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Biomedical subjects

Brian J Miles

Publications and source records attributed to Brian J Miles.

18 recordsLinked to original sources
PubMed2006

Preoperative serum caveolin-1 as a prognostic marker for recurrence in a radical prostatectomy cohort.

PURPOSE: Up-regulation of caveolin-1 (cav-1) is associated with virulent prostate cancer, and serum cav-1 levels are elevated in prostate cancer patients but not in benign prostatic hyperplasia. In this study, we evaluated the potential of high preoperative serum cav-1 levels to predict biochemical progression of prostate cancer. The value of the combined preoperative markers, prostate-specific antigen (PSA), biopsy Gleason score, and serum cav-1 for predicting biochemical recurrence was also investigated. EXPERIMENTAL DESIGN: Serum samples taken from 419 prostate cancer patients before radical prostatectomy were selected from our Specialized Programs of Research Excellence prostate cancer serum and tissue bank. Serum samples were obtained 0 to 180 days before surgery and all patients had complete data on age, sex, race, stage at enrollment, and follow-up for biochemical recurrence. Serum cav-1 levels were measured according to our previously reported ELISA protocol. RESULTS: Cav-1 levels were measured in the sera of 419 prostate cancer patients; the mean serum level was 4.52 ng/mL (median 1.01 ng/mL). Patients with high serum cav-1 levels had a 2.7-fold (P = 0.0493) greater risk of developing biochemical recurrence compared with those with low serum cav-1 levels. Importantly, patients with serum PSA >/= 10 ng/mL and elevated levels of serum cav-1 had 2.44 times higher risk (P = 0.0256) of developing biochemical recurrence compared with patients with low levels of cav-1. In addition, high serum cav-1 levels combined with increasing biopsy Gleason score predicted much shorter recurrence-free survival in the group of patients with PSA >/= 10 ng/mL (P = 0.0353). Cav-1 was also able to distinguish between high- and low- risk patients with biopsy Gleason score of seven, after adjusting, for patients PSA levels (P = 0.0429). CONCLUSIONS: Overall, elevated preoperative levels of serum cav-1 predict decreased time to cancer recurrence. In the subset of patients with serum PSA of >/=10 ng/mL, the combination of serum cav-1 and biopsy Gleason score has the capacity to predict time to biochemical recurrence.

Adult↗
PubMed2006

Selenium accumulation in prostate tissue during a randomized, controlled short-term trial of l-selenomethionine: a Southwest Oncology Group Study.

PURPOSE: Epidemiologic and clinical data suggest that selenium could prevent prostate cancer, but it has not been shown that supplemental selenium leads to an increased concentration of selenium in prostate tissue compared with adjacent tissue. EXPERIMENTAL DESIGN: We conducted a randomized, controlled, short-term trial of l-selenomethionine (SeMet) versus observation in men with organ-confined prostate cancer. The primary endpoint was the measurement of selenium concentration in prostate tissue and seminal vesicle (SV). We assessed baseline selenium levels in serum and in toenail specimens (reflecting long-term intake) and post-intervention selenium levels in serum, and in prostate and SV tissues using hydride generation atomic fluorescence spectroscopy. RESULTS: Sixty-six eligible patients were randomly assigned to the SeMet (n = 34) or observation (n = 32) arm; both arms had similar baseline patient characteristics. Baseline serum selenium was similar in the two groups (P = 0.64). Baseline toenail selenium levels were slightly higher in the SeMet group than in the control group (P = 0.07). After the intervention, the mean serum selenium level increased 15% in the SeMet arm and was higher than in the observation arm (P = 0.001). The selenium concentration in prostate tissue was 22% higher in the SeMet arm (n = 26) than in the observation arm (n = 25; 1.80 versus 1.47 ppm; P = 0.003, Wilcoxon rank sum test) and remained significantly higher after adjusting for chronic selenium intake (P = 0.021, ANCOVA). SV selenium concentration was similar in both groups (P = 0.384) and was lower than in prostate tissue. CONCLUSIONS: The present study is the first to show that selenium taken as oral supplementation accumulates preferentially in the human prostate gland as opposed to the SV. These findings support the hypothesis that oral selenium supplementation may contribute to the cancer preventive effects of selenium.

Adenocarcinoma↗
PubMed2006

Biological response determinants in HSV-tk + ganciclovir gene therapy for prostate cancer.

The limitations of current forms of prostate cancer therapy have driven researchers to search for new alternatives. Previously we showed cytopathic effect related to HSV-tk in prostate cancer. In this study we present initial results of a neoadjuvant HSV-tk gene therapy trial and address some of the potential mechanistic aspects of its effect in human tissues. We enrolled 23 men with clinically localized prostate cancer but high risk for recurrence in this Phase I-II trial. Intraprostatic viral injections (one to four) were followed by 2 weeks of ganciclovir and prostatectomy 2-4 weeks later. Toxicity was modest. Surgical specimens were embedded fully and whole-mount slides were imaged and analyzed for areas of cytopathic effect. The larger the tumor the greater the cytopathic effect. The effect also seems to be related to areas of high CAR expression. However, the number of injection sites did not influence effect. Local (CD8+ cells and macrophages) and systemic immune response (CD8+ and activated CD8+, IL-12) was increased in patients treated with HSV-tk. Increased apoptosis and decreased microvessel density were also noted in these patients. The results suggest a tumor-specific effect mediated by systemic and local immune response, antiangiogenic effect, and modulation of apoptosis.

Aged↗
PubMed2006

Expanding the therapeutic index of radiation therapy by combining in situ gene therapy in the treatment of prostate cancer.

The advances in radiotherapy (3D-CRT, IMRT) have enabled high doses of radiation to be delivered with the least possible associated toxicity. However, the persistence of cancer (local recurrence after radiotherapy) despite these increased doses as well as distant failure suggesting the existence of micro-metastases, especially in the case of higher risk disease, have underscored the need for continued improvement in treatment strategies to manage local and micro-metastatic disease as definitively as possible. This has prompted the idea that an increase in the therapeutic index of radiotherapy might be achieved by combining it with in situ gene therapy. The goal of these combinatorial therapies is to maximize the selective pressure against cancer cell growth while minimizing treatment-associated toxicity. Major efforts utilizing different gene therapy strategies have been employed in conjunction with radiotherapy. We reviewed our and other published clinical trials utilizing this combined radio-genetherapy approach including their associated pre-clinical in vitro and in vivo models. The use of in situ gene therapy as an adjuvant to radiation therapy dramatically reduced cell viability in vitro and tumor growth in vivo. No significant worsening of the toxicities normally observed in single-modality approaches were identified in Phase I/II clinical studies. Enhancement of both local and systemic T-cell activation was noted with this combined approach suggesting anti-tumor immunity. Early clinical outcome including biochemical and biopsy data was very promising. These results demonstrate the increased therapeutic efficacy achieved by combining in situ gene therapy with radiotherapy in the management of local prostate cancer. The combined approach maximizes tumor control, both local-regional and systemic through radio-genetherapy induced cytotoxicity and anti-tumor immunity.

Animals↗
PubMed2004

Enhanced systemic T-cell activation after in situ gene therapy with radiotherapy in prostate cancer patients.

PURPOSE: In situ cytotoxic gene therapy can potentially trigger a systemic immune response, which could impact occult metastatic disease. We are currently conducting three clinical trials using in situ adenoviral vector mediated herpes simplex virus-thymidine kinase (HSV-tk) gene delivery followed by the HSV-tk prodrug ganciclovir (GCV) or valacyclovir (VCV). This study evaluates the systemic T-cell response after gene therapy in each trial. METHODS AND MATERIALS: The study protocol included three separate clinical trials in the Baylor Prostate Cancer SPORE Program: Trial A gene therapy in prostate cancer patients failing radiotherapy (36 patients), Trial B neoadjuvant gene therapy in pre-radical prostatectomy patients (22 patients), and Trial C gene therapy in combination with radiotherapy for prostate cancer (27 patients). Heparinized blood was collected at the time of vector injection and at selected intervals afterward. A complete blood count was performed, and peripheral blood lymphocytes were analyzed by fluorescent antibody cell sorting after labeling with dual color-labeled antibody pairs. RESULTS: The pretreatment mean percentage of activated CD8+ T cells (DR+CD8+ T cells) was 12.23%, 16.72%, and 14.09% (Trials A, B, and C, respectively). Two weeks posttreatment, this increased to 22.87%, 26.15%, and 39.04% (Trials A, B, and C, respectively), and these increases were statistically significant (p = 0.0188, p = 0.0010, p < 0.0001, respectively). The increase of DR+CD8+ T cells was significantly larger in Trial C than in Trial A (p = 0.0044) or Trial B (p = 0.0288). Total CD8+ T cells significantly increased at 2 weeks posttreatment in Trial B and C (p = 0.0013, p = 0.0004, respectively). Interestingly, only in Trial C were significant increases in activated CD4+ T cells seen at 2 weeks (p = 0.0035). CONCLUSIONS: This is the first report of systemic T-cell responses after HSV-tk+GCV/VCV gene therapy under three clinical trial conditions. There was an increase in activated CD8+ T cells in the peripheral blood after vector injection, suggesting the potential for activation of components of cell-mediated immune response in all trial conditions. The addition of radiotherapy to in situ gene therapy seems to further increase the total CD8+ T cells and activated CD4+ T cells.

Acyclovir↗
PubMed2004

Serum BPSA outperforms both total PSA and free PSA as a predictor of prostatic enlargement in men without prostate cancer.

OBJECTIVES: To determine whether the serum concentration of BPSA, a distinct form of free prostate-specific antigen (PSA) enriched in the nodular transition zone (TZ) tissue of benign prostatic hyperplasia (BPH), can predict TZ volume and diagnose BPH-associated prostatic enlargement in patients without prostate cancer. METHODS: We studied 91 consecutive patients without prostate cancer who underwent a 10-core or greater biopsy of the prostate. The associations between prostate volume, age, International Prostate Symptom Score, and serum concentrations of PSA, free PSA, and BPSA were evaluated by receiver operating characteristic curve and linear and binary logistic regression analyses. RESULTS: BPSA and free PSA showed stronger correlations with both age (BPSA = 0.38, free PSA = 0.40, PSA = 0.24) and TZ volume (BPSA = 0.67, free PSA = 0.64, PSA = 0.55) than did PSA. The percent free PSA had no statistically significant correlation with TZ volume (P = 0.08). Subtraction of BPSA from free PSA reduced its correlation with TZ volume to below that of PSA (from 0.64 to 0.48). Linear regression analyses showed that, unlike PSA, both BPSA and free PSA displayed an age-independent relationship to TZ volume. The receiver operating characteristic curve (for TZ greater than 30 cm3) and binary logistic regression analyses showed that BPSA (area under the curve = 0.844) outperformed both free PSA (area under the curve = 0.799) and PSA (area under the curve = 0.749) in its ability to predict clinically significant TZ enlargement. CONCLUSIONS: In patients without prostate cancer, the serum concentration of BPSA displayed an age-independent, log-linear relationship to TZ volume and was a better predictor of prostatic enlargement than either PSA or free PSA. BPSA may also predict clinical parameters of BPH and is under evaluation as a marker of BPH progression and response to therapy.

Adult↗
PubMed2004

Six additional systematic lateral cores enhance sextant biopsy prediction of pathological features at radical prostatectomy.

PURPOSE: We evaluated the contribution of 6 additional systematically obtained, laterally directed biopsy cores to traditional sextant biopsy for the prediction of final pathological findings in the radical prostatectomy specimen. MATERIALS AND METHODS: We studied 178 consecutive patients with no history of prostate biopsy in whom prostate cancer was diagnosed during an initial systematic 12 core biopsy and who subsequently underwent radical prostatectomy. Of the systematic 12 cores we compared the subset of the 6 traditional sextant cores (S6C), the set of 6 laterally directed cores (L6C) and the complete 12 core set, which included the 6 traditional sextant and the 6 laterally directed cores. Biopsy Gleason score, number of positive cores, total cancer length and percent of tumor in the biopsy sets were examined for their ability to predict extracapsular extension, total tumor volume and pathological Gleason score. RESULTS: On univariable analyses the biopsy parameters of the complete 12 core set correlated more strongly with extracapsular extension and total tumor volume than the biopsy parameters of S6C or L6C. On multivariable analyses S6C and L6C were independent predictors of pathological features at prostatectomy. CONCLUSIONS: The addition of 6 systematically obtained, laterally directed cores to traditional sextant biopsy improved the ability to predict pathological features at prostatectomy by a statistically and prognostically significant margin. Preoperative nomograms that use data from a full complement of 12 systematic cores, specifying sextant and laterally directed biopsy cores, should demonstrate improved performance in predicting prostatectomy pathology.

Aged↗
PubMed2004

Improved detection of clinically significant, curable prostate cancer with systematic 12-core biopsy.

PURPOSE: While systematic 12-core (S12C) biopsy detects more cancers than sextant biopsy, to our knowledge the clinical significance of these additionally detected tumors has not been established. We studied pathological parameters of prostatectomy specimens from patients undergoing radical prostatectomy for prostate cancer detected with a S12C biopsy to determine the clinical significance of these cancers in comparison with sextant detected cancers. MATERIALS AND METHODS: A total of 179 consecutive patients undergoing radical prostatectomy for clinically localized prostate cancer detected by S12C biopsy were studied. The groups compared consisted of the sextant core subset of the S12C and the entire S12C set. Total tumor volume, Gleason score, organ confined status, surgical margin status, seminal vesicle invasion, lymph node involvement, and clinical significance of tumors detected by sextant and by S12C templates were compared. RESULTS: S12C biopsy detected a greater number of cancers scored as moderate (Gleason score 2 to 6) or high (Gleason score 7 or greater) grade, and cancers of all sizes regardless of organ confined status than the sextant cores alone (all p <0.05). S12C biopsy identified a greater number of biologically significant and insignificant tumors regardless of how they were defined. CONCLUSIONS: Compared with the sextant set S12C biopsy detects a significantly greater number of surgically curable, biologically significant tumors as well as those that might be considered clinically insignificant.

Aged↗
PubMed2004

Predictors of prostate cancer after initial negative systematic 12 core biopsy.

PURPOSE: We determined the cancer detection rate at initial systematic 12 core (S12C) biopsy and identified features associated with cancer at repeat S12C biopsy after an initial negative S12C biopsy in patients with prostate specific antigen (PSA) parameters associated with a higher risk of prostate cancer. MATERIALS AND METHODS: Between February 1999 and June 2002, 841 patients underwent initial S12C biopsy. Of these patients 99 underwent repeat S12C biopsy after initial negative S12C because of a percent free-to-total PSA of 15.0 or less and/or a yearly PSA velocity of 0.75 ng/ml or greater. The association between parameters revealed by initial biopsy and cancer at repeat biopsy was assessed. RESULTS: Of the 99 patients 21 (21.2%) had cancer at repeat biopsy. Age (p = 0.01), PSA transitional zone density (p = 0.05), and high grade PIN at initial biopsy (p = 0.01) were associated with cancer at repeat biopsy. CONCLUSIONS: In this select group of patients with PSA parameters associated with a higher risk of prostate cancer the cancer detection rate after initially negative S12C biopsy was 21%. Patients with high grade PIN on initial biopsy, advanced age and higher PSA transition zone density are at increased risk for cancer at repeat biopsy. Larger prospective studies are required to confirm these results and construct a nomogram that determines the probability of finding prostate cancer at subsequent biopsy.

Biopsy, Needle↗
PubMed2004

Effects of systematic 12-core biopsy on the performance of percent free prostate specific antigen for prostate cancer detection.

PURPOSE: The performance characteristics of percent free (f) prostate specific antigen (PSA) for differentiating between benign prostatic hyperplasia and prostate cancer were originally established using primarily sextant biopsy. We determined whether the addition of 6 laterally directed cores to the traditional sextant prostate biopsy affects the performance of percent fPSA. MATERIALS AND METHODS: We retrospectively evaluated a cohort of 350 consecutive biopsies in men with negative digital rectal examinations and PSA between 4 and 10 ng/ml who underwent systematic 12 core biopsy (S12C) biopsy at Scott Department of Urology between March 1999 and January 2003. The effects of 6 additional, laterally directed biopsies on the sensitivity, specificity and area under the ROC curve for percent fPSA was evaluated in the 277 men in whom percent fPSA was measured. RESULTS: Cancers detected exclusively in the 6 laterally directed cores were associated with percent fPSA values similar to those in patients with a benign S12C biopsy. This resulted in a modest and yet predictable decrease in the sensitivity of percent fPSA at each biopsy threshold value without affecting specificity. There was a nonstatistically significant decrease in the area under the ROC curve with the addition of 6 laterally directed cores to sextant biopsy (medial sextant cores 0.66 vs S12C 0.60). CONCLUSIONS: The 12 core biopsy strategies have a higher cancer detection rate than sextant biopsies and they are gaining widespread acceptance. The addition of 6 laterally directed cores to traditional sextant biopsy may result in a modest decrease in the sensitivity of percent fPSA at each selected biopsy threshold without affecting specificity.

Aged↗
PubMed2003

Therapeutic targets for metastatic prostate cancer.

Prostate cancer is the most commonly diagnosed non-cutaneous cancer in adult males. Although prostate cancer that is confined to the gland can be cured in many patients using surgery or radiation, these treatments are only effective for localized tumors and the long-term failure rates for these treatments suggests that prostate cancer can metastasize relatively early in the course of the disease. Once prostate cancer has metastasized there are no curative therapies. The greatest challenge in the treatment of advanced prostate cancer is to access and eliminate metastatic cells. Therefore, effective prostate cancer therapy will require novel strategies to target cancer cells both at the site of the primary tumor and at distant metastatic sites. In this article we review several therapeutic targets and approaches that may provide new treatments for metastatic prostate cancer. We discuss the use of small molecules to target specific molecular events associated with metastatic prostate cancer, the use of specific antibodies that target unique metastasis associated molecules and the use of various gene therapy strategies to achieve anti-metastatic activities.

Animals↗
PubMed2002

Post-nerve-sparing prostatectomy, dose-escalated intensity-modulated radiotherapy: effect on erectile function.

PURPOSE: The advent of widespread prostate-specific antigen screening has resulted in more younger, potent men being diagnosed with early-stage, organ-confined prostate cancer amenable to definitive surgery. Nerve-sparing prostatectomy is a relatively new surgical advance in the treatment of prostate cancer. Very few data exist on the effect of postoperative radiotherapy (RT) on erectile function after nerve-sparing prostatectomy. They are based on conventional techniques using moderate doses of radiation, 45-54 Gy. Intensity-modulated RT (IMRT) is becoming more widespread because it allows dose escalation with increased sparing of the surrounding normal tissue. We investigated the effect of postprostatectomy, high-dose IMRT on patients' erectile function. METHODS AND MATERIALS: A review of patient records found 51 patients treated between April 1998 and December 2000 with IMRT after unilateral or bilateral nerve-sparing prostatectomy. The pathologic disease stage in these patients was T2 in 47.4% and T3 in 52.6%. Postoperatively, 4 patients received hormonal ablation consisting of one injection of Lupron Depot (30 mg) 2 months before RT. The median age was 65 years (range 46-77) at the time of RT. The prescribed dose was 64 Gy (range 60-66). The mean dose was 69.6 Gy (range 64.0-72.3). Erectile function was assessed before and after RT by questionnaires. Sexual potency was defined as erectile rigidity adequate for vaginal penetration. RESULTS: Of the 51 patients, 18 (35.3%) maintained their potency and 33 (64.7%) became impotent after nerve-sparing prostatectomy. Patients who underwent bilateral nerve-sparing prostatectomy had higher rates of postoperative potency than did those who underwent unilateral nerve-sparing surgery (72.2% vs. 27.8%; p = 0.025). The follow-up for the entire group was 19.5 months. All 18 patients (100%) who were potent postoperatively remained potent after RT. The median follow-up for the 18 potent patients was 27.2 months, significantly longer than that of the impotent group, 13.0 months (p <0.001). CONCLUSION: This is the first report on the effects of dose-escalated IMRT on men who have undergone nerve-sparing prostatectomy. Despite the high dose (mean dose 69.6 Gy) to the prostate bed and nerves, postoperative IMRT had no negative effect on erectile function for the patients who remained potent after nerve-sparing prostatectomy. Longer term follow-up and a larger cohort of patients are warranted to confirm these findings.

Aged↗
PubMed2002

The role of caveolin-1 in androgen insensitive prostate cancer.

PURPOSE: We summarize the literature regarding androgen insensitive prostate cancer and caveolin-1. Caveolin-1 is a major structural component of caveolae, membrane micro-domains known to have important roles in signal transduction and lipid transport. MATERIALS AND METHODS: A review of the literature relevant to androgen insensitive caveolin-1 and prostate cancer included the first published report in 1998 through those published in March 2002. RESULTS: Caveolin-1 expression is increased in primary and metastatic human prostate cancer with highest levels observed after androgen ablation therapy. Recent studies have documented that caveolin-1 is secreted by prostate cancer cells and can be detected in the serum of men with prostate cancer. CONCLUSIONS: The results presented in this review establish that caveolin-1 is an autocrine/paracrine factor associated with androgen insensitive prostate cancer. They show the potential for caveolin-1 as a biomarker therapeutic target for this important malignancy.

Animals↗
PubMed2002

Squamous cell carcinoma in a female urethral diverticulum.

A 38-year-old woman was found to have a squamous cell carcinoma in a urethral diverticulum after a simple diverticulectomy. The aggressiveness of this histologic subtype of carcinoma, along with this patient's long life expectancy, supported the choice of aggressive therapy. Only nine other cases have been reported. A brief review of the published reports on the presentation, diagnosis, options for treatment, and outcomes is included.

Adult↗
PubMed2002

Gene therapy for prostate cancer.

Prostate cancer is the most common noncutaneous cancer in man. When confined to the prostate it can be cured by radical prostatectomy or irradiation therapy. However, there are no curative therapies for locally advanced, recurrent or metastatic disease. Prostate cancer gene therapy has recently transition from preclinical studies to clinical trials with the goal of developing novel treatments for prostate cancer. The greatest challenge in treating advanced prostate cancer is therapeutic access to and the elimination of metastases. This review details two aspects of prostate cancer gene therapy, the types of delivery systems under development and specific categories of therapeutic genes available with an emphasis on the mechanism of action of specific gene therapy strategies.

Adjuvants, Immunologic↗
PubMedDate not supplied

Carcinosarcoma of the prostate with multiple metastases: case report and review of the literature.

A case of carcinosarcoma of the prostate in a previously healthy 65-year-old man is reported. The tumor was initially diagnosed as adenocarcinoma, but the prostatectomy specimen showed a 717-g prostate, with evidence of adenocarcinoma and carcinosarcoma without heterologous structures. By 3-month follow-up, local recurrence, and liver, lung, and bone metastases had developed in the patient. He died of disease 10 months postoperatively. Carcinosarcoma of the prostate is a very rare but highly aggressive cancer with limited therapeutic options that should be treated with surgery and managed symptomatically. We believe this article is the forty-second case reported in the literature.

Aged↗
PubMedDate not supplied

Benign fibrous histiocytoma: a rare finding on bone scan staging for prostate adenocarcinoma.

Benign fibrous histiocytoma is a rare bone tumor that usually presents with localized pain and/or a pathological fracture. We report on a patient with adenocarcinoma of the prostate who had a radionuclide bone scan for staging, which was suspicious for metastatic disease. Histologic examination of left eleventh rib revealed a Benign Fibrous Histiocytoma (BFH). To our knowledge, this is the first BFH found solely on bone scan.

Adenocarcinoma↗