Even mild changes in free thyroxine could influence the degree of heart failure measured by its biological surrogates.

Both, severe hypo- or hyperthyroidism may alter hemodynamic parameters. The aim of our study was to ascertain, whether also distinct changes within normal range of free thyroxine (fT4) would be associated with an impairment of left ventricle function in patients with chronic heart failure. Hundred-forty-eight patients (m121, f27, mean age 63.8 +/- 1.14 years) with chronic heart failure, fT4 levels within the normal range (9-22 pmol/l) and without thyrostatics or substitution treatment. Degree of heart failure was quantified by plasma B-type natriuretic peptide (BNP) and N-terminal pro-BNP (NT-proBNP). Patients with fT4 in the range 11.9-14.6 pmol/l [optimal, second-third quintile] had significantly lower NT-proBNP (718 +/- 70.4 pg/ml), than those with fT4 < or = 11.8 [low-normal, bottom quintile](1236 +/- 223.6 pg/ml; p<0.03) and those with fT4 over 14.6 pmol/l [high-normal, top two quintiles] (1192 +/- 114.9 pg/ml; p<0.0002). These differences remain significant, also if adjusted for age, gender and other confounders; adjusted odds ratio was 1.30 (1.05-1.59) for optimal vs. low-normal and 1.27 (1.04-1.55) for optimal vs. high-normal. Similar statistical differences were also found in BNP, but only when optimal and high-normal fT4 ranges were compared. In conclusion, the severity of heart failure seems to be also influenced by only mild deviations of fT4 concentrations from optimal levels.

Folate co-administration improves the effectiveness of fenofibrate to decrease the lipoprotein oxidation and endothelial dysfunction surrogates.

Fibrate therapy results in elevation of plasma total homocysteine (tHcy), which is known to induce oxidative stress and endothelial dysfunction. We aimed to establish whether fibrate-induced elevation of tHcy has also similar consequences and whether they may be prevented by folate co-administration. Eighteen subjects with hypercholesterolemia were included in an open, prospective, cross-over study. We compared intra-individually the effect of fenofibrate on tHcy, oxidative stress and endothelial dysfunction surrogates, in monotherapy and when combined with 10 mg of folate. These effects were also compared with fluvastatin monotherapy. Fenofibrate in monotherapy significantly decreased LDL cholesterol, increased the tHcy by 39.5 %, while oxidized LDL (oxLDL), malondialdehyde (MDA), von Willebrand factors (vWf) and thrombomodulin (TMD) remained unchanged. When fibrate was co-administered with folate, the tHcy remained on the initial post-diet level, while both the total and oxLDL as well as MDA, vWf and TMD decreased. In contrast to fenofibrate monotherapy, fluvastatin (80 mg) had a similar effect as combined therapy with fenofibrate and folate, while tHcy remained uninfluenced. In conclusion, fenofibrate decreases the LDL cholesterol, but in contrast to fluvastatin, has no significant antioxidative and endothelium-protective potential, probably due to a concomitant increase of tHcy. These effects may be improved by co-administration of folate.

TPS, thymidine kinase, VEGF and endostatin in cytosol of thyroid tissue samples.

The aim of the study was to determine whether VEGF, TPS, TK or Endostatin determination in tissue cytosol may have some additional value in distinguishing among different types of thyroid lesions. These markers were chosen as representatives of the 2 main pathways (angiogenesis and proliferation) involved in thyroid diseases. VEGF is the most potent angiogenic promoter and Endostatin plays an opposing role. Thymidine kinase (TK) is a marker of DNA synthesis and TPS, cytokeratin 18 fragments, is a marker of the rate of proliferation. We determined qualitatively all four markers in tissue extracts: cytosol from 157 tissue specimens (93 goitre, 12 Hashimoto's thyroiditis, 39 adenomas and 13 carcinomas). In 6 cases we were able to compare both normal and pathological tissue samples from a single patient. Statistically significant differences were found in the measured markers, but outliers were present in all groups. This fact does not permit their use in differential diagnosis. The highest levels of all markers were reached in adenomas, being higher than in carcinomas, probably explained by the higher overall metabolic rate in adenomas.

Clinical relevance of tumor markers for the control of chemotherapy.

This presentation is based on our experience with tumor marker monitoring of surgery therapy and chemotherapy effects. The control of chemotherapy is one of the most important problems in oncological practice. The correlation between the clinical status of the patient and tumor size changes, based on the results of different imaging methods, has been the most important and most frequently used method. However, the therapy effect has been recently assessed by markers of the biological activity of the tumor. Using tumor markers for the assessment of the effect of surgery therapy is already part of routine practice in many different types of cancer. Pre-operative and post-operative values of tumor markers are essential for a proper evaluation. However, tumor marker monitoring of the effect of radiotherapy and chemotherapy has been used very rarely, mostly only for research purposes. Besides monitoring by classical tumor markers, monitoring by markers of angiogenesis and apoptosis seem to be promising for the assessment of chemotherapy effect. Measurement of circulating cancer cells by means of mRNA also seems to be intriguing for therapy effect control and monitoring of the course of disease. Unfortunately, the routine use of these methods has been applied in only a few institutes worldwide. A completely different situation has been observed in palliative treatment. In most cases, changes of serum levels of tumor markers correlate with therapy effect. Thus, the effect of treatment on tumor proliferation can be successfully estimated by decreasing tumor marker levels.

Markers of cellular adhesion in diagnosis and therapy control of colorectal carcinoma.

AIM: Early diagnosis of the progressive tumor disease and control of the effect of therapy in colorectal carcinoma are most frequently performed by monitoring CEA or CA 19-9 tumor markers. Their clinical application is, however, limited. The aim of our study was to demonstrate the contribution of adhesive molecule assessment to the early diagnosis of progression. We also wanted to find out if changes in the levels of cellular adhesion parameters correlate with the effect of antitumor therapy. MATERIALS AND METHODS: Intercellular cell adhesive molecule-1 (ICAM-1) and Vascular cell adhesive molecule-1 (VCAM-1) were assessed using the ELISA method, and the results were correlated with CEA and CA 19-9 tumor markers. Three hundred and sixty-four patients with colorectal carcinoma in Dukes' stages B-D were monitored. The results were processed with the SAS 6.2. statistical program and Statistica. RESULTS: In 92 patients with first clinical progression (occurrence of distant metastases irrespective of localization), significantly increased ICAM-1 and VCAM-1 values were demonstrated. In ROC evaluation of curves, we also demonstrated high sensitivity of adhesive molecules against both the control healthy group (n =89) and the no evidence of disease group (NED) (n=183). Adhesive molecule levels were closely connected with the type and course of therapy and are presented in the form of case reports. CONCLUSION: Soluble adhesive molecules are a prospective parameter both for the early diagnosis of progression and for control of the effect of therapy. There is a need for a large-scale study, preferably multicentric, which would verify the suitability of introducing cellular adhesion parameter assessment into routine practice.

[Epidemiological study of hypothyroidism as cardiovascular risk in population]. / Epidemiologická studie hypotyreózy jako kardiovaskulárního rizika v populaci.

BACKGROUND: Prevalence of hypothyroidism (HT) markedly differs among various populations. We aimed to establish the prevalence of HT in the Czech population and to assess its association with conventional cardiovascular risk factors. METHODS AND RESULTS: 1240 subjects (629 m, 611 f; mean age 52.3); a random, population-based sample were evaluated. Cut-off points for thyroid parameters were defined as follows: thyreostimulating hormone (TSH) 0.58-3.65 mU/I, free thyroxine (fT4) 9-22 pmol/l and thyroid peroxidase antibodies (TPOAb) < or = 14 IU/A. The overall prevalence of HT was 6.8% in males and 13.8% in females (p < 0.0001); subclinical HT (high TSH, normal fT4) was found in 3.0% and 8.0%, overt-untreated (high TSH, low fT4) in 3.2% and 3.0% and overt-treated HT in 0.6% and 2.8% of males and females, respectively. Moreover, in euthyroid subjects, 4.6% of males and 9.3% of females showed positive TPO-Ab (p < 0.0001). The adjusted relative risk of hypothyroidism was significantly increased in males with manifest vascular disease (odds ratio 3.48 (1.56-7.74)]), in females aged > or = 55 years (2.08 (1.29-3.36)) or hypertension (1.80 (1.03-3.13)), and moreover, in males and females with positive TPOAb (5.81 (2.57-13.13) and 5.92 (3.38-10.36), resp.) CONCLUSIONS: Hypothyroidism was found in Czech population highly prevalent and it can contribute to the coronary risk, produced by conventional factors.

[Association between free thyroxin concentration and degree of heart failure in patients with chronic heart insufficiency]. / Vztah mezi hladinami volného thyroxinu a stupnem srdecního selhání u pacientu s chronickou levostrannou kardiální insuficiencí.

BACKGROUND: It is evident, that overt thyroid dysfunction (both, hypo- or hyperthyroidism) could be associated with heart failure. The aim of our study was to establish whether also mild changes in free thyroxin (fT4) may influence the degree of heart failure in patients with chronic heart insufficiency. METHODS AND RESULTS: There were included 148 patients (m 121, f 27, mean age 63.8 +/- 1.14) with clinical chronic heart failure were, with fT4 levels within the normal range (9-22 pmol/l) and without thyroid suppression or substitution treatment. Degree of heart failure was quantified by plasma B-type natriuretic peptide (BNP), N-terminal pro-BNP (NT-proBNP) and big endothelin. Patients with fT4 in the range 11.9-14.6 pmol/l (optimal, 3rd-6th decile) had significantly lower NT-proBNP (718 +/- 70.4 pg/ml), than those with fT4 < or = 11.8 (low-normal, bottom two deciles) (1236 +/- 223.6 pg/ml; p < 0.03) and those with fT4 over 14.6 pmol/l [high-normal, top four deciles] (1192 +/- 114.9 pg/ml; p < 0.0002). These differences remain significant also if adjusted for age, gender and other confounders; adjusted odds ratio was 1.30 (1.05-1.59) for optimal vs. low-normal and 1.27 (1.04-1.55) for optimal vs. high-normal. Similar statistical differences were found also in BNP and high endothelin, but only between optimal and high-normal fT4 strata. CONCLUSIONS: The degree of heart failure could be influenced also by mild changes in fT4 concentration.

Diagnostic role of markers dipeptidyl peptidase IV and thyroid peroxidase in thyroid tumors.

BACKGROUND: In seeking to improve the differential diagnosis between malignant and benign thyroid tumors of follicular cell origin, we assessed the expression of dipeptidyl peptidase IV (DPP IV) and thyroid peroxidase (TPO). DPP IV is a membrane peptidase expressed in many human tissues, excluding the normal thyroid gland. However, aberrant expression has been described in thyroid carcinomas. TPO is an essential enzyme in the biosynthesis of thyroid hormones with various types of expression in pathological thyroid lesions. MATERIALS AND METHODS: A total of 151 thyroid glands were examined: 24 malignant tumors, 29 benign tumors, 98 benign lesions and 5 normal glands. DPP IV expression was analyzed by a histochemical technique in both frozen sections and imprint/aspirate smears. TPO was assessed immunohistochemically in paraffin-embedded specimens. RESULTS: DPP IV sensitivity in frozen section was 56% and its specificity was 99%, in both cases with a 50% threshold. In cytology, the sensitivity was 68% and the specificity was 98% using the 50% threshold. TPO sensitivity and specificity was 64% and 99%, respectively. The sensitivity and specificity of both markers was 92% and 94%, respectively. CONCLUSION: We recommend adding DPP IV and TPO to the list of diagnostic tumor markers for malignant thyroid tumors of follicular cell origin.

The significance of CEA, CA19-9 and CA72-4 in the detection of colorectal carcinoma recurrence.

UNLABELLED: The significance of CEA, CA19-9 and CA72-4 was evaluated the for early detection of disease recurrence, on the basis of retrospective evaluation of routine data in patients with colorectal carcinoma. They also considered the dependence of the results of these data analyses on the definition of groups of patients, both with no evidence of disease (NED) and with recurrence of disease (RD). PATIENTS AND METHODS: From January 1994 to March 1999 serum levels of CEA, CA19-9 and CA72-4 were determined in the follow-up of 517 patients with colorectal cancer and compared with the retrospectively confirmed clinical status of the patients. RESULTS: CEA and CA19-9 showed comparable sensitivities in the detection of locoregional recurrence of colorectal carcinoma, whilst the sensitivity of CA72-4 was considerably lower. CEA is an optimal marker for detecting distant metastases, in particular liver metastases, since its sensitivity considerably exceeds the sensitivities of the other two monitored markers. CONCLUSION: Using routine data required detailed analysis and clear definitions of groups of patients with NED and RD. The following conclusions for the evaluation of data were drawn from this analysis: a) Tumor marker cut-off values and sensitivities related to 95% specificity of remission values depended strongly on the given definition of the groups of patients with NED and RD. b) The patient group with NED is best characterized as the group of patients who never developed progression and where all the values which were assessed within a period shorter than six months from the end of therapy and follow-up, or less than six months before progression, death, or before the last marker assessment in the patient, were excluded. c) For the optimal characterisation of the group of patients with RD it is recommended only to consider values obtained during the first progression, after the period of complete post-operative or post-therapeutic remission. d) These conclusions refer not only to routine data, where this correction represents a condition for reliable evaluation, but also to any research done, since they ensure complete homogeneity of the group and mutual comparability of the results.

Criteria for the selection of referential groups in tumor marker statistical evaluation on the basis of a retrospective study.

The authors of this study are concerned with the analysis of optimal criteria for the selection of referential groups in the statistical evaluation of tumor markers for early detection of recurrent disease. Although criteria for the selection of optimal referential groups have already been published on a number of occasions (EGTM recommendation), these criteria are not followed in daily routine, which leads to a false interpretation of results and the impossibility of comparing individual studies. The commonest problem is an incorrect determination of cut-off, caused by not following the recommended specificities at 95%, which results in an incorrect assessment of tumor marker sensitivities. Other faulty interpretations happen in consequence of inaccurate and not clearly defined referential groups, which differ from each other by, for example, stage of the disease, length of the follow-up and so on. Comparing tumor marker results still remains a problem, since they are assessed with diagnostic kits from different manufacturers which may misrepresent the final value of the results, and thus imitate remission or progression of the tumor disease. Similarly, mutual comparison of results from prospective and retrospective studies without standardization of clinical conditions leads to an unreliable interpretation. The authors show, through concrete examples, the possibility of a completely different interpretation of the results in identical referential groups in consequence of their inaccurate characteristics.

[Biological activity in colorectal carcinoma]. / Biologická aktivita u kolorektálního karcinomu.

The trend of current research is not only to obtain a complete characterisation of the cause of inception of tumor proliferation, but in particular to characterize in detail multi-degree cascades of the metastatic process. Precise description of the effector genes and their protein products which influence individual processes of the metastatic cascade, is of great significance not only for the early diagnosis of the possible tumor invasion into its immediate environment and the creation of distant metastases, but particularly for the development of new therapeutic procedures which will help to change from empirical to causal treatment. In practice this means a shift from those therapeutic procedures which lead only to simple blocking of cell division or cell growth, to addressing the individual stages of tumor development (correction of genetic defects in tumor cells, inhibition of the metastatic cascade, inhibition of angiogenesis and apoptosis, etc.). The article characterizes the biological activity of tumors in connection with the metastatic process in colorectal carcinoma.

[Clinical importance of determination of tumor markers during follow-up in breast carcinoma]. / Klinický význam stanovení nádorových markeru v prubehu follow up u karcinomu prsu.

BACKGROUND: Paper deals with detection of the early disease progression in breast cancer patients during follow up using tumor markers. METHODS AND RESULTS: The basic group of 1184 patients with breast carcinoma in follow up after primary therapy were examined from 1996 to 2002. Sera were tested using commercial kits CA 15-3 (MEIA, Abbot), CEA (IRMA, Immunotech), TPA (IRMA, Byk Sangtec), TPS (IRMA, Beki). Results were compared with the retrospectively confirmed clinical status of individual patients. The authors calculated optimal cut offs and sensitivities and their combinations for particular tumor markers at 95% level of specificity. Best sensitivities for the detection of distant metastases into bone, liver, lung and brain was achieved by CA 15-3 (53-68%). As an optimal combination of tumor markers seems to be the tricombination CA 15-3, CEA and TPA. All the tumor markers have insufficient sensitivity for the metastatic process into the lymphnodes. CONCLUSIONS: As optimal combination of tumor markers during the follow up seem to be tricombination CA 15-3, CEA and TPA, but also the clinical relevance and cost effectiveness of these assessments have to be considered. For the tumor disease follow up only CA 15-3 has sufficient sensitivities (at 95% specificities) for the early diagnosis of the metastatic process.

[Role of the MIB-1 proliferative markers in the diagnosis and prognosis of tumors of the thyroid gland]. / Role proliferacního markeru MIB-1 v diagnostice a stanovení prognózy nádoru stítné zlázy.

Well-differentiated thyroid tumors may sometimes cause diagnostic uncertainty due to difficulties in the evaluation of certain morphological criteria (capsular and/or vascular invasion, cytomorphological features). Therefore, various diagnostic/prognostic markers are currently studied, namely the markers of tumor proliferation. The aim of our study was to evaluate the proliferative MIB-1 index in 155 thyroid tumors, and to correlate it with morphological diagnosis, size of the tumors, and the patients' age. Oncocytic tumors were represented by 59 follicular adenomas, 27 follicular carcinomas and 12 papillocarcinomas. Nononcocytic tumors comprised 24 follicular adenomas and 33 conventional papillary carcinomas. The Ki-67 antigen (formalin resistant epitope MIB-1) was detected immunohistochemically and the proliferative index (PI) of tumors was evaluated. The results were statistically analyzed using analysis of variance (ANOVA) and Wilcoxon tests (significance level p < 0.05). Carcinomas showed significantly higher PI than adenomas. Moreover, PI in oncocytic adenomas was higher than in nononcocytic ones. However, proliferative activity in all types of the carcinomas was similar. The higher rates of proliferation correlated with the advanced age of the patients with follicular carcinomas (p < 0.0016).

[Thyroid disease in pregnant women and its development after childbirth]. / Tyreopatie u tehotných zen a jejich vývoj po porodu.

OBJECTIVE: To assess the incidence of post-partum thyropathies in women with positive antibodies against thyroid peroxidase in the second trimester of pregnancy. MATERIAL AND METHODS: Based on a cross-sectional study of the prevalence of abnormal laboratory parameters of thyroid function in a group of 650 pregnant women in the second trimester of pregnancy the authors invited for subsequent clinical examination and repeated controls women with elevated antibodies against thyroid peroxidase (antiTPO) above 60 mU/l (1). The group comprised 75 pregnant women, incl. 44 (58.7%) who attended the examination. After delivery the authors examined the serum levels of TSH, fT4, antiTPO, if necessary fT3 and TRAK. RESULTS: 18, i.e. 58.1% women developed post-partum thyroiditis, incl. 10, i.e. 55.6% who developed hypothyroidism and 8, i.e. 44.4% who developed hyperthyroidism. CONCLUSION: Based on the presented study the authors recommend in pregnant women in the first trimester of pregnancy to introduce assessment of thyrotropin (TSH) and free thyroxin (fT$) and antibodies against thyroid peroxidase (antiTPO)[to detect neuropsychic sequelae on the infant after delivery. The investigation of serum levels of antiTPO antibodies will make it possible to select a group of women in risk of by the development of post-partum thyropathies which must be followed up.

[Prevalence of thyroid gland disorders in pregnant women in the West Bohemia Region during their 2nd trimester of pregnancy in the year 2000--pilot study]. / Prevalence poruch stítné zlázy u tehotných zen v západoceském regionu ve 2. trimestru tehotenství v roce 2000--pilotní studie.

The diagnostics and the treatment of the disorders of the thyroid gland in pregnancy belong to the most important topics for most endocrinologists in the whole world. Untreated or mistreated thyroid gland disorders may influence the course of pregnancy and development of the foetus and child. Autoimmune thyroiditis, hyperthyroidism and hypothyroidism represent the most common thyreopaties in pregnancy and that is why the aim of the study was to establish their prevalence in population of pregnant women of the West Bohemia region. In our study we assessed serum levels of thyrotropin (TSH), free tyroxin (fT4) and antithyroid peroxidase antibodies (antiTPO) in 650 pregnant women. Sera were acquired during routine blood sampling for Down syndrome screening in the 2nd trimester of pregnancy. In our group we found the prevalence of 1.5% of hypothyroidism and 9.4% of autoimmune thyroiditis and we revealed no case of thyrotoxicosis, only subnormal TSH in 2.3%.