Biomedical subjects

David G McLeod

Publications and source records attributed to David G McLeod.

At least 19 recordsLinked to original sources

PubMed2006

Cancer-specific mortality after radiation therapy with short-course hormonal therapy or radical prostatectomy in men with localized, intermediate-risk to high-risk prostate cancer.

BACKGROUND: The presence of multiple determinants of aggressive cancer biology may impact prostate cancer-specific mortality (PCSM) rates compared with fewer factors. The authors estimated PCSM after radiation therapy with short-course androgen suppression therapy (RT+AST) or radical prostatectomy (RP) in men with clinically localized, intermediate-risk to high-risk prostate cancer. METHODS: The study cohort included 3240 men treated from 1981 to 2002 with RT with 6 months of AST (n = 550) or RP (n = 2690) for localized prostate cancer with at least 1 risk factor (prostate-specific antigen [PSA] >10 ng/mL, biopsy Gleason score 7-10, or clinical tumor category T2b or T2c). Competing risks regression analyses were used to determine whether the number of risk factors present was associated with time to PCSM. RESULTS: Men with all 3 risk factors had significantly shorter time to PCSM after RT+AST (adjusted hazards ratio [HR] of 9.3; 95% confidence interval [95% CI], 1.9-44.5 [P(Gray) = .005]) or RP (adjusted HR of 6.3; 95% CI, 3.2-12.2 [P(Gray) < .001]) when compared with men with any 1 or 2 risk factors. The 7-year estimates of PCSM for men having 1, 2, or 3 risk factors were 0.83% (95% CI, 0.27-1.4%), 2.6% (95% CI, 1.0-4.2%), and 12.6% (95% CI, 7.1-18.1%), respectively. CONCLUSIONS: Men with multiple determinants of intermediate-risk to high-risk prostate cancer have significantly increased estimates of PCSM despite aggressive therapy compared with men with only 1 or 2 determinants. These men are appropriate candidates for enrollment onto randomized controlled trials evaluating the benefit of adding systemic therapies such as docetaxel to RT+AST or RP.

Aged↗

PubMed2006

Lymphovascular invasion in prostate cancer: prognostic significance in patients treated with radiotherapy after radical prostatectomy.

BACKGROUND: Lymphovascular invasion (LVI) is found in approximately 5% to 53% of specimens after radical prostatectomy (RP). Although LVI is associated with higher rates of recurrence after RP, its prognostic significance after postprostatectomy radiotherapy (P-XRT) is unclear. METHODS: The medical records of men who received P-XRT from 1991 to 2001 at 2 institutions were reviewed for the presence of LVI in RP specimens. Multiple patient variables were evaluated for their association with LVI using Fisher exact tests and Wilcoxon rank-sum tests. The time to biochemical recurrence (BCR) and the time to distant metastases (DM) after RP were analyzed using Kaplan-Meier estimations, log-rank tests, and Cox regression analyses. RESULTS: Eighteen of 160 patients (11%) who received P-XRT had LVI in their RP specimen. High Gleason score and seminal vesicle invasion were associated significantly with LVI. After a median follow-up of 8.3 years after RP, 16 patients with LVI had BCR after P-XRT, 9 of whom developed DM. The median time to BCR in patients with LVI was 2.6 years (95% confidence interval [95% CI], 1.8-5.4) compared with 7.8 years (95% CI, 6.8-10.3) in patients without LVI (P < .001). Multivariate analysis revealed an adjusted relative risk for LVI of 5.5 (P < .001). Other significant factors were Gleason score, undetectable post-RP serum prostate-specific antigen (PSA) levels, preradiotherapy serum PSA levels, and the interval from RP to P-XRT. LVI was the only significant factor associated with an increased risk of DM in univariate analysis (hazard ratio, 7.4; P < .001). CONCLUSIONS: LVI was useful as a pathologic marker for reduced efficacy of P-XRT after RP in terms of increased risk of BCR and DM. Future studies will be needed to validate these findings.

Aged↗

PubMed2006

Phenotypic characterization of telomerase-immortalized primary non-malignant and malignant tumor-derived human prostate epithelial cell lines.

In vitro human prostate cell culture models are critical for clarifying the mechanism of prostate cancer progression and for testing preventive and therapeutic agents. Cell lines ideal for the study of human primary prostate tumors would be those derived from spontaneously immortalized tumor cells; unfortunately, explanted primary prostate cells survive only short-term in culture, and rarely immortalize spontaneously. Therefore, we recently have generated five immortal human prostate epithelial cell cultures derived from both the benign and malignant tissues of prostate cancer patients with telomerase, a gene that prevents cellular senescence. Examination of these cell lines for their morphologies and proliferative capacities, their abilities to grow in low serum, to respond to androgen stimulation, to grow above the agar layer, to form tumors in SCID mice, suggests that they may serve as valid, useful tools for the elucidation of early events in prostate tumorigenesis. Furthermore, the chromosome alterations observed in these immortalized cell lines expressing aspects of the malignant phenotypes imply that these cell lines accurately recapitulate the genetic composition of primary tumors. These novel in vitro models may offer unique models for the study of prostate carcinogenesis and also provide the means for testing both chemopreventive and chemotherapeutic agents.

Adult↗

PubMed2006

Prostate-specific antigen-based serial screening may decrease prostate cancer-specific mortality.

OBJECTIVES: To compare the preoperative characteristics, postoperative prostate-specific antigen (PSA) doubling time (DT), and prostate cancer-specific mortality (PCSM) estimates after PSA failure in men diagnosed during a screening study versus a community referral population. A PSA-DT of less than 3 months is a surrogate endpoint for PCSM. METHODS: From 1988 to 2002, 1492 of 9637 patients with clinically localized prostate cancer underwent radical prostatectomy and experienced PSA failure. They were either participating in a screening study (n = 841) or attended 1 of 44 community-based practices (n = 611). The distributions of PSA, Gleason score, tumor stage, and PSA-DT were compared using chi-square metric. The estimates of PCSM after PSA failure were compared using Gray's P value. RESULTS: Compared with the community population, the annually screened men experiencing PSA failure had a lower PSA level at diagnosis (5.1 versus 9.5 ng/mL, P <0.0001), were less likely to have Gleason score 7 to 10 cancer (25.1% versus 42.1%, P <0.0001), and were more likely to have low-risk disease (64.5% versus 23.8%, P <0.0001). Furthermore, the screened cohort had a reduction (P <0.0001) in the proportion with a PSA-DT of less than 3, 3 to 5.99, and 6 to 11.99 months and a significant increase in the proportion with a PSA-DT of 12 months or longer. After a median follow-up of 4.5 and 4.1 years after PSA failure in the screened and community cohorts, respectively, the PCSM estimates were lower (P = 0.0002) in the screened cohort (10-year estimate 3.6% [95% confidence interval 1.3 to 5.8] versus 11.3% [95% confidence interval 5.9 to 17.4]). CONCLUSIONS: Patients diagnosed by annual prostate cancer screening appeared more likely to experience an indolent PSA recurrence and less likely to die of prostate cancer after PSA recurrence compared with patients referred from the community.

Adult↗

PubMed2006

The bicalutamide 150 mg early prostate cancer program: findings of the North American trial at 7.7-year median followup.

PURPOSE: We describe the results of North American Trial 23 of the bicalutamide (Casodex) early prostate cancer program in the context of the overall early prostate cancer program findings. MATERIALS AND METHODS: In Trial 23, 3,292 men with T1b-4, N0-Nx (N+ not allowed) M0 prostate cancer who had undergone radical prostatectomy or radiotherapy at 96 specialist referral centers in the United States (2,974) and Canada (318) were randomized 1:1 to 150 mg bicalutamide daily or placebo in addition to standard care for 2 years. RESULTS: In Trial 23 at a 7.7-year median followup there were few clinical events in the bicalutamide or standard care groups and the rates of objective progression were 15.4% and 15.3%, respectively. Mortality rates were 12.9% in the treatment group and 12.3% in the standard care group, including 11.2% and 11.0% for nonprostate cancer deaths in the absence of objective progression and 1.6% and 0.9%, respectively, for mortality due to prostate cancer. No differences in the primary end points (objective progression-free and overall survival) were seen between patients treated with bicalutamide and those treated with standard care alone. Bicalutamide (150 mg) significantly improved time to PSA progression (HR 0.80, 95% CI 0.72 to 0.90, p <0.001). The tolerability profile of bicalutamide was similar to that previously described. CONCLUSIONS: In Trial 23 the current data suggest that early or adjuvant therapy may not benefit patients at low risk for recurrence, such as those with localized disease. The findings of Trial 23 contrast with the results in the overall early prostate cancer program and in other published literature, in which bicalutamide has been shown to provide significant clinical benefit for locally advanced disease.

Adult↗

PubMed2006

Bicalutamide 150 mg plus standard care vs standard care alone for early prostate cancer.

OBJECTIVE: To evaluate, in the ongoing Early Prostate Cancer (EPC) trial programme, the efficacy and tolerability of bicalutamide 150 mg once daily in addition to standard care for localized or locally advanced, nonmetastatic prostate cancer. PATIENTS AND METHODS: The EPC programme comprises three randomized, double-blind, placebo-controlled trials designed for combined analysis. Following standard care, 8113 men with localized (T1-2, N0/Nx) or locally advanced (T3-4, any N; or any T, N+) prostate cancer (all M0) received oral bicalutamide 150 mg once daily or oral placebo. The primary endpoints were progression-free survival (PFS) and overall survival. RESULTS: The large EPC trial programme is defining men who benefit or do not from early or adjuvant antiandrogen therapy. At a median follow-up of 7.4 years, in localized disease there is no benefit to PFS by adding bicalutamide to standard care, and there is a trend (hazard ratio, HR, 1.16; 95% confidence intervals, CI, 0.99-1.37; P = 0.07) towards decreased survival in patients otherwise undergoing watchful waiting. However, in locally advanced disease, bicalutamide significantly improved PFS irrespective of standard care. Bicalutamide significantly improved overall survival in patients receiving radiotherapy (HR 0.65; 95% CI 0.44-0.95; P = 0.03); this was driven by a lower risk of prostate cancer-related deaths. Bicalutamide produced a trend towards improved overall survival in patients with locally advanced disease otherwise undergoing watchful waiting (HR 0.81; 95% CI 0.66-1.01; P = 0.06). No survival difference was evident in the prostatectomy subgroup. CONCLUSIONS: This ongoing programme is clarifying the role of early or adjuvant antiandrogen therapy in prostate cancer. Patients with localized disease do not appear to derive clinical benefit from added bicalutamide. However, adding bicalutamide 150 mg to standard care provides significant clinical benefits in patients with locally advanced prostate cancer, irrespective of primary therapy.

Aged↗

PubMed2006

The relationship of ultrasensitive measurements of prostate-specific antigen levels to prostate cancer recurrence after radical prostatectomy.

OBJECTIVE: To evaluate ultrasensitive (US) measurements of prostate-specific antigen (PSA) level in men with prostate cancer, and to correlate the findings with currently accepted values for PSA recurrence, as PSA is widely accepted as a surrogate marker for disease recurrence after treatment for prostate cancer, and although USPSA assays can detect minute quantities of PSA, the significance of this is unclear. PATIENTS AND METHODS: In all, 225 patients had a radical prostatectomy (RP) and were followed with USPSA measurements. PSA recurrence was defined as two or more consecutive increasing PSA values after RP of > or = 0.200 ng/mL. This was deemed clinically significant if it was associated with adjuvant treatment with a repeated nadir PSA level, or a PSA level that continued to increase on watchful waiting. USPSA values were compared between patients who recurred and those who did not, to determine any association with PSA recurrence and clinical outcomes. RESULTS: There was a PSA recurrence in 21 patients; all had clinical evidence of recurrence. Although the difference in mean USPSA levels was statistically significant for those patients who did and did not recur, the overlap in values invalidated any clinical utility. However, an undetectable level achieved during the follow-up appeared to confer a favourable prognosis. CONCLUSION: After RP patients might have PSA levels detectable by USPSA assays, i.e. <0.1 ng/mL. The amount of 'background noise' produced within this range precludes the ability to use this test as a clinical indicator of disease recurrence. However, undetectable levels appear to confer a favourable prognosis.

Follow-Up Studies↗

PubMed2006

The emergence of radioimmunoscintigraphy for prostate cancer.

The ability to label tissue-specific antibodies has long been of interest for improving detection and guidance for therapeutic applications. The most studied target for prostate cancer is the prostate-specific membrane antigen, which is upregulated in prostate cancer, hormone-refractive disease, and prostate cancer metastases. Investigations using radioimmunoscintigraphy with the radiolabeled 7E11 antibody capromab pendetide have significantly improved sensitivity for prostate cancer detection compared with standard cross-sectional imaging, based on tissue confirmation of pathologic results. Over the past 5 years, significantly greater image resolution from improved camera technology and the use of co-registration to fuse functional and anatomic (computerized tomography and magnetic resonance imaging) images have dramatically enhanced prostate cancer localization. Outcomes data from several sources have spurred a resurgence in interest in this imaging modality.

Journal Article↗

PubMed2005

Phase I clinical trial of a HER-2/neu peptide (E75) vaccine for the prevention of prostate-specific antigen recurrence in high-risk prostate cancer patients.

PURPOSE: The E75 peptide is an immunogenic peptide from the HER-2/neu protein that is substantially expressed in prostate cancer. We are conducting a clinical trial of an E75/granulocyte macrophage colony-stimulating factor vaccine to prevent post-prostatectomy prostate-specific antigen (PSA) recurrences in high-risk prostate cancer (HRPC) patients. EXPERIMENTAL DESIGN: Prostate cancer patients at high risk for recurrence were prospectively evaluated and identified by the validated Center for Prostate Disease Research (CPDR)/CaPSURE high-risk equation. From these high-risk equation patients, 27 HER-2/neu-expressing prostate cancer patients were enrolled. HLA-A2+ patients (n = 17) were vaccinated, whereas HLA-A2- patients (n = 10) were followed as clinical controls. Local/systemic toxicities, immunologic responses, and time to recurrence were measured. RESULTS: This vaccine is safe with only minor toxicities observed. Additionally, the vaccine is immunogenic with all patients showing both in vivo and in vitro phenotypic and functional immune responses, although variable. HLA-A2+ patients were found to have larger tumors, higher postoperative Gleason scores, and more high-risk CPDR scores than HLA-A2- patients. Despite these differences, disease-free survival was not different between the vaccinated HLA-A2+ patients and the HLA-A2- controls at a median follow up of 23 months. Three of the four vaccinated patients that recurred had rising PSAs at the initiation of the trial. Ex vivo phenotypic assays were predictive of recurrences and correlated in general with functional assays. CONCLUSIONS: The E75 vaccine strategy is safe and effective in eliciting an immune response against the HER-2/neu protein in HRPC patients and may be useful as a preventive strategy against disease recurrence. Vaccination in response to a rising PSA may be too late.

Aged↗

PubMed2005

Prostate-specific antigen nadir and cancer-specific mortality following hormonal therapy for prostate-specific antigen failure.

PURPOSE: For men receiving androgen-suppression therapy (AST) for a rising postoperative or postradiation prostate-specific antigen (PSA), we evaluated whether a PSA nadir of more than 0.2 ng/mL was significantly associated with prostate cancer-specific mortality (PCSM). PATIENTS AND METHODS: The study cohort comprised 747 men with rising PSA and negative bone scan after surgery (n = 486) or radiation therapy (n = 261) who were treated with AST. Cox regression was used to evaluate whether a significant association existed between the PSA nadir level after 8 months of AST and the time to PCSM, controlling for treatment and known prognostic factors. RESULTS: The post-AST PSA nadir (pCox < .0001), the pre-AST PSA doubling time (DT) (pCox = .002), PSA level (P = .0001), and Gleason eight to 10 cancers (pCox = .01) were significantly associated with time to PCSM. The adjusted hazard ratio for PCSM was 20 (95% CI, 7 to 61; pCox < .0001), for men with a PSA nadir of more than 0.2 ng/mL as compared with all others. A PSA DT of less than 3 months was observed in 30% (224 of 747) of the study cohort. Of the 28 observed prostate cancer deaths, 21 (75%) occurred in men whose PSA nadir was more than 0.2 ng/mL and who had a PSA DT of less than 3 months. CONCLUSION: A PSA nadir of more than 0.2 ng/mL after 8 months of AST given for postoperative or postradiation PSA failure is significantly associated with PCSM and is clinically significant because it accounted for 75% of the cancer deaths observed in this study.

Aged↗

PubMed2005

Frequent overexpression of ETS-related gene-1 (ERG1) in prostate cancer transcriptome.

Transcription factors encoded by the ETS family of genes are central in integrating signals that regulate cell growth and differentiation, stress responses, and tumorigenesis. This study, analysing laser microdissected paired benign and malignant prostate epithelial cells from prostate cancer (CaP) patients (n=114; 228 specimen) by GeneChip and quantitative real-time RT-PCR, identifies ETS-related gene (ERG), a member of the ETS transcription factor family, as the most frequently overexpressed proto-oncogene in the transcriptome of malignant prostate epithelial cells. Combined quantitative expression analysis of ERG with two other genes commonly overexpressed in CaP, AMACR and DD3, revealed overexpression of at least one of these three genes in virtually all CaP specimen (54 of 55). Comprehensive evaluation of quantitative ERG1 expression with clinicopathological features also suggested that ERG1 expression level in prostate tumor cells relative to benign epithelial cells is indicator of disease-free survival after radical prostatectomy.

Antigens, Neoplasm↗

PubMed2005

Bicalutamide ('Casodex') 150 mg as adjuvant to radiotherapy in patients with localised or locally advanced prostate cancer: results from the randomised Early Prostate Cancer Programme.

BACKGROUND AND PURPOSE: The ongoing Early Prostate Cancer (EPC) programme is assessing bicalutamide ('Casodex') 150 mg, either alone or as adjuvant to treatment of curative intent, in patients with localised or locally advanced prostate cancer (n=8113). This paper presents an exploratory analysis of the subgroup of the EPC programme who received radiotherapy with curative intent (n=1370) in order to determine the efficacy (in terms of progression-free survival [PFS]) and tolerability of bicalutamide 150 mg in this setting. PATIENTS AND METHODS: 1370 patients with T1-4, MO, any N prostate cancer received bicalutamide 150 mg or placebo adjuvant to radiotherapy of curative intent. This analysis was undertaken at median 5.3 years' follow-up. RESULTS: In patients with locally advanced disease (n=305), bicalutamide adjuvant to radiotherapy significantly increased PFS by 53% (event-time ratio 1.53; 95% confidence intervals [CI] 1.16, 2.02) compared with placebo and reduced the risk of disease progression by 42% (hazard ration [HR] 0.58; 95% CI 0.41, 0.84; P=0.00348). In these patients, objective progression was experienced by 33.5% of those randomised to bicalutamide versus 48.6% for those randomised to placebo. The between-group difference in patients with localised disease (n=1065) failed to reach statistical significance (HR 0.80; 95% CI 0.62, 1.03; P=0.088). The most common adverse events were breast pain (74.8%) and gynaecomastia (66.6%), which were mild to moderate in >90% of cases. CONCLUSIONS: Bicalutamide 150 mg/day given as adjuvant to radiotherapy significantly improved PFS in patients with locally advanced prostate cancer. For patients with localised disease, the results at this stage from the radiotherapy subgroup and the overall EPC programme suggest that adjuvant hormonal therapy is currently not appropriate. There were no unexpected tolerability findings.

Aged↗

PubMed2005

Long-term salvage radiotherapy outcome after radical prostatectomy and relapse predictors.

PURPOSE: We assessed the efficacy of salvage radiotherapy (SRT) and analyzed predictors of biochemical progression-free survival (bPFS) and distant metastasis-free survival in patients with clinically localized disease recurrence after radical prostatectomy. MATERIALS AND METHODS: The records of 114 patients treated with SRT at 2 institutions between 1991 and 2001 were retrospectively reviewed. Time to biochemical recurrence and to distant metastases was analyzed using the Kaplan-Meier estimation. Candidate predictors of bPFS and distant metastasis-free survival were analyzed using the log rank test and Cox regression. Acute and late complications were scored using Radiation Therapy Oncology Group/European Organization for Research and Treatment of Cancer criteria. RESULTS: At a median followup of 6.3 years (range 1.9 to 13.3) for SRT 4 and 6-year bPFS was 50% (95% CI 42% to 61%) and 33% (95% CI 24% to 43%), respectively. The 6-year actuarial probability of distant metastases after SRT was 14%. Multivariate analysis demonstrated an independent association of increasing Gleason score, lymphovascular invasion and lack of a complete response to SRT with decreased 5-year bDFS. These factors were associated with significantly less 5-year distant metastasis-free survival. Pre-RT prostate specific antigen greater than 2.0 ng/ml was associated with significantly decreased 5-year bDFS and distant metastasis-free survival, although it was not maintained on multivariate analysis. CONCLUSIONS: SRT results in durable prostate specific antigen control in select patients. It is well tolerated with few severe late effects. Increasing Gleason score, lymphovascular invasion and lack of a complete response to SRT are significant risks for disease progression requiring additional management.

Aged↗

PubMed2005

Update on magnetic resonance imaging, ProstaScint, and novel imaging in prostate cancer.

PURPOSE OF REVIEW: Despite marked stage migration, approximately a third of patients with clinically organ-confined prostate cancer will have extracapsular extension on pathological analysis. To improve outcomes further, alternative modalities of determining extraprostatic disease must be investigated beyond the current clinical parameters of digital rectal examination, prostate-specific antigen, and Gleason score. In addition, discerning the location of tumor in patients with biochemical recurrence directly affects treatment choice. This review highlights developments in prostate cancer imaging that may improve staging and treatment planning for prostate cancer patients. RECENT FINDINGS: Magnetic resonance imaging is most useful in the initial evaluation of men with prostate cancer. Its high specificity for the diagnosis of extracapsular extension is tempered by its low sensitivity. Positron emission tomography is used to assess regional and distant metastasis in many malignancies. Investigation into the most appropriate radiotracer for prostate cancer is paramount in any future applicability. The unique role of ProstaScint has been in evaluating patients with biochemical failure and in trying to discern metastasis before definitive therapy. The addition of spectroscopic imaging and nanoparticle infusion may lead to further improvements. Therefore, in differentiating local versus distant recurrence, appropriate interventions with radiotherapy or hormonal manipulation may be instituted. SUMMARY: Magnetic resonance imaging, ProstaScint, and to some extent positron emission tomography are all relevant imaging modalities for the evaluation of patients with prostate cancer. Current technological advances in each arena are improving the accuracy of diagnosis. Despite their specific limitations, use in the proper clinical setting may provide essential information to improve management decisions and disease outcomes.

Antibodies, Monoclonal↗

PubMed2005

Perioperative complications of radical retropubic prostatectomy.

The opinions and assertions contained herein are the private views of the authors and are not to be construed as reflective of the views of the US Army or the Department of Defense. Radical retropubic prostatectomy has long been considered one of the most difficult procedures in the urologist's armamentarium. Therefore, we performed a thorough review of recent literature regarding intraoperative and postoperative complications. The intent of this effort is to review established data regarding the most frequently seen complications and to highlight recent developments regarding the prevention or treatment of such complications.

Humans↗

PubMed2005

The effective management of biochemical recurrence in patients with prostate cancer.

Prostate-specific antigen (PSA) testing has become the primary method of monitoring patients following definitive therapy for clinically localized prostate cancer. After surgery, an immediate detectable rise in PSA is correlated with subsequent local recurrence and/or metastasis. Following radiation therapy, biochemical failure is defined as 3 consecutive rises in PSA above the nadir. Treatment of postoperative or postradiation PSA recurrence involves several modalities, including luteinizing hormone-releasing hormone agonists. Although studies have demonstrated the advantages of early hormone therapy, they have not addressed at what PSA level treatment should begin. A better understanding of PSA's kinetics will lead to a sense of when to begin treatment and when watchful waiting is the more appropriate course.

Journal Article↗

PubMed2004

Is the efficacy of hormonal therapy affected by lymph node status? data from the bicalutamide (Casodex) Early Prostate Cancer program.

OBJECTIVES: To report an exploratory subgroup analysis assessing the extent to which the overall benefit found in the Early Prostate Cancer program is dependent on lymph node status at randomization. The program is ongoing, and the overall survival data are immature. The first combined analysis of the bicalutamide (Casodex) Early Prostate Cancer program at 3 years' median follow-up showed that bicalutamide, 150 mg once daily, plus standard care (radical prostatectomy, radiotherapy, or watchful waiting), significantly reduced the risk of objective progression and prostate-specific antigen (PSA) doubling in patients with localized/locally advanced prostate cancer. METHODS: Men (n = 8113) with localized/locally advanced disease received bicalutamide 150 mg or placebo once daily, plus standard care. The time to event data (objective progression, PSA doubling) was analyzed by lymph node status at randomization. RESULTS: Compared with standard care alone, bicalutamide significantly reduced the risk of objective progression, irrespective of lymph node status, with the most pronounced reduction in patients with N+ (hazard ratio [HR] 0.29; 95% confidence interval [CI] 0.15 to 0.56) compared with those with N0 (HR 0.59; 95% CI 0.48 to 0.73) and Nx (HR 0.60; 95% CI 0.50 to 0.72) disease. The largest decrease in risk of PSA doubling with bicalutamide was observed in N+ disease (HR 0.16; 95% CI 0.09 to 0.29), with significantly reduced risks seen in N0 (HR 0.45; 95% CI 0.40 to 0.51) and Nx (HR 0.38; 95% CI 0.33 to 0.44) disease. CONCLUSIONS: The greatest reduction in the risk of objective progression and PSA doubling with bicalutamide was seen in patients with N+ disease. However, bicalutamide also provided a statistically significant benefit in those with N0 and Nx disease.

Adult↗

PubMed2004

Direct measurement of peptide-specific CD8+ T cells using HLA-A2:Ig dimer for monitoring the in vivo immune response to a HER2/neu vaccine in breast and prostate cancer patients.

HER2/neu is a proto-oncogene and a member of the epidermal growth factor receptor family of proteins that is overexpressed in numerous types of human cancer. We are currently conducting clinical trials with the HER2/neu E75 peptide vaccine in breast and prostate cancer patients. We have evaluated the use of HLA-A2 dimer molecule for the immunological monitoring of cancer patients receiving the E75 peptide vaccine. Peripheral blood samples from patients receiving the vaccine were stained with HLA-A2 dimers containing the vaccine peptide E75 or control peptides and analyzed by flow cytometry. We compared the HLA-A2 dimer assay to standard methods of immunologic monitoring (IFN-gamma release, lymphocyte proliferation, and cytotoxicity). The HLA-A2 dimer assay was also compared with the HLA-A2 tetramer assay. E75 peptide-specific CD8 T cells were detected directly in the peripheral blood of patients by staining with E75-HLA-A2 dimers and CD8 antibodies. T cell cultures generated by repeated stimulations using E75 peptide-pulsed dendritic cells showed increased staining with E75-peptide loaded HLA-A2 dimers. Simultaneously analysis by the dimer assay and standard immunologic assays demonstrated that the dimer-staining assay correlated well with these methods of immunologic monitoring. A direct comparison using E75-specific HLA-A2 tetramers and HLA-A2 dimers for the detection of E75-specific CD8 T cells in peripheral blood showed comparable results with the two assays. Our findings indicate that the HLA-A2 dimer is a powerful new tool for directly quantifying and monitoring immune responses of antigen-specific T cells in peptide vaccine clinical trials.

Antibody Formation↗