Prostatic Neoplasms: Walther PJ

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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Montie JE, Abrahams NA, Bahnson RR, Eisenberger MA, El-Galley R, Herr HW, Hudes GR, Kuzel TM, Lange PH, Patterson A, Pollack A, Richie JP, Sexton WJ, Shipley WU, Small EJ, Trump DL, Walther PJ, Wilson TG, Anonymous00097. · No affiliation provided · J Natl Compr Canc Netw. · Pubmed #17112448 No free full text.

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Walther PJ. · No affiliation provided · Curr Opin Urol. · Pubmed #10858901 No free full text.

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Walther PJ. · No affiliation provided · Curr Opin Urol. · Pubmed #10726090 No free full text.

Abstract: As a result of the recent resurgence of interest in interstitial brachytherapy, extended follow-up studies of early experience in this field are now being reported. However, such outcomes must be evaluated within the context of recent comprehensive assessments of the age-specific natural history of conservatively managed prostate cancer ('watchful waiting', i.e. no curative intervention). This raises issue with the contention that treating patients with low-grade cancer using brachytherapy alone results in a treatment-derived, extended, clinical-progression-free survival. The necessity for proposed randomized trials of brachytherapy (compared with conservative management in low-grade disease, and brachytherapy plus external beam radiotherapy) is discussed in this context. There is no consensus regarding the best modality for the treatment of localized prostate cancer, since no well-accepted, adequately powered randomized trial of competing modalities for this disease has ever been completed. Consequently, it has become common while counseling patients with the disease to place substantial emphasis on 'quality of life' considerations and the 'outcomes uncertainty management' issues associated with each option of therapy. There is even a question of whether every patient who is diagnosed with prostate cancer should be treated. However, while the importance of the variable biologic risk is generally widely accepted by experienced physicians caring for such patients, it is extremely difficult for the individual patient to weigh the evidence of the relative risks of progression dispassionately at the time of diagnosis. In this review, I wish to highlight several papers that have been published within the past year that are important in addressing this ongoing clinical problem. Any physician counseling patients about localized prostate cancer treatment should read and become familiar with the data herein: papers addressing the issues of interstitial brachytherapy outcomes, and the natural history of prostate cancer itself.

Walther PJ. · Department of Surgery/Urology, Duke University Comprehensive Cancer Center, Durham, North Carolina, USA. · World J Urol. · Pubmed #10926086 No free full text.

Abstract: The medical management of hormone-refractory prostate cancer remains difficult and largely palliative. The development of effective antineoplastic agents has been frustrated by difficulty in the establishment of satisfactory objective response criteria for clinical trials. Nevertheless, recent trials indicate that mitoxantrone and spindle toxins such as docetaxel do show activity. Estramustine-based regimens have also been promising, and such combination regimens are now being explored rigorously. Benefiting from new molecular-biologic insights into the pathobiology of prostate cancer, novel strategies targeting new molecular pathways of cell regulation and cell-cell interaction (such as angiogenesis) are also being actively pursued.

Demark-Wahnefried W, Price DT, Polascik TJ, Robertson CN, Anderson EE, Paulson DF, Walther PJ, Gannon M, Vollmer RT. · Division of Urologic Surgery, Duke University Medical Center, Durham, North Carolina, USA. · Urology. · Pubmed #11445478 links to  free full text

Abstract: OBJECTIVES: Dietary fat and fiber affect hormonal levels and may influence cancer progression. Flaxseed is a rich source of lignan and omega-3 fatty acids and may thwart prostate cancer. The potential effects of flaxseed may be enhanced with concomitant fat restriction. We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet could affect the biomarkers of prostatic neoplasia. METHODS: Twenty-five patients with prostate cancer who were awaiting prostatectomy were instructed on a low-fat (20% of kilocalories or less), flaxseed-supplemented (30 g/day) diet. The baseline and follow-up levels of prostate-specific antigen, testosterone, free androgen index, and total serum cholesterol were determined. The tumors of diet-treated patients were compared with those of historic cases (matched by age, race, prostate-specific antigen level at diagnosis, and biopsy Gleason sum) with respect to apoptosis (terminal deoxynucleotidyl transferase [TdT]-mediated dUTP-biotin nick end-labeling [TUNEL]) and proliferation (MIB-1). RESULTS: The average duration on the diet was 34 days (range 21 to 77), during which time significant decreases were observed in total serum cholesterol (201 +/- 39 mg/dL to 174 +/- 42 mg/dL), total testosterone (422 +/- 122 ng/dL to 360 +/- 128 ng/dL), and free androgen index (36.3% +/- 18.9% to 29.3% +/- 16.8%) (all P <0.05). The baseline and follow-up levels of prostate-specific antigen were 8.1 +/- 5.2 ng/mL and 8.5 +/- 7.7 ng/mL, respectively, for the entire sample (P = 0.58); however, among men with Gleason sums of 6 or less (n = 19), the PSA values were 7.1 +/- 3.9 ng/mL and 6.4 +/- 4.1 ng/mL (P = 0.10). The mean proliferation index was 7.4 +/- 7.8 for the historic controls versus 5.0 +/- 4.9 for the diet-treated patients (P = 0.05). The distribution of the apoptotic indexes differed significantly (P = 0.01) between groups, with most historic controls exhibiting TUNEL categorical scores of 0; diet-treated patients largely exhibited scores of 1. Both the proliferation rate and apoptosis were significantly associated with the number of days on the diet (P = 0.049 and P = 0.017, respectively). CONCLUSIONS: These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect prostate cancer biology and associated biomarkers. Further study is needed to determine the benefit of this dietary regimen as either a complementary or preventive therapy.

Demark-Wahnefried W, Polascik TJ, George SL, Switzer BR, Madden JF, Ruffin MT, Snyder DC, Owzar K, Hars V, Albala DM, Walther PJ, Robertson CN, Moul JW, Dunn BK, Brenner D, Minasian L, Stella P, Vollmer RT. · Division of Cancer Prevention and Population Sciences, The University of Texas M. D. Anderson Cancer Center, P.O. Box 301439, Unit 1330, Houston, TX 77230-1439, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #19064574 No free full text.

Abstract: BACKGROUND: Prostate cancer affects one of six men during their lifetime. Dietary factors are postulated to influence the development and progression of prostate cancer. Low-fat diets and flaxseed supplementation may offer potentially protective strategies. METHODS: We undertook a multisite, randomized controlled trial to test the effects of low-fat and/or flaxseed-supplemented diets on the biology of the prostate and other biomarkers. Prostate cancer patients (n = 161) scheduled at least 21 days before prostatectomy were randomly assigned to one of the following arms: (a) control (usual diet), (b) flaxseed-supplemented diet (30 g/d), (c) low-fat diet (<20% total energy), or (d) flaxseed-supplemented, low-fat diet. Blood was drawn at baseline and before surgery and analyzed for prostate-specific antigen, sex hormone-binding globulin, testosterone, insulin-like growth factor-I and binding protein-3, C-reactive protein, and total and low-density lipoprotein cholesterol. Tumors were assessed for proliferation (Ki-67, the primary endpoint) and apoptosis. RESULTS: Men were on protocol an average of 30 days. Proliferation rates were significantly lower (P < 0.002) among men assigned to the flaxseed arms. Median Ki-67-positive cells/total nuclei ratios (x100) were 1.66 (flaxseed-supplemented diet) and 1.50 (flaxseed-supplemented, low-fat diet) versus 3.23 (control) and 2.56 (low-fat diet). No differences were observed between arms with regard to side effects, apoptosis, and most serologic endpoints; however, men on low-fat diets experienced significant decreases in serum cholesterol (P = 0.048). CONCLUSIONS: Findings suggest that flaxseed is safe and associated with biological alterations that may be protective for prostate cancer. Data also further support low-fat diets to manage serum cholesterol.

Hoyo C, Grubber J, Demark-Wahnefried W, Marks JR, Freedland SJ, Jeffreys AS, Grambow SC, Wenham RM, Walther PJ, Schildkraut JM. · Department of Community and Family Medicine, Hanes House-Room 347, Trent Drive, Box 2914, Medical Center, Duke University Medical Center, Durham, NC 27710, USA. · J Natl Med Assoc. · Pubmed #17668637 links to  free full text

Abstract: Carrying the cytosine-adenosine (CA)19 repeat polymorphism in insulin-like growth factor-1 (IGF1) is associated with lower serum proteins and decreased prostate cancer risk. Carrying the -202A/C genotype in insulin-like growth factor binding protein-3 (IGFBP3) also has been associated with lower serum levels of the binding protein. However, the association between this variant and prostate cancer is inconsistent. To test the hypothesis that inconsistencies are partly due to cancer grade-specific differences in strength and direction of associations, we reanalyzed data from our previous Durham Veterans Administration Hospital study of blacks and whites comprising 47 cases (19 African Americans) with Gleason sum > or = 7, 50 cases (30 African Americans) with Gleason sum < 7 and 93 controls (49 African Americans). Compared to controls, the association between carrying the IGFBP3 C allele and prostate cancer risk was in OR(Low-Gleason) = 4.0; 95% CI: 1.4-12.3 compared to OR(High-Gleason) = 1.0; 95% CI: 0.4-2.2. Association patterns were similar in African Americans (OR(Low-Gleason) = 3.6; 95% CI: 1.0-13.2 vs. OR(High-Gleason) = 1.4; 95% CI: 0.4-2.3) and whites (OR(Low-Gleason) = 5.6; 95% CI: 0.6-49.0 vs. OR(High-Gleason) = 0.6; 95% CI: 0.2-2.2). The inverse association between carrying the IGF1 (CA)19 repeat variant did not vary by grade or ethnicity. If confirmed in larger studies, these findings support the hypothesis that the association between IGFBP3 C allele and prostate cancer is grade specific in both ethnic groups.

Wiygul JB, Evans BR, Peterson BL, Polascik TJ, Walther PJ, Robertson CN, Albala DM, Demark-Wahnefried W. · Division of Urology, Duke University Medical Center, Durham, North Carolina 27710, USA. · Urology. · Pubmed #15992901 No free full text.

Abstract: OBJECTIVES: To characterize supplement use within a sample population of men diagnosed with prostate cancer. METHODS: A census of men diagnosed with prostate cancer at Duke University Medical Center from 1997 to 2002 (n = 1402) was mailed a survey that ascertained data on health status, education, diet, exercise, smoking status, and information on supplement use. Differences between demographic and treatment subgroups were described and tested, as was change in supplement use after diagnosis. RESULTS: Data from 805 respondents indicated that a majority (73%) used supplements, and 68% claimed that this information was shared with their cancer care provider. The most commonly reported supplements were multivitamins (56%), vitamin E (43%), vitamin C (33%), and calcium (26%). On average, 2.7 +/- 2.8 supplements per day were taken, and use increased significantly after diagnosis for most supplements. Use was significantly higher among men who were white (P = 0.043), were more highly educated (P = 0.002), exercise regularly (P = 0.020), and who consume five or more daily servings of fruits and vegetables (P = 0.040). CONCLUSIONS: A high percentage of men with prostate cancer take supplements, especially those who are white, more educated, and who pursue healthful behaviors. Systematic means of capturing these data are necessary to begin to understand the potential impact of supplements on disease outcome, especially because no data exist to suggest that supplements are of any benefit after diagnosis.

Schildkraut JM, Demark-Wahnefried W, Wenham RM, Grubber J, Jeffreys AS, Grambow SC, Marks JR, Moorman PG, Hoyo C, Ali S, Walther PJ. · Program of Cancer Prevention, Detection and Control Research, Department of Community and Family Medicine, Duke University Medical Center, Durham, NC, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #15734965 links to  free full text

Abstract: We investigated the relationship between the insulin-like growth factor-1 (IGF1) cytosine-adenine repeat (CA)(19) polymorphism located upstream of the gene's transcription start site, the insulin-like growth factor binding protein-3 (IGFBP3) -202 A/C promoter region polymorphism, and prostate cancer risk in Black and White men. Study subjects were U.S. veterans ages 41 to 75 years identified at the Durham Veterans Administration Medical Center over a 2.5-year period. Controls (n = 93) were frequency matched to cases (n = 100) based on race (Black or White) and age. Multivariable unconditional logistic regression was used to calculate odds ratios (OR) and 95% confidence intervals (CI) for the associations between the polymorphisms and prostate cancer risk. For Blacks and Whites combined, an inverse association between prostate cancer and being homozygous for the most common IGF1 repeat allele, (CA)(19), (adjusted OR, 0.3; 95% CI, 0.1-0.7) was observed. Similar associations were noted for both Blacks (OR, 0.2; 95% CI, 0.0-0.8) and Whites (OR, 0.4; 95% CI, 0.1-1.6) separately. No statistically significant associations between the IGFBP3 C allele and prostate cancer were noted for Blacks (adjusted OR, 2.3; 95% CI, 0.8-6.2) or Whites (OR, 1.0; 95% CI, 0.3-3.1). The prevalence of the homozygous IGF1 (CA)(19) genotype was much lower in Black controls (21%) than White controls (46%), which may, in part, explain the increased prostate cancer incidence in Black versus White men. Further research is needed to confirm these findings.

Lippman SM, Goodman PJ, Klein EA, Parnes HL, Thompson IM, Kristal AR, Santella RM, Probstfield JL, Moinpour CM, Albanes D, Taylor PR, Minasian LM, Hoque A, Thomas SM, Crowley JJ, Gaziano JM, Stanford JL, Cook ED, Fleshner NE, Lieber MM, Walther PJ, Khuri FR, Karp DD, Schwartz GG, Ford LG, Coltman CA. · The University of Texas M.D. Anderson Cancer Center, Houston, TX 77030-4009, USA. · J Natl Cancer Inst. · Pubmed #15657339 links to  free full text

Abstract: Prostate cancer continues to be a major health threat, especially among African American men. The Selenium and Vitamin E Cancer Prevention Trial (SELECT), which opened on July 25, 2001, was planned to study possible agents for the prevention of prostate cancer in a population of 32,400 men in the United States, including Puerto Rico, and Canada. SELECT is a phase III randomized, placebo-controlled trial of selenium (200 microg/day from L-selenomethionine) and/or vitamin E (400 IU/day of all rac alpha-tocopheryl acetate) supplementation for a minimum of 7 years (maximum of 12 years) in non-African American men at least 55 years of age and African American men at least 50 years of age. SELECT is a large, simple trial that conforms as closely as possible with community standards of care. This commentary discusses the design problems the SELECT investigators had to resolve in developing the trial, including the role of prostate cancer screening, the best forms and doses of the study agents, and estimation of the event (prostate cancer) rate of men on the placebo arm.

Demark-Wahnefried W, Robertson CN, Walther PJ, Polascik TJ, Paulson DF, Vollmer RT. · Division of Urologic Surgery, Duke University Medical Center, Durham, North Carolina 27710, USA. · Urology. · Pubmed #15134976 links to  free full text

Abstract: OBJECTIVES: Dietary factors may influence the prostate and have an impact on prostatic growth and disease. A small number of studies have suggested that flaxseed-supplemented, fat-restricted diets may thwart prostate cancer growth in both animals and humans. Unknown, however, is the potential effect of such a diet on benign prostatic epithelium. METHODS: We undertook a pilot study to explore whether a flaxseed-supplemented, fat-restricted diet affects the proliferation rates in benign epithelium. We also explored the effects on circulating levels of prostate-specific antigen (PSA), total testosterone, and cholesterol. Fifteen men who were scheduled to undergo repeat prostate biopsy were instructed to follow a low-fat (less than 20% kcal), flaxseed-supplemented (30 g/day) diet and were provided with a supply of flaxseed to last throughout the 6-month intervention period. The PSA, total testosterone, and cholesterol levels were determined at baseline and at 6 months of follow-up. Reports from the original and repeat biopsies were compared, and proliferation (MIB-1) rates were quantified in the benign prostatic epithelium. RESULTS: Statistically significant decreases in PSA (8.47 +/- 3.82 to 5.72 +/- 3.16 ng/mL; P = 0.0002) and cholesterol (241.1 +/- 30.8 to 213.3 +/- 51.2 mg/dL; P = 0.012) were observed. No statistically significant change was seen in total testosterone (434.5 +/- 143.6 to 428.3 +/- 92.5 ng/dL). Although 6-month repeat biopsies were not performed in 2 cases because of PSA normalization, of the 13 men who underwent repeat biopsy, the proliferation rates in the benign epithelium decreased significantly from 0.022 +/- 0.027 at baseline to 0.007 +/- 0.014 at 6 months of follow-up (P = 0.0168). CONCLUSIONS: These pilot data suggest that a flaxseed-supplemented, fat-restricted diet may affect the biology of the prostate and associated biomarkers. A randomized controlled trial is needed to determine whether flaxseed supplementation, a low-fat diet, or a combination of the two regimens may be of use in controlling overall prostatic growth.

Chang CY, Walther PJ, McDonnell DP. · Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, North Carolina 27710, USA. · Cancer Res. · Pubmed #11751389 links to  free full text

Abstract: The pathophysiological mechanism(s) by which androgen independence develops in prostate cancer remains to be determined. The identification in many prostate cancer specimens of a mutant androgen receptor, T877A, with altered ligand specificity has provided an explanation for some treatment failures. The T877A mutant androgen receptor recognizes a number of nonandrogenic compounds, including certain estrogens, progestins, and even antiandrogens as androgens. However, a comprehensive screen for hormonal agents which display agonist activity on this mutant has not been performed. In this study, we characterized this clinically important receptor mutant further and found that it can be activated by a wide range of compounds, including a number of endogenous glucocorticoids. Among the most clinically relevant compounds identified are DOC and corticosterone, both of which can effectively activate the mutant receptor at concentrations normally found in blood. Dexamethasone, a synthetic glucocorticoid frequently used in various contexts for prostate cancer therapy, is also recognized as an androgen by the mutant receptor. These unexpected findings suggest the need to: (a) reassess the role of adrenally derived glucocorticoids in prostate cancer disease progression; and (b) recognize the potential for iatrogenic stimulation of disease progression with certain glucocorticoid interventions.

Denmark-Wahnefried W, Schildkraut JM, Thompson D, Lesko SM, McIntyre L, Schwingl P, Paulson DF, Robertson CN, Anderson EE, Walther PJ. · Division of Urology/Duke University Medical Center, Durham, North Carolina 27710, USA. · Cancer Epidemiol Biomarkers Prev. · Pubmed #10750672 links to  free full text

Abstract: Prostatic carcinoma is the leading cancer among American men, yet few risk factors have been established. Although increased androgen levels have long been associated with both prostatic carcinoma and baldness, to date no studies have shown an association between hair patterning and prostate cancer risk. A lack of standardized instruments to assess baldness or the assessment of hair patterning during uninformative periods of time may have precluded the ability of previous studies to detect an association. We hypothesized that baldness, specifically vertex baldness, should be assessed using standardized instruments and during early adulthood if an association with prostate cancer risk is to be found. To test this hypothesis, we included identical items related to hair patterning in surveys that were administered in two distinct prostate cancer case-control studies (Duke-based study, n = 149; 78 cases; 71 controls and community-based study, n = 130; 56 cases; 74 controls). In each, participants were provided with an illustration of the Hamilton Scale of Baldness and asked to select the diagrams that best represented their hair patterning at age 30 and again at age 40. From these data, the following five categories were created and compared: not bald (referent group); vertex bald early onset (by age 30); vertex bald later onset (by age 40); frontal bald early onset (by age 30); frontal bald later onset (by age 40); and frontal (at age 30) to vertex bald (at age 40). Separate analyses of the two studies are consistent and suggest an association between vertex baldness and prostate cancer [vertex bald early onset odds ratios, 2.44 [confidence interval (CI), 0.57-10.46)] and 2.11 (CI, 0.66-6.73), respectively; vertex bald later onset odds ratios, 2.10 (CI, 0.63-7.00) and 1.37 (CI, 0.47-4.06), respectively]. Although statistical significance was not achieved in either one of these studies, the concordance between the data suggests a need for future studies to determine whether early onset vertex baldness serves as a novel biomarker for prostate cancer and whether androgen production, metabolism, or receptor status differs among these men when compared to those who exhibit other types of hair patterning.