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Tomasz M Beer

Publications and source records attributed to Tomasz M Beer.

At least 19 recordsLinked to original sources
PubMed2006

Phase I study of weekly DN-101, a new formulation of calcitriol, in patients with cancer.

BACKGROUND: DN-101 is a new, high-dose, oral formulation of calcitriol under investigation for the treatment of cancer. We sought to evaluate the tolerability and pharmacokinetics (PK) of weekly doses of DN-101 in patients with advanced cancer. METHODS: Patients who completed a previously reported single dose escalation study of DN-101 [Beer et al. (2005) Clin Cancer Res 11:7794-7799] were eligible for this continuation weekly dosing study. Cohorts of 3-10 patients were treated at doses of 15, 30, 45, 60, and 75 microg calcitriol. Once 45 microg was established as the maximum tolerated dose (MTD), this cohort was expanded to include 18 patients. Dose limiting toxicity (DLT) was defined as > or =grade 2 hypercalcemia or > or =grade 3 persistent treatment-related toxicities. RESULTS: Thirty-seven patients were recruited. DLT of transient reversible grade 2 hypercalcemia (serum calcium of 11.6-12.5 mg/dL) occurred in two of six patients treated with 60 microg of DN-101. No DLT was observed in the 18 patients who received DN-101 weekly at 45 microg. Overall, DN-101 was well tolerated. The most frequent adverse events were fatigue (27%), hypercalcemia (19%, including five grade 1, two grade 2, and no grade 3 or 4 events), and grade 1 nausea (16%). PK parameters following repeat dosing were comparable to those for the initial dose (n = 4). CONCLUSION: The MTD for weekly DN-101 was established as 45 mug. The DLTs observed were two episodes of rapidly reversible grade 2 hypercalcemia in two of the six patients treated at 60 microg weekly. Repeat doses of DN-101 at 45 microg weekly are well tolerated and this dose is suitable for studies of weekly DN-101 in cancer patients.

Adult↗
PubMed2006

High dose calcitriol may reduce thrombosis in cancer patients.

The incidence of venous and arterial thrombosis in a placebo-controlled randomised trial of DN-101 (high dose calcitriol) with docetaxel versus docetaxel was compared. Of the 13 thrombotic events observed in the 250 patients enroled in this study, two occurred in DN-101 and 11 in placebo-treated patients (P = 0.01). This difference remained significant after adjustment for baseline history of thrombosis, atrial fibrillation and use of anti-thrombotic agents. In vitro and vitamin D receptor (VDR) knockout mouse studies predict that nanomolar concentrations of calcitriol may act as an antithrombotic agent. We report the first clinical observation that supports this hypothesis in humans.

Aged↗
PubMed2006

The prognostic value of hemoglobin change after initiating androgen-deprivation therapy for newly diagnosed metastatic prostate cancer: A multivariate analysis of Southwest Oncology Group Study 8894.

BACKGROUND: The objective of this study was to characterize changes in hemoglobin (HGB) levels after the initiation of androgen-deprivation therapy (ADT) in patients with previously untreated, metastatic prostate cancer who were enrolled in a large clinical trial. METHODS: The multivariate associations between 3-month change in HGB and baseline characteristics were evaluated with a linear regression model. The associations between 3-month change in HGB level and time-to-event outcomes, including overall survival and progression-free survival, were evaluated by using proportional hazards regression models. RESULTS: Quartiles of baseline HGB levels were < or =12.0 g/dL, from 12.1 to 13.7 g/dL, from 13.8 to 14.7 g/dL, and >14.7 g/dL. Overall, 3 months after initiating ADT, the mean HGB level declined 0.54 g/dL (standard deviation [SD], 1.68 g/dL); however, the mean HGB level increased by 0.99 g/dL (SD, 1.83 g/dL) in patients who had baseline HGB levels <12 g/dL and decreased 1.04 g/dL (SD, 1.28 g/dL) in patients who had baseline HGB levels > or =12 g/dL. After adjusting for potential confounders, including baseline HGB level, a decline in HGB after 3 months of ADT was associated independently with shorter survival (hazards ratio [HR], 1.10 per 1 g/dL decline; P = .0035) and shorter progression-free survival (HR, 1.08 per 1 g/dL decline; P = .013). An unexpected finding was that the effect of baseline HGB on overall and progression-free survival varied significantly by race. CONCLUSIONS: In a sample of men with newly diagnosed, metastatic prostate cancer, a decline in HGB level after 3 months of ADT was associated with shorter survival and progression-free survival after adjusting for disease status and other baseline covariates. Although race alone was not a strong predictor of death or disease progression, the effect of the baseline HGB level on overall and progression-free survival varied significantly by race.

Aged↗
PubMed2006

A molecular correlate to the Gleason grading system for prostate adenocarcinoma.

Adenocarcinomas of the prostate can be categorized into tumor grades based on the extent to which the cancers histologically resemble normal prostate glands. Because grades are surrogates of intrinsic tumor behavior, characterizing the molecular phenotype of grade is of potential clinical importance. To identify molecular alterations underlying prostate cancer grades, we used microdissection to obtain specific cohorts of cancer cells corresponding to the most common Gleason patterns (patterns 3, 4, and 5) from 29 radical prostatectomy samples. We paired each cancer sample with matched benign lumenal prostate epithelial cells and profiled transcript abundance levels by microarray analysis. We identified an 86-gene model capable of distinguishing low-grade (pattern 3) from high-grade (patterns 4 and 5) cancers. This model performed with 76% accuracy when applied to an independent set of 30 primary prostate carcinomas. Using tissue microarrays comprising >800 prostate samples, we confirmed a significant association between high levels of monoamine oxidase A expression and poorly differentiated cancers by immunohistochemistry. We also confirmed grade-associated levels of defender against death (DAD1) protein and HSD17 beta4 transcripts by immunohistochemistry and quantitative RT-PCR, respectively. The altered expression of these genes provides functional insights into grade-associated features of therapy resistance and tissue invasion. Furthermore, in identifying a profile of 86 genes that distinguish high- from low-grade carcinomas, we have generated a set of potential targets for modulating the development and progression of the lethal prostate cancer phenotype.

Adenocarcinoma↗
PubMed2006

Southwest Oncology Group phase II study of arsenic trioxide in patients with refractory germ cell malignancies.

BACKGROUND: To the authors' knowledge, no satisfactory therapy is available for patients with refractory germ cell neoplasms. The activity and safety of arsenic trioxide in refractory germ cell tumors was assessed. METHODS: Twenty patients were treated with arsenic trioxide at a dose of 0.25 mg/kg/day and administered intravenously over 1 to 2 hours on Days 1-5 and repeated every 28 days. RESULTS: There were no complete or partial responses. The median progression-free survival was 1 month and the median overall survival was 2 months. Three patients died as a result of adverse events believed to be possibly related to treatment: ventricular arrhythmia, adult respiratory distress syndrome, and pneumonitis. CONCLUSIONS: In the current study, arsenic trioxide in the dose regimen and schedule employed was found to have no activity in men with refractory germ cell malignancies. Treatment was associated with severe toxicity. Dismal overall survival reflects the poor outcome in this patient group and highlights the acute need for new agents with activity in refractory germ cell neoplasms.

Adult↗
PubMed2006

Acute bilateral pulmonary emboli occurring while on adjuvant aromatase inhibitor therapy with anastrozole: Case report and review of the literature.

Hormonal therapy is the mainstay of adjuvant treatment for women with early-stage estrogen receptor-positive breast cancer. Recently, the aromatase inhibitors have moved to the forefront of adjuvant hormonal therapy, however, the adverse effects of these agents are not yet fully understood. It is generally accepted that tamoxifen, but not the aromatase inhibitors, is associated with an increased risk of thrombosis in women with breast cancer. Studies comparing aromatase inhibitors to tamoxifen in the adjuvant setting have reported a lower rate of venous thromboembolism with the aromatase inhibitors, yet the incidence of venous thromboembolism with these new agents is higher than that expected in the general population. Here we report a case of acute bilateral pulmonary emboli occurring while on adjuvant aromatase inhibitor therapy with anastrozole, and review the literature on the incidence of venous thromboembolism during the use of aromatase inhibitors in the adjuvant setting.

Acute Disease↗
PubMed2006

Effect of calcitriol on prostate-specific antigen in vitro and in humans.

BACKGROUND: Calcitriol, the natural ligand for the vitamin D receptor, has significant potential in prostate cancer treatment. Measurement of its antineoplastic activity in prostate cancer clinical trials may be complicated by effects of calcitriol on prostate-specific antigen (PSA) production. We examined the effects of calcitriol at similar concentration on cell proliferation, androgen receptor (AR) expression, and PSA production in vitro and on PSA concentrations in prostate cancer patients. EXPERIMENTAL DESIGN: LNCaP prostate cancer cell proliferation was examined by cell counts 6 days after exposure to a range of concentrations of calcitriol. AR and PSA protein was quantified in LNCaP cells over 96 hours after exposure to 1 nmol/L calcitriol. Serum PSA and free PSA was serially measured by immunoassay over a period of 8 days in patients with hormone-naïve prostate cancer after a single dose of 0.5 microg/kg calcitriol. RESULTS: Calcitriol treatment resulted in dose-dependent growth inhibition of LNCaP with approximately 50% growth inhibition at the clinically achievable concentration of 1 nmol/L. Time-dependent up-regulation of AR expression and of PSA production in LNCaP cells was shown at the same concentration. No significant change in serum PSA or free PSA over 8 days was seen in eight subjects treated with a single dose of 0.5 microg/kg calcitriol. The analysis was powered to detect a 1.23-fold change between the baseline and day 8 serum PSA. CONCLUSIONS: At clinically achievable concentrations, calcitriol inhibits growth and induces AR and PSA expression in LNCaP cells. We did not detect similar changes in serum PSA or free PSA in patients exposed to similar concentrations of calcitriol. Thus, a PSA flare, predicted by preclinical systems, is unlikely to occur in patients and therefore unlikely to complicate interpretation of clinical trial outcomes.

Calcitriol↗
PubMed2006

Views on physician-assisted suicide among family members of Oregon cancer patients.

Ninety-eight Oregonians with advanced cancer and their family members participated in a cross-sectional survey to understand agreement in views on physician-assisted suicide (PAS), which was a legal option for these patients. Half of the family members would support the patient's request for PAS, 30% would oppose it, and 19% were undecided. Low religiousness and the family member's personal health concerns were associated with increasing support by the family member for PAS for the patient. Family members were able to predict patients' political views on legalized PAS, and there was moderately high agreement among family members on political views. Family members, however, were not knowledgeable about patients' interest in PAS for themselves, and there was low agreement among dyads on whether they had discussed this issue. Improved knowledge of patient-based barriers to discussing PAS may facilitate interventions for psychosocial distress in cancer patients.

Advance Directives↗
PubMed2006

Zoledronic acid initiated during the first year of androgen deprivation therapy increases bone mineral density in patients with prostate cancer.

PURPOSE: Androgen deprivation therapy in patients with prostate cancer is associated with bone loss and an increased risk of fractures. Zoledronic acid protects against bone mineral density loss when initiated concurrently with androgen deprivation therapy. We evaluated the effect of zoledronic acid initiated subsequent to androgen deprivation therapy on bone mineral density and biochemical markers of bone turnover. MATERIALS AND METHODS: Patients with prostate cancer without bone metastases who had received androgen deprivation therapy for 12 months or less were randomized to 4 mg zoledronic acid or placebo intravenously every 3 months for 1 year. Patients were stratified according to androgen deprivation therapy duration (less than 6 vs 6 to 12 months). The primary end point was the change in femoral neck and lumbar spine bone mineral density in the 2 groups. The secondary end point was the change in serum bone specific alkaline phosphatase and urine N-telopeptide levels. Total hip bone mineral density was also measured. RESULTS: The 120 patients with prostate cancer received zoledronic acid (61) or placebo (59). Compared with placebo, zoledronic acid increased femoral neck, total hip and lumbar spine bone mineral density yearly by 3.6% (p = 0.0004), 3.8% (p <0.0001) and 6.7% (p <0.0001), respectively. The effects of zoledronic acid on bone mineral density at these 3 sites were not differentiated according to androgen deprivation therapy duration. Additionally, mean bone specific alkaline phosphatase and N-telopeptide levels were decreased in the zoledronic acid group (each p <0.0001) and were increased in the placebo group (p <0.0001 and p = 0.004, respectively). CONCLUSIONS: Zoledronic acid increased bone mineral density and suppressed bone turnover markers in patients with prostate cancer without bone metastases when initiated during year 1 of androgen deprivation therapy.

Adenocarcinoma↗
PubMed2006

Metastatic adenocarcinoma of prostate in a healing sternotomy site.

Metastatic prostate cancer has a strong predilection for osseous sites, where the disease spreads in 80% of advanced cases. The molecular mechanisms involved in prostate cancer establishment in bone are largely unknown; however, local tissue factors, including those involved in wound healing, have been suggested to play a critical role. We present a case of tumor explosion in a median sternotomy wound after local prostate cancer therapy. This case highlights that novel therapeutic interventions that disrupt the apparent synergistic relationship between tumor cells and the pro-tumorigenic microenvironment may hold great promise in constraining the proliferation of prostate cancer metastases.

Adenocarcinoma↗
PubMed2006

Prevalence, severity, and health correlates of lower urinary tract symptoms among older men: the MrOS study.

OBJECTIVES: To describe the prevalence, severity, and health correlates of lower urinary tract symptoms (LUTS) in older community-dwelling U.S. men. METHODS: We performed a cross-sectional analysis from a cohort study recruited from six U.S. clinical centers. This analysis included 5284 men without a history of prostate cancer who were at least 65 years of age. Participants completed questionnaires regarding the presence and severity of LUTS, including the American Urological Association Symptom and Bother indexes. Health status measures included the Medical Outcomes Survey SF-12 and self-rated health and instrumental activities of daily living. RESULTS: LUTS were absent in 2.3%, mild in 51.6%, moderate in 39.6%, and severe in 6.6%. Dissatisfaction with the urinary symptoms increased with LUTS severity (P <0.001); 19.8% of moderate and 58.1% of men with severe LUTS reported feeling mostly unsatisfied to terrible with their present urinary symptoms. The prevalence, severity, and dissatisfaction with LUTS increased with age. Men reporting moderate or severe LUTS were 1.41-fold (95% confidence interval 1.23 to 1.61) and 1.51-fold (95% confidence interval 1.23 to 1.85) more likely to rate their overall health quality as fair to very poor for their age instead of good to excellent, even after controlling for age and comorbid conditions. Increased LUTS also was independently associated with increased impairment in instrumental activities of daily living and poorer SF-12 scores. CONCLUSIONS: Moderate-to-severe LUTS is common in community-dwelling elderly U.S. men. In this study, LUTS severity was associated with poorer health quality and a greater prevalence of an inability to perform activities of daily living. The association of LUTS severity with poor health warrants increased clinical attention.

Activities of Daily Living↗
PubMed2006

Testosterone loss and estradiol administration modify memory in men.

PURPOSE: Little is known about the effect of androgen deprivation therapy on the brain despite the fact that sex steroid receptors are abundant in cortical brain regions that mediate memory and other cognitive functions. We characterized the impact of androgen deprivation and of subsequent estradiol therapy on the long-term and working memory of patients with prostate cancer. MATERIALS AND METHODS: Long-term memory (immediate and delayed paragraph recall tests), working memory (SOP and Trails tests) and Profile of Mood States were assessed at baseline and 4 weeks later in 18 patients with androgen independent prostate cancer beginning second line hormonal therapy with transdermal estradiol 0.6 mg/24 hours. The same assessments were performed in 2 age matched control groups of 18 patients with prostate cancer undergoing androgen deprivation continuing on hormonal therapy and 17 community dwelling healthy men. RESULTS: Immediate and delayed verbal memory were significantly worse in patients with prostate cancer on androgen deprivation than in age matched healthy controls. In addition, men with prostate cancer took more time to complete the Trails A task, indicating slower processing speed, but did not differ significantly from healthy controls in working memory tasks. In individual repeated measures analyses, verbal memory performance improved with estradiol therapy but did not change in the 2 control groups. CONCLUSIONS: Sex steroid loss and replacement have effects on specific cognitive processes in older men. Furthermore, estrogen has the potential to reverse the neurotoxic effects on memory performance caused by androgen deprivation.

Affect↗
PubMed2006

Classification and regression tree analysis for the prediction of aggressive prostate cancer on biopsy.

PURPOSE: Prostate cancer screening allows early cancer detection but not all patients benefit from subsequent therapy. Thus, identifying patients who are likely to harbor aggressive cancer could significantly decrease the number of prostate biopsies performed. MATERIALS AND METHODS: Data were collected on 1,563 consecutive referred men with serum PSA 10 ng/ml or less who underwent an initial prostate biopsy. Predictors of aggressive cancer (Gleason sum 7 or greater) were identified using CART analysis. Model building was done in a randomly selected training set (70% of the data) and validation was completed using the remaining data. RESULTS: Cancer was detected in 406 men (26.1%). Gleason 7 or greater cancer was found in 130 men (8.3%). CART created a decision tree that identified certain groups at risk for aggressive cancer, namely 1) PSAD greater than 0.165 ng/ml/cc, and 2) PSAD greater than 0.058 to 0.165 ng/ml/cc or less, age greater than 57.5 years and prostate volume greater than 22.7 cc. The incidence of aggressive prostate cancer was 1.1% when PSAD was 0.058 ng/ml/cc or less in the validation set. The sensitivity and specificity of CART for identifying men with aggressive cancer were 100% and 31.8% for model building data, and 91.5% and 33.5% for the validation data set, respectively. CONCLUSIONS: CART identified groups at risk for aggressive prostate cancer. Application of this CART could decrease unnecessary biopsies by 33.5% when only a diagnosis of high grade prostate cancer would lead to subsequent therapy.

Aged↗
PubMed2006

Dose-escalated abarelix in androgen-independent prostate cancer: a phase I study.

Follicle-stimulating hormone has been shown to be a mitogen in preclinical models of androgen-independent prostate cancer and abarelix has been previously shown to significantly reduce follicle-stimulating hormone levels in patients when administered monthly. Consequently, we evaluated the safety of more frequent (biweekly) dosing of abarelix and characterized the effect of this dosing schedule on serum follicle-stimulating hormone levels in men with prostate cancer that is progressing despite luteinizing hormone-releasing hormone agonist therapy. Twenty-one patients with prostate cancer progressing on gonadotropin-releasing hormone agonist therapy discontinued the gonadotropin-releasing hormone agonist and received abarelix-depot 100 mg by intramuscular injection every 2 weeks for up to 12 weeks. Safety profile and effect on serum follicle-stimulating hormone were the primary end-points, while prostate-specific antigen response was a secondary end-point. Abarelix therapy was generally well tolerated. One patient experienced an acute immediate allergic reaction. The mean follicle-stimulating hormone serum concentration declined from 3.5 mIU/ml (95% confidence interval: 2.7-4.3) to 2.0 mIU/ml (95% confidence interval: 1.3-2.6) on day 57 and to 2.0 mIU/ml (95% confidence interval: 0.9-3.0) on day 85 (P=0.008 in a Kruskal-Wallis test), but no patient's follicle-stimulating hormone has reached the lower limit of quantitation (below 0.15 mIU/ml). No patient met criteria for prostate-specific antigen response. At the end of 12 weeks of therapy, three (14.3%) patients had no change in prostate-specific antigen levels on days 57 and 85 compared with baseline. Twelve patients (57%) had stable disease throughout treatment defined as percent change from baseline within -50 to 50% at a given time-point confirmed by a second measurement at least 4 weeks later. Treatment with biweekly abarelix in patients with androgen-independent prostate cancer is feasible with no unexpected toxicity, but fails to completely suppress serum follicle-stimulating hormone levels or produce prostate-specific antigen responses.

Aged↗
PubMed2005

Effects of transdermal estrogen on levels of lipids, lipase activity, and inflammatory markers in men with prostate cancer.

Androgen deprivation therapy (ADT) for prostate cancer is now used in earlier disease stages and as adjuvant treatment. Recognizing and reducing the toxicity of this therapy, including worsened lipid levels and cardiovascular disease (CVD) risks, has become an important clinical concern. Oral estrogen therapy induces hypogonadism and mitigates many side effects of ADT, but has a high thrombosis risk. Transdermal estrogen therapy (TDE) has a lower thrombosis risk than oral estrogen and may improve CVD risk compared with ADT. This prospective pilot study of 18 men with androgen-independent prostate cancer receiving ADT measured effects of TDE on lipid and inflammatory CVD risk factors before and after 8 weeks of TDE (estradiol 0.6 mg/day). During treatment, estradiol levels rose 17-fold; total cholesterol, LDL cholesterol, and apolipoprotein B levels decreased. HDL2 cholesterol increased, with no changes in triglyceride or VLDL cholesterol levels. Dense LDL cholesterol decreased and LDL buoyancy increased in association with a decrease in HL activity. Highly sensitive C-reactive protein levels and other inflammatory markers did not worsen. Compared with ADT, short-term TDE therapy of prostate cancer improves lipid levels without deterioration of CVD-associated inflammatory markers and may, on longer-term follow-up, improve CVD and mortality rates.

Administration, Cutaneous↗
PubMed2005

Recursive partitioning for risk stratification in men undergoing repeat prostate biopsies.

BACKGROUND: The current study was performed to identify risk factors and risk groups for carcinoma detection in men undergoing repeat prostate biopsies. METHODS: The medical records of all men who had a negative initial prostate biopsy and underwent at least one repeat biopsy between 1992 and 2003 were reviewed to extract age, race, family history of prostate carcinoma, body mass index, referral indication, all prostate-specific antigen (PSA) values, digital rectal examination, PSA density (PSAD), the presence of a hypoechoic lesion, and the presence of high-grade prostatic intraepithelial neoplasia (HGPIN) on initial biopsy. Risk factors for a subsequent diagnosis of prostate carcinoma were identified using the log-rank test and a stepwise, stratified Cox regression model. Based on the risk factors identified by Cox regression analysis, recursive partitioning was further used for risk stratification. RESULTS: A total of 373 patients underwent 975 biopsy procedures. During a median follow-up of 37.0 months, prostate carcinoma was detected in 107 of 373 patients (28.9%). Independent predictors of a positive biopsy (P < 0.05) were PSA doubling time (PSADT), PSAD, referral indication, the presence of HGPIN, patient age, and family history of prostate carcinoma. Recursive partitioning identified 4 distinct risk groups that were characterized by their PSADT and PSAD and the presence of HGPIN and had estimated 2-year and 5-year carcinoma detection rates of 3 +/- 1% and 21 +/- 4%, 28 +/- 5% and 40 +/- 7%, 22 +/- 6% and 58 +/- 8%, and 66 +/- 9% and 100%, respectively. CONCLUSIONS: The authors identified a series of independent risk factors for prostate carcinoma detection after an initial negative prostate biopsy and characterized clinically meaningful and distinct patient risk groups. Despite a negative initial biopsy, patients with high-risk features remain at risk for the detection of prostate carcinoma.

Adult↗