Search PubMed⌕ Search

SEARCH · Search PubMed

Results for “Surrogate variables analysis”

Search indexed PubMed citations on genomics, clinical trials, systematic reviews and public health. Explore titles, authors and supplied subject terms, then open the PubMed record.

Quote a phrase for an exact phrase match. Source license links do not imply unrestricted reuse.

At least 505 records · Page 28Linked to original sources
PubMed1994

Standardization of immunobioassays as surrogate endpoints.

Despite centuries of scientific inquiry and medical effort, breast cancer remains one of the most dreaded human illnesses, emphasizing the need for prevention, early detection, and better management of these patients. Currently, newly recognized biomarkers are being examined as prognostic indicators to identify potentially aggressive cancers and to aid in planning treatment. Although the new prognostic factors are not yet firmly established, recent insights coupled with the availability of new biological markers have provided an opportunity to understand the initial genetic events leading to the development of breast cancer. Knowledge about those genetic events may provide opportunities for prophylactic intervention, improve our ability to predict breast cancer risk, and lead to strategies for early detection. Attention has focused on histomorphological changes and, to a lesser extent, cytomorphological changes in breast lesions associated with increased risk for subsequent breast cancer. However, the goal underlying the detection of early breast cancer is to distinguish patients who will develop breast cancer from those who will not. This task involves complex issues surrounding the selection, validation, quantitation, standardization, and population application of breast cancer biomarkers, and perhaps designing a protocol to control four major sources of cancer marker variability which may confound biomarker clinical application. These include biological and sampling diversity, variability of detection procedures, and validation against acknowledged disease endpoints. Immunocytochemistry has been applied extensively to assess the pattern of expression of different biomarkers in breast cancer. Immunocytochemical assays have permitted the localization of estrogen and progesterone receptors, oncogenes and tumor suppressor genes, growth factors, and other constituents at the cellular level, and also facilitated correlative analysis of morphology with specific expression of gene products.(ABSTRACT TRUNCATED AT 250 WORDS)

Biomarkers, Tumor↗
PubMed2003

Predictive value of serum thymidine kinase level for Ig-V mutational status in B-CLL.

In B-CLL IgV(H) genes mutational status is a major prognostic factor. Since sequencing of IgV(H) genes is not available in most laboratories, an easily performed surrogate assay is desirable. To identify the best surrogate assay, and to better discriminate prognostic subgroups we analyzed clinical and biological data from 58 typical CLL cases. A higher serum thymidine kinase level (>15 U/l) proved to be a strong predictor of mutational status, and the only independent one among the studied parameters. To further identify prognostic subgroups, cluster analysis was employed on 38 cases on which all data were available, which segregated two groups including 25 and 13 patients, respectively. These two clusters differed by their proliferative potential and appeared to discriminate patients with very different clinical course and outcome. s-TK was strikingly different among these two clusters, suggesting that s-TK level could be used routinely to identify patients at risk of progression.

Aged↗
PubMed1998

Molecular mimicry of carcinoembryonic antigen by peptides derived from the structure of an anti-idiotype antibody.

Our goal was to use carcinoembryonic antigen (CEA) as a target for immunotherapy in CEA-positive cancer patients who are all immune tolerant to the native antigen. We isolated and characterized an anti-idiotype monoclonal antibody 3H1, which mimics a distinct and specific epitope of the Mr 180,000 CEA and can be used as a surrogate for CEA. In Phase Ib clinical trials in a group of 23 advanced colorectal cancer patients, 3H1 induced both humoral and cellular anti-3H1 responses, as well as anti-CEA immunity. To study the cellular immunity invoked by 3H1 at the molecular level, we have cloned and sequenced the cDNAs encoding the variable heavy and light chains of 3H1 and deduced the amino acid sequences of the encoded proteins. To identify any cross-reactive peptides of 3H1 and CEA, we compared the amino acid sequences of 3H1 with those of CEA and found several regions of homology in 3H1 heavy and light chain variable domains, as well as in the framework regions. To search for potential cross-reactive T-cell epitopes, a number of peptides were synthesized based on 3H1/CEA homology and were used as stimulants in cell proliferation assays, using peripheral blood mononuclear cells from a group of 3H1-immunized CEA-positive cancer patients in the adjuvant setting. Two partially homologous peptides, designated LCD-2 (from 3H1) and CEA-B (from CEA), were identified in 10 of 21 adjuvant patients by strong proliferation responses (stimulation index, 3-50-fold), which were extensively studied in five of these individuals over an extended period of time (12-24 months). We saw no correlation with the MHC class I haplotype of the patients. Analysis of the subtype of the responding T cells demonstrated that primarily CD4+ T cells were stimulated by both 3H1 and 3H1-derived peptides. Interleukin 2, interleukin 4, and IFN-gamma were assayed in the culture medium of peripheral blood mononuclear cells stimulated with 3H1, CEA, and LCD-2 to determine the T-cell helper subset induced by these stimulants. The in vitro responses were mainly associated with secretion of IFN-gamma, which suggested that the induced T cells were most likely CD4+ Th1 type. Future studies will include the design of second-generation LCD-2 and CEA peptides to further enhance antigenicity, to characterize the responding T-cell populations more fully, and to test refined peptides for immunogenicity.

Amino Acid Sequence↗
PubMed1992

Definition of an immunodominant T cell epitope contained in the envelope gp41 sequence of HIV-1.

The majority of the immunodominant amino acid sequences of HIV-1 that have been characterized to date are coded for by hypervariable gene sequences. These variable sequences are however interspersed with sequences that are highly conserved between HIV strains. Immunogenic viral products with amino acid sequences that vary minimally between strains, and that consistently elicit both humoral and cellular immune responses, may be ideal for inclusion in a subunit vaccine. We studied HIV-seronegative and HIV-infected persons, classified as asymptomatic (AS), ARC or AIDS. Initially, we assessed the cellular immune status of each subject from results of T cell phenotype analyses, assays for serum levels of surrogate markers of disease progression, and responses to mitogens and recall antigen. In addition, we tested whether three short synthetic peptides derived from the conserved sequences of the envelope gp120 (aa 262-284) and gp41 (aa 579-601), and core p17 (aa 106-125) regions of the HTLV-IIIB isolate, could elicit B cell as well as T cell responses in HIV-infected subjects. Only the gp41-derived sequence was immunogenic at both B and T cell levels. To further characterize the gp41 epitope, we used a series of overlapping synthetic peptides derived from a conserved region of the envelope gp41 (aa 572-613). We thus identified an immunodominant 12-mer peptide sequence, gp41(8)(aa 593-604), which consistently elicited both T cell blastogenic and B cell (antibody) responses in AS HIV-seropositive individuals but not in ARC and AIDS patients. Linear regression analysis showed that in AS persons there was a strong positive correlation (P less than 0.0005) between the absolute CD8+ T cell numbers and the magnitude of blastogenic responses to the gp41(8)(aa 593-604). Furthermore, those AS subjects with T cells that proliferated in response to this gp41 analogue also had significantly greater serum levels of antibody to the same short peptide sequence than symptomatic ARC and AIDS patients. These results suggest that cellular responses to the immunodominant and highly conserved envelope sequences of HIV-1, associated with increased CD8+ T cells, may be important in the pathogenesis of HIV disease.

Amino Acid Sequence↗
PubMed1992

Fat mass is an important determinant of whole body bone density in premenopausal women but not in men.

We recently reported that total body fat mass is the principal determinant of bone density in normal postmenopausal women. We have now reexamined the relationships among these variables and lean mass in 68 healthy premenopausal women and 51 men. Areal bone density (BMD), fat mass, and lean mass were measured in total body scans by dual-energy, x-ray absorptiometry. In women, BMD was correlated with weight (r = 0.69), fat mass (r = 0.60), and lean mass (r = 0.55). In men, the respective correlations were 0.56, 0.26 (NS), and 0.51. Multiple regression analysis confirmed a codependence of female BMD on fat and lean masses, whereas male BMD was related only to lean mass. Because BMD is an areal not volumetric density, it is dependent on body size. The analysis was therefore repeated using BMD/height as an index of "true" density. Correlations with fat mass were little changed but those with lean mass were reduced (women) or eliminated (men). By multiple regression, female BMD/height was related to fat mass alone, and in men there was a borderline effect of fat (P = 0.05) but none of lean mass. As a second method to exclude a scale artifact, fat mass was expressed as percent body weight. It was related to BMD (r = 0.48) only in women. It is concluded that bone density is closely related to fat mass in premenopausal women, but less so in men. In both sexes, apparent relationships between BMD and lean mass are artifacts attributable to the use of areal density (which is dependent on body size) as a surrogate for volumetric density. The mechanism of this fat-bone density relationship is an important question to be addressed in bone biology.

Adipose Tissue↗
PubMed2006

Sex hormone status may modulate rate of expansion of proximal femur diameter in older women alongside other skeletal regulators.

CONTEXT: Little is known of associations between hip geometry and skeletal regulators. This is important because geometry is a determinant of both hip function and resistance to fracture. OBJECTIVE: We aimed to determine the effects of sex hormone status and other candidate regulators on hip geometry and strength. SUBJECTS AND METHODS: A random sample of 351 women aged 67-79 had two to four hip dual-energy x-ray absorptiometry scans performed over 8 yr of follow-up. Hip structural analysis software was used to measure subperiosteal diameter (PD) and the distance from the center of mass to the lateral cortical margin (d-lat) on three 5-mm-thick cross-sectional regions: narrow neck, intertrochanter, and shaft. Section modulus (Z), bone mineral density (grams per centimeter squared), and an index of bone mineral content (cross-sectional area) were calculated as estimators of bone strength. Serum analytes measured at baseline included SHBG, estradiol, PTH, creatinine, albumin, vitamin D metabolites, and glutamate- and gamma-carboxyglutamate-osteocalcin (OC). A linear mixed model was used to model associations with predictor variables, including testing whether the predictors significantly modified the effect of aging. RESULTS: Aging was associated with increasing PD and d-lat, and higher baseline SHBG significantly modified this effect, in the case of PD, increasing the rates of change at the narrow neck region by 19% for SHBG level 2 sd higher than population mean (P = 0.026). Higher baseline creatinine was independently associated with faster increases in PD and d-lat with aging (P < 0.041). Z declined faster with aging if baseline PTH was higher, and higher albumin had a contrary effect. Z was positively associated with free estradiol and inversely associated with SHBG and glutamate-OC. CONCLUSION: These results show large effects of SHBG on the regulation of proximal femur expansion and bending resistance, probably acting as a surrogate for low bioavailable estrogen. Potentially important effects for fracture resistance in old age were also revealed for PTH, markers related to renal function and the nutritional markers albumin and undercarboxylated OC.

Aged↗
PubMed2000

Sickness Impact Profile Score versus a Modified Short-Form survey for functional outcome assessment: acceptability, reliability, and validity in critically ill patients with prolonged intensive care unit stays.

BACKGROUND: Quality of life after surgical critical illness is an important measure of outcome. The Sickness Impact Profile Score (SIP) has been validated in critically ill patients, but the Modified Short-Form (MSF) has not been directly compared with it. METHODS: The SIP and MSF-36 were coadministered to 127 patients (surrogates) with a prolonged surgical critical illness at baseline at 1, 3, 6, and 12 months. Reliability, validity, and acceptability were determined for overall and subscores at each time point. RESULTS: The overall SIP and eight subscores, including physical health and psychosocial health, were all significantly improved at 1 year compared with baseline (p < 0.05). However, the MSF-36 was improved only in health perception (p < 0.05), but pain scores were higher (p < 0.05) than at baseline. Internal consistency of the MSF-36 was poor at 1 and 3 months. Correlation between the tools was excellent at baseline and 1 year but variable in overall and subscores at other time points. CONCLUSION: The SIP is more comprehensive, reliable, and acceptable in determining specific quality-of-life abnormalities, but the MSF-36 is easier to administer and correlates well at baseline and 1 year in patients with a prolonged critical illness.

Activities of Daily Living↗
PubMed2004

Motherhood meets epidemiology: measuring risk factors for breast-feeding cessation.

OBJECTIVE: To examine statistical models that have been used to predict the cessation of breast-feeding. SETTING: In nutritional epidemiology, a knowledge of risk factors that lead to breast-feeding cessation is essential to promote optimal infant health by increasing or sustaining breast-feeding rates. However, a number of methodological issues complicate the measurement of such risk factors. It is important when building multivariate models that variables entered into the model are not intervening variables, factors on the causal pathway or surrogate outcomes. Inclusion of these types of variable can lead to inaccurate models and biased results. A factor often cited to predict breast-feeding is 'intention to breast-feed' prior to the birth of the infant, although this factor is directly on the causal decision-making pathway. Another factor often cited is the age of introduction of formula feeding, which is actually part of the outcome variable because formula feeding defines the difference between full, complementary and no breast-feeding. Rather than include these as risk factors in multivariate models, factors removed from the causal pathway such as influences of educational practices, including advice to complementary feed, and beliefs and attitudes of families and health-care practitioners should be measured. CONCLUSIONS: The accurate quantification of modifiable risk factors is essential for designing public health education campaigns that are effective in sustaining or increasing breast-feeding duration.

Adult↗
PubMed2007

Beneficial effects of creatine, CoQ10, and lipoic acid in mitochondrial disorders.

Mitochondrial disorders share common cellular consequences: (1) decreased ATP production; (2) increased reliance on alternative anaerobic energy sources; and (3) increased production of reactive oxygen species. The purpose of the present study was to determine the effect of a combination therapy (creatine monohydrate, coenzyme Q(10), and lipoic acid to target the above-mentioned cellular consequences) on several outcome variables using a randomized, double-blind, placebo-controlled, crossover study design in patients with mitochondrial cytopathies. Three patients had mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS), four had mitochondrial DNA deletions (three patients with chronic progressive external ophthalmoplegia and one with Kearns-Sayre syndrome), and nine had a variety of other mitochondrial diseases not falling into the two former groups. The combination therapy resulted in lower resting plasma lactate and urinary 8-isoprostanes, as well as attenuation of the decline in peak ankle dorsiflexion strength in all patient groups, whereas higher fat-free mass was observed only in the MELAS group. Together, these results suggest that combination therapies targeting multiple final common pathways of mitochondrial dysfunction favorably influence surrogate markers of cellular energy dysfunction. Future studies with larger sample sizes in relatively homogeneous groups will be required to determine whether such combination therapies influence function and quality of life.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed2006

[Minimal residual tumor in gastrointestinal carcinoma. Relevance to prognosis and oncologic surgical consequences].

Isolated tumor cells as a consequence of minimal residual disease are often not detectable by routine diagnostic procedures. However, before or after surgery, isolated tumor cells in lymph nodes, the peritoneal cavity, blood, or bone marrow can frequently be identified by immunohistochemical or molecular methods. Failure to reveal the presence of such cells results in under-staging of tumor patients and may constitute the source of unexpected tumor recurrence after radical surgery. These facts emphasize the importance of isolated tumor cells at least as a surrogate marker. The frequency of appearance of isolated tumor cells in different organ systems also depends on the type of primary tumor. Developments in modern detection methods have led to increasing sensitivity but at the expense of specificity. Isolated tumor cells demonstrate remarkable heterogeneity with respect to proliferative potential and tumorigenicity. This characteristic is also reflected by a striking variability in the expression of various genes conditioning the aforementioned biological behavior. Unfortunately there is also remarkable heterogeneity in methods used for sampling and processing patient material as well as for the enrichment and detection of isolated tumor cells. Despite the ongoing controversies concerning detection methods and biological significance of isolated tumor cells, several clinical trials providing data supporting the prognostic relevance of minimal residual disease should also be considered for gastrointestinal carcinoma. In future this finding should be integrated in the planning of trials in surgical oncology, and "minimal residual disease" should receive stronger attention as a stratification criterion in such clinical studies.

Biomarkers, Tumor↗
PubMed2005

Small-scale spatial variability of particle concentrations and traffic levels in Montreal: a pilot study.

Little is known about the particulate exposure of populations living along major urban roads. The objective of this pilot study was to explore the small-scale spatial and temporal variability of the absorption coefficient of PM2.5 filters, as a surrogate for elemental carbon, in relation to levels of PM2.5, at residential sites with varying traffic densities in a large Canadian city. Concurrent 24-h measurements were performed at four residential sites during 7 weeks. A gradient existed across all four sites for the absorption coefficient of the filters (and NO2 levels). In contrast, the levels of PM2.5 were quite similar at all sites. The difference in the filter absorption coefficient of PM2.5 filters, between an urban background and a residential traffic site (with about 30000 vehicles/day), expressed as a percentage of the background site, was 40%. These results indicate that spatial variability in PM2.5 absorption coefficient can be observed with traffic intensity on a small scale within a North American city and suggests that regression modelling approaches similar to those used in European studies could be used to estimate exposure of the general population to traffic-related particles on a local scale in North America.

Absorption↗
PubMed2005

Accelerated lean body mass loss in incident chronic dialysis patients with diabetes mellitus.

BACKGROUND: End-stage renal disease (ESRD) patients display a higher incidence of poor nutritional status and are at high risk of hospitalization and death. Patients on renal replacement therapy (RRT) with a primary diagnosis of diabetes mellitus have the lowest survival rates along with highest hospitalization incidence. METHODS: In this study, we examined the importance of diabetes mellitus along with certain demographic and clinical variables in predicting the change in lean body mass (LBM) by dual-energy x-ray absorptiometry (DEXA), as a surrogate marker of somatic protein stores, in 142 incident ESRD patients (91 males, 52.8 +/- 1.0 years, 74.2 +/- 1.2 kg body weight) among which 34 had diabetes mellitus (19 insulin-dependent and 15 noninsulin dependent). RESULTS: Our results show that patients with diabetes mellitus had significantly accelerated loss of LBM compared to nondiabetic patients during the first year of RRT (3.4 +/- 0.6 kg vs. 1.1 +/- 0.2 kg) (P < 0.05). Multivariate linear regression analyses revealed that the presence of diabetes mellitus was the strongest predictor of LBM loss independently of several clinically-relevant variables such as age, gender, serum albumin, presence of malnutrition, presence of inflammation, and RRT modality. CONCLUSION: We conclude that the presence of diabetes mellitus is the most significant independent predictor of LBM loss in renal replacement therapy patients, providing a potential explanation as to why ESRD patients with diabetes mellitus are more prone to muscle wasting.

Absorptiometry, Photon↗
PubMed2001

Respiratory symptoms and lung function in workers in heavy and highway construction: a cross-sectional study.

BACKGROUND: Occupational exposures for workers in heavy and highway (HH) construction include cement-containing dusts and diesel exhaust (DE). To investigate possible health effects, respiratory symptoms and lung function were examined in laborers, tunnel workers (TW), and operating engineers (OE) in HH and tunnel construction. The principal outcome of interest was airways disease. METHODS: Subjects were recruited through their unions. Medical and occupational histories and flow-volume loops were obtained. Based on self-report, asthma and chronic bronchitis were categorized as (1) physician-diagnosed or (2) for asthma, undiagnosed likely, and (3) for chronic bronchitis, symptomatic. Trade and time in the union were used as surrogates of exposure. Prevalence of asthma and chronic bronchitis, lung function outcome, and relationships with exposure variables were examined. RESULTS: Data were obtained on 389 workers: 186 laborers, 45 TWs, and 158 OEs. Prevalence of asthma was 13 and 11.4% for laborers (including TW) and OEs, respectively, and of symptomatic chronic bronchitis, 6.5 and 1.9%, respectively. Odds ratios (OR) for undiagnosed asthma likely were significantly elevated in TWs compared to OEs, and marginally elevated for chronic bronchitis. Inverse relationships were observed between time in the union, and risk for asthma and chronic bronchitis. Asthma (physician-diagnosed or undiagnosed likely) predicted lower FEV(1). Current cigarette use was associated with chronic bronchitis but not asthma. CONCLUSIONS: TWs, laborers, and OEs in HH construction are at increased risk for asthma. TWs also appear to be at increased risk for chronic bronchitis. Our data suggest that symptomatic workers are self-selecting out of their trade. Asthma was associated with lower lung function in those affected.

Adult↗
PubMed1998

Lack of association between carotid intima-media thickness and paraoxonase gene polymorphism in non-insulin dependent diabetes mellitus.

Paraoxonase (PON) is an HDL-bound enzyme capable of hydrolyzing lipid peroxides and believed to be in part responsible for the protective effect of HDL against LDL oxidation. Its activity is mainly determined by a gene polymorphism of the PON 1 gene (Glu-Arg 192). Low activity has been related to an elevated incidence of myocardial infarction. In several case-control studies, however, the high activity B allele is paradoxically more prevalent in patients. We have re-investigated this relationship, using carotid intima-media thickness (IMT) as a surrogate continuous variable for macroangiopathy. Genotypes were determined in 197 non insulin-dependent diabetic patients (HbAlc 8.8+/-0.15%, BMI 28.3+/-0.36). IMT, measured by high resolution mode B ultrasound, was the same for all genotypes (AA: 0.83+/-.013, AB 0.82+/-.017 and BB: 0.81+/-.034 mm). Bearers of the B allele displayed higher Lp(a) concentration (AA: 197+/-28, AB: 221+/-26, BB: 225+/-45 mg/l, P=0.024) with a significant linear trend (P < 0.005). Multiple regression showed age and systolic blood pressure, but not Lp(a), to be the main determinants of IMT variability without the contribution of the PON genotype. No consistent differences could be found between genotypes in the peroxidizability of LDL (lag-time, rate of diene production and maximal concentration). Our data support the view that there is no association between the early changes of atherosclerosis as defined by carotid IMT and variation in codon 192 of PON 1.

Age Factors↗
PubMed2006

Agreement in assessing cup-to-disc ratio measurement among stereoscopic optic nerve head photographs, HRT II, and Stratus OCT.

PURPOSE: To compare the level of agreement between subjective and objective methods in estimating horizontal and vertical cup-to-disc ratios (HCDR and VCDR, respectively) to determine if objective techniques may be used as surrogates for subjective cup-to-disc (CDR) estimation. METHODS: Fifty-one glaucoma patients and 49 control subjects underwent full ophthalmic examination, stereoscopic optic nerve head photographs (ONHPs), confocal scanning laser ophthalmoscopy (Heidelberg Retina Tomography II [HRT II]), and optical coherence tomography (Stratus OCT). The intraclass correlation coefficient (ICC) and Bland Altman plots were used to assess the agreement across the three methods. Repeated measures analysis of variance (ANOVA), Tukey adjustment, and pairwise P values were used to compare the HCDR and VCDR estimates between three clinicians who reviewed photos, Stratus OCT, and HRT II. RESULTS: For the clinicians, the agreement in subjectively assessed HCDR and VCDR was substantial (ICC=0.84 and 0.85, respectively), and for all three methods, overall agreement was good (ICC=0.75 and 0.77 for the HCDR and VCDR, respectively). Stratus OCT provided the largest overall mean+/-SD HCDR (0.68+/-0.14) and VCDR (0.62+/-0.13). The smallest overall mean+/-SD HCDR was provided by ONHP (0.32+/-0.16), and the smallest overall mean+/-SD VCDR was provided by HRT II (0.26+/-0.20). Repeated measures ANOVA test demonstrated significant differences across the three methods for glaucomatous (P=0.0017 and 0.0016, HCDR and VCDR, respectively) and normal (P=0.0001 for both HCDR and VCDR) eyes. Tukey adjustment demonstrated specific statistical differences between pairs of methods. CONCLUSIONS: Although the overall agreement between various methods was good, the mean estimates were statistically different. Additional studies are needed to evaluate the sources of variability, their level of significance, and longitudinal agreement between various methods of the CDR estimation.

Adult↗
PubMed1997

Anemia in hemodialysis patients: variables affecting this outcome predictor.

Despite the prevalent use of recombinant human erythropoietin (rhEPO), anemia is a frequent finding in hemodialysis patients. The goal of this study was to evaluate the impact of anemia on patient survival and characterize the determinants of hematopoiesis that may be amenable to therapeutic manipulation to enhance rhEPO responsiveness and reduce death risk. Patient characteristics and laboratory data were collected for 21,899 patients receiving hemodialysis three times per week in dialysis centers throughout the United States in 1993. Hemoglobin concentrations (Hb) < or =80 g/L were associated with a twofold increase in the odds of death (odds ratio = 2.01; P = 0.001) when compared with Hb 100 to 110 g/L. No improvement in the odds of death was afforded for Hb >110 g/L. Using multiple linear regression, variables of rhEPO administration (rhEPO dose and percentage of treatments that rhEPO was administered), variables of iron status (serum iron, transferrin saturation, and ferritin), variables of nutritional status (serum albumin and creatinine concentration), and the dose of dialysis (urea reduction ratio) were found to be significantly associated with hemoglobin concentration (P < 0.001). Age, race, and gender were also found to be significantly associated with hemoglobin concentrations (P < 0.001). From this report, the following conclusions may be made. (1) Anemia may be predictive of an increased risk of mortality in some hemodialysis patients. (2) Hemoglobin concentrations > 110 g/L are not associated with further improvements in the odds of death. (3) Laboratory surrogates of iron stores, nutritional status, and the delivered dose of dialysis are predictive of hemoglobin concentration. Whether manipulation of the factors that improve anemia will also enhance the survival of patients on hemodialysis is unknown and should be evaluated by prospective, interventional studies.

Adult↗
PubMed2001

[Calcified plaque of the extracranial carotid arteries in comparison with traditional risk factors as a predictor for relevant coronary artery stenoses].

BACKGROUND: Intima-media thickness (IMT) of carotid arteries, measured by vascular ultrasound, has widely been used as a surrogate marker for coronary atherosclerosis. As recent studies showed significant but only weak correlation between IMT and coronary artery stenoses, this study evaluated calcified plaques in the extracranial carotid arteries as a reasonable marker for coronary artery disease. PATIENTS AND METHOD: 139 patients underwent cardiac catheterization with selective coronary angiography and ultrasound examination (B-mode, standard Doppler, color Doppler) of the carotid arteries. In case of calcified plaques number and distribution among the extracranial cerebral arteries were determined (Figure 1). Coronary angiograms were analyzed for disease severity and extent (number of main vessels with > 50% stenosis). Besides the traditional vascular risk factors hypertension, diabetes, smoking and hypercholesterolemia as well as body mass index, age and sex were analyzed. RESULTS: Calcified plaques of carotid arteries were significantly correlated (r = 0.502, p < 0.001) with coronary artery stenoses as well as hypercholesterolemia (r = 0.410, p < 0.001), increasing age (r = 0.406, p < 0.001) and diabetes (r = 0.290, p < 0.001) in contrast to hypertension (r = 0.125, p = 0.075), smoking status (r = -0.043, p = 0.311), body mass index (r = -0.122, p = 0.083) and male sex (r = -0.103, p = 0.114) (Table 1). The number of calcified plaques was significantly correlated (r = 0.568, p < 0.001) with severity and extent of coronary artery disease, too (Figure 2). For two and more calcified plaques sensitivity concerning coronary artery stenoses was 80%, specificity 75%, positive predictive value 83%, negative predictive value 73% (Table 2). Multiple stepwise regression analysis was performed for all eight variables (calcified plaques, hypercholestrolemia, diabetes, hypertension, smoking status, age, sex, body mass index). Including calcified plaques the predictive value of all factors was higher (r = 0.644 to r = 0.607). CONCLUSIONS: Determination of calcified carotid plaques by ultrasound is useful to improve the predictive value of risk factor-based multivariate models based on traditional risk factors.

Adult↗
PubMed1995

Role of the pathologist in biomarker studies.

Cancer chemoprevention is defined as intervention by chemical agents prior to invasion to inhibit or slow the carcinogenic process. Using surrogate endpoint biomarkers in chemoprevention studies may reduce the size, length and cost of clinical prospective randomized trials in high-risk populations. Intermediate biomarkers are measurable alterations in the tissues at risk and include differentiation, genetic composition, biochemical expression, and proliferation. Assessment is possible because invasive epithelial neoplasms are known to begin as intraepithelial proliferations with a spectrum of cellular abnormalities extending to carcinoma in situ. Genetic heterogeneity begins in the intraepithelial phase; a stochastic accumulation of genetic errors characterizes the progression of clonal evolution within the tumor through the process of invasion and metastasis. Pathologic features associated with this process include tumor classification as well as whether it is intraepithelial or invasive. If the process is intraepithelial, the grade and extent of the intraepithelial lesion are reported. If the neoplasm is invasive, tumor size, extent, degree of differentiation (histologic and nuclear grade), mitotic rate, vascular invasion, and lymph node involvement are evaluated. In assessing biomarkers relevant chemoprevention, and without complete regression of the neoplasm with the chemopreventive agent or agents, measurable parameters along with histopathologic features are applicable. Three methods readily applicable for this purpose that can be applied to paraffin-embedded, formalin-fixed tissue include quantitative pathology, immunohistochemistry, and molecular biologic applications. These methods require some consistency in handling and processing the tissues under study; results may deteriorate due to a number of processing variables, including time to fixation, time in fixative, and fixative type. Quantitative pathology, including static image analysis and flow cytometry, can determine total DNA content. Using static image analysis, very small tumors can be studied. In addition, adjacent intraepithelial and invasive components of a tumor may be studied from a single slide. Steroid receptors, oncogenes, and other proteins detectable through immunohistochemical or molecular biologic methods can be quantitated by this technique as well. Cell cycle synthetic function is assayable by both methods. Flow cytometry can calculate the total percentage of cells in S-phase, or the tumor cell S-phase fraction based on the percentage of cells detected between the G0, G1 peak and the G2 + M peak. A similar approach is generally not applicable with current image analysis equipment; however, cell cycle related proteins such as MIB-1 (Ki-67 associated) can be quantified. Immunohistochemical methods can employ a wide variety of monoclonal antibodies to detect oncogene related proteins, including HER-2/neu (c-erbB-2) and p53. Molecular biologic methods, including in situ hybridization, polymerase chain reaction, and in situ PCR, can have many applications when applied to paraffin-embedded tissues, including detection of viral DNA, identification and measurement of apoptosis, and defining gene deletions.

Biomarkers, Tumor↗