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Results for “Biomarker variability”

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PubMed2003

Distribution and dose response of laboratory markers to alcohol consumption in a general population: results of the study of health in Pomerania (SHIP).

OBJECTIVE: Biomarker distributions must be well known for use as screening tools for hazardous alcohol consumption in general populations. The aim of this study was to investigate characteristics of carbohydrate-deficient transferrin (CDT) and to compare it with gamma-glutamyltransferase (GGT) and erythrocyte mean corpuscular volume (MCV) in regard to distribution in the general population; the dose response relationship between alcohol consumption and biomarkers; and the effect of gender, age, body mass index (BMI) and smoking. METHOD: In a cross-sectional health survey in northeast Germany (1997-2001), a sample of 7,008 men and women aged 20-79 years was drawn, following stratification by age and gender. Of this sample, 4,310 subjects (2,193 women) took part in the study. Alcohol consumption was evaluated by self-reports with a beverage specific quantity-frequency method. RESULTS: Biomarker distributions differ across age and gender. The distribution of drinkers and nondrinking subjects showed considerable overlap. The association of alcohol consumption to laboratory markers is weak in the general population: strongest for GGT, followed by CDT and MCV For CDT and MCV it is weaker in women than in men. We found increasing risk of all three elevated marker values with increasing alcohol consumption and significant effects of age, gender, smoking and body mass index on the alcohol-biomarker dose response curve. CONCLUSIONS: When biomarkers are used for screening, all confounding effects have to be taken into account and adjusted normal ranges must be used. CDT shows no overall advantage over GGT. Low correlation of biomarkers with alcohol consumption, their high variability and widely spread ranges in nondrinking subjects limit the usefulness of these markers in general population settings.

Adult↗

PubMed2026

Reference-Free Microsatellite Instability Detection from Tumor Sequencing Using Intrasample Variability Modeling.

Microsatellite instability (MSI) is a predictive biomarker in several tumor types. However, many next-generation sequencing-based callers require matched normal samples, reference panels, or pretrained models, limiting their portability across assays and sequencing centers. We developed PROMIS (PROfiling of Microsatellite InStability), a tumor-only, reference-free pipeline that uses a discrete mixture model to characterize intrasample repeat-length distributions at predefined microsatellite loci. Locus-level classifications are then aggregated into a continuous MSI score. We benchmarked PROMIS in colorectal (CRC), endometrial (UCEC), and gastric (STAD) cancers from The Cancer Genome Atlas. PROMIS achieved an overall area under the receiver operating characteristic curve (AUC) of 0.995 and cohort-specific AUCs of 1.00 in CRC and stomach adenocarcinoma and 0.999 in uterine corpus endometrial carcinoma, comparable to established tools despite not using matched normals or pretrained models. Subsampling demonstrated robust performance with substantially fewer loci. In silico dilution showed progressively reduced MSI-microsatellite-stable discrimination, with the pooled AUC declining from 0.83 at 10% tumor fraction to 0.53 at 1%. At low tumor fractions, tumor-type-specific baseline microsatellite variability increasingly influenced PROMIS scores. Finally, in prostate and CRC cell-free DNA cohorts, including Illumina TSO500 data and an 18-gene panel, PROMIS yielded MSI scores concordant with orthogonal tissue- and panel-based classifications across the evaluated Illumina-based sequencing contexts. Accordingly, the present validation should be considered limited to Illumina-based sequencing platforms. PROMIS is intended to complement existing genomic profiling workflows by enabling MSI assessment from sequencing data already generated for broader molecular analyses. Prospective clinical validation remains necessary before clinical implementation.

Journal Article↗

PubMed1993

Chlorinated dibenzo-p-dioxins and dibenzofurans and the human immune system. 1. Blood cell receptors in volunteers with moderately increased body burdens.

Using monoclonal antibodies (mAbs) and flow cytometry, we studied a variety of surface receptors on lymphocyte subpopulations of workers with moderately increased body burdens of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and of other polychlorinated dibenzo-p-dioxins and dibenzofurans (PCDD/PCDF), expressed here as International-Toxicity Equivalencies (I-TE). The hypothesis to be tested was whether or not humans exhibit a similar susceptibility to PCDDs/PCDFs with respect to the surface receptors found previously to respond to small doses of 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in Callithrix jacchus. These are: helper-inducer (memory) T cells (CD4+CD45R0+CD45RA-CD29highCD11a+), CD20+ B cells, and cytotoxic T cells (CD8+CD56+/CD57+). Furthermore, 68 triple-labellings with mAbs were performed on the cells of each volunteer to possibly generate further hypotheses. It was evaluated whether any of the variables might be used as a biomarker of effects for this class of compounds. There were two main goals: (1) to evaluate whether workers with a moderately increased PCDD/PCDF-body burden [25-140 ppt TCDD or 104-522 ppt I-TE in blood fat] exhibit changes in the surface receptors of white blood cells, as observed in previous studies in non-human primates, and (2) to clarify whether persons at the upper range [10-23 ppt TCDD or 30-90 ppt I-TE in blood fat] of the body burden reference values of a not particularly exposed population show detectable deviations in these immunological variables, when compared with persons at the lower and medium range [1-3 ppt TCDD or 9-29 ppt I-TE] of these body burden reference values. Regression analysis of our data revealed slight trends for some of the biomarkers (e.g. CD45R0+). With one exception, these were all increases. None of the alterations observed are of medical relevance. The slight increase in the percentage of CD4+CD45R0+ cells remained significant even after covariant analysis taking age-related changes into account. Altogether, the data do not provide any evidence to support an assumption that moderately increased body burdens of PCDDs/PCDFs in adults induce decreases in the cellular components of the human immune system. Adult humans certainly are less susceptible to this action of PCDDs/PCDFs than adolescent Callithrix jacchus.

Adult↗

PubMed2003

Metabolic polymorphisms and the micronucleus frequency in buccal epithelium of adolescents living in an urban environment.

Micronuclei and other biomarkers were evaluated in oral cells from 11- to 16-year-old girls living in a foster home in the central area of México City. Variables analyzed for possible association with these biomarkers include smoking habits, body mass index, metabolic polymorphisms for NAT1 and GSTM1 and whether the cells were obtained from the cheek or pharynx. The results indicated that individuals having the NAT1*10 homozygous genotype showed a significant increase in chromatin buds and binucleated cells. When the damage in the cheek was compared with damage in the pharynx, a significant increase in micronuclei and binucleated cells was found for the latter tissue in all the individuals analyzed.

Adolescent↗

PubMed2006

Drug-metabolizing enzyme inhibition by ketoconazole does not reduce interindividual variability of CYP3A activity as measured by oral midazolam.

Variable interindividual expression of cytochrome P450 3A presents a challenge in dosing drugs. The use of potent inhibitors of CYP3A such as ketoconazole has been explored to reduce the clearance of CYP3A substrates, thereby resulting in smaller dose requirements; however, the impact of CYP3A inhibition on interindividual variability has not been well characterized. Our objective was to examine the effect of ketoconazole inhibition on CYP3A metabolic variability as measured by the CYP3A biomarker oral midazolam. A single dose of midazolam (0.075 mg/kg) was administered to 19 healthy Caucasian adults (38.7 +/- 8.8 years, nine male/10 female) at baseline and concurrently with ketoconazole (400 mg daily for 10 days) on day 6 or 9 of ketoconazole. Plasma samples were collected over 6 to 30 h. A paired t test and percent coefficient of variation (CV%) were used to evaluate differences in midazolam clearance and interindividual variability during both phases. Monte Carlo simulation was performed to determine probability distribution of area under the concentration-time curves (AUCs). Midazolam apparent oral clearance decreased by 89% (p < 0.0001) during inhibition. Cmax increased from 23 ng/ml (95% CI 19-29 ng/ml) to 55 ng/ml (95% CI 46-66 ng/ml), p < 0.0001. CV% increased from 41 to 58% from baseline to ketoconazole inhibition. AUCs [median (range)] were 0.20 mg . min/ml (0.05-0.81 mg . min/ml) and 1.94 mg . min/ml (0.25-25.4 mg . min/ml) at baseline and inhibition phase, with CV% of 41 and 61%, respectively. Ketoconazole decreased CYP3A activity but did not reduce interindividual variability. Use of a CYP3A inhibitor to standardize dosing of CYP3A substrates may not be feasible in clinical practice.

Administration, Oral↗

PubMed2004

Temporal and spatial variability in the estrogenicity of a municipal wastewater effluent.

The estrogenicity of a municipal wastewater effluent was monitored using the vitellogenin biomarker in adult male fathead minnows (Pimephales promelas). The variability in the expression of vitellogenin was evident among the monitoring periods. Significant (alpha< or =0.05) increases in plasma vitellogenin concentrations were detected in March and December, but not in August or June. Additionally, the magnitude of expression was variable. Variability in the spatial scale was also evident during the March and June exposure months. Concurrent exposures in both the creek receiving the effluent from a wastewater treatment plant and an experimental wetland showed estrogenicity to be different with distance from the respective effluent inflow sites. March exposures showed estrogenicity to be somewhat persistent in the receiving creek (>600 m), but to decrease rapidly within the experimental wetland (<40 m). Results are discussed relative to the monitoring season, to the spatial distribution of the response in both receiving systems, and to possible causative factors contributing to the effluent estrogenicity.

Animals↗

PubMed2004

Liquid chromatographic and tandem mass spectrometric assay for evaluation of in vivo inhibition of rat brain monoamine oxidases (MAO) A and B following a single dose of MAO inhibitors: application of biomarkers in drug discovery.

A simple and selective assay for the evaluation of in vivo inhibition of rat brain monoamine oxidases (MAO) A and B following a single dose of MAO inhibitors was developed through the simultaneous determination of endogenous 5-hydroxy tryptamine, 5-hydroxyindole-3-acetic acid (5-HIAA), tryptophane, and 2-phenethylamine (PEA) in rat brain using liquid chromatography-tandem mass spectrometry (LC/MS/MS). These analytes were separated on a Zorbax SB-C18 column using a gradient elution with acetonitrile and 0.2% formic acid and detected on an electrospray ionization mass spectrometer in positive-ion multiple-reaction-monitoring mode. The susceptibility and variability of these analytes as potential biomarkers in response to MAO inhibition in vivo were evaluated after application to three MAO inhibitors, tranylcypromine, clorgyline, and pargyline. A dramatic increase (about 40-fold) in PEA brain level and a decrease in 5-HIAA by more than 90% were observed after administration of 15 mg/kg of the nonselective MAO inhibitor tranylcypromine. As expected, the brain level of PEA escalated to about 6-fold, while the 5-HIAA level remained unchanged following a dose of the MAO B inhibitor pargyline at 2mg/kg. In contrast, the brain level of 5-HIAA reduced by approximately 53%, but the PEA level was unaffected following the same dose of the MAO A inhibitor clorgyline. The results indicated that 5-HIAA and PEA were susceptible and effective biomarkers in the rat brain in response to MAO A and B inhibition, respectively. The LC/MS/MS method is useful not only for the determination of inhibitory potency but also for the differentiation of the selectivity of a MAO inhibitor against rat brain MAO A and B in vivo.

Animals↗

PubMed2006

Serum chemical biomarkers of cardiac injury for nonclinical safety testing.

There has been a substantial increase in the number and efficacy of laboratory biomarkers for the evaluation of human cardiac injury over the last decade. The advantages of these over traditional laboratory tests have encouraged adoption of comparable markers in nonclinical studies for cardiac injury assessment. Of particular interest are markers that are not only more sensitive and/or specific than traditional parameters for cardiac injury, but also those that may directly bridge human and laboratory animal safety testing. However, a majority of recently developed markers are quantified through antibody-based assays, and cross-reactivity with the comparable analyte in nonhuman samples is difficult to predict and often species-variable. The utility of these novel biomarkers thus, depends upon adequate assay validation with each laboratory species of interest. In contrast, traditional laboratory parameters of cardiac injury lack the properties of an ideal biomarker, but are well established and have an extensive database in nonclinical safety assessment. The current status and utility of both recently developed and traditional biomarkers of cardiac injury in nonclinical testing, and considerations for validation of novel biomarkers of cardiac injury are reviewed.

Animals↗

PubMed2006

Biomarkers of sepsis.

Sepsis is a highly heterogeneous clinical disorder currently characterized almost exclusively by the use of physiologic variables. A burgeoning interest in the potential descriptive role of biomarkers in sepsis holds the promise of transforming the diagnosis from a clinical one to a biologic one, and so permitting better evaluation and use of a spectrum of adjuvant therapies. Biomarkers provide information in one of three domains: diagnosis, prognosis, and monitoring of response to treatment. Their primary prognostic utility, however, is not in forecasting outcome, but in identifying patients who are more likely to benefit from (or be harmed by) a particular intervention. A proposed template for staging sepsis in a manner analogous to systems used in oncology provides a framework for evaluating sepsis biomarkers. The model stratifies patients on the basis of predisposition, insult, response, and organ dysfunction, generating the acronym PIRO. This brief review considers the methodologic basis for biomarker development and validation and situates some emerging sepsis biomarkers within the framework of the PIRO model.

Journal Article↗

PubMed1997

Transitional studies.

Transitional studies are studies using biological markers that bridge the gap between laboratory experiments and population-based epidemiology. The goal of these studies is to characterize and validate biomarkers and to assess the following: intra- and inter-subject variability; the feasibility of marker use in field conditions; confounding and effect-modifying factors for the marker; and mechanisms reflected by the biomarker. Another goal is to optimize the conditions for the use of biomarkers. Transitional studies involving biomarkers of exposure or effect are distinguished from etiological studies because the biomarker is generally the outcome or dependent variable. Despite this difference, transitional studies can be epidemiological studies, but they may also include laboratory studies to assess reliability (and accuracy) and to identify parameters for collecting, processing and storing biological specimens prior to assay. Generally, transitional studies involve healthy people, patients or workers with specific exposures. At some point in the validation of a biomarker the line between transitional and etiological studies becomes blurred. None the less, it is useful to identify transitional studies as a distinct set of efforts to validate and characterize biomarkers. Transitional studies can be divided into three functional categories: developmental, characterization and applied studies.

Animals↗

PubMed2026

Multiparametric flow cytometry immune profiling of pulmonary and extra-pulmonary tuberculosis reveals distinct blood-based biomarker signatures.

This study investigated immune cell distributions, cell-specific immune markers, and selected biomarker targets in pulmonary tuberculosis (PTB) and extrapulmonary tuberculosis (EPTB) using multiparametric flow cytometry (MFC). Whole blood was collected from 45 individuals, including healthy controls (HC), EPTB, and PTB patients (n = 15/group). Peripheral blood leukocytes were analysed by MFC to characterize CD4+ and CD8+ T cells, natural killer (NK), invariant NKT (iNKT) and NKT cells, classical (CM), intermediate (IM) and non-classical monocytes (NCM), and activated monocytes (AM). Expression of GBP1, CALCOCO2, IFIT3, SNX10, ARG1, PD-1, and PD-L1 was assessed across these immune subsets. Increased frequencies of NK, NKT, and monocytes were observed in PTB and EPTB compared with HC, while CD4+, CD8+, iNKT, and AM were reduced. Monocyte-to-lymphocyte ratios were incrementally elevated in EPTB and PTB compared with HC. Despite variability of expression within groups, median biomarker fold-change expression changes were found between HC, EPTB and PTB groups; (i) (>2.0FC) for ARG1 in CD4, CD8, CM and AM, for CALCOCO2 in AM, GBP1 in CD8 and NCM, PD-1 in CD4, CD8, NK, IM and AM, PD-L1 in CD4, CD8, iNKT and NKT, NK, IM and AM and SNX10 in CD4, CD8, NCM, IM and AM (ii) (<2.0FC) in TB vs HC for CALCOCO2 in iNKT and NKT, IFIT3 in NCM, PD-1 in NK and NCM, PD-L1 in NCM, IM and AM and SNX10 in AM. Statistical significance was achieved for ARG1 (P = 0.017) in CD4 cells. Our findings highlight distinct immune cell and biomarker signatures in PTB and EPTB.

Humans↗

PubMed2026

Myeloid-Mediated Immunoregulation and Resistance to Immune Checkpoint Inhibitor Therapy Across Squamous Cell Carcinomas: Mechanisms and Reprogramming Strategies.

Immune checkpoint inhibitors (ICIs) targeting PD-1/PD-L1 have improved outcomes across squamous cell carcinomas (SCCs) of the head and neck, lung, esophagus, and skin, yet durable responses remain confined to a subset of patients in every subtype. Objective response rates vary substantially across SCCs despite overlapping genomic alterations, comparable tumor mutational burden, and high PD-L1 expression, indicating that tumor-intrinsic biomarkers alone do not explain this variability. Growing evidence points to the tumor immune microenvironment, and in particular the myeloid compartment, as a critical determinant of immunotherapy responsiveness. In this review, we synthesize current evidence on myeloid-mediated immune regulation across SCC subtypes, focusing on tumor-associated macrophages, myeloid-derived suppressor cells/tumor-associated neutrophils, and dendritic cells, and the mechanisms by which these populations impair antigen presentation, restrict T cell infiltration, and sustain immunologically "cold" tumor states. We further examine therapeutic strategies aimed at reprogramming rather than simply depleting suppressive myeloid populations, including radiation therapy, STING agonism, and myeloid-targeted agents (CSF1R, PI3Kγ, and CXCR2 inhibition), each of which has shown encouraging preclinical and early clinical activity in combination with ICI. Collectively, this evidence supports a model in which the myeloid compartment functions as an actionable, convergent determinant of ICI resistance across SCC subtypes, rather than merely a passive biomarker. We propose that through the integration of spatial and single-cell profiling of myeloid states with clinical history it will be possible to predict response to immune checkpoint therapy and personalize myeloid-directed combination strategies, though the specific biomarkers needed to match individual patients to a given myeloid-targeted approach remain to be defined. We further discuss the toxicity considerations associated with both immune checkpoint blockade and radiation-based combination approaches, the early-phase status of most myeloid-targeted agents currently in clinical development, and the extent to which mechanistic insight, derived predominantly from HNSCC, generalizes to squamous cell carcinomas arising at other anatomic sites.

dendritic cells↗

PubMedDate not supplied

The use of serum biomarkers to predict outcome after traumatic brain injury in adults and children.

Traumatic brain injury (TBI) is a leading cause of morbidity and mortality in adults and children. Predicting outcome after TBI is difficult, but it is important for acute management, counseling of family members, and provision of rehabilitation services. Serum biomarkers may be useful alone or in combination with clinical variables to predict outcome after TBI. This article reviews the potential uses of serum biomarkers for the clinician, current literature related to the use of serum biomarkers for outcome prediction after adult and pediatric TBI, limitations of the literature, and future direction for this field.

Biomarkers↗

PubMed2004

Ganoderma lucidum ('Lingzhi'); acute and short-term biomarker response to supplementation.

Ganoderma lucidum (Lingzhi) is a popular Chinese herb with an impressive array of reputed health benefits, including antioxidant properties. However, these require scientific validation. The aim of this study was to investigate in vitro antioxidant capacity of Lingzhi, absorption and systemic distribution of Lingzhi antioxidants, and effects of short-term (10 days) supplementation on biomarkers of antioxidant status, coronary heart disease (CHD) risk and DNA damage. In this double-blinded, placebo-controlled, cross-over intervention study, blood and urine samples were collected from 10 healthy volunteers at 0 (fasting) and 45, 90, 135 and 180 min post-ingestion of a single dose (1.1g) of Lingzhi. Repeat fasting samples were collected after 10 days' supplementation with 0.72 g/d Lingzhi. The acute response (up to 3 hours) was also investigated with a larger dose (3.3 g) of Lingzhi (n=7). Results showed that the total antioxidant capacity (as the FRAP value) of an aqueous suspension of Lingzhi was 360 micromol/g. Ingestion of Lingzhi caused a significant post-ingestion increase (mean+/-SEM 23+/-3 micromol/L; P<0.05) in plasma antioxidant capacity, with peak response at 90 min. Average increase of 29+/-11% (P<0.05) in urine antioxidant capacity was seen within 3 hours of ingestion. After 10 days' supplementation with 0.72 g per day of Lingzhi, fasting plasma lipid standardised alpha-tocopherol concentration and urine antioxidant capacity increased (P<0.05). Fasting plasma ascorbic acid and total alpha-tocopherol concentrations and erythrocyte SOD and GPx activities increased slightly but non-significantly with supplementation. Plasma lipids and uric acid tended to decrease, but changes were not statistically significant. No discernable differences were seen in other variables measured. Results indicate that Lingzhi intake causes an acute increase in plasma antioxidant capacity. No deleterious effects on measured variables were seen. The pattern of biomarker response after supplementation indicated possible benefit in terms of antioxidant status and CHD risk, but further study is needed to elucidate the nature and longer-term effects of the absorbable antioxidants from Lingzhi.

Adult↗

PubMed2002

Functional foods: psychological and behavioural functions.

It is easier to demonstrate the consistent effects of foods on satiety than on cognitive performance. This is understandable since the satiety system incorporates physiological signalling systems that mediate the effects of foods on function. Specific manipulations of proteins, carbohydrates and fats have the potential to act as functional foods for appetite control. Because of the importance of the optimal functioning of cognitions for survival, these functions are quite strongly protected against short-term dietary and physiological perturbances. Therefore, food manipulations may be better detected through the degree of effort exerted to maintain performance rather than via changes in the actual performance itself. This procedure has not been widely used hitherto. The concept of biomarkers may have to be interpreted differently from research on physiological systems or clinical endpoints. For satiety, adjustments in the profile of hunger could serve as a biomarker or surrogate endpoint. For cognitions, correlated physiological variables may be more difficult to measure than the functional endpoint itself. Changes related to unitary functions (such as tracking) could serve as biomarkers for more complex, integrated skills (such as car driving). Since food manipulations may affect multiple functions, the challenge is to design foods with good satiety control that do not impair mental performance; or alternatively to engineer foods that optimise cognitive performance without compromising satiety. This rapidly developing field has great potential for close collaboration between academia and industry in the production of commercially successful products that show clear improvements in human functioning with the capacity to protect against disease or impairment.

Affect↗

PubMed1998

Heterogeneity of guanylyl cyclase C expressed by human colorectal cancer cell lines in vitro.

In humans, guanylyl cyclase C (GCC) is expressed by mucosal cells lining the intestine, from the duodenum to the rectum, but not by extraintestinal tissues. Expression of GCC persists after mucosal cells undergo neoplastic transformation, and this protein has been identified in all primary and metastatic colorectal tumors examined to date, suggesting that GCC may be a highly specific biomarker for colorectal cancer. The utility of GCC as a diagnostic biomarker and therapeutic target is predicated, in part, on defining the variability of its expression in colorectal cancer cells. Similarly, the utility of this biomarker to define tumor burden in diagnosing, staging, and postoperative surveillance of patients is predicated on quantifying GCC expression in cancer cells in tissues and blood. The present studies examined the heterogeneity of GCC expression in eight human colorectal carcinoma cell lines in vitro representing the full spectrum of cytological differentiation. Quantification of GCC expression by ligand binding and stimulation of cGMP accumulation demonstrated that functional GCC expression is heterogeneous in different colorectal cancer cell lines. Qualitative reverse transcription (RT)-PCR demonstrated that all colorectal cancer cells examined expressed GCC mRNA. However, GCC expression varied 100-fold in different colorectal cancer cell lines, determined by a novel quantitative RT-PCR assay. Functional and molecular expressions of GCC were unrelated to the differentiation state of cancer cells. These studies suggest that GCC is heterogeneously expressed by colorectal cancer cells in vitro and suggest a role for quantitative RT-PCR analysis in the development of diagnostic tests using GCC as a biomarker for metastatic colorectal cancer.

Biomarkers, Tumor↗

PubMed1996

Validation of p53 accumulation as a predictor of distant metastasis at 10 years of follow-up in 1400 node-negative breast cancers.

Most studies are in favor of a prognostic relevance of p53 accumulation determined by immunohistochemistry in breast cancer, but negative results are not lacking. On a series of 1400 patients with lymph node-negative cancers treated with local-regional therapy alone until relapse and with a median follow-up of 10 years, we validated the prognostic relevance for overall relapse and death of p53 accumulation observed in a pilot study and analyzed its predictivity on different adverse events. p53 protein accumulation was immunocytochemically detected using PAb1801. The case series had also been previously characterized for hormone receptor content [estrogen receptors (ERs) and progesterone receptors (PgRs)] and for cell proliferation [[3H]thymidine labeling index ([3H]dT LI)]. p53 expression, considered as a dichotomous variable with a cutoff value of 5% positive cells, significantly predicted the occurrence of overall relapse, distant metastasis, and death with an interaction with cell proliferation. p53 accumulation, cell proliferation, and their interaction term, along with tumor size and patient age, retained a predictive role for overall relapse, and together with tumor size and PgR, also for overall survival. When considered as continuous variables, we observed that the hazard of metastasis increased linearly with the increase of [3H]dT LI and decreased linearly with the increase of ER and PgR. Conversely, the hazard increased with the increase of p53-positive cells only for tumors with a [3H]dT LI lower than 7.5%. In multivariate analysis, the same prognostic factors for distant metastasis were identified when the biomarkers were considered as continuous or dichotomous variables.

Adult↗

PubMed2006

[Follow-up of osteoporosis treatment].

There is no linear relation between changes in bone mineral density (BMD) and reduction in fracture risk with antiresorptive agents. Interpretation of BMD changes at the individual level requires calculating the smallest significant change at each measurement center. BMD measurement is essential before administration of antiresorptive or anabolic agents for prevention or treatment of postmenopausal osteoporosis. Biochemical markers of bone turnover can be monitored after 6 months of treatment. Their interpretation requires careful assessment of their intraindividual variability.

Aged↗