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Query: UMLS:C0376358 (prostate cancer)
 59,338 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Surrogate endpoint biomarkers (SEBs) are needed in clinical chemoprevention trials to avoid the excessively long study periods and high costs associated with the use of cancer incidence reduction as an endpoint, particularly with relatively slow-growing tumors such as prostatic adenocarcinoma. SEBs should be directly associated with the evolution of neoplasia, and develop with high frequency in abnormal cells of susceptible individuals. If SEBs can be modified by a particular intervention regimen in short-term studies, the rationale for carrying out long-term studies may be strengthened. The consensus panel identified a small and manageable group of biomarkers measured in tissue or serum as the most promising in prostate cancer chemoprevention, including (1) prostate specific antigen (PSA); (2) morphometric markers, such as nuclear size and roundness; (3) proliferation markers, such as MIB-1 and PCNA; (4) nuclear DNA content (ploidy); (5) oncogene c-erbB-2 (HER-2/neu) expression; (6) angiogenesis; and (7) high-grade prostatic intraepithelial neoplasia (PIN). Information regarding many of these and other biomarkers is limited, calling for further investigation. Also, these factors, chosen chiefly for their proven or proposed utility as prognostic factors, may be less useful as SEBs. It was agreed that concurrent study of numerous markers rather than single markers allows comparison of their relative utility, including assessment of ease of quantitation and the sensitivity, specificity, and positive and negative predictive value.
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PMID:The most promising surrogate endpoint biomarkers for screening candidate chemopreventive compounds for prostatic adenocarcinoma in short-term phase II clinical trials. 752 57

Neuroendocrine (NE) differentiation frequently occurs in common prostatic malignancies and has potential prognostic and therapeutic implications. In a recent study we were able to provide immunohistochemical evidence that endocrine-paracrine cell types represent an androgen-insensitive cell population in prostate cancer, documented by the consistent lack of the pertinent receptor. In this study we investigated the proliferative activity of endocrine-paracrine cell types in normal, hyperplastic, and neoplastic prostate tissue. Using double-label techniques for the endocrine marker chromogranin A (chr A) and the proliferation-associated MIB-1 antigen, we evaluated the proliferative status of endocrine-paracrine cell types in the prostate and prostatic adenocarcinoma showing marked NE differentiation. In this series of carcinomas and in nonneoplastic tissue the proliferative activities were exclusively restricted to nonendocrine cell populations, whereas endocrine-paracrine cell types characterized by Chr A consistently lack MIB-1 immunoreactivity. This may indicate that prostatic endocrine-paracrine cell types do not participate in the cell cycle during normal, hyperplastic, and neoplastic prostatic growth. Based on the present information, the endocrine phenotype can be considered to be an androgen-insensitive, postmitotic subpopulation in the prostate and prostate cancer.
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PMID:Endocrine-paracrine cell types in the prostate and prostatic adenocarcinoma are postmitotic cells. 852 16

Eleven routinely processed radical prostatectomy specimens were studied for the presence of numerical chromosomal aberrations by means of in situ hybridization with nucleic acid probes specific for chromosomes 7, 10, 17, X, and Y. Cytogenetic information was correlated with morphology, tumour stage and volume as well as with cell kinetics, the latter being assessed by immunohistochemistry with antibodies raised against the proliferative cell nuclear antigen (PCNA) and against a formalin-resistant epitope of the Ki-67 antigen, MIB 1. In 5 of 11 cases, numerical aberrations of at least one chromosome were found. The cases with normal chromosome numbers were those with the smallest volumes of Gleason grade 4 and/or 5 tumour (mean 0.5 cm3) and represented tumours restricted to the prostate. Tumours with aberrations in the number of detected chromosomes showed advanced stages and large volumes of high-grade tumour (mean 12.5 cm3). All 4 tumours with positive surgical margins were recruited from a group with marked local heterogeneity in chromosome numbers. Immunostaining with MIB 1 and PCNA was most intense in areas of high-grade tumour and was positively correlated with the emergence of chromosomal aberrations. The data suggest that the appearance of numerical chromosomal aberrations in prostate cancer coincides with aggressive tumour behaviour and could be used as an additional prognostic marker.
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PMID:Numerical chromosomal aberrations in prostate cancer: correlation with morphology and cell kinetics. 767 50

The clinical course of prostate cancer is highly variable and cannot satisfactorily be predicted by histological criteria alone. Both tumour cell proliferation and neuroendocrine differentiation have been suggested as additional prognostic parameters, neuroendocrine differentiation being considered to enhance tumour cell proliferation. This study investigated the prognostic value of tumour cell proliferation [Ki67 labelling index (LI), MIB 1] and neuroendocrine differentiation and their relationship to each other. One hundred and thirty-seven paraffin-embedded radical prostatectomy specimens were examined. Neuroendocrine differentiation was found in 58 per cent of cases, but was not associated with pTN stage, Gleason score, Ki67 LI, or tumour progression. Ki67 LI was not significantly associated with pTN stage or with Gleason score. High grade (P = 0.0005), advanced local stage (P = 0.0004), positive lymph nodes (P = 0.02), and high Ki67 LI (P = 0.0203) were predictors of tumour progression if univariate analysis was performed, but Cox stepwise regression showed that only advanced local stage (P = 0.0025) and Ki67 LI (P = 0.0105) were independent predictors of tumour progression, the relative risk being 3.6 and 2.5, respectively. It is concluded that Ki67 is an important prognostic marker in prostate cancer with a potential for routine application.
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PMID:Ki67 labelling index: an independent predictor of progression in prostate cancer treated by radical prostatectomy. 869 23

The expression of epidermal growth factor receptor (EGF-R), transforming growth factor alpha (TGFalpha), and epidermal growth factor (EGF) was evaluated in a series of prostate cancer (CaP; n = 55) and benign prostate hyperplasia (BPH; n = 44) specimens using immunocytochemistry (ICC) and Northern blotting. In situ hybridization (ISH), performed on a subgroup of these specimens, proved to be a more informative technique for the assessment of messenger RNA (mRNA) in this heterogeneous tissue. A comparative analysis was made in relation to the proliferative index, assessed using the MIB-1 antibody. Elevated levels of EGF-R and TGFalpha, mRNA, and protein were observed in carcinoma cells compared with benign, secretory epithelium using in situ hybridization and immunocytochemistry. In carcinoma specimens evidence of an autocrine growth loop is provided by a correlation between EGF-R and TGFalpha, mRNA (P < .0001), and protein expression (P < .01). A trend toward increased expression of EGF-R and TGFalpha protein with dedifferentiation and a similar trend in the growth fraction suggest a role in tumor progression. Although there was a correlation between EGF-R and the proliferative index (P < .01), no relationship was found between this latter parameter and TGFalpha immunoreactivity (P > .05), indicating that this growth factor may be linked with other aspects of malignant activity rather than directly stimulating proliferation.
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PMID:Comparative analysis of mRNA and protein expression for epidermal growth factor receptor and ligands relative to the proliferative index in human prostate tissue. 869 13

The most efficient strategy for chemoprevention clinical trials are short-term studies which focus on surrogate endpoint biomarkers (SEBs) in high-risk target populations. High-grade prostatic intraepithelial neoplasia (PIN) is the most likely precursor of prostate cancer, and is found in a significant number of routine contemporary needle biopsies without cancer. The frequency and extent of PIN are decreased with androgen deprivation therapy, suggesting that it is a suitable endpoint biomarker for modulation. Potential SEBs for screening chemopreventive agents for prostate cancer in short-term Phase II trials include (1) histologic premalignant lesions, such as high-grade PIN; (2) biochemical markers, including prostate-specific antigen (PSA) serum concentration; and (3) morphometric markers, including nuclear texture, shape, and roundness; size and number of nucleoli; and number of apoptotic bodies; (4) proliferation markers, including MIB-1 and PCNA; (5) genetic markers, including nuclear DNA content (ploidy), oncogene c-erbB-2 (HER-2/neu) expression, fluorescence in situ hybridization for chromosome 8; and PSA-producing cells in the blood detected by reverse transcriptase polymerase chain reaction; and (6) differentiation markers, such as microvessel density as a determinant of angiogenesis. Each of these endpoint biomarkers is measured easily and accurately in serum or in tissue specimens such as formalin-fixed, paraffin-embedded needle biopsies, and may be modifiable by intervention. The clinical utility of these biomarkers as modulatable endpoints in prostate cancer chemoprevention needs to be demonstrated in future clinical trials.
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PMID:Prostatic intraepithelial neoplasia (PIN) and other prostatic lesions as risk factors and surrogate endpoints for cancer chemoprevention trials. 902 13

Prostatic intraepithelial neoplasia (PIN) is the most likely precursor of human prostate cancer. The prevalence and immunophenotype of PIN in dogs with spontaneous prostate cancer has not been previously described. To investigate the association between PIN and prostate cancer, we evaluated the prostates of dogs with spontaneous prostate carcinoma. The prevalence of PIN was determined in formalin-fixed prostates from 29 dogs with spontaneous prostate cancer. Using immunoperoxidase techniques, we compared basal cell layer integrity (high molecular weight keratin 34 beta-E12), proliferative index (MIB-1), and microvessel density (Factor VIII-related antigen) in 14 prostates which contained benign epithelium, PIN, and carcinoma. PIN was present in 19 of 29 (66%) prostates from dogs with spontaneous prostate cancer. The basal cell layer was intact in benign epithelium, disrupted in 72% of acini with PIN, and absent in carcinoma. The mean proliferative index was 17%, 25%, and 40% for benign epithelium, PIN, and carcinoma, respectively, and these differences were significant. The mean microvessel density in foci of PIN and carcinoma (32 and 39 vessels per mm2, respectively) was greater than in benign epithelium (23 vessels per mm2). High-grade PIN is common in the prostates of dogs with spontaneous carcinoma. The basal cell layer is partially disrupted in PIN, whereas it is absent in prostate cancer. The proliferative index and microvessel density of PIN are intermediate between benign epithelium and cancer. These results are similar to those reported for human PIN and prostate cancer, and indicate that PIN is part of a morphologic continuum in the progression of prostate cancer. To our knowledge, this is the first description of high-grade PIN spontaneously occurring in animals. The canine prostate may serve as a useful model for examining factors that modulate PIN and prostate cancer progression.
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PMID:Prostatic intraepithelial neoplasia in dogs with spontaneous prostate cancer. 905 Nov 47

Large variability in the biological behavior of prostate cancer makes prognostic markers important. The extent of tumor cell proliferation has been suggested as an important predictor of clinical outcome. Fifty-five patients suspected of having or with previously diagnosed prostate cancer were labeled in vivo with IdUrd (a thymidine analogue incorporated into DNA in S-phase cells) by intravenous infusion before transurethral resection. IdUrd-labeled cells and MIB-1-positive cells were detected by immunohistochemistry. We found statistically significant associations between the tumor cell proliferation rates measured by in vivo IdUrd labeling and MIB-1 expression in formalin-fixed paraffin-embedded tumors. Good correlations were also found between S-phase fraction, MIB-1 expression, clinical stage and malignancy grade. These results make larger retrospective studies on archival tissue meaningful.
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PMID:Association between in vivo iododeoxyuridine labeling, MIB-1 expression, malignancy grade and clinical stage in human prostate cancer. 954 28

This study addresses two issues regarding prostatic atrophy: (1) the histologic features of atrophy as seen on needle biopsy results and how they affect the diagnosis of atrophy and (2) the cellular kinetics of atrophy and what it suggests about the mechanism of atrophy. We reviewed hematoxylin and eosin sections for 103 prostate needle biopsy specimens with atrophy. Each biopsy specimen was classified as either simple atrophy (large atrophic glands without crowding: 53 cases) or postatrophic hyperplasia (PAH) (crowded focus of small atrophic acini: 50 cases). Cell proliferation in both the atrophic and benign glands was evaluated in 103 cases by immunohistochemistry using antibodies against MIB-1. The TdT-mediated dUTP-biotin nick-end labeling technique was performed on 61 cases to quantitate apoptosis in atrophic and benign glands. Thirty-two percent of cases showed chronic inflammation, 21% showed acute inflammation, 14% showed nucleoli, and 1% showed mitoses. In comparison to simple atrophy, PAH contained more frequent prominent nucleoli (p < 0.0001) and acute inflammation (p < 0.0001), yet not chronic inflammation. In a multivariate analysis, acute inflammation and PAH pattern influenced the presence of prominent nucleoli. Staining for MIB-1 was greater in atrophic (27.5 cells/1000 cells) than in benign glands (3.5 cells/1000 cells), greater in PAH than in simple atrophy (p = 0.0015), and greater with acute (p = 0.05) but not chronic inflammation. In a multivariate analysis, only the pattern of atrophy and not acute inflammation was found to influence MIB-1. The rate of apoptosis was negligible in both the benign and atrophic glands, did not vary with pattern of atrophy, and did not correlate with MIB-1. Despite the atrophic appearance, atrophic glands in PAH show more proliferative activity than benign, nonatrophic glands and show no evidence of active involution, justifying the term "postatrophic hyperplasia" for this pattern of atrophy. Prominent nucleoli are seen more frequently in postatrophic hyperplasia, even in the absence of acute inflammation. To avoid a potential erroneous diagnosis of cancer, a constellation of features suggestive of malignancy should be considered, rather than relying on prominent nucleoli as the sole criteria for the diagnosis of prostate cancer.
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PMID:Histology and cellular kinetics of prostatic atrophy. 973 39

Predictive factors stratify cancer patients into homogeneous groups for treatment. There is an acute need for accurate predictive factors in patients with prostate cancer given the marked variation in treatment recommendations. These factors should be obtained prior to therapy and should include patient factors, serum factors and tissue-specific factors derived from biopsies. This review evaluates the current state of knowledge regarding quantitative methods in prostate tissue specimens, classifying predictive factors in prostate cancer into four categories. The first category, predictive factors recommended for widespread clinical use, includes Gleason grade; nontissue markers include clinical stage and serum prostate-specific antigen. The second category, predictive factors that are often collected but of unproven significance, includes DNA ploidy and volume of cancerous material in the needle biopsy. The third category, predictive factors not used for routine patient management, includes cell proliferation markers (mitotic figures, proliferating cell nuclear antigen, Ki-67 and MIB-1), apoptotic markers, microvessel density and perineural invasion. The fourth category, predictive factors under investigation, includes morphometric features, such as nuclear roundness and size, chromatin texture, silver-staining nucleolar organizer regions and nucleolar size. Standards are required for virtually every aspect of morphometric study, and these features require validation before their acceptance as clinically relevant in prostate cancer. Predictive factors in radical prostatectomies include cancer volume and extent in radical prostatectomy specimens and quantitation of number and size of lymph node metastases. Neural network models provide greater accuracy for combinations of predictive factors than traditional statistical methods of analysis, such as logistic regression and Cox models, and are expected to be incorporated into routine use in the next few years.
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PMID:Practical clinical application of predictive factors in prostate cancer. A review with an emphasis on quantitative methods in tissue specimens. 980 50


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