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Results for “Biomarker variability”

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PubMed2006

Interobserver variability in histologic recognition, interpretation of KIT immunostaining, and determining MIB-1 labeling indices in gastrointestinal stromal tumors and other spindle cell tumors of the gastrointestinal tract.

The authors studied the concordance among seven pathologists for the histologic diagnosis, interpretation of KIT immunostaining, and determining MIB-1 labeling indices (LI) in 80 adult patients with primary spindle cell tumors, mainly of the gastrointestinal tract, mesentery, retroperitoneum, and pelvis, based on the review of tissue sections using an immunohistochemical panel of antibodies for KIT/CD117, CD34, desmin, smooth muscle actin (SMA), and S-100 protein. Tumors included 30 gastrointestinal stromal tumors (GISTs), 10 leiomyomas, 10 leiomyosarcomas, 10 schwannomas, 10 solitary fibrous tumors, and 10 desmoid-type fibromatoses. The overall concordance with the original diagnosis of each histologic type was 97.9%, the kappa value ranging from 0.95 to 1.00 (mean 0.97), indicating a perfect agreement. The overall interlaboratory concordance with the original interpretation of KIT immunostaining was 91.3%, the kappa value ranging from 0.77 to 0.90 (mean 0.86). The overall interlaboratory concordance with the original interpretation of KIT immunostaining was 91.9%, the kappa value ranging from 0.72 to 0.93 (mean 0.85). The overall concordance for determining MIB-1 LI was 90% with the original evaluation, and the overall kappa value ranged from 0.62 to 0.86 (mean 0.77). These results indicate that it is possible to reliably diagnose GIST and other spindle cell tumors of the gastrointestinal tract with the use of an immunohistochemical panel of antibodies for KIT, CD34, desmin, SMA, and S-100 protein. Although there is clearly unavoidable inter-observer and interlaboratory variability in the interpretation of KIT immunostained sections and interobserver variability in the determination of MIB-1 LI, the concordance between observes is very acceptable, and in most instances such variability can be eliminated by careful reviewing of the hematoxylin and eosin and immunostained sections.

Adult↗

PubMed2006

Are serum adiponectin concentrations in a population sample of 64-year-old Caucasian women with varying glucose tolerance associated with ultrasound-assessed atherosclerosis?

OBJECTIVE: To examine whether serum adiponectin concentrations were associated with subclinical atherosclerosis assessed as intima media thickness (IMT) in the carotid arteries in Caucasian women with varying degrees of glucose tolerance. RESEARCH DESIGN AND METHODS: From a population-based cohort of 64-year-old Swedish women, 533 subjects with type 2 diabetes (DM2, n=177), impaired glucose tolerance (IGT; n=178) or normal glucose tolerance (NGT, n=178) were recruited. Anthropometrics, usual cardiovascular risk factors were examined and ultrasound examination of the carotid arteries was performed. RESULTS: Women with low adiponectin concentrations were characterized by thick IMT, higher prevalence of DM2, history of previous myocardial infarction, angina pectoris, anti-hypertensive treatment and high body mass index (BMI), waist circumference, plasma insulin, serum triglycerides, fasting glucose, HbA1c, and low serum HDL cholesterol levels. Carotid IMT correlated with HbA1c (r=0.24, P<0.001), waist circumference (r=0.22, P<0.001), plasma insulin (r=0.19, P<0.001), BMI (r=0.18, P<0.001), DM2 (r=0.16, P<0.001), systolic blood pressure (r=0.16, P<0.001), blood glucose (r=0.16, P<0.001), triglycerides (r=0.15, P<0.001), and reversely to adiponectin (r=-0.11, P=0.01), HDL cholesterol (r=-0.13, P=0.004), and alcohol intake (r=-0.087, P<0.05). A more detailed analysis of underlying associations was difficult due to a high co-linearity between these variable. CONCLUSIONS: Low serum adiponectin concentrations were associated with increased carotid artery IMT, and several risk factors for cardiovascular diseases, mainly those constituting the metabolic syndrome.

Adiponectin↗

PubMed2004

Albuminuria as a surrogate marker for drug development: a European Regulatory perspective.

Clinical trials with surrogate end points generally require smaller sample sizes and shorter duration than those with clinical outcomes. However, in practice, surrogate end points are likely to result in less comprehensive conclusions than 'outcome' end points as they sometimes reflect only partial aspects of complex phenomena. A number of conditions help to establish the validity of a particular variable as predictive of clinical outcome. This article discusses to what extent albuminuria fulfills these requisites in two particular clinical scenarios: prevention of renal deterioration and prevention of cardiovascular disease.

Albuminuria↗

PubMed1995

Neurochemical markers in human cutaneous Merkel cells. An immunohistochemical investigation.

Merkel cells (MCs) are specialized sensory cells widely distributed in the epithelia of vertebrates. A variable immunohistochemical pattern of neuronal and neurotransmitter markers has been demonstrated in MCs of several species including man. In the present study, we investigated the expression of neurochemical markers in a selected population of human cutaneous MCs by immunofluorescence. The structural neural proteins protein gene product 9.5 and neuron-specific enolase were found to be the most reliable markers for MC identification. Moreover, neurofilament immunoreactivity was shown in a small subset of epidermal MCs. Among the neurotransmitter markers, evidence for expression of calcitonin gene-related peptide, vasoactive intestinal polypeptide, peptide histidine isoleucine amide, neuropeptide Y, neurokinin A, galanin, substance P, somatostatin and phenylethanolamine N-methyltransferase was found. These immunoreactivities were highly variable as far as number of positive cells and staining intensity were concerned. The results indicate that a complex and heterogeneous immunophenotype can be expressed even within a homogeneous population of human MCs.

Adult↗

PubMed1989

Tumor markers in serum of patients with primary squamous cell carcinoma of the esophagus.

Serum levels of several tumor markers were studied in 96 patients with untreated primary squamous cell carcinoma of the esophagus. Three markers specific for digestive tract malignancies--CEA, CA19.9 and CA50--and two non organ specific indicators of malignancy--ferritin and TPA--were evaluated. Positivity rates of CA19.9 and CA50 were very low (4.4% and 8.6% respectively); the markers were therefore considered ineffective in the disease. CEA, TPA and ferritin showed a fair positivity rate (27.1%, 28.1%, 33.7% respectively); CEA and TPA were directly related to clinical stage, CEA levels being significantly higher in stage IV than in stage III cases (p = 0.016). TPA preoperatory levels were also directly related to a lower survival probability (p = 0.004). CEA showed significantly lower levels in tumors of lower than in those of middle (p = 0.03) and upper esophagus (p = 0.004). TPA showed a similar behaviour with lower levels in tumors of lower than of middle esophagus (p = 0.03). These findings could be due to a bulky metabolism of tumor markers drained via portail vein in the liver. From our data the following conclusions may be drawn: 1) CEA and TPA may be useful in the staging of esophageal cancer as an ancillary tool to assess the extent of the disease; 2) tumor location is an important variable when evaluating blood levels of tumor markers in patients with esophageal cancer.

Adult↗

PubMed1998

Immunohistochemical detection of Ki-67 and PCNA in canine mammary tumors: relationship to clinical and pathologic variables.

The objectives of this study were to measure the proliferation indices in canine mammary tumors using immunohistochemical detection of Ki-67 and proliferating cell nuclear antigen (PCNA), to determine the relationship of these antigens to clinical and pathologic variables, and to investigate the usefulness of these antigens as prognostic indicators. Ninety-six female dogs with 115 primary nonmetastasized spontaneous mammary tumors and dysplasias were included in the study. Immunostaining was performed using MIB-1 and PC10 monoclonal antibodies against Ki-67 and PCNA, respectively. Ki-67 and PCNA proliferation indices were determined. Dogs were followed for 18 months, with clinical examinations every 3-4 months. There was a significant correlation between Ki-67 and PCNA indices in the dogs with dysplasias and benign tumors but not in the dogs with malignant tumors. The clinical stage at first presentation was related to the proliferative index measured with Ki-67 but not to that measured with PCNA. Proliferation indices were significantly lower in the nonmalignant tumors and dysplasias than in the malignant tumors. In malignant tumors, the PCNA index had a positive correlation with the histologic malignant grade and the nuclear grade. High index values of Ki-67 were positively correlated with metastasis, death from neoplasia, low disease-free survival rates, and low overall survival rates. PCNA displayed no significant association with these variables. Multivariate analyses concerning metastasis, disease-free survival, and overall survival revealed that the Ki-67 index had prognostic value.

Animals↗

PubMed1994

Serum tumor marker half-life during chemotherapy in patients with germ cell tumors.

Approximately 80% of previously untreated men with metastatic germ cell tumors will be cured with cisplatin-based chemotherapy. Serum levels of alpha fetoprotein (AFP) or human chorionic gonadotropin (HCG) or both are increased in most of these patients. Pre-treatment clinical characteristics can be used to distinguish between "good" and "poor" risk patients who are either highly likely or unlikely to achieve a complete remission, respectively. A slow rate of decline of either AFP or HCG or both has been associated with an inferior survival in both good and poor risk patients. In multivariate analysis, the pre-treatment risk status and the post-treatment clearance of markers were independent and equal prognostic variables. Similarly, in patients receiving cisplatin+ifosfamide-based salvage chemotherapy, the rate of decline of HCG was an independent predictor variable in addition to the primary site and pre-treatment HCG levels for both overall and event-free survival. Prolonged half-life clearance of serum tumor markers is an important prognostic variable in both previously untreated as well as previously treated germ cel tumor patients. Treatment strategies can be based on marker clearance and prospective clinical trials are warranted.

Antineoplastic Combined Chemotherapy Protocols↗

PubMed2003

Use of plasma brain natriuretic peptide concentration to aid in the diagnosis of heart failure.

Plasma concentration of brain natriuretic peptide (BNP), as measured by the Triage BNP Test, is approved by the Food and Drug Administration to aid in the diagnosis of heart failure. This diagnostic test is available in many institutions. The purpose of this article is to help the physician know the appropriate time to order this test and to aid in interpreting results. To achieve this goal, we review the physiology of BNP, clinical studies that support its use for diagnosing heart failure, and confounding variables to consider when BNP is being used clinically. We show that the BNP test can be extremely helpful when used in the correct clinical setting.

Biomarkers↗

PubMedDate not supplied

Cost-effectiveness of cardiac troponin I in a systematic chest pain evaluation protocol: use of cardiac troponin I lowers length of stay for low-risk cardiac patients.

We evaluated several measures of clinical and fiscal interest to assess the effect of adding an automated cardiac troponin I (c-TnI) assay to our current cardiac panel, which consists of creatine kinase MB (CK-MB), myoglobin, total CK activity, and a calculated CK-MB relative index. Samples were collected on admission and at 3, 6, and 8 hours after admission as part of our diagnostic protocol. Our study was designed to collect data on a control group of patients, implement a change (i.e., c-TnI testing), and then measure the effect of the change on a test population having otherwise equivalent diagnostic and therapeutic pathways. We assessed differences in patient hospital and cardiac care unit length of stay (LOS), time to cardiac catheterization, and hospital and laboratory charges and costs. We found that adding c-TnI to our testing regimen decreased LOS for the large test population. Within this large test population, patients classified as low risk for acute myocardial infarction experienced statistically and clinically significant shorter LOS and lower total and variable hospital costs; for patients with unstable angina, there was an increase (though not statistically significant) in laboratory costs.

Adult↗

PubMed2000

Comparison of the metastasis-inducing protein S100A4 (p9ka) with other prognostic markers in human breast cancer.

Our aim was to compare the occurrence and prognostic significance over 14-20 years of immunocytochemically detected S100A4 and other tumour variables in primary tumours from 349 patients with operable breast cancer. For a cut-off of 1% staining of the malignant cells, the antibody to S100A4 stains positively 56% of the carcinomas. There was a significant association of staining for S100A4 with tumours fixed to the chest wall, staining for c-erbB-2, c-erbB-3, pS2, cathepsin D and, inversely, at borderline levels with staining for estrogen receptor. Using Wilcoxon statistics in univariate analyses, staining for S100A4, nodal status, tumour class, histological grade and staining for c-erbB-2, p53 were associated negatively and staining for estrogen receptor, progesterone receptor were associated positively with patient survival times. The survival times of patients with S100A4-negative carcinomas with or without one of the other tumour variables showed no significant differences, whilst those of patients with S100A4-positive carcinomas showed significant differences in a negative or a positive way. Multivariate regression analysis for 137 patients showed that staining for S100A4 is most highly correlated with patient deaths, but involved lymph nodes, fixed tumours, high histological grade and staining for progesterone receptor were also significant independent prognostic variables. Our results suggest that in this set of patients, the tumour variable most tightly correlated with patient death is S100A4.

Adult↗

PubMed2000

[Breast cancer: prognostic value of a dissemination index based on 4 components of the urokinase-type plasminogen activator system].

Among the proteases involved in the tumor invasion process, components of the plasminogen activator system (plasminogen activator type-urokinase uPA, its membrane receptor uPAR and its two inhibitors PAI-1 and PAI-2) appear to define high risk patients in primary breast cancer. As individual analysis of each component of the plasminogen activator system does not reflect the complex interactions between the different components, we studied the prognostic impact of a dissemination risk index combining the four variables. We found that this index was the most powerful prognostic factor, particularly in node-negative patients.

Adult↗

PubMed2003

Polymorphisms for vinyl chloride metabolism in French vinyl chloride workers.

Genetic polymorphisms of aldehyde dehydrogenase 2 (ALDH2) and cytochrome P450 2E1 (CYP2E1) have been shown to influence the degree of genetic damage in Taiwanese workers exposed to the carcinogen - vinyl chloride(VC). Certain French VC workers have been found to express biomarkers of mutant forms of cancer-related proteins (ras-p21 and p53) that have been related to their exposure. ALDH2 and CYP2E1 polymorphisms were investigated in 211 of these workers in an attempt to correlate differences in VC metabolic capacity with differences in the presence of these biomarkers. All of the workers were found to have the normal, wild-type ALDH2 gene, and none of them were found to be homozygous for the variant CYP2E1 allele. Sixteen workers were found to be heterozygous for the variant CYP2E1 allele. After adjusting for age, smoking, drinking and cumulative VC exposure, the odds ratio for the presence of either the mutant ras-p21 or the mutant p53 biomarker in these heterozygous workers was found to be statistically significantly increased in comparison to their homozygous, wild-type counterparts (OR = 5.05; 95% CI = 1.10-23.25). However, as opposed to the case in Taiwanese workers, these polymorphisms are relatively uncommon, and thus differences in ALDH2 and CYP2E1 can account for only a small proportion of the variability in mutagenic response to VC exposure in a Caucasian population.

Adult↗

PubMed1990

Proliferation markers Ki-67 and p105 in soft-tissue lesions. Correlation with DNA flow cytometric characteristics.

Frozen tissue immunoreactivity with Ki-67, a monoclonal antibody that recognizes a nuclear antigen in nonresting or proliferating cells, was compared to DNA flow cytometry results (from fresh tissue) in a diverse group of 60 soft-tissue lesions. Both DNA index and Ki-67 score were independently reported to be associated with grade and prognosis in sarcomas, but no direct comparison of these two variables was made. It was attempted to measure proliferative activity in fixed paraffin-embedded tissues immunohistochemically in a subset of lesions using an antibody to another nuclear proliferation antigen, p105. Lesions were given a grade according to lesion category (reactive, 1; benign, 2; low-grade malignant, 3; and high-grade malignant, 4). Ki-67 reactivity correlated relatively well with this grading system (r = 0.59); benign lesions usually exhibited a low Ki-67 score and malignant lesions usually but not always exhibited a high score. For example, some malignant fibrous histiocytomas contained only rare positive cells. Some disparity between Ki-67 score and grade and within histologic types indicates some independence from these features, a fact that may be important when correlation with prognosis is performed. However Ki-67 did not correlate well with flow data such as percentage S phase (r = 0.30), percentage S + G2M phases (r = 0.37), or DNA index (r = 0.39). This probably is due to the fact that Ki-67 also marks cells in the G1 phase, whereas these are excluded in flow data analyses. Anti-p105 highlighted almost all nuclei in all cases tested, including fibromatosis, and did not correlate with Ki-67 score, histologic grade or DNA flow cytometric data. Results with p105 could not be favorably affected by titration experiments. It is reasonable to conclude that the Ki-67 score is a variable related to but independent of histologic grade, histologic type, and DNA flow values. Whether it is prognostically important in human sarcomas, as has been suggested, awaits further clinicopathologic study.

Antigens, Surface↗

PubMed1996

Cellular sociology of proliferating tumor cells in invasive ductal breast cancer.

OBJECTIVE: The topology of proliferating cells in tissue sections of breast cancers was studied as the static expression of the cellular sociology of distinct subpopulations of tumor cells. With the terms neighborhood and connectivity, an attempt was made to describe the mutual interrelations of cycling tumor cells objectively in different prognostic subgroups of invasive ductal breast carcinomas. STUDY DESIGN: For these studies the spatial distribution of Ki-67 (Mib1)-positive tumor cells was investigated by means of Voronoi tesselation, minimum spanning tree techniques, cluster analysis and second-order stereology in a series of 80 breast tumors. Thirty-nine basic features were used for describing the topology of tumor cells with different degrees of Mib-1 reactivity. RESULTS: Multivariate analyses demonstrated different proliferation patterns associated with tumor size, nodal status, histopathologic grade, DNA ploidy and flow cytometric proliferation variables. CONCLUSION: Independent of the spatial organization of the tumor cells, their tissue pattern of proliferation activity correlated with the tumor properties.

Antigens, Nuclear↗

PubMed2005

Variability of serum levels of tumor necrosis factor-alpha, interleukin 6, and soluble interleukin 6 receptor over 2 years in young women.

Serum levels of tumor necrosis factor-alpha (TNF-alpha), interleukin 6 (IL-6), and soluble interleukin 6 receptor (sIL-6R) have been studied as risk factors of cardiovascular disease in longitudinal studies. However, it is unknown about their long-term intra-individual variations and whether single measurements of these cytokines and receptor are reliable biomarkers in epidemiological studies. In this study, serum levels of TNF-alpha, IL-6, and sIL-6R were assayed by ELISAs in 36 young, healthy women from whom three blood samples were collected at 12-month intervals over 2 years, and the intraclass correlation coefficients (ICC) were estimated. The ICC of 0.73 (95% CI=0.49-0.79) for TNF-alpha was comparable to those of other commonly used biomarkers, justifying its use in epidemiological studies. The ICC of 0.48 (95% CI=0.25-0.58) for IL-6 was not optimal. However, IL-6 has been demonstrated as a consistent risk factor for cardiovascular disease, suggesting it could still be a useful biomarker if its disease association is substantial. The ICC of 0.36 (95% CI=0.10-0.47) for sIL-6R was relatively low, and multiple samples would need to be collected in prospective studies for this receptor.

Adolescent↗

PubMed2002

The erythrocyte adhesiveness/aggregation test (EAAT). A new biomarker to reveal the presence of low grade subclinical smoldering inflammation in individuals with atherosclerotic risk factors.

BACKGROUND: Multiple acute phase proteins and atherosclerotic risk factors increase the aggregability of erythrocytes. METHODS AND RESULTS: We used a simple slide test and image analysis to determine the degree of erythrocyte adhesiveness/aggregation in the peripheral blood of 222 women and 221 men with no, one, two or more atherosclerotic risk factors. The degree of erythrocyte adhesiveness/aggregation correlated significantly with the concentration of commonly used variables of the acute phase response. We also showed that individuals with low erythrocyte adhesiveness/aggregation tend to be younger and to have fewer risk factors for atherosclerosis, including diabetes mellitus, hypertension, hyperlipidemia and smoking. CONCLUSIONS: The association between increased erythrocyte adhesiveness/aggregation, higher concentrations of acute phase proteins, and increased atherosclerotic risk factors points to a possible clinical applicability of the erythrocyte adhesiveness/aggregation test (EAAT) to reveal the presence of both low-grade subclinical smoldering inflammation and morbid biology in individuals with risk factors for atherosclerosis.

Adult↗

PubMed2005

Influence of hOGG1, XRCC1 and XRCC3 genotypes on biomarkers of genotoxicity in workers exposed to cobalt or hard metal dusts.

Identification of genetic polymorphisms responsible for reduced DNA repair capacity may allow better cancer prevention. We examined whether variations in genes involved in base-excision (hOGG1, XRCC1) and double strand break (XRCC3) DNA repair contribute to inter-individual differences in genotoxic effects induced in the lymphocytes of 21 cobalt (Co) exposed, 26 hard metal (WC-Co) exposed and 26 matched control male workers. Genotyping was performed by PCR-RFLP. DNA single strand breaks and alkali-labile sites were measured by the alkaline Comet assay. Chromosomal rearrangements resulting from chromosome loss or acentric fragments were assessed as micronucleated mononucleates (MNMC) and binucleates (MNCB) with the cytokinesis-block micronucleus test. Urinary 8-hydroxydeoxyguanosine (8-OHdG) levels were used as an indicator of systemic oxidative DNA damage. A significantly higher frequency of MNMC was observed in WC-Co exposed workers with variant hOGG1(326) genotype. Multivariate analysis performed with genotypes, age, exposure status, type of plant, smoking and their interaction terms as independent variables indicated that MNMC and Comet tail DNA (TD) were influenced by genetic polymorphisms. In the exposed and total populations, workers variant for both XRCC3 and hOGG1 had elevated MNMC frequencies. Further studies will demonstrate whether genotyping for hOGG1 and XRCC3 polymorphisms is useful for a better individual monitoring of workers.

8-Hydroxy-2'-Deoxyguanosine↗

PubMed2004

Comparison of two sites in Mobile Bay using in vivo biomarkers in largemouth bass, sediment bioassays, and sediment contaminant analysis.

This research addresses whether chemical contaminants are having a biologically measurable effect on largemouth bass (Micropterus salmoides), an important fish species in the Mobile Bay National Estuary. Bass and sediment samples were collected in September 2001 from Big Bateau and D'Olive Bays; the latter has been suggested to be an environmentally impacted site. There was a significant difference in the age distribution of bass collected from the two sites. However, none of the animals showed any evidence of reproductive activity or had mature gametes. The age and gonadosomatic index were greater in animals collected from the Bateau site. Fish liver microsome ethoxyresorufin-O-deethylase (EROD) activities (elevated in the presence of CYP1A-inducing contaminants) were not significantly different between sites but were significantly higher in older bass. Plasma steroid concentrations in younger animals (less than 1 year old) tended to be higher and more variable than the concentrations found in older animals. Once the significant effects of age on plasma steroid concentrations were removed, an analysis of the residual change in steroids revealed no differences in testosterone or estradiol between animals collected at the two sites. Sediments were collected for chemical extraction and analysis in two bioassays: the H4IIE rat hepatoma EROD assay and the yeast estrogen screen (YES assay). The H4IIE bioassay indicated the presence of sediment BaP induction equivalents between 72 and 320 ng/g, whereas the YES assay indicated that potent estrogenic substances were not present in the sediment samples. The H4IIE bioassay results were higher for D'Olive samples, which was consistent with higher PAH concentrations in those sediments. Taken together the biomarkers and chemical analysis suggested generally low organic contamination at these two sites.

Alabama↗