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Biomedical subjects

David G Bostwick

Publications and source records attributed to David G Bostwick.

At least 19 recordsLinked to original sources
PubMed2006

Amplifications of EGFR gene and protein expression of EGFR, Her-2/neu, c-kit, and androgen receptor in phyllodes tumor of the prostate.

Phyllodes tumor of the prostate is a rare neoplasm with an unpredictable clinical behavior. It may undergo early recurrence with sarcomatous transformation or may even metastasize. Because targeted therapies have shown great success against several malignancies, there is hope that these same therapies may show similar promise in the treatment of other neoplasms. This study was undertaken to investigate both amplification of the epidermal growth factor receptor (EGFR) gene by fluorescence in situ hybridization and the overexpression of EGFR, Her-2/neu, CD117 (c-kit), and androgen receptor by immunohistochemical staining in a series of 11 phyllodes tumors of the prostate. In the stromal elements, EGFR gene amplification was present in four of 11 tumors and polysomy chromosome 7 was present in two of 11 tumors. No amplification was present in the epithelial components. Only one of 11 tumors had polysomy of chromosome 7 in the epithelial components. Immunohistochemically, in the stromal components, EGFR expression was demonstrable in four of 11 tumors and androgen receptor was demonstrated in six of 10 tumors. Neither Her-2/neu nor c-kit expression was seen in the stromal components of any of the 11 tumors. In the epithelial components, EGFR expression was present in all 11 tumors with strong staining in the basal cell layers and weak or no staining in luminal epithelium; androgen receptor expression was seen in seven of 10 tumors; Her-2/neu was weakly positive in four of 11 tumors; and c-kit expression was present focally and weakly in two of 11 cases with only 2-5% of cells staining. The highest staining intensity and the highest percentage of positively staining cells were seen with EGFR immunostaining in both the stromal and epithelial (mainly basal cells) components. Androgen receptor staining showed the next highest staining intensity and percentage of positive cells in both components. Her-2/neu and c-kit were only weakly or infrequently expressed in the epithelial components of prostatic phyllodes tumors. Our data indicate that EGFR and androgen receptor are frequently and strongly expressed in both epithelial and stromal components of prostatic phyllodes tumors. EGFR gene amplification is frequently present in prostatic phyllodes tumors and may account for one of the mechanisms leading to protein overexpression in some but not all cases. Anti-EGFR and/or antiandrogen agents may be potentially useful for management of patients with tumors expressing EGFR and/or androgen receptor.

Adult↗
PubMed2006

Effect of testosterone replacement therapy on prostate tissue in men with late-onset hypogonadism: a randomized controlled trial.

CONTEXT: Prostate safety is a primary concern when aging men receive testosterone replacement therapy (TRT), but little information is available regarding the effects of TRT on prostate tissue in men. OBJECTIVE: To determine the effects of TRT on prostate tissue of aging men with low serum testosterone levels. DESIGN, SETTING, AND PARTICIPANTS: Randomized, double-blind, placebo-controlled trial of 44 men, aged 44 to 78 years, with screening serum testosterone levels lower than 300 ng/dL (<10.4 nmol/L) and related symptoms, conducted at a US community-based research center between February 2003 and November 2004. INTERVENTION: Participants were randomly assigned to receive 150 mg of testosterone enanthate or matching placebo intramuscularly every 2 weeks for 6 months. MAIN OUTCOME MEASURES: The primary outcome measure was the 6-month change in prostate tissue androgen levels (testosterone and dihydrotestosterone). Secondary outcome measures included 6-month changes in prostate-related clinical features, histology, biomarkers, and epithelial cell gene expression. RESULTS: Of the 44 men randomized, 40 had prostate biopsies performed both at baseline and at 6 months and qualified for per-protocol analysis (TRT, n = 21; placebo, n = 19). Testosterone replacement therapy increased serum testosterone levels to the mid-normal range (median at baseline, 282 ng/dL [9.8 nmol/L]; median at 6 months, 640 ng/dL [22.2 nmol/L]) with no significant change in serum testosterone levels in matched, placebo-treated men. However, median prostate tissue levels of testosterone (0.91 ng/g) and dihydrotestosterone (6.79 ng/g) did not change significantly in the TRT group. No treatment-related change was observed in prostate histology, tissue biomarkers (androgen receptor, Ki-67, CD34), gene expression (including AR, PSA, PAP2A, VEGF, NXK3, CLU [Clusterin]), or cancer incidence or severity. Treatment-related changes in prostate volume, serum prostate-specific antigen, voiding symptoms, and urinary flow were minor. CONCLUSIONS: These preliminary data suggest that in aging men with late-onset hypogonadism, 6 months of TRT normalizes serum androgen levels but appears to have little effect on prostate tissue androgen levels and cellular functions. Establishment of prostate safety for large populations of older men undergoing longer duration of TRT requires further study. Trial Registration clinicaltrials.gov Identifier: NCT00161304.

Adult↗
PubMed2006

Atypical foci suspicious but not diagnostic of malignancy in prostate needle biopsies (also referred to as "atypical small acinar proliferation suspicious for but not diagnostic of malignancy").

OBJECTIVE: To review atypical focus suspicious but not diagnostic of malignancy in needle biopsies of the prostate, also referred to as "atypical small acinar proliferation suspicious for but not diagnostic of malignancy." METHODS: A number of descriptive and somewhat confusing terms have been used to refer to a prostate tissue biopsy with small focus of atypical glands. Based on MEDLINE database searches, all aspects, including the synonymous terms, of atypical focus suspicious but not diagnostic of malignancy were examined. RESULTS: An average of 5% of needle biopsy pathology reports show a diagnosis of atypical focus suspicious for malignancy. It may be composed of acini of small size, that is, smaller than normal ducts and acini, but may also include glands with a diameter similar to that of normal ducts and acini. It encompasses a variety of lesions, including benign mimickers of cancer and small foci of carcinoma that, for a variety of reasons, cannot be accurately diagnosed. Maximal diagnostic information should be gained on section stained with haematoxylin and eosin, with immunohistochemical stains used for confirmation. Its presence in a biopsy set is a strong predictor for concurrent or subsequent adenocarcinoma. The values range from 17% to 60%, the mean being 40.7%. The precise labelling of the initial biopsies is mandatory so that rebiopsy of patients with atypical foci can be directed in a more concentrated fashion into the region of the initial biopsy. CONCLUSION: The presence of atypical focus suspicious but not diagnostic of malignancy in needle biopsies is an important predictor of cancer compared with biopsies from patients who lack this finding.

Biopsy, Needle↗
PubMed2006

Prostate cancer detected by uPM3: radical prostatectomy findings.

uPM3 is the first urine-based genetic test that is highly specific for detecting prostate cancer. The histopathologic characteristics of uPM3-detected cancer in radical prostatectomy specimens have not been previously described. We evaluated a consecutive series of radical prostatectomies to determine the extent, zonal distribution and other features of prostate cancer following uPM3 detection. A total of 24 whole-mounted, totally embedded radical prostatectomy specimens were evaluated. All patients had clinically localized cancer and none received preoperative therapy. Zonal location of cancer, distance to the urethra, cancer volume, Gleason grade and multicentricity were recorded; volume of cancer was measured using the grid-counting method. Patients ranged in age from 43 to 75 years (mean 65 years). In 21/24 cases, cancer involved the transition and peripheral zones and was multicentric (87%). Mean cancer volume was 3.96 cm3 (range 0.08-16.86 cm3). Mean distance to the urethra was 0.50 cm for the closest cancer and 0.61 cm for the most distant cancer. Mean Gleason score was 7 (range 5-9); pathologic stage was pT2 for 17 cases and pT3 for seven cases. The uPM3 is an independent and specific biomarker that detects prostate cancers of similar volume, location, extent and grade as other tests for early detection. uPM3 does not preferentially identify large or aggressive prostate cancers.

Adult↗
PubMed2006

Atypical small acinar proliferation in the prostate: clinical significance in 2006.

About 2% of contemporary prostate needle biopsy specimens contain collections of small acini that are suspicious for cancer but that fall below the diagnostic threshold and are reported as atypical small acinar proliferation suspicious for but not diagnostic of malignancy. Prostate cancer has been identified in specimens from subsequent biopsies in up to 60% of cases of atypical small acinar proliferation, indicating that this finding is a significant predictor of cancer. Identification of atypical small acinar proliferation warrants repeat biopsy for concurrent or subsequent invasive carcinoma.

Adenocarcinoma↗
PubMed2005

Prostate cancer risk and DNA damage: translational significance of selenium supplementation in a canine model.

Daily supplementation with the essential trace mineral selenium significantly reduced prostate cancer risk in men in the Nutritional Prevention of Cancer Trial. However, the optimal intake of selenium for prostate cancer prevention is unknown. We hypothesized that selenium significantly regulates the extent of genotoxic damage within the aging prostate and that the relationship between dietary selenium intake and DNA damage is non-linear, i.e. more selenium is not necessarily better. To test this hypothesis, we conducted a randomized feeding trial in which 49 elderly beagle dogs (physiologically equivalent to 62-69-year-old men) received nutritionally adequate or supranutritional levels of selenium for 7 months, in order to mimic the range of dietary selenium intake of men in the United States. Our results demonstrate an intriguing U-shaped dose-response relationship between selenium status (toenail selenium concentration) and the extent of DNA damage (alkaline Comet assay) within the prostate. Further, we demonstrate that the concentration of selenium that minimizes DNA damage in the aging dog prostate remarkably parallels the selenium concentration in men that minimizes prostate cancer risk. By studying elderly dogs, the only non-human animal model of spontaneous prostate cancer, we have established a new approach to bridge the gap between laboratory and human studies that can be used to select the appropriate dose of anticancer agents for large-scale human cancer prevention trials. From the U-shaped dose-response, it follows that not all men will necessarily benefit from increasing their selenium intake and that measurement of baseline nutrient status should be required for all individuals in prevention trials to avoid oversupplementation.

Age Factors↗
PubMed2005

Tubulocystic carcinoma, mucinous tubular and spindle cell carcinoma, and other recently described rare renal tumors.

In the past 10 years, several new renal tumors have been identified. Some have been reviewed in this article, and others have been reviewed elsewhere in this issue. Most have been included in the 2004 edition of the WHO classification of tumors of the urinary system and male genital organs. Tubulocystic carcinoma needs to be studied and characterized more fully.

Adenocarcinoma, Mucinous↗
PubMed2005

Incidentally detected prostate cancer in cystoprostatectomies: pathological and morphometric comparison with clinically detected cancer in totally embedded specimens.

There are limited data regarding the pathological features of incidentally detected prostate cancer. Examination of cystoprostatectomy specimens obtained during bladder cancer treatment affords a unique opportunity to examine incidentally detected prostate cancer and determine its relationship with clinically detected prostate cancer obtained during radical prostatectomy. We compared the pathological findings of incidentally detected prostate cancer in 132 consecutive cystoprostatectomy specimens from patients treated for bladder cancer with a consecutive series of 228 radical prostatectomy specimens from patients treated for prostate cancer. All specimens were totally embedded and whole-mounted. Karyometry was evaluated in select subsets of patients from the study groups. Incidentally detected cancer was found in 42% of cystoprostatectomy specimens, and the cancers were of lower Gleason score and lower pathological stage with fewer positive surgical margins than in clinically detected cancers in age-matched radical prostatectomies. High-grade prostatic intraepithelial neoplasia (PIN) was present in 82% of radical prostatectomy specimens, in 70% of cystoprostatectomies with incidentally detected prostate cancer, and in 54% of cystoprostatectomies without prostate cancer. Mean nuclear and nucleolar area was lower in incidentally detected cancer and PIN when compared with clinically detected cancer and PIN, respectively, similar to the results with proliferative indices. We conclude that incidentally detected cancer is less aggressive than clinically detected cancer.

Humans↗
PubMed2005

The dual 5-alpha-reductase inhibitor dutasteride induces atrophic changes and decreases relative cancer volume in human prostate.

OBJECTIVES: To perform the first evaluation of the effects of the 5-alpha-reductase inhibitor class of drugs on cancer histopathologic features at radical prostatectomy in a placebo-controlled multicenter trial. METHODS: We analyzed prostatectomy slides in a blinded manner from 17 men treated with dutasteride, an inhibitor of types 1 and 2 isoenzymes of 5-alpha-reductase, and 18 men treated with placebo for 5 to 11 weeks before radical prostatectomy. The histopathologic features of benign epithelium, high-grade prostatic intraepithelial neoplasia, and cancer were recorded, and the treatment effect was scored. Digital imaging analysis was used to measure the stroma/epithelium ratio and epithelial height, as well as the nuclear area in cancer. RESULTS: In benign epithelium, treatment caused distinctive cytoarchitectural changes of atrophy and a decrease in the epithelial height (P = 0.053). The peripheral zone showed the most marked response to treatment. In cancer tissue, the tumor volume was significantly lower in the dutasteride-treated men than in the placebo-treated men (mean 15% versus 24%, respectively, P = 0.025), the percentage of atrophic epithelium was increased (P = 0.041), and the stroma/gland ratio was doubled (P = 0.046). The treatment alteration effect score was doubled (P = 0.055) and did not correlate with any Gleason score changes. CONCLUSIONS: After short-term dutasteride treatment, benign epithelium showed involution and epithelial shrinkage, and prostate cancer tissue demonstrated a decrease in epithelium relative to stroma. These findings indicate that dutasteride induces significant phenotypic alterations in both the benign and the neoplastic prostate, supportive of a chemopreventive or chemoactive role.

5-alpha Reductase Inhibitors↗
PubMed2005

Corpora amylacea in adenocarcinoma of the prostate: incidence and histology within needle core biopsies.

Corpora amylacea in the prostate are a frequent finding in benign acini, but are only rarely observed in adenocarcinoma. To determine the incidence and comparative histopathology of this finding, we prospectively reviewed all consecutive needle core biopsies (excluding consultations) received at Bostwick Laboratories between December 2001 and July 2003. Among 5130 cases of adenocarcinoma (34% of 15,279 total needle biopsy cases), we identified 19 (31 biopsy specimens) with corpora amylacea within cancerous acini (0.4% incidence). Patients ranged in age from 51 to 89 years (mean, 68 years). The corpora amylacea were located within cancers with Gleason pattern 3 (28 of 31 specimens), Gleason pattern 4 (one specimen), and Gleason pattern 5 (two specimens), and ranged from less than 0.1-0.3 mm in diameter. Coexistent eosinophilic proteinaceous debris was noted in all 31 specimens, luminal mucin in 19, crystalloids in 15, and collagenous micronodules in two specimens. Our results indicate that the incidence of corpora amylacea in adenocarcinoma is low, but the presence of such inclusions cannot be used to exclude malignancy.

Adenocarcinoma↗
PubMed2005

Epidemiology and statistical methods in prediction of patient outcome.

Substantial gaps exist in the data of the assessment of risk and prognosis that limit our understanding of the complex mechanisms that contribute to the greatest cancer epidemic, prostate cancer, of our time. This report was prepared by an international multidisciplinary committee of the World Health Organization to address contemporary issues of epidemiology and statistical methods in prostate cancer, including a summary of current risk assessment methods and prognostic factors. Emphasis was placed on the relative merits of each of the statistical methods available. We concluded that: 1. An international committee should be created to guide the assessment and validation of molecular biomarkers. The goal is to achieve more precise identification of those who would benefit from treatment. 2. Prostate cancer is a predictable disease despite its biologic heterogeneity. However, the accuracy of predicting it must be improved. We expect that more precise statistical methods will supplant the current staging system. The simplicity and intuitive ease of using the current staging system must be balanced against the serious compromise in accuracy for the individual patient. 3. The most useful new statistical approaches will integrate molecular biomarkers with existing prognostic factors to predict conditional life expectancy (i.e. the expected remaining years of a patient's life) and take into account all-cause mortality.

Adult↗
PubMed2005

Performance of urine test in patients monitored for recurrence of bladder cancer: a multicenter study in the United States.

PURPOSE: We assessed the performance of the ImmunoCyt immunocytochemical test for detecting bladder cancer recurrence in patients with prior superficial bladder cancers compared with cystoscopic and histological findings. MATERIALS AND METHODS: A total of 341 patients with a history of bladder cancer undergoing monitoring were evaluated at 4 sites. The results of cytology and/or ImmunoCyt were analyzed for sensitivity and specificity compared with biopsy confirmed cancer. RESULTS: The overall sensitivity of cytology alone, ImmunoCyt alone and the 2 methods combined was 23%, 81% and 81%, respectively. The specificity of cytology alone, ImmunoCyt alone and of the 2 methods combined was 93%, 75% and 73%, respectively. The immunocytochemical test was more sensitive than cytology for detecting grades 1 and 2, and stages Ta, T1, and T2 urothelial carcinoma, and it was equally sensitive for detecting grade 3 cancers and carcinoma in situ (CIS). The sensitivity of the combined tests for grades 1 to 3/CIS was 79%, 90% and 82%, while for stages Ta, T1, T2+ and CIS it was 83%, 75%, 100% and 100%, respectively. The overall positive and negative predictive values of the combined tests were 37% and 95%, respectively. Importantly the immunocytochemical test could detect 71% of small (less than 1 cm) tumors. CONCLUSIONS: ImmunoCyt is a sensitive test for detecting bladder cancer. Because of its high sensitivity for detecting small tumors, even those of low histological grade, and its high negative predictive value, this test may have a role in decreasing the frequency of cystoscopic examinations for monitoring patients with low risk bladder cancer.

Antibodies, Monoclonal↗
PubMed2005

High-grade prostatic intraepithelial neoplasia and atypical small acinar proliferation: predictive value for cancer in current practice.

In earlier studies, prostate cancer (PCa) has been reported to appear in 21% to 48% of subsequent biopsies for isolated high-grade prostatic intraepithelial neoplasia (PIN) and in 34% to 60% for isolated atypical small acinar proliferation suspicious for, but not diagnostic of, malignancy (ASAP). We report results of follow-up biopsies in a recent cohort of community practice patients who underwent biopsy for PSA abnormalities. The study group consisted of 336 men with initial diagnoses of PIN (n = 204), ASAP (n = 78), or both lesions (n = 54) who underwent at least one repeat biopsy. Mean follow-up intervals in months were 6.0 for PIN, 3.8 for ASAP, and 4.9 for PIN/ASAP. Follow-up PCa detection rates were 23%, 37%, and 33%, respectively. The predictive value of ASAP was significantly higher than that for PIN (P = 0.0188). In 23 PIN studies with chronologic midpoints in the early 1990s, follow-up PCa was detected in a mean of 36% of cases, whereas this value was 21% after the year 2000. In 13 ASAP studies, mean PCa detection on follow-up was 45% until 1996 and 39% from 1997 to present. PIN/ASAP predicted PCa in 33% of cases in our study, similar to ASAP alone (P = 0.65) and had a mean predictive value of 44% in the literature. Factors that may account for the decline in PIN predictive values include: 1) extended biopsy techniques that yield higher rates of initial cancer detection, 2) lower detection rate for the remaining small cancers that may accompany PIN, and 3) remaining PIN cases may lack concomitant cancer.

Aged↗
PubMed2005

Atypical adenomatous hyperplasia (adenosis) of the prostate: DNA ploidy analysis and immunophenotype.

Atypical adenomatous hyperplasia (AAH) of the prostate is a microscopic proliferation of small acini that may be mistaken for adenocarcinoma. Although some data suggest that AAH is associated with adenocarcinoma arising in the transition zone, the clinical significance of this lesion is uncertain. Therefore we studied the DNA ploidy pattern and immunophenotype of AAH as compared with nodular hyperplasia and well-differentiated adenocarcinoma in 23 formalin-fixed, paraffin-embedded, whole-mounted retropubic prostatectomies. Representative sections were immunostained for keratin 34beta-E12, chromogranin, bcl-2, c-erbB-2, ki67-MIB1, and factor VIII (microvessel density). DNA ploidy was determined by image analysis and Feulgen-stained sections. There were rare scattered immunoreactive cells for chromogranin, bcl-2, and c-erbB-2 in nodular hyperplasia and AAH (mainly in the basal cell compartment) and in carcinoma. The ki67-MIB1 labeling index was different between nodular hyperplasia and AAH (p<0.001) and carcinoma (p=0.003) but not between AAH and carcinoma (p=0.203). Microvessel density was different between AAH and carcinoma (p=0.001) but not between nodular hyperplasia and AAH (p=0.105) or carcinoma (p=0.0820). All foci of nodular hyperplasia, AAH, and carcinoma were diploid. Ploidy status and our selected panel of antibodies did not discriminate among these 3 entities reliably.

Adenocarcinoma↗
PubMed2005

Pleomorphic giant cell carcinoma of the prostate.

We report the clinical and pathologic features of 2 cases of pleomorphic giant cell carcinoma of the prostate. One case was found at autopsy in a 77-year-old man and was composed of high-grade prostatic adenocarcinoma with prominent anaplastic giant cells. The patient presented with metastases to multiple retroperitoneal lymph nodes, liver, and lumbar vertebrae. The second case occurred in a 45-year-old man who underwent transurethral resection of the prostate and was found to have high-grade prostatic adenocarcinoma with an extensive anaplastic giant cell component. The patient presented with distant metastases and died within 9 months. Both regular adenocarcinoma and anaplastic giant tumor cells displayed cytoplasmic immunoreactivity for prostate-specific antigen, prostatic acid phosphatase, and keratin AE1/AE3; in one case, scattered cells were also positive for chromogranin and epithelial membrane antigen. Pleomorphic giant cell carcinoma is a rare variant of prostatic adenocarcinoma with a poor prognosis that should be considered in the differential diagnosis of prostatic pleomorphic tumors.

Adenocarcinoma↗
PubMed2005

Prostate cancer outcome: epidemiology and biostatistics.

Substantial gaps exist in our ability to accurately predict prognosis, and these gaps limit our understanding of the complex mechanisms that contribute to the greatest cancer epidemic of our time, prostate cancer. This review addresses contemporary epidemiologic and biostatistical issues in prostate cancer. It covers the science of outcome prediction and biomarker evaluation, recognition of the need to combine biomarkers to improve the accuracy of our outcome estimates and an analysis of current outcome assessment methods, including the TNM staging system and multivariate regression models. The simplicity and intuitive ease of the current TNM staging system must be balanced against its serious limitations in predictive accuracy and its loss of clinical utility. Statistical regression methods are required as we move to the new era of personalized medicine. We must implement statistical approaches that integrate the new molecular biomarkers with existing prognostic biomarkers to accurately predict which patients require treatment and to determine the optimal therapy.

Biomarkers, Tumor↗
PubMed2004

Human prostate cancer risk factors.

Prostate cancer has the highest prevalence of any nonskin cancer in the human body, with similar likelihood of neoplastic foci found within the prostates of men around the world regardless of diet, occupation, lifestyle, or other factors. Essentially all men with circulating androgens will develop microscopic prostate cancer if they live long enough. This review is a contemporary and comprehensive, literature-based analysis of the putative risk factors for human prostate cancer, and the results were presented at a multidisciplinary consensus conference held in Crystal City, Virginia, in the fall of 2002. The objectives were to evaluate known environmental factors and mechanisms of prostatic carcinogenesis and to identify existing data gaps and future research needs. The review is divided into four sections, including 1) epidemiology (endogenous factors [family history, hormones, race, aging and oxidative stress] and exogenous factors [diet, environmental agents, occupation and other factors, including lifestyle factors]); 2) animal and cell culture models for prediction of human risk (rodent models, transgenic models, mouse reconstitution models, severe combined immunodeficiency syndrome mouse models, canine models, xenograft models, and cell culture models); 3) biomarkers in prostate cancer, most of which have been tested only as predictive factors for patient outcome after treatment rather than as risk factors; and 4) genotoxic and nongenotoxic mechanisms of carcinogenesis. The authors conclude that most of the data regarding risk relies, of necessity, on epidemiologic studies, but animal and cell culture models offer promise in confirming some important findings. The current understanding of biomarkers of disease and risk factors is limited. An understanding of the risk factors for prostate cancer has practical importance for public health research and policy, genetic and nutritional education and chemoprevention, and prevention strategies.

Animals↗