Showing papers on "Biomarker (medicine) published in 1997"

Use of fluorescence in situ hybridization (FISH) to assess effects of smoking, caffeine, and alcohol on aneuploidy load in sperm of healthy men.

Abstract: Aneuploidy is a common cause of poor reproductive outcomes in humans and is associated with severe medical problems in liveborn offspring, yet little is known about its underlying cause A substantial amount of aneuploidy is known to be contributed by the father through cytogenetically abnormal sperm The purpose of this cross-sectional, observational study was to investigate the potential contribution of common lifestyle exposures (smoking, caffeine, and alcohol) to the aneuploidy load in sperm from 45 healthy male volunteers 19-35 years of age Sperm FISH (fluorescence in situ hybridization) was used to determine aneuploidy and diploidy frequencies for chromosomes X, Y and 18 across varying exposure levels of smoking, caffeine, and alcohol Caffeine was significantly associated with increased frequencies of sperm aneuploidy XX18 and XY18, diploidy XY18-18 and the duplication phenotype YY18-18 controlling for alcohol, smoking and donor age Alcohol was significantly associated with increased frequencies of sperm aneuploidy XX18, diploidy XY18-18 and the duplication phenotype XX18-18 controlling for caffeine, smoking and donor age There was a suggestive, but unstable, association between smoking and XX18 Even within our truncated age range, we were able to confirm an increased risk for XX18 aneuploidy with increasing donor age Sperm FISH proved to be a useful biomarker to detect and compare numerical cytogenetic abnormalities in human sperm cells across differing levels of exposure to smoking, caffeine, and alcohol

Cardiac troponin T is a sensitive, specific biomarker of cardiac injury in laboratory animals.

Abstract: A reliable serum assay that can discriminate between cardiac and skeletal muscle injury is not available for diagnostic use in laboratory animals. We tested and supported the hypotheses that serum cardiac troponin T (cTnT) was widely applicable in laboratory animals as a biomarker of cardiac injury arising from various causes; that it increased in proportion to severity of cardiac injury; and that it was more cardiospecific than creatine kinase (CK) or lactate dehydrogenase (LD) isozyme activities. In canine and rat models of myocardial infarction, cTnT concentration increased 1,000- to 10,000-fold and was highly correlated with infarct size within 3 h of injury. Serum CK and LD isozymes were substantially less effective biomarkers and, in contrast to cTnT, were ineffective markers in the presence of moderate skeletal muscle injury, with resulting serum CK activity > 5,000 U/L. Using these animal models, and mouse and ferret models, we also showed cTnT to be an effective biomarker in doxorubicin cardiotoxicosis, traumatic injury, ischemia, and cardiac puncture. Reference range serum concentrations for all species were at the detection limit of the assay, except those for mice, in which they were slightly increased, possibly because mice were used to generate assay monoclonal antibodies. We conclude that cTnT is a powerful biomarker in laboratory animals for the sensitive and specific detection of cardiac injury arising from various causes.

Prognostic Value of Specific KRAS Mutations in Lung Adenocarcinomas

Abstract: Adenocarcinomas of the lung remain a significant public health problem. Locally defined (stage I) tumors are considered amenable to resection with curative intent. However, only about 45% of these patients survive for 5 years. The median survival for more advanced tumors is drastically lower. Much research has been focused on identifying a valid genetic biomarker of prognosis. Mutations of the proto-oncogene KRAS have been identified by some groups as being a valid prognostic indicator for adenocarcinoma of the lung. To evaluate the effect of KRAS gene mutation on the survival of patients with lung adenocarcinoma, 181 archival tumors were examined by PCR and denaturing gradient gel electrophoresis. Mutations in either codon 12 or 13 were found in 31.5% of the samples. The most common mutation was a G-->T transversion in codon 12, representing 66.7% of the mutations. No difference was observed in the survival of patients with a KRAS mutation versus those whose tumors contained wild-type KRAS. This lack of difference was also observed when the analysis was restricted to those with stage I tumors or when patients with stage I or II disease were grouped together. However, certain amino acid substitutions, including cysteine, arginine, and aspartate, indicated a significantly poorer prognosis, whereas hydrophobic amino acid substitutions showed a significantly better prognosis than wild-type (P = 0.04). Sample sizes were small for this analysis due to the number of possible mutations. As expected, the stage of tumor at resection was the most significant predictor of outcome. Based on this study of 181 patients from two major medical centers located in different cities, we conclude that KRAS mutation status is not a satisfactory predictor of prognosis in lung adenocarcinoma, but the substitution of a polar or charged amino acid for the wild-type glycine residue may be a negative prognostic indicator.

c‐erbB‐2 oncoprotein: A potential biomarker of advanced prostate cancer

Abstract: BACKGROUND Overexpression of the c-erbB-2 oncogene has been implicated in the development and/or prognosis of several human carcinomas, including that of the prostate. Recently, c-erbB-2 protein was found to be released in the circulation. The present study was undertaken to study the significance of serum c-erbB-2 protein determination in men with prostate cancer. METHODS Serum c-erbB-2 protein determination was performed via immunoradiometric assay using two monoclonal antibodies that react with the extracellular domain of the protein. The study population consisted of 71 untreated prostate cancer patients. Of those, 33 with stage D2 disease entered a follow-up study. As control, serum c-erbB-2 protein levels were determined in 92 patients with benign prostatic hypertrophy. In addition, elevations of c-erbB-2 protein were examined in patients with various disease statuses: clinically well controlled (28 patients), disease progression (24 patients), and end-stage disease (17 patients). RESULTS Elevation of serum c-erbB-2 protein level was observed in patients in advanced stages, such as stage D2 disease (30%), disease progression (42%), and end-stage disease (82.4%). In the follow-up study, patients with an elevated c-erbB-2 level had a significantly shorter interval to disease progression than did those with a normal level. CONCLUSIONS The results suggest that c-erbB-2 can be used as a biomarker to identify a malignant subgroup in prostate cancer. Prostate 30:195–201, 1997. © 1997 Wiley-Liss, Inc.

Prognostic Value of Specific KRAS Mutations in Lung

Abstract: Adenocarcinomas of the lung remain a significant public health problem. Locally defined (stage I) tumors are considered amenable to resection with curative intent. However, only about 45% of these patients survive for S years. The median survival for more advanced tumors is drastically lower. Much research has been focusedon identifying a valid genetic biomarker of prognosis. Mutations of the proto-oncogene KRAS have been identified by some groups as being a valid prognostic indicator for adenocarcinoma of the lung. To evaluate the effect of KRAS gene mutation on the survival of patients with lung adenocarcinoma, 181 archival tumors were examined by PCR and denaturing gradient gel ebectrophoresis. Mutations in either codon 12 or 13 were found in 31.5% of the samples. The most common mutation was a G-*T transversion in codon 12, representing 66.7% of the mutations. No difference was observed in the survival of patients with a

Breast cytology and biomarkers obtained by random fine needle aspiration: Use in risk assessment and early chemoprevention trials

Abstract: In a prospective pilot study, we performed breast fine needle aspirations (FNAs) on 224 high-risk and 30 low-risk women and analyzed these aspirates for cytologic changes and biomarker abnormalities of aneuploidy and overexpressed estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53 and HER-2/neu. High-risk women had a first-degree relative with breast cancer (74%), prior biopsy indicating premalignant breast disease (25%), a history of breast cancer (13%), or some multiple of these risk factors (12%). Median ages of the high- and low-risk groups were 44 and 42, respectively. Seventy percent of high-risk and 17% of low-risk women had cytologic evidence of hyperplasia with or without atypia (P<. 0001). Aneuploidy and overexpression of EGFR and p53 occurred in 27, 37, and 29% of high-risk subjects but only 0, 3, and 3% of low-risk subjects (P<. 0023). Overexpression of ER and HER-2/neu occurred in 7 and 20% of high-risk women but in none of the low-risk subjects. Biomarker abnormalities were more frequent with increasing cytologic abnormality. Restricting the analysis to those 3 biomarkers most frequently overexpressed in the high-risk group (ploidy, EGFR, p53), 13% of high-risk women with normal cytology, 19% of high-risk women with epithelial hyperplasia, and 49% of high-risk women with hyperplasia with atypia had abnormalities of 2 or more of these 3 biomarkers (P =. 00004). At a median follow-up of 32 months, four women have been diagnosed with invasive cancer and two with ductal carcinomain situ (DCIS). Later detection of these neoplastic conditions was associated (P ≤. 016) by univariate analysis with prior FNA evidence of hyperplasia with atypia; overexpression of p53 and EGFR; the modified Gail risk of breast cancer development at 10 years; and multiple biomarker abnormalities. By multivariate analysis, later detection of cancer was primarily predicted by the number of biomarker abnormalities in the 3-test battery (P=. 0005) and secondarily by the Gail risk at 10 years (P =. 0049). In turn, hyperplasia with atypia was associated with multiple biomarker abnormalities, particularly p53 and EGFR overexpression. Thus, hyperplasia with atypia and cytologic markers in breast FNAs have promise as risk predictors and as surrogate endpoint biomarkers for breast cancer chemoprevention trials. J. Cell. Biochem. Suppls. 28/29:101–110. Published 1998 Wiley-Liss, Inc.

Changes in Biomarker Expression in the Development of Prostatic Adenocarcinoma

Abstract: In spite of the prevalence of prostatic adenocarcinoma, the development and natural history of this malignancy is poorly understood. This paper reviews the current knowledge of biomarker expression during the development and progression of prostatic adenocarcinoma. Emphasis is placed on the comparison of biomarker expression in benign prostatic epithelium, intraepithelial neoplasia (PIN), a putative preinvasive lesion, and prostatic adenocarcinoma. Within the benign epithelium, the proliferative potential is restricted to the basal cells as demonstrated by the expression of proliferating cellular nuclear antigen (PCNA). The strong expression of the bcl-2 protein, an inhibitor of apoptosis, supports the concept that the basal cells or a subpopulation of the basal cells represent the stem cell of the epithelium. In addition, the strong expression of growth factor receptors such as the epidermal growth factor receptor (EGFr), p185erbB-2, p180erbB-3, and c-met suggests that the growth of the basal cells is re...

Angiogenesis in ovarian carcinoma: a formidable biomarker.

Abstract: Epithelial ovarian carcinoma is the fourth leading cause of cancer death in women. Although there has been progress in its treatment with the earlier development of the platinums and the more recent addition of paclitaxel to the therapeutic armamentarium, recurrence is frequent and long term survival continues to be poor for patients with advanced stage disease. Advances in scientific and clinical investigation into the molecular and cellular biology of epithelial ovarian carcinoma have led to new biomarkers to identify those patients at high risk for recurrence and death. The article by Schoell et al. in this issue of Cancer uses a uniquely matched cohort of advanced stage patients, differing only in documented disease free survival, to demonstrate an independent role for neovascularization in patients with a poor prognosis. This leads to the question of how best to incorporate molecular markers into diagnostic, therapeutic, and prognostic parameters. Current categories of molecular markers include assessment of gene expression, gene function, and biologic parameters. A biologic rationale is important in the identification of new biomarkers for prognostication and treatment planning. Incumbent in the use and development of these molecular markers is the development of reliable, sensitive, specific, accurate, and reproducible assay systems that can be used readily. Finally, once the assay of choice has been validated, the clinical utility of the biomarker should be demonstrated prospectively. The role of angiogenesis as a biomarker target in cancer was defined through identification of a relationship between neovascularization and patient outcome. The most common assay test used is the quantitation of microvessel number or mass in the form of microvessel area. This has been shown by retrospective analysis of human cancer cohorts to be significant in a wide variety of cancers since its earliest preclinical reports. A variety of potential angiogenesis See referenced original article on pages 2257– 62, this issue. biomarkers have been disclosed to date. Those reported include semiquantitative measurements of numbers and areas of immunohistoAddress for reprints: Elise C. Kohn, M.D., Labochemically highlighted tumor neovessels, molecular expression of ratory of Pathology, National Cancer Institute, angiogenic cytokines such as vascular endothelial growth factor and/ 10 Center Drive, MSC 1500, Room 2A33, or their receptors (for example), measurement of circulating or exBethesda, MD 20892. creted vascular cytokines, and functional or molecular expression of proteins involved in neovessel formation, such as matrix-degrading Received September 18, 1997; accepted September 24, 1997. enzymes critical for capillary sprout formation. Despite these ad-

Effects of biomarker measurement error on epidemiological studies

Abstract: This chapter presents an overview of how measurement error in a biomarker affects epidemiological studies which use the biomarker. To estimate the effects of biomarker error, one must first measure the error using an appropriate validity or reliability study design and using appropriate parameters, i.e. parameters that are informative about the effects of measurement error on the 'parent' epidemiological study. These measures of the biomarker measurement error from the validity or reliability study can then be applied to what is known about the association under study in the parent study, in order to estimate the effects of the biomarker error on the results of the epidemiological study.

Biomarkers of gene expression: growth factors and oncoproteins.

Abstract: This article reviews the literature on the application of methods for the detection of growth factors, oncogene proteins, and tumor-suppressor gene proteins in the blood of humans with cancer or who are at risk for the development of cancer. The research summarized here suggests that many of these biomarker assays can be used to distinguish between diseased and nondiseased states and in some instances may be able to predict susceptibility for future disease. Thus, these biomarkers could be valuable tools for monitoring at-risk populations for purposes of disease prevention and control.

The use of biological markers as predictive early-outcome measures in epidemiological research.

Abstract: One of the possible uses of biomarkers in epidemiological research is as early-outcome measures to predict the occurrence of clinical disease and to elucidate the biological mechanism of pathogenesis. This use is conceptually less straightforward than the well established use of biomarkers to improve or extend exposure assessment or to study interindividual variations in disease susceptibility. In principle, this form of use could accelerate or otherwise facilitate etiological research. However, in practice, the recent review literature suggests that this mode of biomarker use, especially in cancer epidemiology, is the least clear-cut and the least well developed. The recurrent problem is identifying biomarkers that: (1) are on the causal pathway, (2) have a high probability of progression to clinical disease, and (3) account for all or most of the cases of the specified clinical outcome. Such biomarkers would be most useful if they conferred a long lead-time relative to clinical disease occurrence.

Acetylation as an indicator of risk.

Abstract: Aromatic amine acetylation has been recognized for many years as an important metabolic polymorphism in humans because of its relationship to disease. This system serves as a model in risk assessment because of its role in drug and carcinogen activation and detoxification and because of the case with which it is measured. However, possible interactions of NAT1-NAT2 phenotypes or genotypes illustrate the complexity of xenobiotic metabolism pathways. Moreover, the use of such information for risk assessment is further complicated by the association of the rapid phenotype with increased risk in colon cancer and the slow phenotype with increased risk in urinary bladder cancer. Before this biomarker can be effectively utilized as a significant predictor of individual risk, it will be necessary to identify specific sources of aromatic amine exposure and to characterize further the substrate specificity of NAT1 and NAT2 in relation to the multiplicity of enzyme variants occurring in human populations.

Prohibitin: A New Biomarker for Breast Tumors

Abstract: Prohibitin is an evolutionarily conserved protein that is significantly overexpressed in cell lines derived from breast tumors. In this study, prohibitin expression was analyzed in normal tissue and compared to specimens from patients diagnosed with various stages of breast disease: hy-perplasia, atypical hyperplasia, carcinoma in situ, and invasive carcinoma. Prohibitin expression in both epithelial and stromal elements increases with the severity of the disease state, progressing from low levels in normal tissue to three- to fivefold elevation in patients with invasive carcinoma. These results parallel those previously obtained with in vitro model systems and show that prohibitin expression is a biomarker for breast cancer.

Biomarkers Predictive of Short-Interval Breast Cancer Development in High-Risk Women

Abstract: Biomarkers highly predictive of short-term risk of breast cancer are needed to identify women most likely to benefit from prophylactic measures or chemopreventive agents. We have utilized random fine-needle aspiration (FNA) of breast ductal tissue because FNA is minimally traumatic, allowing aspiration to easily be repeated at follow-up intervals of months to years. We performed breast FNA on 213 women at high risk and 30 women at low risk for breast cancer. High-risk women were those with a first-degree relative with breast cancer, prior breast biopsy indicating atypical hyperplasia or carcinoma in situ, a history of prior breast cancer, or some multiple of these factors. Aspirates were analyzed for cytologic changes and biomarker abnormalities of DNA aneu-ploidy and overexpression of estrogen receptor (ER), epidermal growth factor receptor (EGFR), p53, and HER-2Ineu. Cytologic evidence of hyperplasia with or without atypia as well as individual or multiple biomarker abnormalities were more frequent in the high-risk than the low-risk group. At a median follow-up of 32 months, five women have been diagnosed with ductal carcinoma in situ (2) or invasive cancer (3). By multivariate analysis, development of cancer, detection of cancer, or both was primarily predicted by atypical hyperplasia and secondarily by Gail risk at 10 years, menopausal status, and p53 overexpression. The combination of atypical hyperplasia and multiple biomarker abnormalities (restricted to the three-marker set of ploidy, p53, and EGFR) was observed in four of the five cases of cancer. Cytology and biomarker expression in cells obtained from random FNA sampling of breast tissue are being explored as risk predictors as well as surrogate response biomarkers for phase II cancer chemoprevention trials.

Markers of internal dose: chemical agents.

Abstract: Biomarkers of internal dose measure the level of a carcinogen or one of its metabolites in a tissue or a body fluid such as urine or blood. The choice of a biomarker of internal dose for a particular epidemiological study or type of study requires careful consideration of the period of exposure to which the biomarker relates, host factors related to carcinogen metabolism, invasiveness of sampling, reliability and cost of the biomarker. Before a new biomarker is adopted, it is important to assess these characteristics in transitional studies to ensure that the biomarker will be applied appropriately. Biomarkers of internal dose have been applied most successfully in ecological studies and nested case-control studies, and are especially useful when they provide information about long-term carcinogen exposure.

Serum free beta-hCG, a biomarker for bladder carcinoma patients?

Abstract: The free B subunit of hCG (free B-hCG) may be of importance as an indicator of tumor growth, not only in trophoblastic tumors or those of germ cell origin, but in a wide range of solid tumors (1). Marcillac et al (2, 3), using a modified C.I.S. method to determine the free ~­ hCG, reported that in 29 selected bladder cancer patients having a free B-hCG of> 100 pg/ml, the levels of the hormone decrease in case of regression and increase in case of progression of the disease. In this subgroup of patients serum free B-hCG was interpreted as a reliable tumor marker for follow-up of bladder cancer. Mora et al (4) reported a diagnostic sensitivity of free BhCG, using the C.A.C. method, in 72.7% of the patients. All these patients had deeply infiltrating bladder tumors, stage T2 or deeper. Also other studies, reviewed by Iles (5), revealed the possibility of serum free B-hCG as a marker of poor prognosis in patients having bladder cancer. We examined pre-operatively the free B-hCG in serum of 20 consecutive patients who consulted our hospital. The diagnosis was confirmed histopathologically. From 2 patients the specimen, removed by transurethral resection, was diagnosed as non-malignant (TOGO). The remaining 18 patients all showed transitional cell carcinoma (TCC) and were staged as non-infiltrating (Ta) in