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.

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.

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.

[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.

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.

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.

[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).

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.