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Identifier 000442617
Title Identification of prognostic biomarkers in metastatic colorectal and loccally advanced rectal cancer
Alternative Title Ανίχνευση προγνωστικών βιολογικών δεικτών στο μεταστατικό καρκίνο του παχέος εντέρου και τοπικώς προχωρημένο καρκίνο του ορθού
Author Νικολουζάκης, Ταξιάρχης Κωνσταντίνος
Thesis advisor Τσιαούσης, Ιωάννης
Reviewer Σουγκλάκος, Ιωάννης
Τσατσάκης, Αριστείδης
Abstract Colorectal cancer (CRC) is the third most common type of cancer for both sexes and one of the leading causes of cancer-related mortality worldwide. These characteristics have attracted numerous research teams across the globe, creating the right conditions for significant advances on unveiling the underlying molecular biology, identifying new diagnostic tests and expanding treatment options while introducing personalized ones. However, despite numerous attempts to identify effective prognostic and predictive tools only little progress has been made. This is because in most studies the size of patient sets is rather small which prevents safe conclusions to be drawn. At the same time, the relatively high cost and complexity of the proposed techniques makes the implementation of these tools deterrent. Therefore, current practice in CRC management continues to evaluate patient response after completion of their treatment. This is of great importance, since patients who develop chemoresistance will be identified with substantial delay, leaving both them and health care systems challenging with the unnecessary side effects and increased cost of ineffective treatments. Thus, in order to optimize clinical practice, the identification of sensitive and easy-to-use tools that will provide valuable information about the prognosis of each patient is emerging as crucial. Such tools are expected to benefit patients with CRC and clinicians directly (as they will be able to discontinue ineffective treatment at an early stage) but also indirectly the health care system given the more efficient management of resources to treat these patients. In addition, it should be noted the possibility of expanding the validation of the prognostic value of these tools to other types of cancer. It is well established that molecular biomarkers can serve as promising candidates for this purpose. In view of the above, the present study focused on validating the clinical value of two new biomarkers: a) micronuclei frequency (MNf) in 55 metastatic CRC (mCRC) and 21 locally advanced rectal cancer (laRC) patients using cytokinesis block micronucleus assay (CBMN assay) and b) telomerase activity (TA) in 23 mCRC and 5 laRC patients using TRAP-ELISA. These biomarkers were chosen on the basis of their close relationship to chromosomal instability (CIN) and aberrant genetic function, both major hallmarks in colorectal carcinogenesis. All biomarkers were evaluated in peripheral blood lymphocytes (PBLs) before, in the middle and at the end of treatment (approximately 0, 3 and 6 months) for mCRC patients and before, at the end of treatment and after surgery for patients with laRC. Overall, MNf demonstrated significant prognostic value, since a reduction of <29% between middle and initial MNf measurements can discriminate between progressive and stable/responsive disease with a sensitivity of 36% and a specificity of 87.0%. It also appeared to be able to identify responsive disease with sensitivity of 72.7% and specificity 59.3%. Regarding TA, no statistically significant difference was found between the disease response groups in any of the sampling points (before the beginning of chemotherapy p = 0.256, in the middle of the chemotherapy p = 0.072, at the end of the chemotherapy p = 0.096). However, it was observed that in the middle and last sampling points, the patients with progressive disease had an increase in TA while the concomitant comparison between groups (disease progression vs stable disease, disease progression vs partial response, disease progression vs complete response) revealed a significant trend to increase TA in patients with disease progression (middle sampling point p = 0.072, final sampling point p = 0.096). However, it was not possible to further statistically compare TA values of patients with progressive disease between the three sampling points due to the absence of a normal distribution of TA values, possibly due to the small sample we studied. In conclusion, the findings of this study demonstrate the value of MN frequency as a promising prognostic biomarker for monitoring the response to treatment of patients with CRC, while TA should be evaluated in a larger group of patients to document its possible change during chemotherapy and its related clinical significance.
Language English
Subject Metastatic colorectal cancer
Κολοορθικός καρκίνος
Issue date 2021-12-01
Collection   School/Department--School of Medicine--Department of Medicine--Doctoral theses
  Type of Work--Doctoral theses
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