Background
In recent years, many automated immunoassay analyzers have been developed for accurate diagnosis of various disease states and to improve effective drug administration. Amperometric immunoassay has been increasingly applied to laboratory medicine due to its ease in automation, rapid speed and low detection limits. It is important to develop reusable immunologically-sensitive elements for prostate-specific antigen (PSA) detection.
Methods
The strategy for the immunosensor construction is based on the enzyme-conjugated prostate-specific antibody (HRP-anti-PSA) reversible binding with a self-assembled phenylboronic acid monolayer on gold.
Results
After incubating an HRP-anti-PSA modified electrode in a prostate-specific antigen (PSA) solution, a decrease in the electrocatalytic response of the HRP-anti-PSA modified electrode to the reduction of H2O2 is observed. The photometric activity assays show that this decrease of the electrocatalytic response arises from the formation of immunocomplexes of HRP-conjugated anti-PSA and its antigen, not from the loss of bound HRP-anti-PSA from the electrode surface. Analytical performances and optimal conditions of the described immunosensor are also investigated. Under the optimal conditions, the amperometric immunosensor shows a linear increase of the relative intensity in 2 PSA concentration range from 2 to 15 ng/ml and 15 to 120 ng/ml, respectively.
Conclusion
This method could be used for rapid analysis of prostate-specific antigen (PSA) and potentially other antigens.
ARTICLE
Negative influence of changing biopsy practice patterns on the predictive value of prostate-specific antigen for cancer detection on prostate biopsy.
BACKGROUND: A correlation between prostate specific antigen (PSA) level and positive prostate biopsy rate was established in an era when biopsy practice patterns were different from what they are today. We evaluated if changes in biopsy practice patterns have affected the ability of PSA to predict cancer detection on prostate biopsy in the current era.
METHODS: Of 3634 prostate biopsies performed from 1993-2005, 1607 met criteria for analysis. Biopsy data were divided into 3 time-cohorts (1993-1997, 1998-2001, and 2002-2005) to assess for practice patterns shifts and correlation between PSA and biopsy results.
RESULTS: Significant changes in biopsy practice patterns included an increase in biopsy cores and more frequent use of PSA 2.5-3.99 ng/mL as a biopsy indication. In men with normal DRE, a moderate correlation between PSA and positive biopsy rate did exist from 1993-1997, but was subsequently lost. On multivariate analysis, prostate specific antigen (PSA) was not a significant predictor of biopsy result in men with normal DRE.
CONCLUSIONS: Early in the PSA era, the predictive power of PSA depended on multiple factors: high prevalence of disease, higher prevalence of high-grade disease, and low likelihood of prostate cancer diagnosis in men with low PSA. Now, beyond the culling effect of increased biopsy incidence and with shifted biopsy practice patterns, the correlation between PSA and biopsy result is lost in men with normal DRE. Diagnosing a higher proportion of tumors in men with a PSA between 2.0-4.0 ng/mL has negatively influenced the predictive value of prostate specific antigen (PSA) for cancer detection.
METHODS: Of 3634 prostate biopsies performed from 1993-2005, 1607 met criteria for analysis. Biopsy data were divided into 3 time-cohorts (1993-1997, 1998-2001, and 2002-2005) to assess for practice patterns shifts and correlation between PSA and biopsy results.
RESULTS: Significant changes in biopsy practice patterns included an increase in biopsy cores and more frequent use of PSA 2.5-3.99 ng/mL as a biopsy indication. In men with normal DRE, a moderate correlation between PSA and positive biopsy rate did exist from 1993-1997, but was subsequently lost. On multivariate analysis, prostate specific antigen (PSA) was not a significant predictor of biopsy result in men with normal DRE.
CONCLUSIONS: Early in the PSA era, the predictive power of PSA depended on multiple factors: high prevalence of disease, higher prevalence of high-grade disease, and low likelihood of prostate cancer diagnosis in men with low PSA. Now, beyond the culling effect of increased biopsy incidence and with shifted biopsy practice patterns, the correlation between PSA and biopsy result is lost in men with normal DRE. Diagnosing a higher proportion of tumors in men with a PSA between 2.0-4.0 ng/mL has negatively influenced the predictive value of prostate specific antigen (PSA) for cancer detection.
Hierarchical Changepoint Models for Biochemical Markers Illustratedby Tracking Postradiotherapy Prostate-Specific Antigen Series inMen With Prostate C
PURPOSE: Biomarkers provide valuable information when detecting disease onset or monitoring diseaseprogression; examples include bone mineral density (for osteoporosis), cholesterol (for coronary artery dis-eases), or prostate-specific antigens (PSA, for prostate cancer). Characteristics of markers series can then beused as prognostic factors of disease progression, such as the postradiotherapy PSA doubling time in mentreated for prostate cancer. The statistical analysis of such data has to incorporate the within and be-tween-series variabilities, the complex patterns of the series over time, the unbalanced format of thedata, and the possibly nonconstant precision of the measurements.
METHODS: We base our analysis on a population-based cohort of 470 men treated with radiotherapy forprostate cancer; after treatment, the log2PSA concentrations follow a piecewise-linear pattern. We illus-trate the flexibility of Bayesian hierarchical changepoint models by estimating the individual and popula-tion postradiotherapy log2PSA profiles; parameters such as the PSA nadir and the PSA doubling time wereestimated, and their associations with baseline patient characteristics were investigated. The residual PSA variability was modeled as a function of the prostate-specific antigen concentration. For comparison purposes, two alternative models were briefly considered.
RESULTS: Precise estimates of all parameters of the PSA trajectory are provided at both the individualand population levels. Estimates suggest greater PSA variability at lower PSA concentrations, as well as anassociation between shorter PSAdts and greater baseline PSA levels, higher Gleason scores, and older age.
CONCLUSIONS: The use of Bayesian hierarchical changepoint models accommodates multiple com-plex features of longitudinal data, permits realistic modeling of the variability as a function of the markerconcentration, and provides precise estimates of all clinically important parameters. This type of model should be applicable to the study of marker series in other diseases.
ARTICLE
METHODS: We base our analysis on a population-based cohort of 470 men treated with radiotherapy forprostate cancer; after treatment, the log2PSA concentrations follow a piecewise-linear pattern. We illus-trate the flexibility of Bayesian hierarchical changepoint models by estimating the individual and popula-tion postradiotherapy log2PSA profiles; parameters such as the PSA nadir and the PSA doubling time wereestimated, and their associations with baseline patient characteristics were investigated. The residual PSA variability was modeled as a function of the prostate-specific antigen concentration. For comparison purposes, two alternative models were briefly considered.
RESULTS: Precise estimates of all parameters of the PSA trajectory are provided at both the individualand population levels. Estimates suggest greater PSA variability at lower PSA concentrations, as well as anassociation between shorter PSAdts and greater baseline PSA levels, higher Gleason scores, and older age.
CONCLUSIONS: The use of Bayesian hierarchical changepoint models accommodates multiple com-plex features of longitudinal data, permits realistic modeling of the variability as a function of the markerconcentration, and provides precise estimates of all clinically important parameters. This type of model should be applicable to the study of marker series in other diseases.
ARTICLE
The effect of 5alpha-reductase inhibition with dutasteride and finasteride on bone mineral density, serum lipoproteins, hemoglobin, prostate specific
PURPOSE: Dutasteride and finasteride are 5alpha-reductase inhibitors that dramatically decrease serum levels of dihydrotestosterone. Because androgens affect bone, lipids, hematopoiesis, prostate and sexual function, we determined the impact of 5alpha-reductase inhibitors on these end points.
MATERIALS AND METHODS: We conducted a randomized, double-blinded, placebo controlled trial of 99 men 18 to 55 years old randomly assigned to receive 0.5 mg dutasteride (33), 5 mg finasteride (34) or placebo (32) daily for 1 year. Bone mineral density was measured at baseline, after 1 year of treatment and 6 months after drug discontinuation. In addition, markers of bone turnover, fasting serum lipoprotein concentrations, hemoglobin and prostate specific antigen were measured at baseline, after 26 and 52 weeks of treatment, and again 24 weeks after drug discontinuation. Sexual function was assessed at these points by a validated questionnaire.
RESULTS: Significant suppression of circulating dihydrotestosterone levels with the administration of dutasteride or finasteride did not significantly affect bone mineral density or markers of bone metabolism. Similarly serum lipoproteins and hemoglobin were unaffected. Serum prostate specific antigen and self-assessed sexual function decreased slightly during treatment with both 5alpha-reductase inhibitors but returned to baseline during followup.
CONCLUSIONS: Profound suppression of circulating serum dihydrotestosterone induced by 5alpha-reductase inhibitors during 1 year does not adversely impact bone, serum lipoproteins or hemoglobin, and has a minimal, reversible effect on serum prostate specific antigen and sexual function in normal men. Circulating dihydrotestosterone does not appear to have a clinically significant role in modulating bone mass, hematopoiesis or lipid metabolism in normal men.
MATERIALS AND METHODS: We conducted a randomized, double-blinded, placebo controlled trial of 99 men 18 to 55 years old randomly assigned to receive 0.5 mg dutasteride (33), 5 mg finasteride (34) or placebo (32) daily for 1 year. Bone mineral density was measured at baseline, after 1 year of treatment and 6 months after drug discontinuation. In addition, markers of bone turnover, fasting serum lipoprotein concentrations, hemoglobin and prostate specific antigen were measured at baseline, after 26 and 52 weeks of treatment, and again 24 weeks after drug discontinuation. Sexual function was assessed at these points by a validated questionnaire.
RESULTS: Significant suppression of circulating dihydrotestosterone levels with the administration of dutasteride or finasteride did not significantly affect bone mineral density or markers of bone metabolism. Similarly serum lipoproteins and hemoglobin were unaffected. Serum prostate specific antigen and self-assessed sexual function decreased slightly during treatment with both 5alpha-reductase inhibitors but returned to baseline during followup.
CONCLUSIONS: Profound suppression of circulating serum dihydrotestosterone induced by 5alpha-reductase inhibitors during 1 year does not adversely impact bone, serum lipoproteins or hemoglobin, and has a minimal, reversible effect on serum prostate specific antigen and sexual function in normal men. Circulating dihydrotestosterone does not appear to have a clinically significant role in modulating bone mass, hematopoiesis or lipid metabolism in normal men.
Early Versus Delayed Hormonal Therapy for Prostate Specific Antigen Only Recurrence of Prostate Cancer After Radical Prostatectomy
Purpose
Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach.
Materials and Methods
Of 5,382 men in the database who underwent primary radical prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1,352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome.
Results
Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05).
Conclusions
The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue
Judd W. Moula, d, Hongyu Wua, Leon Suna, David G. McLeodd, Christopher Amlinge, Timothy Donahueb, Leo Kusudaf, Wade Sextong, Keith O’Reilly, Javier Hernandezh, , Andrew Chungc, and Douglas Soderdahl
Hormonal therapy (HT) is the current mainstay of systemic treatment for prostate specific antigen (PSA) only recurrence (PSAR), however, there is virtually no published literature comparing HT to observation in the clinical setting. The goal of this study was to examine the Department of Defense Center for Prostate Disease Research observational database to compare clinical outcomes in men who experienced PSAR after radical prostatectomy by early versus delayed use of HT and by a risk stratified approach.
Materials and Methods
Of 5,382 men in the database who underwent primary radical prostatectomy (RP), 4,967 patients were treated in the PSA-era between 1988 and December 2002. Of those patients 1,352 men who had PSAR (PSA after surgery greater than 0.2 ng/ml) and had postoperative followup greater than 6 months were used as the study cohort. These patients were further divided into an early HT group in which patients (355) received HT after PSA only recurrence but before clinical metastasis and a late HT group for patients (997) who received no HT before clinical metastasis or by current followup. The primary end point was the development of clinical metastases. Of the 1,352 patients with PSAR clinical metastases developed in 103 (7.6%). Patients were also stratified by surgical Gleason sum, PSA doubling time and timing of recurrence. Univariate and multivariate Cox proportional hazard models were used to evaluate the effect of early and late HT on clinical outcome.
Results
Early HT was associated with delayed clinical metastasis in patients with a pathological Gleason sum greater than 7 or PSA doubling time of 12 months or less (Hazards ratio = 2.12, p = 0.01). However, in the overall cohort early HT did not impact clinical metastases. Race, age at RP and PSA at diagnosis had no effect on metastasis-free survival (p >0.05).
Conclusions
The retrospective observational multicenter database analysis demonstrated that early HT administered for PSAR after prior RP was an independent predictor of delayed clinical metastases only for high-risk cases at the current followup. Further study with longer followup and randomized trials are needed to address this important issue
Judd W. Moula, d, Hongyu Wua, Leon Suna, David G. McLeodd, Christopher Amlinge, Timothy Donahueb, Leo Kusudaf, Wade Sextong, Keith O’Reilly, Javier Hernandezh, , Andrew Chungc, and Douglas Soderdahl
Prostate Cancer Vaccine Effective In Mice, Study Shows
Researchers at the University of Southern California have developed a prostate cancer vaccine that prevented the development of cancer in 90 percent of young mice genetically predestined to develop the disease. In the February 1 issue of Cancer Research, they suggest the same strategy might work for men with rising levels of PSA (prostate specific antigen) , a potential diagnostic indicator of prostate cancer.
By early vaccination, we have basically given these mice life-long protection against a disease they were destined to have," said the study's lead investigator, W. Martin Kast, Ph.D., a professor of Molecular Microbiology & Immunology and Obstetrics & Gynecology at the Norris Comprehensive Cancer Center. "This has never been done before and, with further research, could represent a paradigm shift in the management of human prostate cancer."
Now, men with rising prostate specific antigen PSA levels but no other signs of cancer are advised "watchful waiting" -- no treatment until signs of the cancer appear, Kast says. "But what if instead of a watchful wait, we vaccinate" That could change the course of the disease."
The study findings also represent a new way to think about the use of therapeutic prostate cancer vaccines, Kast says. Vaccines now in testing are designed to treat men whose cancers are advanced and unresponsive to therapy, and results have offered limited clinical benefit, he says. This novel approach targets the precancerous state with the aim of preventing cancer from developing, he says.
The Kast team's preventive vaccine is designed to mount an immune response against prostate stem cell antigen (PSCA), the protein target of some therapeutic vaccines under development. PSCA, a membrane protein, is over-expressed in about one-third of early-stage prostate cancers, but expression ramps up in all prostate tumors as they grow and advance. PSCA is also expressed at low-levels in normal prostate gland tissue as well as in the bladder, colon, kidney and stomach.
The researchers created a prime-boost vaccination scheme using two kinds of vaccines and tested it in 8-week-old mice that were genetically altered to develop prostate cancer later in life. The first vaccine simply delivered a fragment of DNA that coded for PSCA, thus producing an influx of PSCA protein to alert the immune system. The booster shot, given two weeks later, used a modified horse virus to deliver the PSCA gene.
"Confronting the immune system in two different ways forces it to mount a strong response," Kast said.
In the experimental group, two of 20 mice developed prostate cancer at the end of one year, and by contrast, all control mice had died of the disease. Researchers found that mice in the experimental group had all developed very small tumors that did not progress. "There were tiny nodules of prostate cancer in the mice that were surrounded by an army of immune system cells," Kast said. "The vaccination turned the cancer into a chronic, manageable disease."
The vaccination strategy also works with other antigens, Kast says. The researchers recently tried another prostate cancer membrane target and found that after 1.5 years, 65 percent of experimental mice were still alive, and of those that died, the suspected cause was old age.
Crucially, investigators further found that treated mice did not develop autoimmune disease, a side effect that could develop if the vaccine had also targeted PSCA expression in normal cells. "Theoretically, the vaccine could produce a response in any tissue that expresses the antigen, but the fact that PSCA is expressed in such low levels in normal tissue may prevent that complication," he said.
Still, studies in humans are needed to ensure autoimmunity does not develop, Kast says.
"We feel this is a very promising approach," he said. "With just two shots, the vaccine will prime immune cells to be on the lookout for any cell that over-expresses PSCA."
The study was funded by a pre-doctoral training grant from the National Institutes of Health and a grant from the Margaret E. Early Medical Research Trust. Co-authors include researchers from the University of Southern California as well as from AlphaVax, inc., of Research Triangle Park, North Carolina.
Adapted from materials provided by American Association for Cancer Research.
By early vaccination, we have basically given these mice life-long protection against a disease they were destined to have," said the study's lead investigator, W. Martin Kast, Ph.D., a professor of Molecular Microbiology & Immunology and Obstetrics & Gynecology at the Norris Comprehensive Cancer Center. "This has never been done before and, with further research, could represent a paradigm shift in the management of human prostate cancer."
Now, men with rising prostate specific antigen PSA levels but no other signs of cancer are advised "watchful waiting" -- no treatment until signs of the cancer appear, Kast says. "But what if instead of a watchful wait, we vaccinate" That could change the course of the disease."
The study findings also represent a new way to think about the use of therapeutic prostate cancer vaccines, Kast says. Vaccines now in testing are designed to treat men whose cancers are advanced and unresponsive to therapy, and results have offered limited clinical benefit, he says. This novel approach targets the precancerous state with the aim of preventing cancer from developing, he says.
The Kast team's preventive vaccine is designed to mount an immune response against prostate stem cell antigen (PSCA), the protein target of some therapeutic vaccines under development. PSCA, a membrane protein, is over-expressed in about one-third of early-stage prostate cancers, but expression ramps up in all prostate tumors as they grow and advance. PSCA is also expressed at low-levels in normal prostate gland tissue as well as in the bladder, colon, kidney and stomach.
The researchers created a prime-boost vaccination scheme using two kinds of vaccines and tested it in 8-week-old mice that were genetically altered to develop prostate cancer later in life. The first vaccine simply delivered a fragment of DNA that coded for PSCA, thus producing an influx of PSCA protein to alert the immune system. The booster shot, given two weeks later, used a modified horse virus to deliver the PSCA gene.
"Confronting the immune system in two different ways forces it to mount a strong response," Kast said.
In the experimental group, two of 20 mice developed prostate cancer at the end of one year, and by contrast, all control mice had died of the disease. Researchers found that mice in the experimental group had all developed very small tumors that did not progress. "There were tiny nodules of prostate cancer in the mice that were surrounded by an army of immune system cells," Kast said. "The vaccination turned the cancer into a chronic, manageable disease."
The vaccination strategy also works with other antigens, Kast says. The researchers recently tried another prostate cancer membrane target and found that after 1.5 years, 65 percent of experimental mice were still alive, and of those that died, the suspected cause was old age.
Crucially, investigators further found that treated mice did not develop autoimmune disease, a side effect that could develop if the vaccine had also targeted PSCA expression in normal cells. "Theoretically, the vaccine could produce a response in any tissue that expresses the antigen, but the fact that PSCA is expressed in such low levels in normal tissue may prevent that complication," he said.
Still, studies in humans are needed to ensure autoimmunity does not develop, Kast says.
"We feel this is a very promising approach," he said. "With just two shots, the vaccine will prime immune cells to be on the lookout for any cell that over-expresses PSCA."
The study was funded by a pre-doctoral training grant from the National Institutes of Health and a grant from the Margaret E. Early Medical Research Trust. Co-authors include researchers from the University of Southern California as well as from AlphaVax, inc., of Research Triangle Park, North Carolina.
Adapted from materials provided by American Association for Cancer Research.
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