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Serum levels of phytanic acid are associated with prostate cancer risk.
J Urol. 2005 Nov;174(5):1824
Authors: Walsh PC
PMID: 16217297 [PubMed - indexed for MEDLINE]
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Can docetaxel plus estramustine prolong survival of men with metastatic hormone-refractory prostate cancer?
Nat Clin Pract Oncol. 2005 Feb;2(2):70-1
Authors: Sleijfer S, Stoter G
PMID: 16264874 [PubMed - indexed for MEDLINE]
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Regulation of prostaglandin metabolism by calcitriol attenuates growth stimulation in prostate cancer cells.
Cancer Res. 2005 Sep 1;65(17):7917-25
Authors: Moreno J, Krishnan AV, Swami S, Nonn L, Peehl DM, Feldman D
Calcitriol exhibits antiproliferative and pro-differentiation effects in prostate cancer. Our goal is to further define the mechanisms underlying these actions. We studied established human prostate cancer cell lines and primary prostatic epithelial cells and showed that calcitriol regulated the expression of genes involved in the metabolism of prostaglandins (PGs), known stimulators of prostate cell growth. Calcitriol significantly repressed the mRNA and protein expression of prostaglandin endoperoxide synthase/cyclooxygenase-2 (COX-2), the key PG synthesis enzyme. Calcitriol also up-regulated the expression of 15-hydroxyprostaglandin dehydrogenase, the enzyme initiating PG catabolism. This dual action was associated with decreased prostaglandin E2 secretion into the conditioned media of prostate cancer cells exposed to calcitriol. Calcitriol also repressed the mRNA expression of the PG receptors EP2 and FP, providing a potential additional mechanism of suppression of the biological activity of PGs. Calcitriol treatment attenuated PG-mediated functional responses, including the stimulation of prostate cancer cell growth. The combination of calcitriol with nonsteroidal anti-inflammatory drugs (NSAIDs) synergistically acted to achieve significant prostate cancer cell growth inhibition at approximately 2 to 10 times lower concentrations of the drugs than when used alone. In conclusion, the regulation of PG metabolism and biological actions constitutes a novel pathway of calcitriol action that may contribute to its antiproliferative effects in prostate cells. We propose that a combination of calcitriol and nonselective NSAIDs might be a useful chemopreventive and/or therapeutic strategy in men with prostate cancer, as it would allow the use of lower concentrations of both drugs, thereby reducing their toxic side effects.
PMID: 16140963 [PubMed - indexed for MEDLINE]
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Phase II trial of tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate cancer: high subjective and objective response in patients with symptomatic metastases.
J Urol. 2005 Nov;174(5):1808-13; discussion 1813
Authors: Raghavan D, Brandes LJ, Klapp K, Snyder T, Styles E, Tsao-Wei D, Lieskovsky G, Quinn DI, Ramsey EW
PURPOSE: Symptomatic, hormone refractory prostate cancer (HRCAP) is a major cause of morbidity with a median survival of less than 12 months and a 2-year survival of only up to 10% in most series. Mitoxantrone has been approved by the Food and Drug Administration for HRCAP. Preliminary data suggest that DPPE (N,N-diethyl-2-[4-(phenylmethyl) phenoxy]-ethanamine) or tesmilifene modulates cytotoxics to enhance the anticancer effect. In this phase II trial we assessed whether there is sufficient evidence of enhanced efficacy of DPPE and mitoxantrone to lead to a phase III clinical trial. MATERIALS AND METHODS: A total of 29 patients with a median age of 73 years, of whom 10% were older than 80 years, with progressive HRCAP received 5.3 mg/kg DPPE intravenously every 3 weeks, 12 mg/m mitoxantrone intravenously every weeks and 5 mg prednisone orally twice daily. All patients had pain at presentation, while 97% had bone metastases, 10% had liver metastases and 17% had lung metastases. Median prostate specific antigen (PSA) was 210 ng/ml (IQR 77 to 430). RESULTS: Of the patients 75% had some pain improvement, 66% had decreased analgesia, 59% had a PSA decrease of 50% or greater and 45% had a PSA decrease of 75% or greater. Actual (not actuarial) 2-year survival was 21%. CONCLUSIONS: Despite major limitations of historical comparison the PSA decrease and decreased symptoms with DPPE-mitoxantrone-prednisone compare favorably to those of mitoxantrone-prednisone and docetaxel-estramustine in the literature. The 2-year survival rate of 21% mandates further assessment. This will be tested in a phase III Southwest Oncology Group trial.
PMID: 16217292 [PubMed - indexed for MEDLINE]
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Re: luteinizing hormone-releasing hormone agonist effects on skeletal muscle: how hormonal therapy in prostate cancer affects muscular strength.
J Urol. 2005 Nov;174(5):2068-9
Authors: Marcora S, Oliver S, Callow N, Lemmey A, Stuart N
PMID: 16217402 [PubMed - indexed for MEDLINE]
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Phase II trial of tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate cancer: high subjective and objective response in patients with symptomatic metastases.
J Urol. 2005 Nov;174(5):1808-13; discussion 1813
Authors: Raghavan D, Brandes LJ, Klapp K, Snyder T, Styles E, Tsao-Wei D, Lieskovsky G, Quinn DI, Ramsey EW
PURPOSE: Symptomatic, hormone refractory prostate cancer (HRCAP) is a major cause of morbidity with a median survival of less than 12 months and a 2-year survival of only up to 10% in most series. Mitoxantrone has been approved by the Food and Drug Administration for HRCAP. Preliminary data suggest that DPPE (N,N-diethyl-2-[4-(phenylmethyl) phenoxy]-ethanamine) or tesmilifene modulates cytotoxics to enhance the anticancer effect. In this phase II trial we assessed whether there is sufficient evidence of enhanced efficacy of DPPE and mitoxantrone to lead to a phase III clinical trial. MATERIALS AND METHODS: A total of 29 patients with a median age of 73 years, of whom 10% were older than 80 years, with progressive HRCAP received 5.3 mg/kg DPPE intravenously every 3 weeks, 12 mg/m mitoxantrone intravenously every weeks and 5 mg prednisone orally twice daily. All patients had pain at presentation, while 97% had bone metastases, 10% had liver metastases and 17% had lung metastases. Median prostate specific antigen (PSA) was 210 ng/ml (IQR 77 to 430). RESULTS: Of the patients 75% had some pain improvement, 66% had decreased analgesia, 59% had a PSA decrease of 50% or greater and 45% had a PSA decrease of 75% or greater. Actual (not actuarial) 2-year survival was 21%. CONCLUSIONS: Despite major limitations of historical comparison the PSA decrease and decreased symptoms with DPPE-mitoxantrone-prednisone compare favorably to those of mitoxantrone-prednisone and docetaxel-estramustine in the literature. The 2-year survival rate of 21% mandates further assessment. This will be tested in a phase III Southwest Oncology Group trial.
PMID: 16217292 [PubMed - indexed for MEDLINE]
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Accumulation of p53 and reductions in XIAP abundance promote the apoptosis of prostate cancer cells.
Cancer Res. 2005 Sep 1;65(17):7717-23
Authors: Mohapatra S, Chu B, Zhao X, Pledger WJ
Toward the goal of developing effective treatments for prostate cancers, we examined the effects of cyclin-dependent kinase inhibitors on the survival of prostate cancer cells. We show that roscovitine, R-roscovitine, and CGP74514A (collectively referred to as CKIs) induce the apoptosis of LNCaP and LNCaP-Rf cells, both of which express wild-type p53. Apoptosis required caspase-9 and caspase-3 activity, and cytochrome c accumulated in the cytosol of CKI-treated cells. Amounts of p53 increased substantially in CKI-treated cells, whereas amounts of the endogenous caspase inhibitor XIAP decreased. CKIs did not appreciably induce the apoptosis of LNCaP cells treated with pifithrin-alpha, which prevents p53 accumulation, or of prostate cancer cells that lack p53 function (PC3 and DU145). Ectopic expression of p53 in PC3 cells for 44 hours did not reduce XIAP abundance or induce apoptosis. However, p53-expressing PC3 cells readily apoptosed when exposed to CKIs or when depleted of XIAP by RNA interference. These findings show that CKIs induce the mitochondria-mediated apoptosis of prostate cancer cells by a dual mechanism: p53 accumulation and XIAP depletion. They suggest that these events in combination may prove useful in the treatment of advanced prostate cancers.
PMID: 16140939 [PubMed - indexed for MEDLINE]
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Re: individualization of the biopsy protocol according to the prostate gland volume for prostate cancer detection.
J Urol. 2005 Nov;174(5):2068; author reply 2068
Authors: Kommu SS
PMID: 16217404 [PubMed - indexed for MEDLINE]
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Calcitonin increases invasiveness of prostate cancer cells: role for cyclic AMP-dependent protein kinase A in calcitonin action.
Int J Cancer. 2005 Nov 20;117(4):551-60
Authors: Sabbisetti VS, Chirugupati S, Thomas S, Vaidya KS, Reardon D, Chiriva-Internati M, Iczkowski KA, Shah GV
Calcitonin (CT) is synthesized and secreted in prostate epithelium, and its secretion from malignant prostates is several-fold higher than from benign prostates. CT receptor (CTR) is expressed in malignant prostate epithelium, and its activation stimulates growth of prostate cancer (PC) cells via activation of adenylyl cyclase and calcium/phospholipid pathways. To identify the role of "CT System" in prostate cancer, we tested the expression of CT and CTR mRNAs in invading tumor cells of prostate cancer specimens. The effect of CT on in vitro invasion of PC cell lines and on activation of gelatinases was also examined. The cells of primary tumors and those invading stroma co-expressed CT/CTR mRNAs. Exogenously added CT increased in vitro invasion of PC cell lines and caused a rapid, several-fold but transient increase in protein kinase A activity. In contrast, anti-CT serum caused a dose-dependent inhibition of in vitro invasion of PC-3M cells. CT also increased the concentration and activities of MMP-2 and MMP-9. Rp.cAMP, a competitive inhibitor of cAMP-dependent protein kinase A, myristoylated protein kinase A inhibitory peptide (PKI) as well as the expression of dominant negative form of PKA all attenuated basal in vitro invasion of PC-3M cells, and CT could not increase in vitro invasiveness in their presence. These results suggest that overexpression of "CT System" in invasive PC tumors significantly contributes to increased invasiveness of prostate cancer cells. The action of CT may be mediated by protein kinase A signaling, which subsequently leads to increased cell invasion and secretion of gelatinases.
PMID: 15929083 [PubMed - indexed for MEDLINE]
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Re: individualization of the biopsy protocol according to the prostate gland volume for prostate cancer detection.
J Urol. 2005 Nov;174(5):2068; author reply 2068
Authors: Kommu SS
PMID: 16217404 [PubMed - indexed for MEDLINE]
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HYAL1 hyaluronidase in prostate cancer: a tumor promoter and suppressor.
Cancer Res. 2005 Sep 1;65(17):7782-9
Authors: Lokeshwar VB, Cerwinka WH, Isoyama T, Lokeshwar BL
Hyaluronidases degrade hyaluronic acid, which promotes metastasis. HYAL1 type hyaluronidase is an independent prognostic indicator of prostate cancer progression and a biomarker for bladder cancer. However, it is controversial whether hyaluronidase (e.g., HYAL1) functions as a tumor promoter or as a suppressor. We stably transfected prostate cancer cells, DU145 and PC-3 ML, with HYAL1-sense (HYAL1-S), HYAL1-antisense (HYAL1-AS), or vector DNA. HYAL1-AS transfectants were not generated for PC-3 ML because it expresses little HYAL1. HYAL1-S transfectants produced < or = 42 milliunits (moderate overproducers) or > or = 80 milliunits hyaluronidase activity (high producers). HYAL1-AS transfectants produced <10% hyaluronidase activity when compared with vector transfectants (18-24 milliunits). Both blocking HYAL1 expression and high HYAL1 production resulted in a 4- to 5-fold decrease in prostate cancer cell proliferation. HYAL1-AS transfectants had a G2-M block due to decreased cyclin B1, cdc25c, and cdc2/p34 expression and cdc2/p34 kinase activity. High HYAL1 producers had a 3-fold increase in apoptotic activity and mitochondrial depolarization when compared with vector transfectants and expressed activated proapoptotic protein WOX1. Blocking HYAL1 expression inhibited tumor growth by 4- to 7-fold, whereas high HYAL1 producing transfectants either did not form tumors (DU145) or grew 3.5-fold slower (PC-3 ML). Whereas vector and moderate HYAL1 producers generated muscle and blood vessel infiltrating tumors, HYAL1-AS tumors were benign and contained smaller capillaries. Specimens of high HYAL1 producers were 99% free of tumor cells. This study shows that, depending on the concentration, HYAL1 functions as a tumor promoter and as a suppressor and provides a basis for anti-hyaluronidase and high-hyaluronidase treatments for cancer.
PMID: 16140946 [PubMed - indexed for MEDLINE]
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The influence of extent of surgical margin positivity on prostate specific antigen recurrence.
J Clin Pathol. 2005 Oct;58(10):1028-32
Authors: Emerson RE, Koch MO, Jones TD, Daggy JK, Juliar BE, Cheng L
BACKGROUND: Positive surgical margins are an adverse prognostic factor in patients undergoing prostatectomy for prostate cancer. The extent of margin positivity varies and its influence on clinical outcome is uncertain. AIMS: To evaluate the linear extent of margin positivity and the number and location of positive sites as prognostic indicators in a series of prostatectomy specimens evaluated with the whole mount technique. METHODS: Eighty six consecutive margin positive prostatectomy specimens were evaluated, and all pathology data were collected prospectively. The linear extent of margin positivity was measured with an ocular micrometer and the total extent of all positive sites was summed. The total number of sites with positive margins and anatomical sites of the positive margins were analysed. RESULTS: The linear extent of margin positivity ranged from 0.01 to 68 mm (mean, 6.8; median, 3.0) and was associated with prostate specific antigen (PSA) recurrence in univariate logistic regression (p = 0.031). In addition, the extent of margin positivity weakly correlated with preoperative PSA (p = 0.017) and tumour volume (p = 0.013), but not with age, prostate weight, Gleason score, pathological stage, or perineural invasion. The total number of positive sites was significantly higher in patients with PSA recurrence (p = 0.037). The location of the positive margin site was not associated with PSA recurrence. The extent of margin positivity correlated with PSA recurrence in univariate analysis, although it had only marginal predictive value when adjusted for Gleason score (p = 0.076). CONCLUSIONS: The extent of margin positivity correlates with PSA recurrence in univariate analysis, although it has no predictive value independent of Gleason score.
PMID: 16189146 [PubMed - indexed for MEDLINE]
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Intra-operative prostate examination: predictive value and effect on margin status.
BJU Int. 2005 Nov;96(7):1005-8
Authors: Rapp DE, Orvieto MA, Lucioni A, Gong EM, Shalhav AL, Brendler CB
OBJECTIVE: To evaluate the ability of intra-operative prostate examination (IOPE) to predict extraprostatic extension (EPE) and its effect on margin status in the region of the neurovascular bundle (NVB) when combined with wide excision. PATIENTS AND METHODS: We retrospectively reviewed 403 patients with clinical stage T1c prostate adenocarcinoma undergoing radical retropubic prostatectomy (RRP). All patients had IOPE during RRP, and those with palpable abnormalities in the region of the NVB underwent wide excision. Pathological outcomes were analysed. RESULTS: Of 403 patients, 49 (12%) had a palpable abnormality in the region of the NVB. After wide excision, 18 (37%) of these 49 patients were found to have EPE at the site of the palpable abnormality; with wide excision of the NVB, only one of these 18 patients (6%) had a corresponding positive surgical margin (PSM). In 354 patients with a normal IOPE and who underwent bilateral NVB preservation, 30 were found to have EPE in the region of the NVB. The PSM rate in this subset was 23% (seven of 30). The positive predictive value of IOPE for detecting EPE was 37%. CONCLUSION: IOPE detects abnormalities in 12% of patients with preoperative stage T1c prostate cancer. Although the predictive value of this test is limited, IOPE may decrease PSMs in a subset of patients with EPE in the region of the NVB. The present study reaffirms the value of IOPE for assessing the risk of extraprostatic disease, and for guiding surgical management.
PMID: 16225517 [PubMed - indexed for MEDLINE]
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Androgen deprivation use with external beam radiation for prostate cancer: results from CaPSURE.
J Urol. 2005 Nov;174(5):1802-7
Authors: Park S, Meng MV, Elkin EP, Speight JL, DuChane J, Carroll PR
PURPOSE: Recent data support the role of androgen deprivation in men undergoing external beam radiotherapy for prostate cancer. The benefits of neoadjuvant, concurrent or adjuvant treatment have been limited to men at intermediate and high risk. We examined the patterns and predictors of androgen deprivation in men undergoing external beam radiation therapy in CaPSURE. MATERIALS AND METHODS: CaPSURE is an observational, longitudinal disease registry, from which 932 men met study inclusion criteria. Androgen deprivation was classified as neoadjuvant-within 9 months of radiation or adjuvant-from the start of radiation to 6 months after completion. Time trends in androgen deprivation as well factors associated with combined therapy were elucidated using multivariate analyses. RESULTS: In this study 40%, 39% and 21% of men could be categorized into high, intermediate and low risk groups, respectively. Overall 42% and 33% of patients received neoadjuvant and adjuvant androgen deprivation therapy, respectively. Between 1997 and 2002 neoadjuvant hormone use increased significantly in all risk groups, including patients at low risk. On multivariate analyses only the year of diagnosis and clinical risk group were associated with receiving androgen deprivation with radiation. CONCLUSIONS: A significant increase in combined androgen deprivation and external radiation was observed in the last decade in men with intermediate and high risk disease. Nevertheless, more widespread acceptance is necessary since a substantial minority continue to receive radiation alone. Many patients with low risk disease that is amenable to radiation monotherapy also receive androgen deprivation. No clinical or sociodemographic features predicted the use of androgen deprivation with external radiation.
PMID: 16217291 [PubMed - indexed for MEDLINE]
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Phase II trial of tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate cancer: high subjective and objective response in patients with symptomatic metastases.
J Urol. 2005 Nov;174(5):1808-13; discussion 1813
Authors: Raghavan D, Brandes LJ, Klapp K, Snyder T, Styles E, Tsao-Wei D, Lieskovsky G, Quinn DI, Ramsey EW
PURPOSE: Symptomatic, hormone refractory prostate cancer (HRCAP) is a major cause of morbidity with a median survival of less than 12 months and a 2-year survival of only up to 10% in most series. Mitoxantrone has been approved by the Food and Drug Administration for HRCAP. Preliminary data suggest that DPPE (N,N-diethyl-2-[4-(phenylmethyl) phenoxy]-ethanamine) or tesmilifene modulates cytotoxics to enhance the anticancer effect. In this phase II trial we assessed whether there is sufficient evidence of enhanced efficacy of DPPE and mitoxantrone to lead to a phase III clinical trial. MATERIALS AND METHODS: A total of 29 patients with a median age of 73 years, of whom 10% were older than 80 years, with progressive HRCAP received 5.3 mg/kg DPPE intravenously every 3 weeks, 12 mg/m mitoxantrone intravenously every weeks and 5 mg prednisone orally twice daily. All patients had pain at presentation, while 97% had bone metastases, 10% had liver metastases and 17% had lung metastases. Median prostate specific antigen (PSA) was 210 ng/ml (IQR 77 to 430). RESULTS: Of the patients 75% had some pain improvement, 66% had decreased analgesia, 59% had a PSA decrease of 50% or greater and 45% had a PSA decrease of 75% or greater. Actual (not actuarial) 2-year survival was 21%. CONCLUSIONS: Despite major limitations of historical comparison the PSA decrease and decreased symptoms with DPPE-mitoxantrone-prednisone compare favorably to those of mitoxantrone-prednisone and docetaxel-estramustine in the literature. The 2-year survival rate of 21% mandates further assessment. This will be tested in a phase III Southwest Oncology Group trial.
PMID: 16217292 [PubMed - indexed for MEDLINE]
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Deregulated expression of prostate apoptosis response gene-4 in less differentiated lymphocytes and inverse expressional patterns of par-4 and bcl-2 in acute lymphocytic leukemia.
Hematol J. 2001;2(2):103-7
Authors: Boehrer S, Chow KU, Puccetti E, Ruthardt M, Godzisard S, Krapohl A, Schneider B, Hoelzer D, Mitrou PS, Rangnekar VM, Weidmann E
INTRODUCTION: Prostate apoptosis response gene-4, known as par-4, is a new proapoptotic factor functionally required but not sufficient for apoptosis. Since there is evidence from prostate cancer cells that par-4 is involved in regulation of bcl-2 we assessed expression of par-4 and bcl-2 in different populations of normal and neoplastic lymphocytes. MATERIALS AND METHODS: Expression of par-4 mRNA and protein in different subpopulations of normal and neoplastic lymphocytes was assessed by reverse transcription polymerase chain reaction and Western blot. RESULTS: Par-4 mRNA was not detectable in lymphocytes of healthy volunteers (n = 10), but was present in the majority of samples of chronic lymphocytic leukemia (n = 30), chronic lymphocytic leukemia/prolymphocytic leukemia (n = 6) and acute lymphocytic leukemia (n = 10). Par-4 protein was expressed unanimously in samples of mononuclear cells from healthy volunteers and patients with CLL, but less frequently in immature lymphocytes, including neoplastic cells of CLL/PLL and ALL. The decreased frequency of par-4 expression in immature subpopulations was confirmed by results on lymphocytic cell lines at various stages of maturation. Comparing the expressional patterns of par-4 and bcl-2 there was an inverse relationship of both proteins in ALL and different lymphocytic cell lines, indicating a functional relationship of par-4 and bcl-2. CONCLUSIONS: This study establishes par-4 as a factor expressed in the majority of normal and neoplastic lymphocytic cells, demonstrating a decreased frequency of protein expression in less differentiated lymphocytes and an inverse expressional pattern of par-4 and bcl-2 in lymphocytic cell lines and ALL.
PMID: 11424002 [PubMed - indexed for MEDLINE]
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Vascular endothelial growth factor expression in untreated and androgen-deprived patients with prostate cancer.
Pathol Res Pract. 2005;201(8-9):593-8
Authors: Aslan G, Cimen S, Yorukoglu K, Tuna B, Sonmez D, Mungan U, Celebi I
The aim of the study was to investigate immunohistochemically the expression of vascular endothelial growth factor (VEGF) in untreated and androgen-deprived patients with prostate cancer. The study included 20 patients with prostate cancer who had undergone transurethral prostatectomy due to infravesical obstruction. All patients had been receiving androgen deprivation therapy for at least 3 months. Transurethral prostatectomy specimens were examined for VEGF expression after androgen deprivation, and the biopsy samples of the same patients were used for the evaluation of VEGF expression before androgen deprivation. VEGF expression was analyzed using immunohistochemistry. Staining patterns determined by the staining scores were compared before and after treatment. The correlation of VEGF expression with PSA, Gleason score, and the percent change in PSA after treatment was also investigated. Eligible biopsy specimens were available in 15 of the 20 patients, allowing for the evaluation of VEGF expression before treatment. All prostate cancer specimens were positive. VEGF was localized mainly in the cytoplasm or on the membrane of carcinoma cells. Staining was strong in 86.7% of patients before androgen deprivation. Heterogeneous staining (strong in 25%, moderate in 35%, and weak in 40%) was observed after treatment. Staining scores were significantly higher in patients before androgen deprivation and showed a significant decrease after androgen deprivation (p = 0.007). Tumor staining correlated with Gleason score. No significant correlation was determined between VEGF expression and pre-treatment PSA and percent change of PSA after treatment. Immunohistochemical results indicate that VEGF expression is downregulated by androgen deprivation therapy. VEGF may be a potential target for therapeutic intervention in prostate cancer.
PMID: 16259113 [PubMed - indexed for MEDLINE]
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Estimation of treatment benefits when PSA screening for prostate cancer is discontinued at different ages.
Urology. 2005 Nov;66(5):1038-42
Authors: Ross KS, Guess HA, Carter HB
OBJECTIVES: To estimate the declining benefits of screening for prostate cancer as patient age at screening increases. The benefits of prostate cancer screening decline with age because of the long natural history of prostate cancer and competing causes of death among older men. METHODS: We used a previously described Monte Carlo simulation based on a Markov model of prostate cancer detection in men aged 40 to 90 years and simulated prostate cancer screening in 1000 populations of 1,000,000 men each. The age at the final prostate-specific antigen test in the model was varied to simulate the discontinuation of screening from age 50 to 80 years. The model outputs were the number of men treated, the number of prostate cancer deaths prevented by treatment, and person-years of life saved. RESULTS: The relationship between treatments required to prevent a death was not constant but widened with age. Compared with screening to age 65 years, screening to age 75 and 80 years required twice and three times, respectively, the number of treatments per person-year of life saved. CONCLUSIONS: Our results have helped to quantify the declining treatment benefit as the patient age at screening and treatment for prostate cancer increases. We believe that men older than 70 years should be carefully counseled about the declining benefits of prostate cancer detection with screening.
PMID: 16286120 [PubMed - in process]
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Estimation of treatment benefits when PSA screening for prostate cancer is discontinued at different ages.
Urology. 2005 Nov;66(5):1038-42
Authors: Ross KS, Guess HA, Carter HB
OBJECTIVES: To estimate the declining benefits of screening for prostate cancer as patient age at screening increases. The benefits of prostate cancer screening decline with age because of the long natural history of prostate cancer and competing causes of death among older men. METHODS: We used a previously described Monte Carlo simulation based on a Markov model of prostate cancer detection in men aged 40 to 90 years and simulated prostate cancer screening in 1000 populations of 1,000,000 men each. The age at the final prostate-specific antigen test in the model was varied to simulate the discontinuation of screening from age 50 to 80 years. The model outputs were the number of men treated, the number of prostate cancer deaths prevented by treatment, and person-years of life saved. RESULTS: The relationship between treatments required to prevent a death was not constant but widened with age. Compared with screening to age 65 years, screening to age 75 and 80 years required twice and three times, respectively, the number of treatments per person-year of life saved. CONCLUSIONS: Our results have helped to quantify the declining treatment benefit as the patient age at screening and treatment for prostate cancer increases. We believe that men older than 70 years should be carefully counseled about the declining benefits of prostate cancer detection with screening.
PMID: 16286120 [PubMed - in process]
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Lidocaine suppositories for prostate biopsy.
BJU Int. 2005 Nov;96(7):1028-30
Authors: Fink KG, Gnad A, Meissner P, G tschl R, Schmeller NT
OBJECTIVES: To evaluate, in a randomized prospective study, the efficiency of transrectal lidocaine suppositories to reduce pain during transrectal prostate biopsy, as suppositories allow longer for the agent to be effective. PATIENTS AND METHODS: In all, 100 patients were randomized to receive either a placebo suppository or 10 mL of 2% (200 mg) lidocaine gel rectally 10 min before biopsy, or a suppository containing 60 mg lidocaine 1 or 2 h before biopsy. Costs (in euros) per application were 0.82 for gel and 0.63 for suppositories. In all patients the same 10-core biopsy technique was used. Pain was evaluated using a visual linear pain scale ranging from 0 to 100 points; the patient's side of the scale did not show the number of points. RESULTS: The mean pain scores in the placebo, lidocaine gel, and lidocaine suppositories applied 1 h and 2 h before biopsy were 36.2, 40.9, 29.2 and 21.2, respectively. Thus patients with no anaesthesia reported 25% more pain than those receiving lidocaine suppositories 1 h before and 71% more pain than those receiving lidocaine suppositories 2 h before biopsy (P = 0.002). CONCLUSIONS: Lidocaine suppositories at a lower dose and with longer to take effect can be used to reduce pain significantly more effectively than the commonly used gel. As suppositories are easy to use and cheap, they are recommended in daily routine prostate biopsy.
PMID: 16225522 [PubMed - indexed for MEDLINE]
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Clinical staging of prostate cancer: a computer-simulated study of transperineal prostate biopsy.
BJU Int. 2005 Nov;96(7):999-1004
Authors: Crawford ED, Wilson SS, Torkko KC, Hirano D, Stewart JS, Brammell C, Wilson RS, Kawata N, Sullivan H, Lucia MS, Werahera PN
OBJECTIVE: To identify the precise location of prostate cancer within the gland and thus possibly permit more aggressive therapy of the lesion, while potentially sparing the noncancerous gland from ablative therapy. MATERIALS AND METHODS: Three-dimensional "solid" computer models were reconstructed for 86 autopsy specimens and 20 stage T1c radical prostatectomy specimens. Transperineal biopsies were simulated for grid sizes of 5-mm (method A) and 10-mm (method B) with an 18 G, 23-mm long biopsy needle. One or two biopsies per grid point were obtained for a total of 12-108 biopsies, depending on the size of the prostate. Clinically threatening cancers were defined as having volumes of > or = 0.5 mL or Gleason sum > or = 7. RESULTS: Method A detected significantly more carcinomas than method B in both the autopsy and prostatectomy specimens (autopsy, 72 vs 51; prostatectomy, 50 vs 32, both P < 0.001). Method A also detected more clinically threatening cancers found at autopsy (38/40 vs 31/40, P = 0.008). Among autopsy patients with negative sextant biopsies whose disease was localized to one side, method A detected 72% and method B detected 29-43% (P < 0.001). CONCLUSIONS: The results of this computer simulation show that 5- and 10-mm grid biopsies detect three-quarters and a third, respectively, at autopsy, of patients with the disease localized to one side of the prostate, which may be useful when planning highly selective ablative treatments in the future.
PMID: 16225516 [PubMed - indexed for MEDLINE]
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Germline mutations of the MSR1 gene in prostate cancer families from Germany.
Hum Mutat. 2005 Nov 14;27(1):98-102
Authors: Maier C, Vesovic Z, Bachmann N, Herkommer K, Braun AK, Surowy HM, Assum G, Paiss T, Vogel W
The MSR1 gene at 8p22 has been suggested as a candidate gene for hereditary prostate cancer because germline variants have been found to be associated with the disease. Aside from a single nonsense mutation (R293X) that was found repeatedly at low frequencies in several samples, little evidence has been gained by follow-up studies to confirm the gene's relevance for prostate cancer. Prompted by reasonable support for a linkage to 8p22, we sought to determine the mutation spectrum of MSR1 in our family sample. Screening of 139 probands (representing 139 prostate cancer families) revealed 15 novel and a total of 20 sequence variants within the 10 coding exons and their intronic proximities. Aside from the known mutation c.877C>T (R293X) present in two of our families, we identified a second nonsense allele (c.251C>G; S84X) and a splice-site mutation (c.818-1G>A) that results in mRNA instability (each in a single pedigree). The novel missense alleles were c.703C>T (H235Y), c.856C>T (P286S), c.905C>T (P302L), c.1193C>G (A398G), and c.1289A>G (K430R). Of the eight variants that affect the encoded protein (splice site, nonsense, and missense), only R293X as well as the polymorphism c.823C>G (P275A) were additionally present at remarkable frequencies in further samples of sporadic prostate cancer and controls. Of note, carriers of R293X were equally frequent in 367 sporadic prostate cancer cases (1.9%) and in 197 controls (2.0%). To our knowledge, our study is the first to demonstrate further loss of function variants of MSR1 apart from R293X. Nevertheless, the low frequencies of deleterious alleles, in addition to an apparently moderate penetrance, does not support MSR1 as a major susceptibility gene in this family sample. Hum Mutat 27(1), 98-102, 2006. (c) 2005 Wiley-Liss, Inc.
PMID: 16287155 [PubMed - as supplied by publisher]
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Phase II trial of tesmilifene plus mitoxantrone and prednisone for hormone refractory prostate cancer: high subjective and objective response in patients with symptomatic metastases.
J Urol. 2005 Nov;174(5):1808-13; discussion 1813
Authors: Raghavan D, Brandes LJ, Klapp K, Snyder T, Styles E, Tsao-Wei D, Lieskovsky G, Quinn DI, Ramsey EW
PURPOSE: Symptomatic, hormone refractory prostate cancer (HRCAP) is a major cause of morbidity with a median survival of less than 12 months and a 2-year survival of only up to 10% in most series. Mitoxantrone has been approved by the Food and Drug Administration for HRCAP. Preliminary data suggest that DPPE (N,N-diethyl-2-[4-(phenylmethyl) phenoxy]-ethanamine) or tesmilifene modulates cytotoxics to enhance the anticancer effect. In this phase II trial we assessed whether there is sufficient evidence of enhanced efficacy of DPPE and mitoxantrone to lead to a phase III clinical trial. MATERIALS AND METHODS: A total of 29 patients with a median age of 73 years, of whom 10% were older than 80 years, with progressive HRCAP received 5.3 mg/kg DPPE intravenously every 3 weeks, 12 mg/m mitoxantrone intravenously every weeks and 5 mg prednisone orally twice daily. All patients had pain at presentation, while 97% had bone metastases, 10% had liver metastases and 17% had lung metastases. Median prostate specific antigen (PSA) was 210 ng/ml (IQR 77 to 430). RESULTS: Of the patients 75% had some pain improvement, 66% had decreased analgesia, 59% had a PSA decrease of 50% or greater and 45% had a PSA decrease of 75% or greater. Actual (not actuarial) 2-year survival was 21%. CONCLUSIONS: Despite major limitations of historical comparison the PSA decrease and decreased symptoms with DPPE-mitoxantrone-prednisone compare favorably to those of mitoxantrone-prednisone and docetaxel-estramustine in the literature. The 2-year survival rate of 21% mandates further assessment. This will be tested in a phase III Southwest Oncology Group trial.
PMID: 16217292 [PubMed - indexed for MEDLINE]
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Link between exercise and lower risk for prostate cancer found.
J Am Vet Med Assoc. 2005 Sep 15;227(6):858-9
Authors:
PMID: 16190576 [PubMed - indexed for MEDLINE]
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Effects of 2,4-D and DCP on the DHT-induced androgenic action in human prostate cancer cells.
Toxicol Sci. 2005 Nov;88(1):52-9
Authors: Kim HJ, Park YI, Dong MS
2,4-Dichlorophenoxyacetic acid (2,4-D) and its metabolite 2,4-dichlorophenol (DCP) are used extensively in agriculture as herbicides, and are suspected of potential endocrine disruptor activity. In a previous study, we showed that these compounds exhibited synergistic androgenic effects by co-treatment with testosterone in the Hershberger assay. To elucidate the mechanisms of the synergistic effects of these compounds on the androgenicity of testosterone, the androgenic action of 2,4-D and DCP was characterized using a mammalian detection system in prostate cancer cell lines. In in vitro assay systems, while 2,4-D or DCP alone did not show androgenic activity, 2,4-D or DCP with 5alpha-dihydroxytestosterone (DHT) exhibited synergistic androgenic activities. Co-treatment of 10 nM 2,4-D or DCP with 10 nM DHT was shown to stimulate the cell proliferation by 1.6-fold, compared to 10 nM DHT alone. In addition, in transient transfection assays, androgen-induced transactivation was also increased to a maximum of 32-fold or 1.28-fold by co-treatment of 2,4-D or DCP with DHT, respectively. However, 2,4-D and DCP exerted no effects on either mRNA or protein levels of AR. In a competitive AR binding assay, 2,4-D and DCP inhibited androgen binding to AR, up to 50% at concentrations of approximately 0.5 microM for both compounds. The nuclear translocation of green fluorescent protein-AR fusion protein in the presence of DHT was promoted as the result of the addition of 2,4-D and DCP. Collectively, these results that 2,4-D and DCP enhanced DHT-induced AR transcriptional activity might be attributable, at least in part, to the promotion of AR nuclear translocation.
PMID: 16107550 [PubMed - indexed for MEDLINE]
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Satraplatin in the treatment of hormone-refractory prostate cancer.
BJU Int. 2005 Nov;96(7):990-4
Authors: Sternberg CN
PMID: 16225514 [PubMed - indexed for MEDLINE]
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Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression.
Cancer Res. 2005 Sep 1;65(17):7959-67
Authors: Agoulnik IU, Vaid A, Bingman WE, Erdeme H, Frolov A, Smith CL, Ayala G, Ittmann MM, Weigel NL
Prostate cancer is initially androgen dependent and there is evidence that androgen receptor continues to play a role in androgen-independent prostate cancer. Androgen receptor activity depends both on the level of androgens and on the level of coactivators that interact with androgen receptor. Our goal was to evaluate the role of the androgen receptor coactivator SRC-1 in prostate cancer progression. Using tissue arrays to measure SRC-1 protein levels, we found that increased SRC-1 expression in clinically localized, androgen-dependent cancer is associated with clinical and pathologic variables of increased tumor aggressiveness. Interestingly, there was variable expression of SRC-1 in normal prostate tissue which correlated with the staining intensity of the corresponding cancer tissue. To test the contribution of SRC-1, we examined its role in androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cell lines. Using small interfering RNA to reduce expression of androgen receptor, we found that androgen receptor was required both for cell growth and for basal expression of prostate-specific antigen in the androgen-independent C4-2 cell line. Thus, although the cells can grow in an androgen-depleted medium, they remained androgen receptor dependent. Reduction of SRC-1 expression significantly reduced growth and altered androgen receptor target gene regulation in both LNCaP and C4-2 cell lines whereas it had no effect on the growth of the androgen receptor-negative PC-3 and DU145 prostate cancer cell lines. Although the requirement for androgens and androgen receptor in the development of prostate cancer is well established, our study implicates enhanced androgen receptor activity through elevated expression of SRC-1 in the development of more aggressive disease in men with prostate cancer.
PMID: 16140968 [PubMed - indexed for MEDLINE]
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[Prostate neoplasms--tumor grading and magnetic resonance spectroscopy]
Rofo. 2005 Oct;177(10):1342
Authors:
PMID: 16170697 [PubMed - indexed for MEDLINE]
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Role of SRC-1 in the promotion of prostate cancer cell growth and tumor progression.
Cancer Res. 2005 Sep 1;65(17):7959-67
Authors: Agoulnik IU, Vaid A, Bingman WE, Erdeme H, Frolov A, Smith CL, Ayala G, Ittmann MM, Weigel NL
Prostate cancer is initially androgen dependent and there is evidence that androgen receptor continues to play a role in androgen-independent prostate cancer. Androgen receptor activity depends both on the level of androgens and on the level of coactivators that interact with androgen receptor. Our goal was to evaluate the role of the androgen receptor coactivator SRC-1 in prostate cancer progression. Using tissue arrays to measure SRC-1 protein levels, we found that increased SRC-1 expression in clinically localized, androgen-dependent cancer is associated with clinical and pathologic variables of increased tumor aggressiveness. Interestingly, there was variable expression of SRC-1 in normal prostate tissue which correlated with the staining intensity of the corresponding cancer tissue. To test the contribution of SRC-1, we examined its role in androgen-dependent LNCaP and androgen-independent C4-2 prostate cancer cell lines. Using small interfering RNA to reduce expression of androgen receptor, we found that androgen receptor was required both for cell growth and for basal expression of prostate-specific antigen in the androgen-independent C4-2 cell line. Thus, although the cells can grow in an androgen-depleted medium, they remained androgen receptor dependent. Reduction of SRC-1 expression significantly reduced growth and altered androgen receptor target gene regulation in both LNCaP and C4-2 cell lines whereas it had no effect on the growth of the androgen receptor-negative PC-3 and DU145 prostate cancer cell lines. Although the requirement for androgens and androgen receptor in the development of prostate cancer is well established, our study implicates enhanced androgen receptor activity through elevated expression of SRC-1 in the development of more aggressive disease in men with prostate cancer.
PMID: 16140968 [PubMed - indexed for MEDLINE]
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Acute genitourinary toxicity after high-dose-rate (HDR) brachytherapy combined with hypofractionated external-beam radiation therapy for localized prostate cancer: correlation between the urethral dose in HDR brachytherapy and the severity of acute genitourinary toxicity.
Int J Radiat Oncol Biol Phys. 2005 Oct 1;63(2):463-71
Authors: Akimoto T, Ito K, Saitoh J, Noda SE, Harashima K, Sakurai H, Nakayama Y, Yamamoto T, Suzuki K, Nakano T, Niibe H
PURPOSE: Several investigations have revealed that the alpha/beta ratio for prostate cancer is atypically low, and that hypofractionation or high-dose-rate (HDR) brachytherapy regimens using appropriate radiation doses may be expected to yield tumor control and late sequelae rates that are better or at least as favorable as those achieved with conventional radiation therapy. In this setting, we attempted treating localized prostate cancer patients with HDR brachytherapy combined with hypofractionated external beam radiation therapy (EBRT). The purpose of this study was to evaluate the feasibility of using this approach, with special emphasis on the relationship between the severity of acute genitourinary (GU) toxicity and the urethral dose calculated from the dose-volume histogram (DVH) of HDR brachytherapy. METHODS AND MATERIALS: Between September 2000 and December 2003, 70 patients with localized prostate cancer were treated by iridium-192 HDR brachytherapy combined with hypofractionated EBRT at the Gunma University Hospital. Hypofractionated EBRT was administered in fraction doses of 3 Gy, three times per week; a total dose of 51 Gy was delivered to the prostate gland and the seminal vesicles using the four-field technique. No elective pelvic irradiation was performed. After the completion of EBRT, all the patients additionally received transrectal ultrasonography (TRUS)-guided HDR brachytherapy. The fraction size and the number of fractions in HDR brachytherapy were prospectively changed, whereas the total radiation dose for EBRT was fixed at 51 Gy. The fractionation in HDR brachytherapy was as follows: 5 Gy x 5, 7 Gy x 3, 9 Gy x 2, administered twice per day, although the biologic effective dose (BED) for HDR brachytherapy combined with EBRT, assuming that the alpha/beta ratio is 3, was almost equal to 138 in each fractionation group. The planning target volume was defined as the prostate gland with 5-mm margin all around, and the planning was conducted based on computed tomography images. The number of patients in each fractionation group was as follows: 13 in the 5-Gy group; 19 in the 7-Gy group, and 38 in the 9-Gy group. The tumor stage was T1 in 10 patients, T2 in 36 patients, and T3 in 24 patients. The Gleason score was 2-6 in 11 patients, 7 in 34 patients, and 8-10 in 25 patients. Androgen ablation was performed in all the patients. The median follow-up duration was 14 months (range 3-42 months). The toxicities were graded based on the Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer toxicity criteria. RESULTS: The main symptoms of acute GU toxicity were dysuria and increase in urinary frequency or nocturia. The grade distribution of acute GU toxicity in the patients was as follows: Grade 0-1, 39 patients (56%), and Grade 2-4, 31 patients (44%). One patient who developed acute urinary obstruction was classified as having Grade 4 toxicity. Comparison of the distribution of the grade of acute GU toxicity among the different fractionation groups revealed no statistically significant differences among the groups. The urethral dose in HDR brachytherapy was evaluated using the following DVH parameters: V30 (percentage of the urethral volume receiving 30% of the prescribed radiation dose), V80, V90, V100, V110, V120, V130, and V150. The V30-110 values in the patients with Grade 2-4 acute GU toxicity were significantly higher than those in patients with Grade 0-1 toxicity. On the other hand, there were no significant differences in the V120-150 values between patients with Grade 0-1 and Grade 2-4 toxicity. Regarding the influence of the number of needles implanted for the radiation therapy, patients with 11 needles or less showed a significantly higher incidence of Grade 2-4 acute GU toxicity compared with those with 12 needles or more (p < 0.05). CONCLUSIONS: It was concluded that HDR brachytherapy combined with hypofractionated EBRT is feasible for localized prostate cancer when considered from the viewpoint of acute toxicity. Increase in the fraction dose or reduction in the number of fractions in HDR brachytherapy did not affect the severity of acute GU toxicity, and the volume of urethra receiving an equal or lower radiation dose than the prescribed dose was more closely associated with the grade severity of acute GU toxicity than that receiving a higher than the prescribed dose.
PMID: 16168838 [PubMed - indexed for MEDLINE]
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Prostate cancer among African-American males: understanding the current issues.
J Natl Black Nurses Assoc. 2005 Jul;16(1):55-62
Authors: Jones RA, Wenzel J
Prostate cancer affects African-American males within the United States in a disproportionate number compared to White males. African-American males are 1.7 times more likely to develop and 2-3 times more likely to die from prostate cancer than White males. Numerous reasons for this disparity exist, including low socioeconomic status, distrust, conflicting cultural beliefs, and past health-care experiences. Controversies surrounding this topic and perhaps contributing to the disparity include cancer-screening recommendations, cancer-related myths, and potential prevention modalities. Nursing research must focus on cancer-related issues among African-Americans to increase the awareness and knowledge of health-care professionals and the public to help decrease morbidity and mortality within African-Americans and other minority populations, and particularly among more vulnerable sections of at-risk minority populations. This article focuses on current issues related to African-American men and prostate health.
PMID: 16255315 [PubMed - in process]