = .03) and the FACT-P instrument (P = .0006) over the 3 months compared with baseline measurements. Pain medicine use also improved: The median morphine equivalents among patients who were taking pain medications at the time of study enrollment showed a substantial decline after 1 cycle of treatment that was maintained. Pain (as assessed by the Brief Pain Inventory) improved compared with baseline pain at the 2nd-month assessment (worst pain, P = .08; least pain, P = .02; and average pain, P = .003). Overall, the regimen was tolerated well. The most common side effects were mild fatigue and gastrointestinal complaints (all of which were Grade 1 or 2 [according to Version 2.0 of the Expanded Common Toxicity Criteria]). Seventeen patients (37%) experienced Grade 3 or 4 neutropenia. Five patients (11%) developed a cardiac ejection fraction of <50% during treatment and had doxorubicin discontinued. No patients developed clinical congestive heart failure. CONCLUSIONS: The NAP combination produced substantive palliation and a moderate response rate in men with AIPC.

Clark PE, Hall MC, Borden LS, Miller AA, Hu JJ, Lee WR, Stindt D, D'Agostino R, Lovato J, Harmon M, Torti FM. · Department of Urology and Comprehensive Cancer Center, Wake Forest University Health Sciences, Winston-Salem, North Carolina 27157, USA. · Urology. · Pubmed #16765186 No free full text.

Abstract: OBJECTIVES: To report a prospective trial of lycopene supplementation in biochemically relapsed prostate cancer. METHODS: A total of 36 men with biochemically relapsed prostate cancer were enrolled in a dose-escalating, Phase I-II trial of lycopene supplementation. Six consecutive cohorts of 6 patients each received daily supplementation with 15, 30, 45, 60, 90, and 120 mg/day for 1 year. The serum levels of prostate-specific antigen (PSA) and plasma levels of lycopene were measured at baseline and every 3 months. The primary endpoints were PSA response (defined as a 50% decrease in serum PSA from baseline), pharmacokinetics, and the toxicity/tolerability of this regimen. RESULTS: A total of 36 patients were enrolled. The median age was 74 years (range 56 to 83), with a median serum PSA at entry of 4.4 ng/mL (range 0.8 to 24.9). No serum PSA responses were observed, and 37% of patients had PSA progression. The median time to progression was not reached. Toxicity was mild, with 1 patient discontinuing therapy because of diarrhea. Significant elevations of plasma lycopene were noted at 3 months and then appeared to plateau for all six dose levels. The plasma levels for doses between 15 and 90 mg/day were similar, with additional elevation only at 120 mg/day. CONCLUSIONS: Lycopene supplementation in men with biochemically relapsed prostate cancer is safe and well tolerated. The plasma levels of lycopene were similar for a wide dose range (15 to 90 mg/day) and plateaued by 3 months. Lycopene supplementation at the doses used in this study did not result in any discernible response in serum PSA.

Clark PE, Peereboom DM, Dreicer R, Levin HS, Clark SB, Klein EA. · Urology Institute, Cleveland Clinic Foundation, Cleveland, Ohio, USA. · Urology. · Pubmed #11182337 No free full text.

Abstract: OBJECTIVES: To report the results of a Phase II trial of neoadjuvant estramustine and etoposide before radical prostatectomy in patients with locally advanced disease. METHODS: Treatment consisted of three cycles of estramustine (10 mg/kg/day) and etoposide (50 mg/m(2)/day) orally on days 1 through 21, repeated every 28 days, followed by radical prostatectomy. The eligibility criteria included locally advanced prostate cancer (clinical Stage T2b/c or T3, prostate-specific antigen [PSA] level of 15 ng/mL or greater, or Gleason score of 8 or higher) without evidence of metastatic disease. The median PSA level was 14 ng/mL (range 5.3 to 50), the median Gleason score was 7 (range 6 to 9), and 44% had Stage T2b/c or T3 disease. The primary endpoint was feasibility of neoadjuvant therapy and radical prostatectomy, including drug and surgery-related toxicities. Secondary endpoints included the pre-prostatectomy PSA level, local response, pathologic outcomes, and time to PSA failure. RESULTS: Eighteen patients were entered and completed all three cycles of therapy, and 16 (89%) underwent radical prostatectomy. A local response occurred in 15 (94%) of 16 patients with palpable tumors, and the serum PSA reached undetectable levels after therapy and before radical prostatectomy in 9 patients (50%). Five patients (28%) experienced grade 3 toxicity (two with deep venous thrombosis, two with neutropenia, and one with diarrhea) and one (6%) experienced grade 4 toxicity (pulmonary embolus) before surgery. The median operative time was 125 minutes, the mean blood loss was 665 mL, and the mean length of stay was 2.5 nights. Five minor surgical complications occurred in 4 patients. The pathologic analysis demonstrated residual carcinoma with squamous metaplasia and androgen deprivation effect in all patients. Five patients (31%) had organ-confined disease and 9 patients (56%) had specimen-confined disease. All patients achieved an undetectable PSA level postoperatively and at a median follow-up of 14 months (range 5 to 20) and without additional therapy, all 14 patients with negative lymph nodes were disease free. CONCLUSIONS: This trial confirms the feasibility of radical prostatectomy with acceptable surgical morbidity after neoadjuvant therapy with estramustine and etoposide in patients with locally advanced prostate cancer. However, this regimen is associated with estramustine-induced thromboembolic toxicity. The results of the pathologic analysis suggest a higher than expected rate of organ-confined and specimen-confined disease, but little histologic evidence of antitumor effect beyond that associated with androgen deprivation. Additional study of this paradigm with other drug regimens is warranted.

Lewis JE, Soler-Vilá H, Clark PE, Kresty LA, Allen GO, Hu JJ. · Department of Psychiatry and Behavioral Sciences, University of Miami Miller School of Medicine, 1120 NW 14th Street, Miami, FL 33136, USA. · Nutr Cancer. · Pubmed #19235037 No free full text.

Abstract: Plant foods and associated nutrients may impact prostate cancer (PC) risk and survival. Therefore, we compared dietary intake, mainly plant food groups among 382 controls and 478 PC cases (373 incident and 105 prevalent cases). Caucasian controls had significantly higher daily servings of vegetables (3.4 vs. 2.5, P= 0.002) and fruits and/or fruit juices (1.6 vs. 1.3, P = 0.02) compared to African American controls. In Caucasians, incident cases reported lower intake of fiber, vitamin C, vitamin A, alpha -carotene, beta -carotene, cryptoxanthin, folate, genistein, daidzein, and fruits and/or fruit juice than controls and/or prevalent cases. In African Americans, incident cases had lower intake of alpha -carotene compared to controls and prevalent cases. Reduced PC risk was associated with the highest tertile of cryptoxanthin (OR = 0.51; 95% CI = 0.35-0.75), fiber (OR = 0.56; 95% CI = 0.35-0.89), vitamin C (OR = 0.60; 95% CI = 0.41-0.88), and fruits and/or fruit juices (OR = 0.46; 95% CI = 0.31-0.68), with significant linear trends. Increased risk of PC was associated with the highest tertile of protein (OR = 1.99; 95% CI = 1.05-3.79) and daily servings of grains (OR = 1.99; 95% CI = 1.23-3.22) with significant linear trends. In summary, we demonstrate racial/ethnic differences in dietary intake of plant foods. The significantly higher consumption of protective dietary constituents among prevalent cases compared to incident cases suggests that PC survivors may be amenable to dietary change.

Blum DL, Koyama T, M'Koma AE, Iturregui JM, Martinez-Ferrer M, Uwamariya C, Smith JA, Clark PE, Bhowmick NA. · Department of Urologic Surgery, Vanderbilt-Ingram Cancer Center, Vanderbilt University, Nashville, Tennessee 37232, USA. · Clin Cancer Res. · Pubmed #19047106 No free full text.

Abstract: PURPOSE: Stratifying patients who have a high risk of prostate cancer recurrence following prostatectomy can potentiate the use of adjuvant therapy at an early stage. Inflammation has emerged as a mediator of prostate cancer metastatic progression. We hypothesized that chemokines can be biomarkers for distinguishing patients with high risk for biochemical recurrence of prostate cancer. EXPERIMENTAL DESIGN: In a nested case-control study, 82 subjects developed biochemical recurrence within 5 years of prostatectomy. Prostate tissues from 98 age-matched subjects who were recurrence-free following prostatectomy in the same period were the controls. A high-throughput lectin-based enrichment of prostate tissue enabled multiplex ELISA to identify the expression of three chemokines to discriminate the two patient populations. RESULTS: The expression of CX3CL1 and IL-15 in prostate tissue was associated with 5-year biochemical recurrence-free survival following prostatectomy. However, the expression of chemokine ligand 4 (CCL4) was associated with biochemical recurrence. Multivariable logistic regression model combining preoperative prostate-specific antigen, Gleason score, surgical margin, and seminal vesicle status with the three chemokines doubled the specificity of prediction at 90% sensitivity compared with use of the clinicopathologic variables alone (P < 0.0001). Survival analysis yielded a nomogram that supported the use of CX3CL1, IL-15, and CCL4 in predicting 1-, 3-, and 5-year recurrence-free survival after prostatectomy. CONCLUSIONS: Each of the three chemokines can serve as independent predictors of biochemical recurrence. However, the combination of chemokine biomarkers plus clinicopathologic variables discriminated prostatectomy subjects for the probability of biochemical recurrence significantly better than clinicopathologic variables alone.

Rossi PJ, Urbanic J, Clark PE, McCullough DL, Lee WR. · Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA 30322, USA. · Brachytherapy. · Pubmed #18928924 No free full text.

Abstract: PURPOSE: This report examines the relationship between pretreatment prostate-specific antigen (PSA) velocity (PSAV) and freedom from biochemical recurrence (FFBR) in men with prostate cancer treated with low-dose-rate prostate brachytherapy (LDRPB). METHODS AND MATERIALS: This is a report of 51 men treated with LDRPB between 1997 and 1999. Inclusion criteria: two or more evaluable PSA values >3 months apart and <18 months before treatment. PSAV is calculated using a linear regression equation. All patients had biopsy confirmed, clinically localized prostate cancer. All men were treated with (125)I LDRPB. The prescription dose was 144Gy. Biochemical failure is determined from PSA values over time using the ASTRO Consensus Definition. FFBR is estimated using Kaplan-Meier method. Pretreatment variables analyzed include percentage positive biopsy cores, D(90), risk group, and PSAV. All p values are two-sided. RESULTS: The median followup is 60 months. The median pretreatment PSA is 6.5, 75% of men were Stage T1c, and 88% had Gleason score > or =6; 10% developed evidence of biochemical recurrence at a median of 13 months (range, 6-36). The 6-year estimate of FFBR is 90% for the entire cohort. On univariate analysis, pretreatment PSAV and risk group are associated with FFBR. The 6-year estimate of FFBR in patients with a PSAV <2 ng/mL/yr is 100% vs. 80% (95% confidence interval: 64-96%) when the pretreatment PSAV is > or =2 ng/mL/yr before LDRPB (p = 0.017). CONCLUSIONS: Pretreatment PSAV is a predictor of FFBR after LDRPB in this population of men with prostate cancer. Men with a pretreatment PSAV > or =2 ng/mL/yr may warrant more aggressive treatment.

Chan RC, Barocas DA, Chang SS, Herrell SD, Clark PE, Baumgartner R, Smith JA, Cookson MS. · Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, TN 37232-2765, USA. · BJU Int. · Pubmed #18399829 No free full text.

Abstract: OBJECTIVE: To evaluate the outcomes based on gland size between robotically assisted radical prostatectomy (RALP) and open RP (RRP), as larger prostates might increase the difficulty of RP. PATIENTS AND METHODS: We reviewed 660 patients who had RALP and 340 who had RRP from May 2003 to August 2006; the patients were divided into two groups, with a prostate of >75 and <or=75 g. The clinical characteristics, surgical approach, perioperative and postoperative outcomes were evaluated. RESULTS: Patients with large prostates were significantly older (P < 0.001), but had a lower pathological stage (RALP, P = 0.046, and RRP, P = 0.008) than patients with small glands, regardless of technique. There was no difference in length of stay or transfusion rates between the groups. A large prostate increased the operative duration of RALP (P < 0.001) but not of RRP. For both RALP and RRP, positive margin rates were lower with larger glands (RALP, P = 0.014; RRP, P = 0.033). Overall, the positive margin rates were lower with RALP (9.9% and 19.0%) than RRP (18.5% and 35.5%) among patients with larger or smaller (P < 0.001) glands, respectively. CONCLUSIONS: Prostates of >or=75 g had fewer positive margins than smaller glands, regardless of surgical technique. There was also a significant decrease in positive margin rate in among prostates of >75 g in favour of RALP. Thus, RALP appears to be comparable with RRP for patients with large glands, and might reduce the positive margin rate.

Zabaleta J, Lin HY, Sierra RA, Hall MC, Clark PE, Sartor OA, Hu JJ, Ochoa AC. · Department of Genetics, Louisiana State University Health Sciences Center, 533 Bolivar Street, CSRB 455, New Orleans, LA 70112, USA. · Carcinogenesis. · Pubmed #18174250 links to  free full text

Abstract: Prostate cancer (CaP) is the second leading cause of cancer death in American men. Chronic inflammation has been one of several factors associated with the development of CaP. Single-nucleotide polymorphisms (SNPs) in cytokine genes have been associated with increased inflammation, increased cytokine production and possibly increased CaP risk. However, the effects of cytokine SNPs on CaP susceptibility have not been consistent. Using the genomic DNA collected in a CaP case-control study (557 cases and 547 controls), we pilot tested the interactions of nine functionally characterized SNPs of three cytokine genes in CaP risk using the multivariate adaptive regression splines (MARS)-logit models. African-Americans with the IL10-819TT genotype had a lower CaP risk [odds ratio (OR) = 0.27, 95% confidence interval (CI) = 0.07-1.01], but subjects with the genotype combination of IL1B-511CT/TT and IL10-592CC had a higher CaP risk (OR = 2.56, 95% CI = 1.09-6.02). In Caucasians, higher CaP risk was associated with the IL10-1082AG/GG genotype (OR = 3.62, 95% CI = 1.42-9.28), the genotype combination of IL10-1082AA plus IL1B-31TT/TC (OR = 2.92, 95% CI = 1.13-7.55) and the genotype combination of TNF-238GG plus IL10-592AA (OR = 2.14, 95% CI = 1.05-4.38). Our results highlight the importance of cytokine SNPs and their interactions in CaP risk.

Smith JA, Chan RC, Chang SS, Herrell SD, Clark PE, Baumgartner R, Cookson MS. · Department of Urologic Surgery, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2765, USA. · J Urol. · Pubmed #17936849 No free full text.

Abstract: PURPOSE: Surgical technique, patient characteristics and method of pathological review may influence surgical margin status. We evaluated the incidence and location of positive surgical margins in 200 sequential robotic assisted laparoscopic radical prostatectomy and 200 sequential open radical retropubic prostatectomy cases. MATERIALS AND METHODS: From July 2002 until December 2006 a total of 1,747 patients underwent radical prostatectomy at our institution (robotic assisted laparoscopic radical prostatectomy in 1,238, radical retropubic prostatectomy in 509). From these we selected the last 200 consecutive radical retropubic prostatectomies and 200 robotic assisted laparoscopic radical prostatectomies performed before August 2006. Preoperative clinical characteristics including age, clinical stage, prostate specific antigen and Gleason score were evaluated. Postoperatively pathological specimens were assessed for specimen weight, Gleason score, tumor volume, pathological stage and margin status. The incidence and location of positive surgical margins were compared between robotic assisted laparoscopic radical prostatectomy and radical retropubic prostatectomy. RESULTS: Patients undergoing robotic assisted laparoscopic radical prostatectomy compared to radical retropubic prostatectomy had more favorable tumor characteristics including lower prostate specific antigen, clinical stage and Gleason score. No statistically significant differences were found between groups for prostate volume or tumor volume. However, tumor volume as a percentage of prostate volume was higher among radical retropubic prostatectomy compared to robotic assisted laparoscopic radical prostatectomy cases (17.7% vs 13%, p = 0.001). The overall incidence of positive surgical margins was significantly lower among the robotic assisted laparoscopic radical prostatectomy compared to radical retropubic prostatectomy cases (15% vs 35%, p <0.001). The incidence of positive surgical margins according to pathological stage for robotic assisted laparoscopic radical prostatectomy vs radical retropubic prostatectomy cases was 16 of 171 (9.4%) vs 33 of 137 (24.1%) for pT2 (p <0.001) and 14 of 28 (50%) vs 36 of 60 (60%) for pT3. In both groups the apex was the most common site of positive surgical margins with 52% in the robotic assisted laparoscopic radical prostatectomy group vs 37% in the radical retropubic prostatectomy group (p >0.05). CONCLUSIONS: In the hands of surgeons experienced in robotic assisted laparoscopic radical prostatectomy and radical retropubic prostatectomy, there was a statistically significant lower positive margin rate for patients undergoing robotic assisted laparoscopic radical prostatectomy. The most common location of a positive surgical margin in robotic assisted laparoscopic radical prostatectomy and radical retropubic prostatectomy cases was at the apex. Patients treated with radical retropubic prostatectomy had higher risk features which may have independently influenced these results. The method of pathological specimen analysis and reporting may account for the higher positive margin rates in both groups compared to some reports.

Yacoub J, Richardson C, Farmer M, Lee WR, Clark PE, Hurt G, Levine EA. · Department of Radiation Oncology, Wake Forest University, Winston-Salem, NC 27157, USA. · Clin Adv Hematol Oncol. · Pubmed #17679929 No free full text.

This publication has no abstract.

Phillips JJ, Hall MC, Lee WR, Clark PE. · Department of Urology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. · Urol Oncol. · Pubmed #17483015 No free full text.

Abstract: PURPOSE: To assess whether a delay in initiating definitive therapy for clinically localized prostate cancer affects outcome. METHODS: We retrospectively reviewed 393 men with localized prostate cancer treated with radiation therapy or surgery without systemic therapy between 1991 and 2004. Data included: time from diagnosis to treatment initiation (more or less than 3 months); biopsy Gleason score grouped by low (2-6), intermediate (7), or high risk (8-10); clinical stage grouped by low (T1/T2a) or high risk (T2b or higher); pretreatment prostate-specific antigen (PSA) grouped by low (<10 ng/ml), intermediate (10-20), or high risk (>20); and biochemical recurrence-free survival. RESULTS: Median patient age was 63.1 years (range 39.7-79.5). Median pretreatment PSA was 6.5 ng/ml (range 0.4-411). Median time from diagnosis to treatment was 57 days (range 8-2927). A total of 310 patients (79%) were treated within 3 months. Median follow-up was 2.3 years (range 0.1-14.0). On univariate analysis using Kaplan-Meier survival curves and the log-rank test, only pretreatment PSA was associated with worse biochemical recurrence-free survival (P = 0.008). Biochemical recurrence-free survival was not associated with time from diagnosis to treatment (P = 0.28), clinical stage (P = 0.50), or biopsy Gleason score (P = 0.19). The results were the same when analyzed in a multivariable analysis using the Cox proportional hazards model. CONCLUSION: A delay in treatment of > or =3 months does not appear to affect adversely biochemical recurrence-free survival in patients who undergo definitive therapy for clinically localized prostate cancer in those with low risk features.

Papagikos MA, Rossi PJ, Urbanic JJ, deGuzman AF, McCullough DL, Clark PE, Lee WR. · Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, USA. · Am J Clin Oncol. · Pubmed #17414471 No free full text.

Abstract: OBJECTIVE: The objective of this study was to describe a simple model that predicts freedom from biochemical recurrence (FFBR) in men with prostate cancer after treatment with low-dose rate prostate brachytherapy (LDRPB) alone. MATERIALS AND METHODS: One hundred thirty-two men were treated with LDRPB alone between September 1997 and April 2001. Sixty-four percent of men had low-risk disease (prostate-specific antigen [PSA] <10, Gleason <7, and T stage <T2b) and 36% had intermediate-risk disease (PSA > or =10, Gleason > or =7, or T stage T2b). The dosimetric quantifier D90 was calculated from a computed tomography scan performed 1 month after LDRPB. The percent positive biopsies (PPB) were determined for all patients. FFBR was estimated using the product limit method. All P values are 2-sided. RESULTS: The median follow-up is 65 months. The median D90 is 138 Gy (range, 47-221 Gy). Fourteen men have developed evidence of biochemical relapse at a median of 27 months (range, 6-42 months). The 5-year FFBR rate for the entire cohort is 88%. On univariate analysis, variables found to be associated with FFBR included: PSA, Gleason score, T stage, risk group, PPB, and D90. Multivariate analysis indicated that D90, PPB, and risk group were independently associated with FFBR. Patients were categorized based on the following 3 adverse prognostic factors: D90 <140 Gy, PPB > or =50%, and intermediate-risk group. Group 1 (0 factors, n = 30), group 2 (1 factor, n = 72), and group 3 (> or =2 factors, n = 30) patients had 5-year FFBR rates of 100% (+/-0%), 92% (+/-6%), and 67% (+/-18%) (P < 0.0001). CONCLUSIONS: We have developed a simple, robust model based on implant quality and disease factors that predicts FFBR in men with prostate cancer treated with LDRPB alone.

Rossi PJ, Clark PE, Papagikos MA, McCullough DL, Lee WR. · Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, North Carolina 27157-1030, USA. · Urology. · Pubmed #16461084 No free full text.

Abstract: OBJECTIVES: To examine the relationship between the percentage of positive biopsies (PPBs) and freedom from biochemical recurrence (FFBR) in men treated with low-dose-rate prostate brachytherapy (LDRPB) alone. The PPBs has been associated with FFBR in men treated with radical prostatectomy and external beam radiotherapy for prostate cancer. METHODS: This report concerns 108 men treated with LDRPB alone between November 1997 and December 1999. All patients had clinically localized prostate cancer confirmed by biopsy. All men were treated with iodine-125 to 144 Gy. FFBR was estimated using the product-limit method. Putative covariates for FFBR, including T stage, Gleason score, pretreatment prostate-specific antigen level, minimal dose received by 90% of the target volume, and PPBs, were examined using the proportional hazards regression model. RESULTS: The median follow-up was 61 months. Of the 108 men, 13 developed evidence of biochemical relapse at a median of 25 months. The 5-year estimate of FFBR was 87% (95% confidence interval 81% to 93%) for the entire cohort. On univariate analysis, prostate-specific antigen, T stage, minimal dose received by 90% of the target volume, and PPBs were associated with FFBR. In the multivariate model, the PPBs was the only variable that predicted for FFBR (P = 0.002). The 5-year estimate of FFBR was 95% for patients with less than 50% PPB disease versus 63% in patients with more than 50% PPB disease (P < 0.0001). CONCLUSIONS: The PPBs is an important independent predictor of FFBR after LDRPB alone. The FFBR after LDRPB in the group of patients with more than 50% PPBs was poor.

Lockett KL, Hall MC, Clark PE, Chuang SC, Robinson B, Lin HY, Su LJ, Hu JJ. · Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA. · Carcinogenesis. · Pubmed #16364923 links to  free full text

Abstract: This study used the alkaline Comet assay to evaluate whether basal or H2O2-induced DNA damage is associated with prostate cancer (CaP) risk. Using lymphocyte samples from 158 CaP cases and 128 controls, collected in an ongoing case-control study, our results showed that basal DNA damage did not differ between cases and controls. However, the H2O2-induced DNA damage level was significantly higher in incident cases (mean +/- SD; 6.61 +/- 4.43, n = 102) than controls (5.30 +/- 3.60, n = 128) or prevalent cases (4.47 +/- 3.19; n = 56). Incident cases with a positive smoking history had significantly higher H2O2-induced DNA damage than never-smokers (7.57 +/- 4.82 versus 4.52 +/- 2.40; P < 0.001). Above-median H2O2-induced DNA damage was associated with a 1.61-fold increase in CaP risk [95% confidence interval (CI) = 0.92-2.81], after adjustment for age, race, benign prostatic hyperplasia (BPH), smoking history and family history (FH). Using the lowest quartile of H2O2-induced DNA damage as the referent group, the adjusted ORs for the 25th, 50th and 75th quartiles were 0.90 (95% CI = 0.39-2.05), 1.06 (95% CI = 0.48-2.35) and 2.05 (95% CI = 0.96-4.37), respectively (P = 0.046, test for linear trend). The association between CaP and DNA damage was modified by age, smoking history, family history and body mass index. Our results suggest that DNA damage may be associated with CaP risk. However, larger case-control and follow-up studies are warranted to further evaluate the potential application of the alkaline Comet assay in CaP risk assessment and prevention.

Papagikos MA, Deguzman AF, Rossi PJ, McCullough DL, Clark PE, Lee WR. · Department of Radiation Oncology, Wake Forest University School of Medicine, Winston-Salem, NC 27157-1030, USA. · Brachytherapy. · Pubmed #16344254 No free full text.

Abstract: PURPOSE: The purpose of the present report is to describe the relationship between two dosimetric quantifiers (V(100) and D(90)) and freedom from biochemical recurrence (FFBR) in a cohort of men treated with low-dose-rate prostate brachytherapy (LDRPB) alone. METHODS AND MATERIALS: One hundred three men were treated with LDRPB alone between September 1997 and December 1999. All men had histologically confirmed clinically localized prostate cancer. Fifty-nine percent of the cohort had low-risk disease (defined as PSA<10, Gleason <7, and T stage <T2b), and 41% had intermediate-risk disease (defined as PSA>/=10, Gleason>/=7, or T stage T2b). The prescription dose was 144Gy according to the Task Group 43 formalism. LDRPB was performed jointly by a radiation oncologist and a urologist. Dosimetric quantifiers (D(90), V(100)) were calculated from a CT scan performed 1 month after LDRPB. Biochemical recurrence was defined according to the ASTRO Consensus Definition. FFBR was estimated using the product-limit method. Disease-specific and treatment variables were examined as putative covariates for FFBR using the proportional hazards regression method. Univariate and multivariate methods were used. All p values are two sided. RESULTS: The median followup for the entire cohort is 61 months. The median followup of patients at risk for biochemical failure is 66 months. The median D(90) is 129Gy (range 47-221Gy), and the median V(100) is 86% (range 51-99%). Thirteen men have developed evidence of biochemical relapse at a median of 25 months (range 6-42 months). The 5-year estimate of FFBR for the entire cohort is 87% (95% CI 80-94%). On univariate analysis, disease-specific variables found to be significantly associated with FFBR included pretreatment PSA and percent positive biopsies. When considered as a continuous variable, each of the dosimetric quantifiers was associated with FFBR (V(100): p=0.007; D(90): p=0.05). D'Amico risk group classification is highly predictive of FFBR after LDRPB (HR 5.68, p=0.003). Multivariate analysis indicated that each dosimetric quantifier was independently associated with FFBR, but due to the high degree of correlation (Pearson correlation coefficient 0.94, p<0.0001) between the dosimetric quantifiers both could not be included simultaneously in the model. In the two models explored, V(100) was at least as good as D(90) in predicting FFBR. CONCLUSIONS: Dosimetric quantifiers (V(100) and D(90)) are independent predictors of FFBR after treatment with LDRPB alone. In our experience, V(100) seems to be at least equivalent (and perhaps superior) to D(90) for predicting FFBR.

Lockett KL, Hall MC, Xu J, Zheng SL, Berwick M, Chuang SC, Clark PE, Cramer SD, Lohman K, Hu JJ. · Department of Cancer Biology, Wake Forest University School of Medicine, Winston-Salem, North Carolina, 27157, USA. · Cancer Res. · Pubmed #15342424 links to  free full text

Abstract: The ADP-ribosyltransferase (ADPRT) gene encodes a zinc-finger DNA-binding protein, poly(ADP-ribose) polymerase-1 (PARP-1), that modifies various nuclear proteins by poly(ADP-ribosyl)ation and functions as a key enzyme in the base excision repair pathway. We have conducted two studies to test whether an amino acid substitution variant, ADPRT V762A (T2444C), is associated with prostate cancer (CaP) risk and decreased enzyme function. The first study used genomic DNA samples from an ongoing, clinic-based case-control study (488 cases and 524 controls) to show that a higher percentage of the CaP cases carried the ADPRT 762 AA genotype than controls (4% versus 2%). In Caucasians, the AA genotype was significantly associated with increased CaP risk [odds ratio (OR), 2.65; 95% confidence interval (CI), 1.08-6.49], and the VA genotype was associated with a slight but not significantly increased CaP risk (OR, 1.18; 95% CI, 0.85-1.64) using VV as the referent group after adjustment for age, benign prostatic hyperplasia, and family history. Furthermore, this association was stronger in younger (<65) men (OR, 4.77; 95% CI, 1.01-22.44) than older (> or =65) men (OR, 1.78; 95% CI, 0.55-5.82). The second study used freshly isolated peripheral lymphocytes from 354 cancer-free subjects to demonstrate that the ADPRT 762 A allele contributed to significantly lower adenosine diphosphate ribosyl transferase (ADPRT)/PARP-1 activities in response to H2O2 in a gene dosage-dependent manner (P < 0.0001, test for linear trend). The PARP-1 activities (mean +/- SD dpm/10(6) cells) were 18,554 +/- 9,070 (n=257), 14,847 +/- 7,082 (n=86), and 12,155 +/- 6,334 (n=11) for VV, VA, and AA genotypes, respectively. This study is the first to provide evidence that the ADPRT V762A-genetic variant contributes to CaP susceptibility and altered ADPRT/PARP-1 enzyme function in response to oxidative damage.

Jia L, Kim J, Shen H, Clark PE, Tilley WD, Coetzee GA. · Department of Urology, Norris Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, CA 90033, USA. · Mol Cancer Res. · Pubmed #12651911 links to  free full text

Abstract: Ligand-activated androgen receptors (ARs) occupy target genes and recruit histone modifiers that influence transcriptional competency. In LNCaP prostate cancer cells, the natural ligand 5alpha-dihydrotestosterone (DHT) activates transiently transfected AR-responsive promoter constructs; concurrent treatment with the protein kinase A activator forskolin enhanced AR stimulation induced by DHT. Additional treatment with the cytokine IL-6, purportedly an AR activator, markedly inhibited receptor activity. To assess AR activity on natural chromatin-integrated promoters/enhancers, we determined AR occupancy of the endogenous prostate specific antigen (PSA) promoter/enhancer as well as PSA expression in LNCaP cells treated with DHT; AR occupancy of the PSA enhancer was rapid (within 1 h of stimulation), robust (10-fold over background), and sustained (8-16 h). In contrast, AR occupancy of the PSA promoter was only increased by 2-fold. Histone H3 acetylation at both the enhancer and promoter was evident 1-2 h after DHT treatment. Detectable pre- and mature PSA mRNA levels appeared after 1 and 6 h treatment, respectively. Substantial qualitative and quantitative differences in PSA expression and AR occupancy of the PSA enhancer were observed when DHT-induced and ligand-independent activations of the AR were compared; forskolin stimulated PSA mRNA and protein expression, whereas IL-6 inhibited both DHT- and forskolin-stimulated expression. IL-6 did not diminish DHT-dependent AR occupancy of the PSA enhancer but inhibited CBP/p300 recruitment, histone H3 acetylation, and cell proliferation. These findings provide a contextual framework for interpreting the contribution of non-steroidal activation of the AR to signaling in vivo, and have implications for prostate cancer cell growth.