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HBP1 - Recherche cliniqueLe toucher rectal a une valeur prédictive positive de 94% pour identifier les prostates de plus de 30 et de moins de 80grammes.Can J Urol. 2011 Dec;18(6):6025-30. Estimation of clinically significant prostate volumes by digital rectal examination: a comparative prospective study. Ahmad S, Manecksha RP, Cullen IM, Flynn RJ, McDermott TE, Grainger R, Thornhill JA. 2 - Recherche fondamentaleDes signatures spécifiques par un ensemble d’ auto-anticorps permettent de différencier l’HBP du cancer de prostate chez des patients dont le PSA sérique est élevé.Clin Chim Acta. 2011 Nov 29. Autoantibody signatures as biomarkers to distinguish prostate cancer from benign prostatic hyperplasia in patients with increased serum prostate specific antigen. O'Rourke DJ, Dijohnson DA, Caiazzo RJ Jr, Nelson JC, Ure D, O'Leary MP, Richie JP, Liu BC. CANCER DE LA PROSTATE1 - Recherche cliniqueUne limite ¨¤ 20 pour le PCA3 a une valeur pr¨¦dictive n¨¦gative de pr¨¨s de 90% pour les patients ayant d¨¦j¨¤ eu des biopsies en saturation.Anticancer Res. 2011 Dec;31(12):4445-9. PCA3 score vs PSA Free/Total accuracy in prostate cancer diagnosis at repeat saturation biopsy. Pepe P, Aragona F. Par rapport au traitement immédiat, la surveillance active du cancer de prostate constitue une option très intéressante économiquement. Cancer. 2011 Dec 16. Active surveillance for prostate cancer compared with immediate treatment: an economic analysis. Keegan KA, Dall'era MA, Durbin-Johnson B, Evans CP. Dans une étude cas-témoins, un traitement par statines diminue la mortalité par cancer de prostate. Cancer. 2011 Dec 16. Statin use and fatal prostate cancer: a matched case-control study. Marcella SW, David A, Ohman-Strickland PA, Carson J, Rhoads GG. 2 - Recherche fondamentaleUn nouvel analogue de la vitamine D3, le ZK191784, grâce à son action régulatrice sur l’activité des métalloprotéinases, inhibe l’invasion par les cellules cancéreuses prostatiques.Anticancer Res. 2011 Dec;31(12):4091-8. The novel vitamin D analog ZK191784 inhibits prostate cancer cell invasion. Stio M, Martinesi M, Simoni A, Zuegel U, Steinmeyer A, Santi R, Treves C, Nesi G. La diminution de la prohibitine augmente l’acétylation des histones et favorise l’hormono-indépendance en augmentant l’activation du récepteur des androgènes par les androgènes surrénaliens. Oncogene. 2011 Dec 19. Reducing prohibitin increases histone acetylation, and promotes androgen independence in prostate tumours by increasing androgen receptor activation by adrenal androgens. Dart DA, Brooke GN, Sita-Lumsden A, Waxman J, Bevan CL. LA LETTREHBP1 - Recherche cliniqueLe toucher rectal a une valeur prédictive positive de 94% pour identifier les prostates de plus de 30 et de moins de 80grammes.Can J Urol. 2011 Dec;18(6):6025-30. Estimation of clinically significant prostate volumes by digital rectal examination: a comparative prospective study. Ahmad S, Manecksha RP, Cullen IM, Flynn RJ, McDermott TE, Grainger R, Thornhill JA. Résumé: INTRODUCTION: Reliable quantification of prostate volume is important to correctly select patients with benign prostatic hyperplasia (BPH) most likely to benefit from medical therapy [e.g. 5 alpha-reductase inhibitors (5-ARIs)] and in selecting appropriate surgical approach. We aim to determine the reliability of digital rectal examination (DRE) in estimation of prostate volume which may be helpful in patient selection for 5-ARIs therapy. MATERIALS AND METHODS: Patients requiring transrectal ultrasound (TRUS) guided prostate biopsy were recruited in this prospective study. DRE was performed twice for each patient. Clinicians categorized prostate volume on DRE into small, medium and large, and estimated prostate volume. Volume estimated by DRE at the first examination was intentionally unavailable at second DRE. TRUS volumes were measured using 2101 Falcon ultrasound machine. RESULTS: Comparative analysis of prostate volume (n = 248) by DRE and TRUS was performed. There was no significant difference between DRE-estimated prostate volume at the first and second examinations (p = 0.8). DRE-estimated volumes for prostates categorized as small, medium or large were underestimated in 59%, 58% and 53% of patients respectively. However, for clinical relevant volumes (> 30 cc), 94.5% patients were accurately estimated on DRE. CONCLUSIONS: We have shown that DRE had positive predictive value of 94% in identifying prostate above 30 cc. Hence, when considering treatment with 5-ARIs, DRE may be sufficient to identify suitable patients for 5-ARIs therapy. However, for prostate volumes between 25 cc-30 cc and above 80 cc, TRUS may be required. 2 - Recherche fondamentaleDes signatures spécifiques par un ensemble d’ auto-anticorps permettent de différencier l’HBP du cancer de prostate chez des patients dont le PSA sérique est élevé.Clin Chim Acta. 2011 Nov 29. Autoantibody signatures as biomarkers to distinguish prostate cancer from benign prostatic hyperplasia in patients with increased serum prostate specific antigen. O'Rourke DJ, Dijohnson DA, Caiazzo RJ Jr, Nelson JC, Ure D, O'Leary MP, Richie JP, Liu BC. Résumé: BACKGROUND: Serum prostate specific antigen (PSA) concentrations lack the specificity to differentiate prostate cancer from benign prostate hyperplasia (BPH), resulting in unnecessary biopsies. We identified 5 autoantibody signatures to specific cancer targets which might be able to differentiate prostate cancer from BPH in patients with increased serum PSA. METHODS: To identify autoantibody signatures as biomarkers, a native antigen reverse capture microarray platform was used. Briefly, well-characterized monoclonal antibodies were arrayed onto nanoparticle slides to capture native antigens from prostate cancer cells. Prostate cancer patient serum samples (n=41) and BPH patient samples (collected starting at the time of initial diagnosis) with a mean follow-up of 6.56y without the diagnosis of cancer (n=39) were obtained. One hundred micrograms of IgGs were purified and labeled with a Cy3 dye and incubated on the arrays. The arrays were scanned for fluorescence and the intensity was quantified. Receiver operating characteristic curves were produced and the area under the curve (AUC) was determined. RESULTS: Using our microarray platform, we identified autoantibody signatures capable of distinguishing between prostate cancer and BPH. The top 5 autoantibody signatures were TARDBP, TLN1, PARK7, LEDGF/PSIP1, and CALD1. Combining these signatures resulted in an AUC of 0.95 (sensitivity of 95% at 80% specificity) compared to AUC of 0.5 for serum concentration PSA (sensitivity of 12.2% at 80% specificity). CONCLUSION: Our preliminary results showed that we were able to identify specific autoantibody signatures that can differentiate prostate cancer from BPH, and may result in the reduction of unnecessary biopsies in patients with increased serum PSA. CANCER DE LA PROSTATE1 - Recherche cliniqueUne limite ¨¤ 20 pour le PCA3 a une valeur pr¨¦dictive n¨¦gative de pr¨¨s de 90% pour les patients ayant d¨¦j¨¤ eu des biopsies en saturation.Anticancer Res. 2011 Dec;31(12):4445-9. PCA3 score vs PSA Free/Total accuracy in prostate cancer diagnosis at repeat saturation biopsy. Pepe P, Aragona F. R¨¦sum¨¦: PCA3 score and PSA free/total (F/T) accuracy in PCa diagnosis at repeat saturation prostate biopsy (SPBx) in patients with PSA between 4 and 10 ng/mL was evaluated. MATERIALS AND METHODS: From October 2009 to September 2011 74 men (median 64 years) with persistent high or increasing PSA values, negative DRE, median PSA values of 8.9 ng/mL and primary negative extended biopsy underwent a SPBx (median 28 cores) for persistent suspicion for PCa. RESULTS: PCA3 >20 and >35, PSA F/T ¡Ü15%, ¡Ü20% and ¡Ü25% identified 25, 21, 18, 23 and 26 out 27 cancer, respectively. PCA3 cut-off of 20 demonstrated the best accuracy with an AUC-ROC curve of 0.73. CONCLUSION: The NPV equal to 88.9% suggests to use PCA3 cut-off 20 as an exclusion tool; moreover, PCA3 cut-off of 35 combined with PSA F/T ¡Ü15% allows to spare 32.4% of unnecessary repeat biopsies. Par rapport au traitement immédiat, la surveillance active du cancer de prostate constitue une option très intéressante économiquement. Cancer. 2011 Dec 16. Active surveillance for prostate cancer compared with immediate treatment: an economic analysis. Keegan KA, Dall'era MA, Durbin-Johnson B, Evans CP. Résumé: BACKGROUND: The costs associated with a contemporary active surveillance strategy compared with immediate treatment for prostate cancer are not well characterized. The purpose of this study is to elucidate the health care costs of an active surveillance paradigm for prostate cancer. METHODS: A theoretical cohort of 120,000 men selecting active surveillance for prostate cancer was created. The number of men remaining on active surveillance and those exiting to each of 5 treatments over 5 years were simulated in a Markov model. Estimated total costs after 5 years of active surveillance with subsequent delayed treatment were compared with immediate treatment. Sensitivity analyses were performed to test the effect of various surveillance strategies and attrition rates. Additional analyses to include 10 years of follow-up were performed. RESULTS: The average simulated cost of treatment for 120,000 men initiating active surveillance with 5 years of follow-up and subsequent delayed treatment resulted in per patient cost savings of $16,042 (95% confidence interval [CI], $16,039-$16,046) relative to initial curative treatment. This represents a $1.9 billion dollar savings to the cohort. The strict costs of active surveillance exceeded those of brachytherapy in the ninth year of follow-up. A yearly biopsy within the active surveillance cohort increased costs by 22%, compared with every other year biopsy. At 10 years of follow-up, active surveillance still resulted in a cost benefit; however, the savings were reduced by 38% to $9944 (95% CI, $9941-$9948) per patient relative to initial treatment. CONCLUSIONS: These data demonstrate that active surveillance represents a considerable cost savings over immediate treatment for prostate cancer in a theoretical cohort after 5 and 10 years of follow-up. Dans une étude cas-témoins, un traitement par statines diminue la mortalité par cancer de prostate. Cancer. 2011 Dec 16. Statin use and fatal prostate cancer: a matched case-control study. Marcella SW, David A, Ohman-Strickland PA, Carson J, Rhoads GG. Résumé: BACKGROUND: Statins are some of the most commonly prescribed medications in medical practice, and prostate cancer is the most common malignancy among men. Although there has been no consistent evidence that statins affect cancer incidence, including prostate cancer, several reports suggest they may decrease the rate of advanced prostate cancer. However, no study to date has specifically examined statin use and prostate cancer mortality. The authors conducted this population-based case-control investigation to examine this association. METHODS: This was a matched case-control study. Cases were residents of New Jersey ages 55 to 79 years who died from prostate cancer between 1997 and 2000. The cases were matched individually to population-based controls by 5-year age group and race. Medication data were obtained identically for cases and controls from blinded medical chart review. Conditional logistic regression was used to adjust for confounders. RESULTS: In total, 718 cases were identified, and cooperation was obtained from 77% of their spouses (N = 553). After a review of medical records, 387 men were eligible, and 380 were matched to a control. The unadjusted odds ratio was 0.49 (95% confidence interval, 0.34-0.70) and decreased to 0.37 (P < .0001) after adjusting for education, waist size, body mass index, comorbidities, and antihypertensive medication. There was little difference between lipophilic and hydrophilic statins, but more risk reduction was noted for high-potency statins (73%; P < .0001) compared with low-potency statins (31%; P = .32). CONCLUSIONS: Statin use was associated with substantial protection against prostate cancer death, adding to the epidemiologic evidence for an inhibitory effect on prostate cancer. 2 - Recherche fondamentaleUn nouvel analogue de la vitamine D3, le ZK191784, grâce à son action régulatrice sur l’activité des métalloprotéinases, inhibe l’invasion par les cellules cancéreuses prostatiques.Anticancer Res. 2011 Dec;31(12):4091-8. The novel vitamin D analog ZK191784 inhibits prostate cancer cell invasion. Stio M, Martinesi M, Simoni A, Zuegel U, Steinmeyer A, Santi R, Treves C, Nesi G. Résumé: BACKGROUND: Low serum levels of 1,25(OH)(2)D(3) (1,25D), have been associated with aggressive biologic behavior of prostate cancer (PCa). In the present study, we examined the effects of 1,25D and its novel, low-calcemic analog ZK191784 (ZK) on matrix metalloproteinases (MMPs), as well as on intercellular adhesion molecule-1 (ICAM-1) protein levels in human PCa cell lines LNCaP and DU-145. MATERIALS AND METHODS: Cells were incubated with either vehicle (control), 1,25D or ZK. MMP-2 and MMP-9 activity was determined by gelatin zymography, while ICAM-1 levels were assessed by Western blot analysis and immunocytochemistry. RESULTS: Compared to the controls, 1,25D and ZK caused a marked dose-dependent decrease in the gelatinolytic activity of the MMPs under study, particularly when ZK was used. Likewise, ICAM-1 was down-regulated in the cells incubated with 1,25D or ZK. CONCLUSION: Vitamin D analogs appear to be involved in the regulation of extracellular MMP activity and membrane adhesion molecule expression. Further studies, both in vitro and in vivo, are needed to define their role as potential therapeutic tools. La diminution de la prohibitine augmente l’acétylation des histones et favorise l’hormono-indépendance en augmentant l’activation du récepteur des androgènes par les androgènes surrénaliens. Oncogene. 2011 Dec 19. Reducing prohibitin increases histone acetylation, and promotes androgen independence in prostate tumours by increasing androgen receptor activation by adrenal androgens. Dart DA, Brooke GN, Sita-Lumsden A, Waxman J, Bevan CL. Résumé: Prostate cancers (PCs), initially responsive to anti-androgen therapies, often advance to a hormone-refractory 'castrate-resistant' PC (CRPC) stage. However, the androgen receptor (AR) pathway remains active and key for cell growth and gene expression within tumours, even in the apparent absence of hormone. Proposed mechanisms to explain progression, including AR amplification/mutation, are insufficient to completely explain CRPC and possible roles of AR cofactors such as prohibitin (PHB) are poorly understood. We investigated whether PHB loss could sensitise PC cells and tumours to adrenal gland-derived androgens, which persist even after androgen ablation, hence contribute to development of CRPC. Using a pair of PC cell lines, inducibly expressing ectopic cDNA or RNAi for PHB, responses to different androgens and hormone concentrations were studied both in vitro and in vivo. PHB was found at the promoters of several genes, both AR and non-AR-regulated, and knockdown increased histone acetylation at these promoters. Further, PHB knockdown increased the rate of AR ligand-induced chromatin binding, and binding rate and occupancy of AR upon the PSA promoter. This resulted in increased cell growth and AR activity in response to all androgens, including promoting a response to the weaker adrenal androgens previously absent at physiological concentrations. In vivo this had functional consequences such that PHB knockdown resulted in androstenedione being sufficient to promote tumour growth, under conditions mimicking those in patients undergoing androgen ablation therapy. We conclude that reduction in PHB levels is sufficient to lower the threshold of AR activity in vitro and in vivo; this may be via a general increase in histone acetylation that could potentially affect signalling by other transcription factors. PHB loss may provide a mechanism for progression to CRPC by sensitising PC cells to 'castrate' conditions-that is, low levels of testicular androgens in the continued presence of weak adrenal and dietary androgens. |
