Miyazawa Serial Numbers
Hex Rays Plw Download Youtube. Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats.
Original Article Effect of Dutasteride on the Risk of Prostate Cancer Gerald L. Andriole, M.D., David G. Bostwick, M.D., Otis W. Brawley, M.D., Leonard G.
I play a 'vintage' circa 1978 MS-958R, serial number 2896 (roughly equivalent to today's PA-202, so I'm told). While I would expect Miyazawa flutes to continuously improve over the years, are there any obvious features or qualities of older Miyazawas? I love my flute, but am considering an upgrade. If anyone has a. THE MIYAZAWA FLUTE - Trademark Details. Status: 710 - Cancelled - Section 8. Image for trademark with serial number 73677791. Serial Number. Registration Number. THE MIYAZAWA FLUTE. 710 - Cancelled - Section 8.
Gomella, M.D., Michael Marberger, M.D., Francesco Montorsi, M.D., Curtis A. Pettaway, M.D., Teuvo L. Tammela, M.D., Claudio Teloken, M.D., Ph.D., Donald J.
Tindall, Ph.D., Matthew C. Somerville, M.S., Timothy H. Wilson, M.S., Ivy L. Fowler, B.S.N., and Roger S.
Rittmaster, M.D., for the REDUCE Study Group N Engl J Med 2010; 362:1192-1202 DOI: 10.1056/NEJMoa0908127. Methods In this 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study, we compared dutasteride, at a dose of 0.5 mg daily, with placebo. Men were eligible for inclusion in the study if they were 50 to 75 years of age, had a prostate-specific antigen (PSA) level of 2.5 to 10.0 ng per milliliter, and had had one negative prostate biopsy (6 to 12 cores) within 6 months before enrollment. Subjects underwent a 10-core transrectal ultrasound-guided biopsy at 2 and 4 years. Results Among 6729 men who underwent a biopsy or prostate surgery, cancer was detected in 659 of the 3305 men in the dutasteride group, as compared with 858 of the 3424 men in the placebo group, representing a relative risk reduction with dutasteride of 22.8% (95% confidence interval, 15.2 to 29.8) over the 4-year study period (P. Figure 2 Proportions of Men with a Positive Biopsy for Prostate Cancer, According to Treatment Period and Group. Data are shown for the efficacy population (i.e., all randomly assigned subjects with a baseline prostate biopsy that had been reviewed centrally and determined to be negative and who received at least one dose of study medication).
Restricted crude rates of prostate cancer are shown (i.e., from analysis that included men who underwent at least one biopsy after baseline). The P value is for the comparison of dutasteride with placebo, with the use of the Mantel–Cox test. The numbers in the bars are numbers of men.
The 5α-reductase inhibitors that are used to treat benign prostatic hyperplasia block the conversion of testosterone to dihydrotestosterone and may reduce the risk of prostate cancer. The results of the Prostate Cancer Prevention Trial showed that finasteride, as compared with placebo, reduced the risk of prostate cancer by 25%, but among the tumors that were detected, there was a 27% increase in the number of those that had Gleason scores of 7 to 10. (The Gleason score is the sum of the two most common histologic patterns or grades in a prostate tumor, each of which is graded on a scale of 1 to 5, with 5 being the most cytologically aggressive.) A subsequent analysis showed that the odds ratio for tumors with Gleason scores of 7 to 10 in the finasteride group decreased from 1.27 to 1.03 in a logistic model that included both baseline variables that are known to affect the risk of cancer and the post-baseline prostate volume. Guidance on the use of 5α-reductase inhibitors to prevent prostate cancer has been published recently. There are two isoforms of 5α-reductase, type 1 and type 2. Expression of type 1 in the prostate is enhanced during the development of prostate cancer, whereas the expression of type 2 is decreased or unchanged. Unlike finasteride, dutasteride inhibits both isoforms of 5α-reductase.
In this trial, we examined the effect of dutasteride on the incidence of prostate cancer detected on biopsy among men at increased risk for the disease. Study Conduct Investigators at GlaxoSmithKline designed the study, in consultation with external consultants. The study protocol and analysis plan can be found in the, available with the full text of this article at NEJM.org. The investigators at GlaxoSmithKline had access to the data when the data were unblinded, and all the authors had access to the data approximately 2 weeks thereafter.
Bhojpuri Video Download Wap there. Investigators at GlaxoSmithKline and members of the steering committee and the independent data and safety monitoring committee monitored the study and collected and analyzed the data. The steering committee was responsible for overseeing the conduct of the trial; the independent data and safety monitoring committee was responsible for ensuring patient safety and had access to unblinded data. The first draft was written by one of the academic authors. All the coauthors, along with a consultant who was paid by GlaxoSmithKline for his help, contributed to subsequent versions, and the coauthors made the decision to submit the manuscript for publication.
The first author vouches for the accuracy and completeness of the data and analyses. All authors who were not affiliated with GlaxoSmithKline signed confidentiality agreements with GlaxoSmithKline regarding the data in this trial; these agreements have remained in force pending publication of the data. Participants The design of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) study has been described previously. We enrolled men who were considered to be at high risk for prostate cancer, on the basis of their age, an elevated prostate-specific antigen (PSA) level, and a previous suspicion of prostate cancer that led to a prostate biopsy. Men were eligible for the study if they were 50 to 75 years of age; had a serum PSA level of 2.5 to 10.0 ng per milliliter, in the case of men 50 to 60 years of age, or 3.0 to 10.0 ng per milliliter, in the case of men older than 60 years of age; and had undergone a single prostate biopsy (6 to 12 cores) within 6 months before enrollment.
Men were excluded if they had undergone more than one biopsy; had prostate cancer of any grade, high-grade intraepithelial neoplasia, atypical small acinar proliferation, a history of prostate cancer, or a prostate volume greater than 80 ml; had undergone previous prostate surgery; or had an International Prostate Symptom Score of 25 or higher, or 20 or higher in the case of men taking alpha-blockers. The International Prostate Symptom Score assesses symptoms related to benign prostatic hyperplasia on a scale of 0 to 35, with 0 to 7 indicating mild symptoms; 8 to 20, moderate symptoms; and 21 to 35, severe symptoms. The protocol was approved by the institutional review board at each research site, and all participants provided written informed consent.
Study Design We conducted a 4-year, multicenter, randomized, double-blind, placebo-controlled, parallel-group study. After a 4-week placebo-based run-in period, eligible subjects were randomly assigned to receive dutasteride at a dose of 0.5 mg daily or placebo; randomization was stratified according to center. Visits were scheduled every 6 months; the International Prostate Symptom Score and free and total serum PSA levels were measured at each visit. To maintain the blinded nature of the study, the PSA levels in the dutasteride-treated men were doubled, since dutasteride reduces PSA levels by a mean of about 50%, and then were randomly adjusted by 0.1 ng per milliliter so that the final reported values were equally even and odd.
Prostate volume was measured by ultrasonography at the time of randomization and 2 and 4 years later. Ten-core transrectal, ultrasound-guided biopsies were performed as part of the protocol at 2 and 4 years; biopsies were performed independently of the protocol when they were clinically indicated.
Assessment of Prostate Biopsies Baseline biopsies had been performed before the start of the study (and independently of the study) and were reread centrally (Bostwick Laboratories) to confirm that the results were negative. Biopsies that were performed as part of the study were also read centrally. The central pathology laboratory had no access to the randomization codes. Biopsies that were performed independently of the study protocol were processed and read locally, and representative slides were read centrally. All positive biopsies were reviewed by the author affiliated with Bostwick Laboratories, who remained unaware of the treatment assignments; the diagnosis and Gleason score that he recorded were the ones that were used in the study. During the first 2 years, a randomly chosen set of 200 biopsies (100 showing cancer and 100 showing no cancer) were reread by an outside expert pathologist; a predefined rate of disagreement on cancer diagnosis of less than 3% was considered to be acceptable.
There were two cases (1%) in which the outside pathologist disagreed with the recorded diagnosis of cancer. End Points The primary end point was prostate cancer detected on biopsy after 2 or 4 years of treatment. A participant with prostate cancer detected on biopsy at 2 years was withdrawn from the study medication. Biopsies that were performed because of a clinical indication between months 19 and 24 and between months 43 and 48 were classified as per-protocol biopsies and replaced the protocol-mandated biopsies at years 2 and 4, respectively. Those that were performed between months 1 and 18 (360 biopsies) and between months 25 and 42 (450 biopsies) were classified as protocol-independent biopsies. Other end points related to the detection of prostate cancer on biopsy included the Gleason score, the tumor volume, the percent of the biopsy cores that were positive for prostate cancer, the percent of core involvement with cancer, and the presence of high-grade intraepithelial neoplasia or atypical small acinar proliferation (which are lesions that are associated with a higher incidence of cancer on repeat biopsy).
End points related to benign prostatic hyperplasia included the International Prostate Symptom Score, the change in total prostate volume from baseline, and the proportions of men who received alpha-blocker therapy, had acute urinary retention, underwent surgery related to benign prostatic hyperplasia, or had a urinary tract infection. Statistical Analysis For the primary end point, two-sided P values of 0.01 or less were considered to indicate statistical significance in the assessment of the superiority of dutasteride over placebo. We estimated that with 8000 subjects, the study would have approximately 90% power to show a 20% reduction with dutasteride in the incidence of prostate cancer detected on biopsy (i.e., an estimated rate of 19.0% in the placebo group and 15.2% in the dutasteride group), at a two-sided alpha level of 0.01. The efficacy population included all randomly assigned subjects who had a baseline prostate biopsy that was considered to be negative on central review and who received at least one dose of the assigned study medication. The safety population included all subjects who underwent randomization. Calculation of three rates of prostate cancer was planned: a restricted crude rate, which included men who had at least one biopsy after baseline; a crude rate, which included all men in the efficacy population; and a modified crude rate, which included men who had a positive result on biopsy and men who underwent the biopsy at the end of the study.
All three rates are reported for the primary end point; for other end points, the restricted crude rate is reported. The statistical analysis of the primary end point was performed with the use of the Mantel–Cox test, stratified according to time period and predefined clusters of study sites. The Mantel–Haenszel estimate of the relative risk of prostate cancer with dutasteride as compared with placebo for years 1 through 4 was calculated on the basis of the results from years 1 and 2 and from years 3 and 4. For all end points, statistical analyses were performed for years 1 and 2 and for years 1 through 4. Prespecified subgroup analyses of prostate-cancer rates were performed according to baseline age (. Participants Table 1 Baseline Characteristics of the Study Participants. Provides a summary of the baseline characteristics of the participants.
Of the 8231 men who underwent randomization (safety population), 109 (1.3%) did not undergo a baseline biopsy, had a positive or suspicious result on the baseline biopsy, or did not receive the study medication ( Figure 1 Randomization and Numbers of Study Participants Who Underwent Biopsy. Participants could undergo a biopsy independently of the protocol, if it was clinically indicated, and subsequently undergo a per-protocol biopsy. Of the remaining 8122 men, 81.6% of the men in the dutasteride group and 84.1% of the men in the placebo group underwent at least one post-baseline study biopsy (P=0.004); 96.9% of the biopsies were needle biopsies. Overall Population During the 4 years of the study, 659 of the 3305 men in the dutasteride group (19.9%) and 858 of the 3424 men in the placebo group (25.1%) received a diagnosis of prostate cancer, representing an absolute risk reduction with dutasteride of 5.1 percentage points. For the restricted crude rate of prostate cancer detected on biopsy, dutasteride was associated with a relative risk reduction of 22.8% (95% confidence interval [CI], 15.2 to 29.8; P.
Prespecified Subgroups The risks of prostate cancer detected on biopsy were significantly lower with dutasteride across all prespecified major subgroups, including subgroups according to age (. Gleason Scores Table 3 Detection of Prostate Cancer on Biopsy, According to Gleason Score, Treatment Period, and Treatment Group. Shows the numbers and proportions of men with prostate cancer according to Gleason score, treatment period, and study group. Over the 4 years of the study, there were 437 tumors with Gleason scores of 5 to 6 in the dutasteride group and 617 in the placebo group (P. Biopsy Results Among the subjects with biopsy specimens that showed cancer, the two study groups were similar with respect to the mean number of positive cores (1.8 in the dutasteride group and 1.9 in the placebo group), percentage of cores with cancer (12.2% and 13.4%, respectively), and tumor volume (0.0022 ml and 0.0024 ml, respectively). These features were also similar between the two groups for tumors with Gleason scores of 7 to 10 (number of positive cores, 2.5 in both groups; percentage of cores with cancer, 20.6% in the dutasteride group and 22.7% in the placebo group), and tumor volume (0.0043 and 0.0049 ml, respectively).
High-Grade Intraepithelial Neoplasia and Atypical Small Acinar Proliferation The men in the dutasteride group had lower rates of high-grade intraepithelial neoplasia (without atypical small acinar proliferation or prostate cancer) than did the men in the placebo group (3.7% vs. 6.0%; relative risk reduction with dutasteride, 39.2%; 95% CI, 24.2 to 51.1; P.
End Points Related to Benign Prostatic Hyperplasia In the placebo group, the mean (±SE) prostate volume increased from 45.8±0.30 ml at baseline to 52.3±0.40 ml at year 2 (a mean increase of 13.0%) and to 56.2±0.44 ml at year 4 (a mean overall increase of 19.7%). In the dutasteride group, the mean prostate volume decreased from 45.7±0.28 ml at baseline to 38.6±0.31 ml at year 2 (a mean decrease of 17.4%) and to 39.0±0.32 ml at year 4 (a mean overall decrease of 17.5%). The difference in the prostate volume between the groups was significant at each time point (P. Safety and Side Effects Table 4 Incidence of Adverse Events. Provides a summary of adverse events, as reported by the investigators. The nature and frequency of common adverse events with dutasteride were similar to those reported in previous studies of dutasteride therapy for men with benign prostatic hyperplasia. A drug-related decrease in libido was reported by 3.3% of the men in the dutasteride group, as compared with 1.6% of the men in the placebo group (P.
Discussion We found that the dual 5α-reductase inhibitor dutasteride reduced the incidence of prostate cancer detected on biopsy among men who had an increased risk of prostate cancer. This reduction in the incidence of prostate cancer was observed mainly among men who had tumors with Gleason scores of 5 to 6.
It is likely that most tumors that were diagnosed during the trial were present at the time of randomization but had not been detected in the baseline biopsy, performed before the study. Modeling data from the Prostate Cancer Prevention Trial and an analysis of prostate-biopsy specimens from men treated with dutasteride for 4 months before surgery support the hypothesis that the major effect of dutasteride is the shrinkage of prostate tumors or inhibition of their growth. During the first 2 years of the trial, there were 141 more tumors with a Gleason score of 5 to 7 in the placebo group than in the dutasteride group (558 among 3346 participants vs. 417 among 3239 participants); the number of tumors with a Gleason score of 8 to 10 was similar in the two groups (18 and 17, respectively). During years 3 and 4, however, only 1 tumor with a Gleason score of 8 to 10 was detected among the 2343 men in the placebo group, whereas 12 such cancers were found among the 2447 men in the dutasteride group (P=0.003).
We speculate that if the men in the placebo group who had the 141 excess tumors with a Gleason score of 5 to 7 detected during years 1 and 2 had remained in the study (i.e., if they had not been withdrawn as the trial required), a proportion of the cancers might have been upgraded on biopsy during years 3 and 4 to higher-grade tumors, thus narrowing the difference between the two groups in the number of tumors with a Gleason score of 8 to 10 in years 3 and 4. Supporting this speculation is a study involving 105 men who had prostate tumors with Gleason scores of 7 or lower and who were being followed without treatment (“active surveillance”); a repeat biopsy after a median follow-up period of 22 months showed that in 8 of the men (7.6%) the tumor was upgraded to a Gleason score of 8 to 10. An alternative explanation, which is also consistent with our data, is that the difference in the number of cancers with a Gleason score of 8 to 10 was due in part to dutasteride therapy. The detection of prostate cancer in a biopsy specimen is a function of tumor volume, prostate volume, and the number of cores in the sample.
Serfling et al. Predicted an 11 to 17% increase in biopsy-detected cancer among men treated with dutasteride, as compared with men receiving placebo, assuming that dutasteride did not reduce tumor volume and reduced prostate volume by 25%. In our study, the between-group difference in the mean percent change from baseline in prostate volume was 30.4±0.79% at year 2 and 37.1±0.93% at year 4 (P. Supported by GlaxoSmithKline.
Rittmaster, Ms. Fowler, and Messrs. Somerville and Wilson report being employees of and owning stock and stock options in GlaxoSmithKline; Dr. Andriole, receiving consulting or advisory fees from Aeterna Zentaris, Ferring Pharmaceuticals, EMD Serono, Gen-Probe, Onconome, Veridex, Amgen, GlaxoSmithKline, Steba Biotech, and the France Foundation, lecture fees from GlaxoSmithKline, and grant support from Aeterna Zentaris, owning stock in Cambridge Endo and Envisioneering Medical Technologies, and holding stock options in Viking Medical; Dr. Bostwick, receiving consulting or advisory fees from GlaxoSmithKline, lecture fees from GlaxoSmithKline, and grant support from Accuray, Bioniche, Endo, Capstone, Dendreon, EDAP, Gilead, GlobeImmune, GlaxoSmithKline, GTx, Protox Therapeutics, Sanofi–Aventis, Schering–Plough, Spectrum Pharmaceuticals, and Stiefel Laboratories, and owning stock in GlaxoSmithKline and stock and stock options in Bostwick Laboratories; Dr. Brawley, receiving consulting or advisory fees from GlaxoSmithKline and Sanofi–Aventis; Dr.
Gomella, receiving consulting or advisory fees from GlaxoSmithKline, Sanofi–Aventis, Watson Pharmaceuticals, Ferring, and AstraZeneca, lecture fees from the France Foundation, and grant support from Cougar Biotechnology, VIVUS, GE Healthcare, GlaxoSmithKline, Photocure, Dendreon, Antigenics, AstraZeneca, EDAP Technomed and Prostate Conditions Education Council; Dr. Marberger, receiving consulting or advisory fees from Antigenics, Allergan, GlaxoSmithKline, GP Pharm, Merck, Rottapharm–Madaus, and Astellas, and lecture fees from Astellas, Ferring, GE Healthcare, GlaxoSmithKline, and Merck; Dr. Montorsi, receiving consulting or advisory fees from Bayer Schering, GlaxoSmithKline, Pierre Fabre Medicament, and Recordati; Dr.
Pettaway, receiving consulting or advisory fees from Ferring Pharmaceuticals and GlaxoSmithKline and lecture fees from Takeda–Abbott Pharmaceuticals; Dr. Tammela, receiving consulting or advisory fees from GlaxoSmithKline, Orion Pharma, and Astellas and lecture fees from GlaxoSmithKline, Orion Pharma, and Astellas; Dr. Teloken, receiving consulting or advisory fees from GlaxoSmithKline and Pfizer; Dr. Tindall, receiving grant support from T.J. Martell Foundation and GlaxoSmithKline; and Dr. Rittmaster, being listed as an inventor on a patent application for the use of dutasteride and testosterone for the treatment of prostate cancer. No other potential conflict of interest relevant to this article was reported.
We thank the patients, the study investigators, the members of the data and safety monitoring committee and the steering committee, and the staff at GlaxoSmithKline for their dedication in the initiation and conduct of the REDUCE study. References • 1 McConnell JD, Roehrborn CG, Bautista OM, et al. The long-term effect of doxazosin, finasteride, and combination therapy on the clinical progression of benign prostatic hyperplasia. N Engl J Med 2003;349:2387-2398 • 2 Thompson IM, Goodman PJ, Tangen CM, et al. The influence of finasteride on the development of prostate cancer. N Engl J Med 2003;349:215-224 • 3 Cohen YC, Liu KS, Heyden NL, et al. Detection bias due to the effect of finasteride on prostate volume: a modeling approach for analysis of the Prostate Cancer Prevention Trial.
J Natl Cancer Inst 20-1374 • 4 Kramer BS, Hagerty KL, Justman S, et al. Use of 5alpha-reductase inhibitors for prostate cancer chemoprevention: American Society of Clinical Oncology/American Urological Association 2008 Clinical Practice Guideline. J Urol 2009;181:1642-1657 • 5 Iehle C, Delos S, Guirou O, Tate R, Raynaud JP, Martin PM. Human prostatic steroid 5 alpha-reductase isoforms -- a comparative study of selective inhibitors. J Steroid Biochem Mol Biol 1995;54:273-279 • 6 Thomas LN, Lazier CB, Gupta R, et al.
Differential alterations in 5alpha-reductase type 1 and type 2 levels during development and progression of prostate cancer. Prostate 2005;63:231-239 • 7 Bramson HN, Hermann D, Batchelor KW, Lee FW, James MK, Frye SV.
Unique preclinical characteristics of GG745, a potent dual inhibitor of 5AR. J Pharmacol Exp Ther 1997;282:1496-1502 • 8 Andriole G, Bostwick D, Brawley O, et al.
Chemoprevention of prostate cancer in men at high risk: rationale and design of the Reduction by Dutasteride of Prostate Cancer Events (REDUCE) trial. J Urol 2004;172:1314-1317 • 9 Stokes ME, Davis CS, Koch GG. Categorical data analysis using the SAS system. Cary, NC: SAS Institute, 2000. • 10 Serfling R, Shulman M, Thompson GL, et al.
Quantifying the impact of prostate volumes, number of biopsy cores and 5alpha-reductase inhibitor therapy on the probability of prostate cancer detection using mathematical modeling. J Urol 2007;177:2352-2356 • 11 Gleave M, Qian J, Andreou C, et al. The effects of the dual 5 alpha-reductase inhibitor dutasteride on localized prostate cancer -- results from a 4-month pre-radical prostatectomy study. Prostate 20-1685 • 12 Choo R, Danjoux C, Morton G, et al. How much does Gleason grade of follow-up biopsy differ from that of initial biopsy in untreated, Gleason score 4-7, clinically localized prostate cancer? Prostate 20-1620 • 13.