Prostate Cancer Research

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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]

Posted by blogposter at 10:36 PM | Permalink

Cancer of the prostate.

Crit Rev Oncol Hematol. 2005 Nov 22;56(3):379-396

Authors: Bracarda S, de Cobelli O, Greco C, Prayer-Galetti T, Valdagni R, Gatta G, de Braud F, Bartsch G

Prostate carcinoma, with about 190,000 new cases occurring each year (15% of all cancers in men), is the most frequent cancer among men in northern and western Europe. Causes of the disease are essentially unknown, although hormonal factors are involved, and diet may exert an indirect influence; some genes, potentially involved in hereditary prostate cancer (HPC) have been identified. A suspect of prostate cancer may derive from elevated serum prostate-specific antigen (PSA) values and/or a suspicious digital rectal examination (DRE) finding. For a definitive diagnosis, however, a positive prostate biopsy is requested. Treatment strategy is defined according to initial PSA stage, and grade of the disease and age and general conditions of the patient. In localized disease, watchful waiting is indicated as primary option in patients with well or moderately differentiated tumours and a life expectancy <10 years, while radical prostatectomy and radiotherapy (with or without hormone-therapy) could be appropriate choices in the remaining cases. Hormone-therapy is the treatment of choice, combined with radiotherapy, for locally advanced or bulky disease and is effective, but not curative, in 80-85% of the cases of advanced disease. Patients who develop a hormone-refractory prostate cancer disease (HRPC) have to be evaluated for chemotherapy because of the recent demonstration of improved overall survival (2-2.5 months) and quality of life with docetaxel in more than 1600 cases.

PMID: 16310371 [PubMed - as supplied by publisher]

Posted by blogposter at 10:32 PM | Permalink

Posted by blogposter at 10:11 PM | Permalink

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]

Posted by blogposter at 10:11 PM | Permalink

[Therapy of hormone-refractory prostate cancer.]

Urologe A. 2005 Nov 26;

Authors: Heidenreich A

PSA-progression following primary ADT defines an androgen-refractory but still hormone sensitive PCA which might respond to secondary hormonal manipulations. Secondary hormonal manipulations will result in a PSA decline >50% in about 60-80% of the patients with a mean duration of 7-17 months depending on the type of treatment. PSA-progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of 2 prospective, randomized clinical phase-III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA- and pain response and represents the treatment of choice in the management of HRPCA. Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain. The current article critically reflects the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer.

PMID: 16311709 [PubMed - as supplied by publisher]

Posted by blogposter at 10:10 PM | Permalink

Related Articles

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]

Posted by blogposter at 10:10 PM | Permalink

Therapeutic vaccines for prostate cancer: a review of clinical data.

Curr Opin Investig Drugs. 2005 Jun;6(6):592-6

Authors: Arlen PM, Gulley JL

Prostate cancer is the most common, non-cutaneous cancer and the second leading cause of cancer death among men in the US. A greater understanding of basic immunological principles has led to the development of a variety of new techniques, which in turn has led to advances in the field of prostate cancer vaccines. This review will discuss the rationale for the development of vaccines involving whole tumor cells and dendritic cells, as well as pox viral vectors, and will summarize selected clinical studies that have incorporated these strategies.

PMID: 15988910 [PubMed - indexed for MEDLINE]

Posted by blogposter at 10:10 PM | Permalink

Epidural spinal cord compression.

Crit Rev Oncol Hematol. 2005 Nov 22;56(3):397-406

Authors: Spinazz S, Caraceni A, Schrijvers D

Spinal cord compression from epidural metastases (epidural spinal cord compression, ESCC) is the most common neurological complication of cancer after brain metastases. Extradural compression represents 97% of spinal cord metastatic lesions. ESCC usually occurs in patients with disseminated disease. The most common tumours associated with ESCC are lung and breast cancers, followed by lymphoma, myeloma, prostate cancer and sarcoma. ESCC represents a medical emergency because delayed treatment can be responsible for irreversible deficits, such as paralysis and loss of sphincter control. Patients with ESCC require a multidisciplinary diagnostic and therapeutic approach. Clinical suspect is radiologically detected for confirmation. The median expected survival time from diagnosis usually ranges from 3 to 6 months. The nature of the primary tumour and the degree of the neurological deficit are the most important factors affecting survival. The lack of prospective randomized trials makes the optimal treatment of ESCC controversial and the decision is to be tailored to the individual. Treatment options include: bed rest, administration of corticosteroids, surgery followed by radiation therapy, radiotherapy alone and, to a limited extent, chemotherapy and hormonal therapy.

PMID: 16310372 [PubMed - as supplied by publisher]

Posted by blogposter at 10:10 PM | Permalink

Epidural spinal cord compression.

Crit Rev Oncol Hematol. 2005 Nov 22;56(3):397-406

Authors: Spinazzé S, Caraceni A, Schrijvers D

Spinal cord compression from epidural metastases (epidural spinal cord compression, ESCC) is the most common neurological complication of cancer after brain metastases. Extradural compression represents 97% of spinal cord metastatic lesions. ESCC usually occurs in patients with disseminated disease. The most common tumours associated with ESCC are lung and breast cancers, followed by lymphoma, myeloma, prostate cancer and sarcoma. ESCC represents a medical emergency because delayed treatment can be responsible for irreversible deficits, such as paralysis and loss of sphincter control. Patients with ESCC require a multidisciplinary diagnostic and therapeutic approach. Clinical suspect is radiologically detected for confirmation. The median expected survival time from diagnosis usually ranges from 3 to 6 months. The nature of the primary tumour and the degree of the neurological deficit are the most important factors affecting survival. The lack of prospective randomized trials makes the optimal treatment of ESCC controversial and the decision is to be tailored to the individual. Treatment options include: bed rest, administration of corticosteroids, surgery followed by radiation therapy, radiotherapy alone and, to a limited extent, chemotherapy and hormonal therapy.

PMID: 16310372 [PubMed - as supplied by publisher]

Posted by blogposter at 10:10 PM | Permalink

[Expression of prostate stem cell antigen (PSCA) and selection of its specific binding peptide]

Sheng Wu Gong Cheng Xue Bao. 2004 Sep;20(5):694-8

Authors: Hou LH, Du Y, Zhang XP, An XP, Chen W

Prostate stem cell antigen (PSCA), a homologue of the Ly-6/Thy-1 family of cell surface antigen, is expressed by a majority of human prostate cancers and is a promising target for prostate cancer immunotherapy. To obtain the specific peptide binding with PSCA for targeted immunotherapy, PSCA gene was obtained by RT-PCR from human prostate cancer cell line DU145 and the transcated PSCA (tPSCA) gene was cloned into vector pQE30 for soluble expression in E. coli. The identity of recombinant tPSCA was confirmed through ELISA and western blot by use of anti-PSCA monoclonal antibody. Then the 12-peptide phage display library was screened with the purified tPSCA protein for its specific binding peptide through 3 rounds panning. For identifying the peptide's specificity, the peptide was coupled with EGFP (enhanced green fluorecent protein) by recombinant DNA technology and the recombinant coupled protein was termed 11-EGFP. The binding specificity with tPSCA of 11-EGFP was further confirmed by ELISA and competitive inhibition experiment. Flow cytometry demonstrated its binding specificity with cell line DU145. In conclusion, a 12-amino-acid peptide which could bind with PSCA specifically was found and it may be a potential tool for targeted immunotherapy of prostate carcinoma.

PMID: 15973992 [PubMed - in process]

Posted by blogposter at 10:10 PM | Permalink

[Therapy of hormone-refractory prostate cancer.]

Urologe A. 2005 Nov 26;

Authors: Heidenreich A

PSA-progression following primary ADT defines an androgen-refractory but still hormone sensitive PCA which might respond to secondary hormonal manipulations. Secondary hormonal manipulations will result in a PSA decline >50% in about 60-80% of the patients with a mean duration of 7-17 months depending on the type of treatment. PSA-progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of 2 prospective, randomized clinical phase-III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA- and pain response and represents the treatment of choice in the management of HRPCA. Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain. The current article critically reflects the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer.

PMID: 16311709 [PubMed - as supplied by publisher]

Posted by blogposter at 10:09 PM | Permalink

[Therapy of hormone-refractory prostate cancer.]

Urologe A. 2005 Nov 26;

Authors: Heidenreich A

PSA-progression following primary ADT defines an androgen-refractory but still hormone sensitive PCA which might respond to secondary hormonal manipulations. Secondary hormonal manipulations will result in a PSA decline >50% in about 60-80% of the patients with a mean duration of 7-17 months depending on the type of treatment. PSA-progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of 2 prospective, randomized clinical phase-III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA- and pain response and represents the treatment of choice in the management of HRPCA. Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain. The current article critically reflects the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer.

PMID: 16311709 [PubMed - as supplied by publisher]

Posted by blogposter at 10:09 PM | Permalink

Posted by blogposter at 03:17 PM | Permalink

Related Articles

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]

Posted by blogposter at 03:17 PM | Permalink

[Therapy of hormone-refractory prostate cancer.]

Urologe A. 2005 Nov 26;

Authors: Heidenreich A

PSA-progression following primary ADT defines an androgen-refractory but still hormone sensitive PCA which might respond to secondary hormonal manipulations. Secondary hormonal manipulations will result in a PSA decline >50% in about 60-80% of the patients with a mean duration of 7-17 months depending on the type of treatment. PSA-progression following secondary endocrine treatment defines hormone-refractory prostate cancer (HRPCA) which might be treated by systemic chemotherapy. Based on the results of 2 prospective, randomized clinical phase-III trials comparing docetaxel and mitoxantrone, docetaxel results in a statistically significant survival benefit of 2.5 months, a significantly higher PSA- and pain response and represents the treatment of choice in the management of HRPCA. Bisphosphonates such as zoledronate represent another cornerstone in the management of PSA-progressive PCA demonstrating a significant benefit with regard to the prevention of skeletal related events. Furthermore, bisphosphonates might be indicated in the treatment of symptomatic bone pain. The current article critically reflects the various therapeutic options in the management of PSA progression following primary androgen deprivation for advanced prostate cancer.

PMID: 16311709 [PubMed - as supplied by publisher]

Posted by blogposter at 03:17 PM | Permalink

Related Articles

Health motivation and emotional vigilance in genetic testing for prostate cancer risk.

Clin Genet. 2004 Dec;66(6):512-6

Authors: Li Y, Doukas DJ

Actual uptake of genetic testing for cancer susceptibility is generally lower than 50%, despite a high initial interest above 80%. As population-based genetic testing for cancer susceptibility becomes more widespread, there will be an increasing need to understand the relationship of patient-affective factors to test intention and actual uptake behavior. Using hypothetical genetic testing for prostate cancer susceptibility as an example, we used surveys of 400 men in the general population of Philadelphia to develop a Structural Equation Modeling diagram to reveal the influence of affective factors implicated in the intention to undergo genetic testing for prostate cancer risk. Results showed that most men want genetic testing for prostate cancer, believe strongly in its benefits, and are not deterred by negative affect. Our data suggest that high positive expectations, plus a high desire to comply with physician and family suggestions, result in an increased test intention. Informed consent assessment, therefore, requires an appreciation not only of patient risk, but awareness of patient motivation and affect as well.

PMID: 15521978 [PubMed - indexed for MEDLINE]

Posted by blogposter at 03:17 PM | Permalink

Related Articles

Human CTLs to wild-type and enhanced epitopes of a novel prostate and breast tumor-associated protein, TARP, lyse human breast cancer cells.

Cancer Res. 2004 Apr 1;64(7):2610-8

Authors: Oh S, Terabe M, Pendleton CD, Bhattacharyya A, Bera TK, Epel M, Reiter Y, Phillips J, Linehan WM, Kasten-Sportes C, Pastan I, Berzofsky JA

Vaccine therapy for prostate and breast cancer may have potential for treating these major causes of death in males and females, respectively. Critical to the development of tumor-specific vaccines is finding and characterizing novel antigens to be recognized by CD8(+) T cells. To define new CD8(+) T-cell tumor antigens, we determined two wild-type HLA-A2 epitopes from a recently found tumor-associated protein, TARP (T-cell receptor gamma alternate reading frame protein), expressed in prostate and breast cancer cells. We were also able to engineer epitope-enhanced peptides by sequence modifications. Both wild-type and enhanced epitopes induced peptide-specific CD8(+) T-cell responses in A2K(b) transgenic mice. In vitro restimulation of human CD8(+) T cells from a prostate cancer patient resulted in CD8(+) T cells reactive to the peptide epitopes that could lyse HLA-A2(+) human breast cancer cells (MCF-7) expressing TARP. Epitope-specific human CD8(+) T cells were also enumerated in patients' peripheral blood by tetramer staining. Our data suggest that HLA-A2-binding TARP epitopes and enhanced epitopes discovered in this study could be incorporated into a potential vaccine for both breast and prostate cancer.

PMID: 15059918 [PubMed - indexed for MEDLINE]

Posted by blogposter at 03:17 PM | Permalink

Epidural spinal cord compression.

Crit Rev Oncol Hematol. 2005 Nov 22;56(3):397-406

Authors: Spinazz S, Caraceni A, Schrijvers D

Spinal cord compression from epidural metastases (epidural spinal cord compression, ESCC) is the most common neurological complication of cancer after brain metastases. Extradural compression represents 97% of spinal cord metastatic lesions. ESCC usually occurs in patients with disseminated disease. The most common tumours associated with ESCC are lung and breast cancers, followed by lymphoma, myeloma, prostate cancer and sarcoma. ESCC represents a medical emergency because delayed treatment can be responsible for irreversible deficits, such as paralysis and loss of sphincter control. Patients with ESCC require a multidisciplinary diagnostic and therapeutic approach. Clinical suspect is radiologically detected for confirmation. The median expected survival time from diagnosis usually ranges from 3 to 6 months. The nature of the primary tumour and the degree of the neurological deficit are the most important factors affecting survival. The lack of prospective randomized trials makes the optimal treatment of ESCC controversial and the decision is to be tailored to the individual. Treatment options include: bed rest, administration of corticosteroids, surgery followed by radiation therapy, radiotherapy alone and, to a limited extent, chemotherapy and hormonal therapy.

PMID: 16310372 [PubMed - as supplied by publisher]

Posted by blogposter at 03:16 PM | Permalink

Cancer of the prostate.

Crit Rev Oncol Hematol. 2005 Nov 22;56(3):379-396

Authors: Bracarda S, de Cobelli O, Greco C, Prayer-Galetti T, Valdagni R, Gatta G, de Braud F, Bartsch G

Prostate carcinoma, with about 190,000 new cases occurring each year (15% of all cancers in men), is the most frequent cancer among men in northern and western Europe. Causes of the disease are essentially unknown, although hormonal factors are involved, and diet may exert an indirect influence; some genes, potentially involved in hereditary prostate cancer (HPC) have been identified. A suspect of prostate cancer may derive from elevated serum prostate-specific antigen (PSA) values and/or a suspicious digital rectal examination (DRE) finding. For a definitive diagnosis, however, a positive prostate biopsy is requested. Treatment strategy is defined according to initial PSA stage, and grade of the disease and age and general conditions of the patient. In localized disease, watchful waiting is indicated as primary option in patients with well or moderately differentiated tumours and a life expectancy <10 years, while radical prostatectomy and radiotherapy (with or without hormone-therapy) could be appropriate choices in the remaining cases. Hormone-therapy is the treatment of choice, combined with radiotherapy, for locally advanced or bulky disease and is effective, but not curative, in 80-85% of the cases of advanced disease. Patients who develop a hormone-refractory prostate cancer disease (HRPC) have to be evaluated for chemotherapy because of the recent demonstration of improved overall survival (2-2.5 months) and quality of life with docetaxel in more than 1600 cases.

PMID: 16310371 [PubMed - as supplied by publisher]

Posted by blogposter at 03:16 PM | Permalink

Posted by blogposter at 01:11 PM | Permalink

Related Articles

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]

Posted by blogposter at 01:11 PM | Permalink

Operating characteristics of prostate-specific antigen in men with an initial PSA level of 3.0 ng/ml or lower Thompson IM, Ankerst DP, Chi C, Lucia MS, Goodman PJ, Crowley JJ, Parnes HL, Coltman CA Jr., Department of Urology, University of Texas Health Science Center at San Antonio, TX.

Urol Oncol. 2005 Nov-Dec;23(6):459

Authors: Carroll PR

CONTEXT: Three fourths of US men older than 50 years have been screened with prostate-specific antigen (PSA) for prostate cancer. OBJECTIVE: To estimate the receiver operating characteristic (ROC) curve for PSA. DESIGN, SETTING, AND PARTICIPANTS: Calculation of PSA ROC curves in the placebo group of the Prostate Cancer Prevention Trial, a randomized, prospective study conducted from 1993 to 2003 at 221 US centers. Participants were 18 882 healthy men aged 55 years or older without prostate cancer and with PSA levels less than or equal to 3.0 ng/mL and normal digital rectal examination results, followed up for 7 years with annual PSA measurement and digital rectal examination. If PSA level exceeded 4.0 ng/mL or rectal examination result was abnormal, a prostate biopsy was recommended. After 7 years of study participation, an end-of-study prostate biopsy was recommended in all cancer-free men. MAIN OUTCOME MEASURES: Operating characteristics of PSA for prostate cancer detection, including sensitivity, specificity, and ROC curve. RESULTS: Of 8575 men in the placebo group with at least 1 PSA measurement and digital rectal examination in the same year, 5587 (65.2%) had had at least 1 biopsy; of these, 1225 (21.9%) were diagnosed with prostate cancer. Of 1213 cancers with Gleason grade recorded, 250 (20.6%) were Gleason grade 7 or greater and 57 (4.7%) were Gleason grade 8 or greater. The areas under the ROC curve (AUC) for PSA to discriminate any prostate cancer vs no cancer, Gleason grade 7 or greater cancer vs no or lower-grade cancer, and Gleason grade 8 or greater cancer vs no or lower-grade cancer were 0.678 (95% confidence interval [CI] 0.666-0.689), 0.782 (95% CI 0.748-0.816), and 0.827 (95% CI 0.761-0.893), respectively (all P values <.001 for AUC vs 50%). For detecting any prostate cancer, PSA cutoff values of 1.1, 2.1, 3.1, and 4.1 ng/mL yielded sensitivities of 83.4%, 52.6%, 32.2%, and 20.5%, and specificities of 38.9%, 72.5%, 86.7%, and 93.8%, respectively. Age-stratified analyses showed slightly better performance of PSA in men younger than 70 years vs those 70 years or older with AUC values of 0.699 (SD, 0.013) vs 0.663 (SD, 0.013) (P = .03). CONCLUSION: There is no cutpoint of PSA with simultaneous high sensitivity and high specificity for monitoring healthy men for prostate cancer, but rather a continuum of prostate cancer risk at all values of PSA.

PMID: 16301130 [PubMed - in process]

Posted by blogposter at 01:11 PM | Permalink

Related Articles

Cancer chemotherapy by deoxynucleotide depletion and E2F-1 elevation.

Cancer Res. 2005 Sep 1;65(17):7809-14

Authors: Wang A, Li CJ, Reddy PV, Pardee AB

We propose that the lethality of commonly used anticancer drugs, e.g., methotrexate and cis-platinum are due, at least in part, to an increase of the E2F-1-mediated apoptotic cascade. The drugs directly or indirectly decrease deoxynucleoside triphosphates. The E2F family acts to provide control of S phase by transcribing genes required for deoxynucleoside triphosphate and DNA synthesis. Thus, a mechanism for control of E2F-1 is essential, a signal safeguarding against aberrant or uncontrolled cell proliferation. We have proposed a feedback control by NTPs that down-regulates E2F-1. Here, we provide evidence in support of this hypothesis.

PMID: 16140949 [PubMed - indexed for MEDLINE]

Posted by blogposter at 01:10 PM | Permalink

Related Articles

Delayed disease progression after allogeneic cell vaccination in hormone-resistant prostate cancer and correlation with immunologic variables.

Clin Cancer Res. 2005 Jun 15;11(12):4469-78

Authors: Michael A, Ball G, Quatan N, Wushishi F, Russell N, Whelan J, Chakraborty P, Leader D, Whelan M, Pandha H

PURPOSE: There are a significant number of patients with asymptomatic hormone-resistant prostate cancer who have increasing prostate-specific antigen (PSA) levels but little or no evaluable disease. The immunogenicity and minimal toxicity associated with cell-based vaccine therapy makes this approach attractive for these patients. EXPERIMENTAL DESIGN: We have evaluated a vaccine comprising monthly intradermal injection of three irradiated allogeneic prostate cell lines (8 x 10(6) cells each) over 1 year. The first two doses were supplemented with bacille Calmette-Gu rin as vaccine adjuvant. Twenty-eight hormone-resistant prostate cancer patients were enrolled. Patients were assessed clinically and PSA levels were measured monthly. Radiologic scans (X-ray, computed tomography, and bone scan) were taken at baseline and at intervals throughout the treatment period. Comprehensive monthly immunologic monitoring was undertaken including proliferation studies, activation markers, cytokine protein expression, and gene copy number. This longitudinal data was analyzed through predictive modeling using artificial neural network feed-forward/back-propagation algorithms with multilayer perceptron architecture.RESULTS: Eleven of the 26 patients showed statistically significant, prolonged decreases in their PSA velocity (PSAV). None experienced any significant toxicity. Median time to disease progression was 58 weeks, compared with recent studies of other agents and historical control values of around 28 weeks. PSAV-responding patients showed a titratable T(H)1 cytokine release profile in response to restimulation with a vaccine lysate, while nonresponders showed a mixed T(H)1 and T(H)2 response. Furthermore, immunologic profile correlated with PSAV response by artificial neural network analysis. We found predictive power not only in expression of cytokines after maximal stimulation with phorbol 12-myristate 13-acetate, but also the method of analysis (qPCR measurement of IFN-gamma > qPCR measurement tumor necrosis factor-alpha > protein expression of IFN-gamma > protein expression of interleukin 2). CONCLUSIONS: Whole cell allogeneic vaccination in hormone-resistant prostate cancer is nontoxic and improves the natural history of the disease. Longitudinal changes in immunologic function in vaccinated patients may be better interpreted through predictive modeling using tools such as the artificial neural network rather than periodic "snapshot" readouts.

PMID: 15958632 [PubMed - indexed for MEDLINE]

Posted by blogposter at 01:10 PM | Permalink

CXCL12 overexpression and secretion by aging fibroblasts enhance human prostate epithelial proliferation in vitro.

Aging Cell. 2005 Dec;4(6):291-8

Authors: Begley L, Monteleon C, Shah RB, Macdonald JW, Macoska JA

Summary The direct relationship between the aging process and the incidence and prevalence of both benign prostatic hyperplasia (BPH) and prostate cancer (PCa) implies that certain risk factors associated with the development of both diseases increase with the aging process. In particular, both diseases share an overly proliferative phenotype, suggesting that mechanisms that normally act to suppress cellular proliferation are disrupted or rendered dysfunctional as a consequence of the aging process. We propose that one such mechanism involves changes in the prostate microenvironment, which 'evolves' during the aging process and disrupts paracrine interactions between epithelial and associated stromal fibroblasts. We show that stromal fibroblasts isolated from the prostates of men 63-81 years of age at the time of surgery express and secrete higher levels of the CXCL12 chemokine compared with those isolated from younger men, and stimulate CXCR4-mediated signaling pathways that induce cellular proliferation. These studies represent an important first step towards a mechanistic elucidation of the role of aging in the etiology of benign and malignant prostatic diseases.

PMID: 16300481 [PubMed - in process]

Posted by blogposter at 01:10 PM | Permalink

Monotherapeutic brachytherapy for clinically organ-confined prostate cancer.

W V Med J. 2005 Jul-Aug;101(4):168-71

Authors: Merrick GS, Butler WM, Wallner KE, Galbreath RW, Adamovich E

Since the mid-1980s, permanent prostate brachytherapy has been utilized increasingly as a potentially curative treatment for patients of all ages with clinically localized prostate cancer To determine the 8-year biochemical progression-free survival rate for patients who had undergone monotherapeutic brachytherapy for clinically organ-confined prostate cancer, we conducted a study of 202 patients at Schiffler Cancer Center at Wheeling Hospital in Wheeling, W.Va. These patients had undergone brachytherapy without supplemental external beam radiation therapy or androgen deprivation therapy for clinical T1b-T2c NxM0 (2002 AJCC) prostate cancer from April 1995 through May 2001. No patient underwent seminal vesicle biopsy or pathologic lymph node staging. The median follow-up was 5.2 years. All patients underwent brachytherapy more than 3 years prior to analysis. Biochemical success was defined as a PSA < 0.4 ng/mL after a nadir. Clinical, treatment and dosimetric parameters evaluated for biochemical progression-free survival included patient age, clinical T-stage, Gleason score, pretreatment PSA, risk group, percent positive biopsies, isotope, prostate volume, brachytherapy planning volume, V100/150/200, D90, tobacco status, hypertension and diabetes. For the entire group, 8-year biochemical progression-free survival was 97.4% for Pd-103 and 93.3% for I-125. The median post-treatment PSA for the entire group was < 0.1 ng/mL. In multivariate analysis, only pretreatment PSA predicted biochemical outcome with a trend for better outcome with younger patient age and lesser percent positive biopsies. The results of our study indicate that permanent interstitial brachytherapy as a monotherapeutic approach for patients with clinically organ-confined disease results in a high probability of 8-year biochemical progression-free survival with a median PSA < 0.1 ng/mL. Generous periprostatic treatment margins with documented high quality day 0 postoperative dosimetry are mandatory for such outcomes.

PMID: 16296198 [PubMed - in process]

Posted by blogposter at 01:10 PM | Permalink

Advanced prostate cancer: the future.

Can J Urol. 2005 Jun;12 Suppl 2:42-7

Authors: Armstrong AJ, Carducci MA

The demonstration of a survival benefit with docetaxel for the treatment of metastatic hormone refractory prostate cancer (HRPC) is an important step forward in advancing treatment options for advanced prostate cancer. While docetaxel-based therapy has demonstrated improvement in symptomatic and quality-of-life endpoints, certainly there is a pressing need for improvement in outcomes. A number of novel agents are in basic and clinical development for advanced prostate cancer, some of which are specific to mechanisms that may be important in the development and spread of prostate cancer. Novel approaches including novel cytotoxics, immunotherapy, PSMA targeted monoclonal antibodies are among the broad categories that will be discussed in this brief review.

PMID: 16018833 [PubMed - indexed for MEDLINE]

Posted by blogposter at 01:10 PM | Permalink

[Prostate cancer chemotherapy, myth or reality?]

Actas Urol Esp. 2005 Sep;29(8):723-4

Authors: Rioja Sanz LA

PMID: 16304901 [PubMed - in process]

Posted by blogposter at 01:09 PM | Permalink

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Non-genomic effects of the androgen receptor and Vitamin D agonist are involved in suppressing invasive phenotype of prostate cancer cells.

Steroids. 2005 Nov 8;

Authors: Bonaccorsi L, Marchiani S, Ferruzzi P, Muratori M, Crescioli C, Forti G, Maggi M, Baldi E

Suppression of invasive phenotype is essential in developing new therapeutic tools to treat prostate cancer (PC). Evidence indicates that androgen-dependent (AD) prostate cancer cells are characterized by a lower malignant phenotype. We have demonstrated that transfection with an androgen receptor (AR) expression vector of the androgen-independent (AI) prostate cancer cell line PC3 decreases invasion of these cells through modulation of alpha6beta4 integrin expression, indicating a genotropic effect of androgens in inhibiting invasion ability of AD PC cells. Later on, we have shown that also a non-genotropic mechanism is involved in such an effect. By using immunoconfocal fluorescent microscopy, we demonstrated that AR in PC3-AR cells co-localizes with the EGFR receptors (EGFR) in PC3-AR cells. Co-immunoprecipitation studies both in PC3-AR cells and in the AD cell line LNCaP that physiologically express both receptors, confirm the occurrence of an interaction between of the two proteins. In PC3-AR cells, we demonstrated a disruption of EGFR signalling properties (reduced EGF-induced EGFR autotransphosphorylation, reduced EGF-stimulated PI3K activity as well as EGFR-PI3K interaction) contributing to the lower invasive phenotype of these cells. In another study, we investigated the effects of a new Vitamin D analogue, BXL628, on invasion in response to KGF in the androgen-independent PC cell line DU145. We found that the compound was able to reduce proliferation and invasion of the cells in response to the growth factor. In addition, we found that KGF-induced autotransphosphorylation of KGF receptor (KGFR) and PI3K activation were suppressed after short-term (5min) pre-treatment with the analogue before addition of KGF. Collectively, these studies demonstrate that a non-genotropic effect due to a direct interaction of the androgen receptor with EGFR and to a rapid effect of a Vitamin D agonist on KGFR may disrupt signalling of GF leading to decreased tumorigenicity and a less malignant phenotype of PC cells in vitro.

PMID: 16289173 [PubMed - as supplied by publisher]

Posted by blogposter at 01:09 PM | Permalink

20-year outcomes following conservative management of clinically localized prostate cancer Albertsen PC, Hanley JA, Fine J, Division of Urology, University of Connecticut Health Center, Farmington, CT.

Urol Oncol. 2005 Nov-Dec;23(6):459-60

Authors: Carroll PR

CONTEXT: The appropriate therapy for men with clinically localized prostate cancer is uncertain. A recent study suggested an increasing prostate cancer mortality rate for men who are alive more than 15 years following diagnosis. OBJECTIVE: To estimate 20-year survival based on a competing risk analysis of men who were diagnosed with clinically localized prostate cancer and treated with observation or androgen withdrawal therapy alone, stratified by age at diagnosis and histological findings. DESIGN, SETTING, AND PATIENTS: A retrospective population-based cohort study using Connecticut Tumor Registry data supplemented by hospital record and histology review of 767 men aged 55 to 74 years with clinically localized prostate cancer diagnosed between January 1, 1971, and December 31, 1984. Patients were treated with either observation or immediate or delayed androgen withdrawal therapy, with a median observation of 24 years. MAIN OUTCOME MEASURES: Probability of mortality from prostate cancer or other competing medical conditions, given a patient's age at diagnosis and tumor grade. RESULTS: The prostate cancer mortality rate was 33 per 1000 person-years during the first 15 years of follow-up (95% confidence interval [CI] 28-38) and 18 per 1000 person-years after 15 years of follow-up (95% CI 10-29). The mortality rates for these 2 follow-up periods were not statistically different, after adjusting for differences in tumor histology (rate ratio 1.1; 95% CI 0.6-1.9). Men with low-grade prostate cancers have a minimal risk of dying from prostate cancer during 20 years of follow-up (Gleason score of 2-4, 6 deaths per 1000 person-years; 95% CI 2-11). Men with high-grade prostate cancers have a high probability of dying from prostate cancer within 10 years of diagnosis (Gleason score of 8-10, 121 deaths per 1000 person-years; 95% CI 90-156). Men with Gleason score of 5 or 6 tumors have an intermediate risk of prostate cancer death. CONCLUSION: The annual mortality rate from prostate cancer appears to remain stable after 15 years from diagnosis, which does not support aggressive treatment for localized low-grade prostate cancer.

PMID: 16301129 [PubMed - in process]

Posted by blogposter at 01:09 PM | Permalink

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Pretreatment predictors of posttreatment PSA doubling times for patients undergoing three-dimensional conformal radiotherapy for clinically localized prostate cancer.

Urology. 2005 Nov;66(5):1020-3

Authors: Beard C, Chen MH, Cote K, Loffredo M, Renshaw A, Hurwitz M, D'Amico AV

OBJECTIVES: To determine whether pretreatment risk groups also predict for posttreatment prostate-specific antigen (PSA) doubling times (PSADTs). Pretreatment risk groups predict for posttreatment biochemical failure (BF) after conformal radiotherapy in patients with prostate cancer and posttreatment PSADTs can predict for prostate cancer-related deaths. METHODS: The study cohort consisted of 416 patients with clinically localized prostate cancer treated with conformal radiotherapy between 1989 and 2001. The patients were divided into low, intermediate, and high-risk groups. BF was defined using the American Society for Therapeutic Radiology and Oncology consensus definition. Patients with BF were grouped according to their PSADT (3 months or less, longer than 3 months to less than 6 months, 6 months to less than 12 months, and 12 months or longer). A Mantle-Haenszel chi-square metric tested for an association between the pretreatment risk group and the PSADT. Logistic regression multivariate analysis was performed to evaluate whether the pretreatment risk group predicted the PSADT. RESULTS: Of the 416 patients, 96 (23%), 194 (47%), and 126 (30%) were categorized as low, intermediate, and high risk, respectively. A total of 92 patients (22%) experienced BF. Of these 92 patients, the PSADT was 3 months or less in 6 (7%), longer than 3 months to less than 6 months in 13 (14%), 6 months to less than 12 months in 35 (36%), and 12 months or longer in 38 (41%). The pretreatment risk group correlated significantly with the PSADT (P = 0.026). Logistic regression analysis revealed that intermediate and high-risk disease was significantly associated with shorter PSADTs (P = 0.039). CONCLUSIONS: A significant association between the pretreatment risk group and posttreatment PSADT was demonstrated. Use of this selection criterion at diagnosis for more aggressive treatment appears warranted.

PMID: 16286116 [PubMed - in process]

Posted by blogposter at 08:22 PM | Permalink

[In Process Citation]

Ann Urol (Paris). 2005 Oct;39 Su