Search

Background/aim: Per literature, patients with epidermal growth factor receptor (EGFR) exon-20 insertions respond poorly to tyrosine kinase inhibitors (TKIs). This study analyzed real-world data to examine the prognostic and predictive value of these mutations., Patients and Methods: We conducted a retrospective cohort study using Czech TULUNG Registry data, with data on multiple mutation types, collected in 2011-2020., Results: We analyzed 554 (95.85%) patients with EGFR exon-19 deletions or exon-21 L858R substitutions and 24 (4.15%) patients with exon-20 insertions who received first-line high-value therapies. We summarized clinical characteristics and outcomes in all patients and by cohort. The risk of progression was statistically significantly higher (86%) in the exon-20 insertion cohort compared to the cohort with other mutations. Although not statistically significant, the risk of death was 44% higher in patients with exon-20 insertions., Conclusion: Advanced NSCLC patients with rare EGFR exon-20 insertions have a high risk of progression., (Copyright © 2021 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Introduction: Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor characterized by pathological vascularization. Mutations in isocitrate dehydrogenases 1 and 2 (IDH1 and IDH2) were observed in GBM. We aimed to assess the intra-tumor hypoxia, angiogenesis and microvessel formation in GBM and to find their associations with IDH1 mutation status and patients prognosis., Methods: 52 patients with a diagnosis of GBM were included into the study. IDH1 R132H mutation was assessed by RT-PCR from FFPE tumor samples obtained during surgery. The expression of markers of hypoxia (HIF2α), angiogenesis (VEGF), tumor microvascularity (CD31, CD34, vWF, CD105), and proliferation (Ki-67) were assessed immunohistochemically (IHC). IDH1 mutation and IHC markers were correlated with the patient survival., Results: 20 from 52 GBM tumor samples comprised IDH1 R132H mutation (38.5%). The majority of mutated tumors were classified as secondary glioblastomas (89.9%). Patients with IDH1 mutated tumors experienced better progression-free survival (P = 0.037) as well as overall survival (P = 0.035) compared with wild type tumors. The significantly lower expression of VEGF was observed in GBM with IDH1 mutation than in wild type tumors (P = 0.01). No such association was found for microvascular markers. The increased expression of newly-formed microvessels (ratio CD105/CD31) in tumor samples was associated with worse patient's progression-free survival (P = 0.026)., Summary: No increase in HIF/VEGF-mediated angiogenesis was observed in IDH1-mutated GBM compared with IDH1 wild type tumors. The histological assessment of the portion of newly-formed microvessels in tumor tissue can be used for the prediction of GBM patient's prognosis., Competing Interests: CONFLICTS OF INTEREST Authors declare that they have no conflicts of interests regarding the publication of this paper.

Febrile neutropenia (FN) is a common and potentially fatal complication of anticancer treatment, particularly in patients receiving myelosuppressive chemotherapy. It has been shown that prophylaxis with granulocyte colony-stimulating factor (G-CSF), especially its pegylated forms, significantly reduces the incidence of FN, the likelihood of chemotherapy dose intensity reduction and, also, the number of hospitalizations due to FN. This review discusses currently published results from clinical trials dealing with FN prophylaxis in routine clinical practice in patients with solid tumors and myeloproliferative malignancies with a focus on lipegfilgrastim, which is the newest modification of the original molecule filgrastim. The discussed results proved that prophylactic administration of lipegfilgrastim can almost eliminate the risk of FN and significantly reduce the risk of chemotherapy (CHT) dose reduction in routine clinical practice in cases of a clear high-risk chemotherapy regimen or in the presence of risk factors (such as age, comorbidities, performance status, etc.) in patients who received chemotherapy with medium risk of FN., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: The behavior of tumor markers in biliary tract malignancies is not well-known and has been scarcely studied. Such markers could play important roles in diagnostic and prognostic schemes as well as in decision-making about the best treatment strategies. This study analyzed the preoperative serum levels of conventional tumor markers (AFP, CEA, CA 19-9, CA 72-4), proliferative marker thymidine kinase (TK) and cytokeratins (TPA, TPS and CYFRA 21.1) in patients with gallbladder carcinoma, bile duct carcinoma (Klatskin) and cholangiocellular carcinoma, in relation to the patient prognosis. The study aimed in finding the role of tumor markers in not properly investigated diseases, where their importance is often marginalized., Materials and Methods: The study included 43 patients, who underwent either radical surgical procedure (n=21) or explorative laparotomy without any surgical treatment (n=22) for gallbladder carcinoma, bile duct carcinoma (Klatskin tumor) and cholangiocellular carcinoma (24, 8 and 11 patients, respectively) between 2003 and 2010 at our Department. The association of serum tumor markers and patients' prognosis were assessed for the entire cohort and for each cancer type and also with regard to treatment (radical surgery versus explorative laparotomy). Overall survival (OS) and disease-free interval (DFI) were estimated by the Kaplan-Meier method and statistically evaluated using the LogRank test. DFI was computed only in the subgroup of patients treated by radical surgery., Results: The statistical analysis of tumor markers revealed TK as a poor prognostic factor for shorter DFI (HR=3.5, 95%CI=0.6-21.3, p<0.05) and also OS (HR=4.6, 95%CI=1.0-4.7, p<0.05) in patients with gallbladder carcinoma treated with radical surgery. TPS was demonstrated as a poor prognostic factor for OS in patients with gallbladder carcinoma (HR=12.7, 95%CI=1.4-117.7, p<0.05). CEA was proven to be a factor of poor prognosis with shorter OS in patients after explorative laparotomy for all cumulated studied diagnoses (HR=9.8, 95%CI=1.05-92.7, p<0.05)., Conclusion: The results of this study suggested the importance of tumor markers for assessment of prognosis (OS or DFI) in patients with gallbladder carcinoma, bile duct carcinoma, and cholangiocellular carcinoma., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Glioblastoma multiforme (GBM) represents the most malignant primary brain tumor in adults with generally dismal prognosis, early clinical deterioration and high mortality. GBM is extremely invasive, characterized by intense and aberrant vascularization and high resistance to multimodal treatment. Standard therapy (surgery, radiotherapy and chemotherapy with temozolomide) has very limited effectiveness, with median overall survival of patients no longer than 15 months. Progress in genetics and epigenetics of GBM over the past decade has revealed various aberrations in cellular signaling pathways, the tumor microenvironment, and pathological angiogenesis. A number of targeted anticancer drugs, such as small-molecule kinase inhibitors and monoclonal antibodies, have been evaluated in clinical trials with newly-diagnosed, as well as recurrent GBM. Unfortunately, to date, only a single anti-angiogenic agent, bevacizumab, has been approved for the treatment of recurrent GBM in the USA and Canada. The novel possibilities of cancer immunotherapy, especially immune checkpoint inhibitors, are being evaluated in clinical trials of patients with GBM. The most recent clinical experiences with targeted therapy as well as immunotherapy of GBM are given in this review. The relative lack of success of some of these approaches recently revealed in well-designed randomized clinical trials is also discussed., (Copyright© 2017 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background/aim: Minimal residual disease (MRD) in patients with acute myeloid leukemia (AML) before allogeneic hematopoietic stem cell transplantation (alloHSCT) can influence the results of therapy. With the aim of evaluating the potential role of pre-transplant MRD, we studied the impact of pre-transplant MRD level on the outcome of alloHSCT in patients with AML in complete remission (CR)., Patients and Methods: From 2/2005 to 9/2014, 60 patients with a median age of 54 years (range=30-66 years) with normal karyotype-AML harboring nucleophosmin 1 (NPM1) mutation [53% Fms-related tyrosine kinase receptor 3 internal tandem duplication (FLT3/ITD)-positive] in first (n=45) or second (n=15) CR underwent myeloablative (n=16) or reduced-intensity (n=44) alloHSCT (27% related, 73% unrelated). The MRD level was determined from bone marrow samples using real-time polymerase chain reaction for detection of NPM1 mutations before starting the conditioning regimen., Results: The estimated probabilities of 3-year relapse, event-free survival (EFS) and overall survival (OS) for the whole cohort were 28%, 54%, and 59%, respectively. Statistical analysis showed that only age over 63 years and high MRD level affected alloHSCT outcome. Pre-transplant MRD level of 10 mutant copies of NPM1 per 10,000 Abelson murine leukemia viral oncogene homolog 1 (ABL) copies had the strongest statistical significance, and detection of higher MRD level (>10 NPM1-mutant copies) before alloHSCT was associated with increased overall mortality (hazard ratio=3.71; 95% confidence interval=1.55-9.06; p=0.004). The estimated probabilities of 3-year relapse, EFS, and OS were 6%, 72%, and 75% for patients with a low level of MRD and 48%, 35%, and 40% for patients with a higher level., Conclusion: Our data showed that the pre-transplant level of MRD in patients with normal karyotype AML harboring NPM1 mutation in CR provides important prognostic information, which as an independent prognostic factor predicts transplant results., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Monoclonal antibodies binding the epidermal growth factor receptor (EGFR), such as cetuximab or panitumumab, are widely used targeted therapeutics for the treatment of patients with colorectal cancer. The clinical significance of these drugs has so far been associated with combined chemotherapy or radiation. It has been shown that these treatment strategies have their clinical limitations and do not fully exploit the immunomodulatory effect of these drugs. In this review, we discuss the mechanisms of immunomodulation together with the anticancer immune response to the monoclonal antibodies targeted to the EGFR. The combination of anti-EGFR monoclonal antibodies with other immunotherapeutic treatment modalities certainly brings new opportunities for targeted therapy in patients with colorectal cancer., (Copyright© 2016 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Aim: To identify tissue biomarkers that are predictive of the therapeutic effect of sunitinib in treatment of metastatic clear cell renal cell carcinoma (mCRCC)., Materials and Methods: Our study included 39 patients with mCRCC treated with sunitinib. Patients were stratified into two groups based on their response to sunitinib treatment: non-responders (progression), and responders (stable disease, regression). The effect of treatment was measured by comparing imaging studies before the initiation treatment with those performed at between 3rd and 7th months of treatment, depending on the patient. Histological samples of tumor tissue and healthy renal parenchyma, acquired during surgery of the primary tumor, were examined with immunohistochemistry to detect tissue targets involved in the signaling pathways of tumor growth and neoangiogenesis. We selected mammalian target of rapamycine, p53, vascular endothelial growth factor, hypoxia-inducible factor 1 and 2 and carbonic anhydrase IX. We compared the average levels of biomarker expression in both, tumor tissue, as well as in healthy renal parenchyma. Results were evaluated using the Student's t-test., Results: For responders, statistically significant differences in marker expression in tumor tissue versus healthy parenchyma were found for mTOR (4%/16.7%; p=0.01031), p53 (4%/12.7%; p=0.042019), VEGF (62.7%/45%; p=0.019836) and CAIX (45%/15.33%; p=0.001624). A further significant difference was found in the frequency of high expression (more than 60%) between tumor tissue and healthy parenchyma in VEGF (65%/35%; p=0.026487) and CAIX (42%/8%; p=0.003328). CAIX was expressed at high levels in the tumor tissue in both evaluated groups., Conclusion: A significantly higher expression of VEGF in CRCC in comparison to healthy parenchyma can predict a better response to sunitinib., (Copyright© 2015 International Institute of Anticancer Research (Dr. John G. Delinassios), All rights reserved.)

Background: The efficacy of anticancer therapy is regularly evaluated using the following indicators -  objective response rate, progression free survival and overall survival. The change in the tumor burden extent is assessed by the cumulative change in the size of target tumor lesions using imaging methods where WHO and RECIST criteria are most frequently used. The main problem of these criteria is that they use different definitions of response rate evaluation. Generally, existing results of these evaluations do not confirm a direct correlation between the objective response rate and survival (progression free survival or overall survival). Another problem of these methods is that the results of the assessment do not correlate with the bio-logical activity of tumor growth, since it is a static evaluation of clinical status., Aim: This review article provides an overview of results related to new possibilities for evaluating the efficacy of anticancer therapy using the concept of depth of response and the concept of early tumor shrinkage in patients with metastatic colorectal cancer., Conclusion: The results of numerous posthoc and exploratory analyses of clinical studies consistently suggest that early tumor shrinkage and depth of response are important variables in assessing the efficacy of systemic anticancer treatment.

Background: Chylous ascites is a rare complication of the gastrointestinal neuroendocrine tumor. There are two mechanisms of its origin: mechanical obstruction by the tumor mass and fibrosis of the surrounding tissue due to overproduction of serotonin. Its presence restricts treatment options., Case: We report a case of 66year old man suffering from recurrent diarrhoea and ascites. We found elevated tumor marker Chromogranin A and elevation of hydroxyindoleacetic acid (5- HIAA) in the urine. A subsequent whole body scintigraphy scan by octreoscan confirmed multinodal process with increased somatostatin receptors activity in the wall of the ileum, rectosigmoideum, lymph nodes of the retroperitoneum and mesenterium and left supraclavicular area. We performed bio-psy from the lymph node of supraclavicular area, and there was metastasis of the neuroendocrine tumor. Start of cytostatic therapy was repeatedly complicated by recurrent massive chylous ascites. The patient underwent only one series of palliative chemotherapy. Another procedure was again complicated by chylous ascites that caused hospitalization at the internal department, and the patient died four months after dia-gnosis., Conclusion: Chylous ascites is a very rare complication of gastrointestinal neuroendocrine tumor. It is not only a marker of poor prognosis, but also a complication that makes systemic treatment very difficult.

Background: Tapentadol is a µ -opioid receptors agonist as well as an inhibitor of noradrenaline reuptake. This pharmacologic profile of tapentadol makes it a suitable drug of choice in nociceptive and neuropathic pain control., Case Report: This clinical report pressents a 65year old man with poorly differentiated prostate cancer -  Gleason score 8 (4 + 4) with metastatic bone disease. Besides the initial application of bisphosphonates, the patient had been treated with androgen deprivation therapy (cyproterone acetate + leuprolide acetate) for the period of 18 months. This therapy was terminated due to an increase of PSA levels. Subsequently, the patient underwent palliative docetaxelbased chemotherapy. There were eight cycles applied with positive clinical and laboratory effect. However, the further application was limited by the averse effects, namely the peripheral neuropathy manifested by pain in arms and legs. The peripheral neuropathy had progressive tendency even after the end of chemotherapy, and supportive treatment with gabapentin and amitryptiline failed to succeed. Four months after zoledronic acid monotherapy, the patient was started on tapentadol in 50-mg dose b.i.d., consequently escalated to 100 mg b.i.d. (to this point, 25 µg of transdermal fentanyl were used for pain management). Significant relief from neuropathic discomfort was observed three weeks from the onset of tapentadol therapy. Patients state of health normalized within three months after the initiation of therapy. Consequently, the patient was able to receive docetaxel chemotherapy again, without any neuropathic pain exacerbation on the maintenance dose of tapentadol 50 mg b.i.d., Conclusion: Tapentadol administration resulted in stable and longtime relief from neuropathic pain which is a frequent side effect in the course of castrate-resistant prostate cancer therapy with taxanes.

Purpose: DNA repair capacity (DRC) is a determinant not only of cancer development but also of individual response to therapy. Previously, altered base and nucleotide excision repair (BER and NER) have been described in lymphocytes of patients with sporadic colorectal cancer. We, for the first time, evaluate both excision repair capacities in human colon biopsies to study their participation in colorectal tumorigenesis., Experimental Design: Seventy pairs of tumor and adjacent healthy tissues were analyzed for BER- and NER-specific DRC by a comet repair assay. Tissue pairs were further compared for expression levels of a panel of 25 BER and NER genes complemented by their promoter methylation status., Results: We observed a moderate increase of NER-DRC (P = 0.019), but not of BER-DRC in tumors. There was a strong correlation between both tissues for all investigated parameters (P < 0.001). However, 4 NER (CSB, CCNH, XPA, XPD) and 4 BER (NEIL1, APEX1, OGG1, PARP1) genes showed a 1.08- to 1.28-fold change difference in expression in tumors (P < 0.05). Individual gene expression levels did not correlate with overall DRC, and we did not detect any aberrant methylation of the investigated genes., Conclusions: Our complex analysis showed that tumor cells are not deficient in BER and NER, but rather follow patterns characteristic for each individual and are comparable with adjacent tissue. Alteration of excision repair pathways is not a pronounced event in colorectal carcinogenesis. This study shows the feasibility of DRC evaluation in human solid tissues, representing a complex marker of multigene DNA repair processes., (©2012 AACR.)

Targeted biological therapy is becoming a standard in personalized medicine for patients with advanced stages of cancer. Treatment with cetuximab, an anti-epidermal growth factor receptor (EGFR) antibody, represents an example of personalized anticancer therapy for patients with metastatic colorectal cancer and wild (non-mutated) type of the Kirsten rat sarcoma viral oncogene (KRAS). Here the role of cetuximab in treating metastatic colorectal cancer is discussed with a focus on the treatment of hepatic metastases.

Background: The aim of this work was to study the influence of isolated biological therapy administered immediately before extended liver resection on liver function and regenerative capacity of future liver remnant (FLR) in a large-animal experiment., Materials and Methods: Nineteen piglets were included in this study (10 in the control group and 9 in the experimental group). A port-a-cath was introduced into the superior caval vein. On days 11 and 4 before liver resection, cetuximab was administered via this port at 400 mg/m2 of piglet body surface. Physiological solution was applied to the control group. Resection of the left lateral, left medial and right medial hepatic lobes was followingly performed (reduction of 50-60% of liver parenchyma). Blood samples were collected at different times before the operation and after liver resection. Serum levels of bilirubin, urea, creatinine, alkaline phosphatase, gamma glutamyltransferase, cholinesterase, aspartate aminotransferase, alanine aminotransferase, albumin, C-reactive protein and transforming growth factor-β1 were assessed. The ultrasonographic examinations at different time points were performed pre-operatively and after liver resection in order to assess the liver volume. The biopsies from the liver parenchyma were examined for proliferative activity, binocluated hepatocytes, size of hepatocytes, and the length of the lobuli. The comparison of distribution of the studied parameters between the groups was carried out using the Wilcoxon test. The Spearman rank correlation co-efficient was used because of the non-Gaussian distribution of the parameter values. The whole development of the studied parameters over time was compared between the groups using ANOVA., Results: There were no important complications of administration of biologic therapy during the operation or throughout the peri-operative period. There was no statistically significant difference in the regeneration of FLR nor were any differences in biochemical, immunoanalytical and histological parameters detected., Conclusion: The achieved results of comparable liver regeneration in both the experimental and control groups confirms the use of biological treatment with cetuximab in the pre-operative period for minimizing the recovery period.

Background: Circulating cytokeratins have shown to be important for management of patients with lung cancer. Here we investigated their role for differential diagnosis, therapy monitoring and prognosis in colorectal cancer (CRC)., Patients and Methods: Pretherapeutic levels of cytokeratin-19 fragments (CYFRA 21-1), carcino-embryonic antigen (CEA) and cancer antigen (CA) 19-9 were measured in 42 patients with CRC, 45 with benign colorectal diseases and 51 healthy controls. Furthermore, courses of CYFRA 21-1, tissue polypeptide antigen (TPA), tissue polypeptide specific antigen (TPS), M30-antigen, CEA and CA 19-9 were analyzed in prospectively collected sera of 15 patients with CRC during primary chemotherapy and were correlated with therapy response and overall survival (OS)., Results: Similar to CEA and CA 19-9, CYFRA 21-1 was significantly elevated in serum from patients with CRC (median 2.1 ng/ml) as compared with healthy (1.2 ng/ml; p<0.0001) and benign gastrointestinal controls (1.7 ng/ml; p=0.0178) and showed stage dependency in CRC (p=0.0118). CYFRA 21-1 correlated with CEA in benign diseases and CRC but not with CA 19-9. The best discrimination between healthy controls and patients with CRC was achieved by combination of CYFRA 21-1 and CA 19-9 (area under the curve; AUC=86.7%), while the combination of CEA and CA 19-9 discriminated best between benign diseases and CRC (AUC=73.9%). In CRC patients during primary chemotherapy, levels of cytokeratins CYFRA 21-1, TPA, TPS, CEA and CA 19-9 tended to be higher in patients with poor response to therapy and with poor prognosis., Conclusion: Cytokeratins are elevated in patients with CRC and show some association with response to primary therapy and prognosis.

Background: S100(+) dendritic cells and CD57(+) lymphocytes are factors reflecting the immune system's ability to suppress the progress of tumor growth. CD57(+) cells include natural killer cells and late stages of T-effector lymphocytes. We evaluated the relationship between the known clinical and histological factors and tumor markers as well as the presence of S100(+) and CD57(+) cells in the tissue of colorectal carcinoma with the aim of detecting patients at high risk of short overall survival (OS) or short disease-free interval (DFI) after radical surgical treatment and we further analyzed whether S100(+) and CD57(+) positivity could bring on new information regarding the treatment regimen., Materials and Methods: Data of 150 patients (97 males and 53 females) that underwent an elective radical surgical procedure for colorectal cancer were studied. The influence on DFI and on OS of the following parameters was evaluated: grading, staging and positivity for S100 and CD57 by immunohistochemical staining. We also analyzed the relation of preoperative serum levels of the tumor markers Carcinoembryonic Antigen (CEA), Cancer Antigen 19-9 (CA19-9), Cancer Antigen 72-4 (CA72-4), Thymidine kinase (TK), Tissue-Specific Polypeptide Antigen (TPS) and Tissue Polypeptide Antigen (TPA) in relation to S100 and CD57 positivity/negativity for the same patients., Results: OS at 1, 3 and 5 years was 92.2%, 76.5% and 70.2%; the DFI at 1, 3 and 5 years was 85.3%, 64.3% and 49.4%. CD57 positivity in the tumor mass was proven as a positive prognostic factor for OS. Risk of short OS was 2.5-fold higher in patients with low tumor infiltration by CD57(+) lymphocytes. The combination of N2 stage for lymph nodes and the absence of CD57(+) cells was proven to be the strongest negative prognostic factor for OS. No significant influence of CD57 positivity on DFI appeared. There was no significant influence of S100 positivity on OS or DFI; nor was there any statistical dependence of CD57 and S100 positivity or negativity on preoperative serum levels of CEA, CA19-9, CA72-4, TK, TPS or TPA. Both studied factors were shown to be statistically independent factors., Conclusion: The present study showed infiltration of colorectal cancer tissue by CD57(+) cells as being an important independent positive prognostic factor for OS.

Objectives: Classical and proliferative tumour markers and matrix metalloproteinases and their tissue inhibitors reflect the features of malignancy and are useful in prediction of prognosis in patients with colorectal liver metastases. There is very limited information about their physiological functions during regeneration and healing of liver parenchyma after any type of liver surgery for malignancy., Methods: The presented study included the patients, who underwent following surgical procedures for CLM, benign liver lesions and inguinal hernias: Group A: 22 patients with inguinal hernias, Group B: 26 patients with benign liver lesions, Group C: 30 patients with colorectal liver metastases (CLM) who were treated by radiofrequency ablation, Group D: 41 patients with CLM who underwent a radical surgical therapy - resection, and Group E: 22 patients with inoperable CLM who underwent an explorative laparotomy without any surgical procedure., Results: The preoperative and postoperative serum levels of CEA, CA 19-9, TK, TPA, TPS, MMP-2, MMP-9, TIMP-1, and TIMP-2 were statistically analyzed and compared within the groups to estimate the influence of a surgical procedure type. These results reflect the influence of surgical procedure on the serum levels of studied tumour markers during operation., Conclusions: It was the first description using these types of comparison to all metalloproteinases, their inhibitors, and proliferative and classical tumour markers. It could help us to estimate the critical relations of these tumour markers in prognoses of disease free survival or overall survival in patients after a surgical procedure for CLM (Tab. 5, Ref. 26).

Unlabelled: Tissue inhibitor of metalloproteinases 1 (TIMP1) regulates not only extracellular matrix catabolism but the major effect in tumor tissue is promotion of cell growth and anti-apoptotic activity. The aim of our study was to evaluate plasma TIMP1 levels and tissue TIMP1 mRNA expression as prognostic markers in NSCLC patients., Patients and Methods: We studied a group of 108 patients with NSCLC who had undergone lung surgery. Estimation of TIMP1 mRNA was performed by quantitative polymerase chain reaction (qPCR) and estimation of plasma TIMP1 protein using enzyme-linked immunosorbent assay (ELISA)., Results: There was shorter disease-free interval (DFI) for NSCLC patients at stage II, with a higher expression of TIMP1 mRNA in tumor tissue (p=0.0246). We recorded a relationship between tumor tissue TIMP1 mRNA expression and DFI in squamous cell carcinoma (SCC) (p=0.0117). Shorter overall survival was found in patients at stages IIIa+IIIb+IV, with a higher expression of TIMP1 mRNA (p=0.0389). We found differences in plasma TIMP1 levels between patients with SCC and those with adenocarcinoma (p=0.0491)., Conclusion: A higher tissue level of TIMP1 mRNA is related to an adverse prognosis of patients. However, our results did not show any relation of TIMP1 protein in blood plasma to prognosis.

Background: Many studies have demonstrated the relationship between vitamin D and cancer of many different sites, including of the breast, colorectum, prostate and lung. Most epidemiological studies have assessed the effects of dietary intake only, although endogenous production after sun exposure is the main source of vitamin D. The aim of our pilot study was to study serum levels of vitamin D in general population and in patients with different type of cancer., Patients and Methods: The control group consisted of 214 healthy individuals. Pathological groups of patients included 170 patients with different cancer types (28 patients with prostate cancer, 43 patients with breast cancer, 49 patients with colorectal cancer and 50 patients with lung cancer). All of the patients were enrolled in the early clinical stage of cancer up to clinical stage III. Advanced stages were not included into the study. Vitamin D serum levels were measured using ECLIA Roche method., Results: All the results for serum vitamin D from pathological groups were significantly lower compared to the levels of the control group. All the cancer types had a high incidence rate of very low serum levels of vitamin D. Lung cancer had the highest incidence rate of very low vitamin D serum levels., Conclusion: We found a high incidence of hypovitaminosis D in cancer patients compared to a healthy control group among a Czech population. This incidence rate is higher in comparison to data found in literature from the other parts of the world. Based on the data from this study, a large epidemiological study monitoring vitamin D serum levels in the healthy population and in cancer patients in the Czech Republic has been already proposed.

Background: A new cytokeratin tumor marker, MonoTotal was studied in lung cancer, the most common cause of cancer mortality worldwide. In non-small cell lung cancer (NSCLC) patients MonoTotal serum levels and their relationship to the tumor stage, histological subtype, early relapse and cancer-related death were evaluated., Patients and Methods: MonoTotal serum levels were studied, using immunoradiometric assay in a group of 93 patients with newly diagnosed NSCLC undergoing radical surgery, and were compared to those with benign lung diseases., Results: A diagnostic power of MonoTotal in distinguishing patients with NSCLC from benign lung diseases was demonstrated. Higher levels of MonoTotal were associated with advanced stages of squamous cell carcinoma and there was a positive correlation of marker with tumor size. Marker levels showed significant relation to disease-free survival and overall survival., Conclusion: MonoTotal seems to be a potentially very interesting serum marker that, in conjunction with other clinical data, might be used for monitoring of patients with NSCLC.

Aim: The liver is the site of breast cancer metastasis in 50% of patients with advanced disease. Tumour markers have been demonstrated as being useful in follow-up of patients with breast cancer, in early detection of recurrence of breast cancer after radical surgical treatments, and in assessing oncologic therapy effect, but no study has been carried out on their usefullness in distinguishing benign liver lesions from breast cancer metastases. The aim of this study was therefore to evaluate the importance of tumour markers carcinoembryonic antigen (CEA), carbohydrate antigen CA19-9 (CA19-9), thymidine kinase (TK), tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS) and cytokeratin 19 fragment (CYFRA 21-1) in differential diagnosis between benign liver lesions and liver metastases of breast cancer., Patients and Methods: The study includes 3 groups: 22 patients with liver metastases of breast cancer; 39 patients with benign liver lesions (hemangioma, focal nodular hyperplasia, liver cyst, hepatocellular adenoma); and 21 patients without any liver disease or lesion that were operated on for benign extrahepatic diseases (groin hernia, varices of lower limbs) as a control group. The serum levels of tumour markers were assessed by means of immunoanalytical methods., Results: Preoperative serum levels of CYFRA 21-1, TPA, TPS and CEA were significantly higher in patients with liver metastases of breast cancer in contrast to healthy controls and patients with benign liver lesions (p-value<0.05). Serum levels of CA19-9 and TK were higher in patients with malignancy in comparison with benign liver disease and healthy controls but these differences were not statistically significant., Conclusion: Tumour markers CEA, CYFRA 21-1, TPA and TPS can be recommended as a good tool for differential diagnosis between liver metastases of breast cancer and benign liver lesions.

Background: The aim of this study was to measure several parameters in patients with early-stage colorectal cancer (CRC) and to evaluate them for their utility in routine clinical practice., Patients and Methods: Pre-operative serum levels of the following parameters were measured in 174 patients with CRC (clinical stage I-III): carcinoembryonic antigen (CEA), carbohydrate antigen CA 19-9, proliferative marker thymidine kinase (TK), tissue polypeptide antigen (TPA), tissue polypeptide-specific antigen (TPS), interleukin-6 (IL-6), interleukin-10 (IL-10), matrix metalloproteinase-9 (MMP-9), tissue inhibitor of metalloproteinase-1 (TIMP-1), intercellular adhesion molecule-1 (ICAM-1), vascular cell adhesion molecule-1 (VCAM-1), vascular endothelial growth factor (VEGF), C-peptide, insulin, adiponectin and leptin. The control group consisted of 50 patients who were undergoing a complete preventive medical examination and in these patients at the time of blood collection there was no evidence of any cancer disease., Results: Significant increase of the following parameters was found in patients with CRC: CEA, CA 19-9, TPA, IL-6, IL-10, TIMP-1, C-peptide, insulin and adiponectin. Only two of these, CA 19-9 and adiponectin, represent highly unfavorable prognostic factors. If elevated, they affect both progression-free interval and overall survival., Conclusion: Based on our results, we can conclude that none of the measured parameters fulfills the criteria for use for screening nor for primary diagnosis of CRC. Some of the parameters are important for prognosis estimate: Elevated CA 19-9 is related to an unfavorable prognosis, in terms of cancer recurrence and mortality rate. Angiogenetic factor VEGF represents a prognostic factor important for OS. CEA represents a parameter which is related to disease progression. Interleukins seem to be prospective complementary tumor markers. Adiponectin may be used for estimation of advanced stage of cancer and for estimate of risk of cancer recurrence.

Background: MicroRNAs (miRNAs), which are endogenously expressed regulatory noncoding RNAs, have an altered expression in tumor tissues. MiRNAs regulate cancer-related processes such as cell growth and tissue differentiation, and therefore, might function as oncogenes or tumor-suppressor genes. The aim of our study was to assess the expression of mir-20a, let-7a, miR-15a and miR-16 in prostate cancer (PCa) and benign prostatic hyperplasia (BPH) tissue and to investigate the relation between the expression of miRNAs and the clinicopathological features of PCa., Patients and Methods: The study group comprised 138 patients: 85 patients with BPH and 53 patients with PCa. The total RNA was isolated from the tissue specimen core and miRNA expressions were quantified using a real-time RT-PCR method (TaqMan MicroRNA Assays). U6snRNA was used for the normalization of the miRNA expression., Results: miR-20a expression was significantly higher in the group of patients with a Gleason score of 7-10 in comparison with the group of patients with a Gleason score of 0-6 (p=0.0082). We found no statistical differences in the miRNA expressions (mir-20a, let-7a, miR-15a and miR-16) in the PCa tissue samples in comparison with the BPH tissue samples., Conclusion: Our result shows that the more dedifferentiated PCa cells have a higher expression of miR-20a and this supports the oncogenic role of miR-20a in PCa carcinogenesis. The evaluation of miRNA expression could yield new information about PCa pathogenesis.

Background: Early diagnosis of prostate cancer (PCa) in an organ-confined stage following radical treatment is the only potential curative approach in PCa. Prostatic-specific antigen (PSA) is very helpful in early diagnosis, but the main disadvantage is that it has a low positive predictive value in the range of the grey zone of 2.5-10 ng/mL, which results in a high number of needless biopsies. For this reason, new tests with better parameters are needed. One promising test is that for differential display code 3 (DD3(PCA3)), which is a prostate-specific non-coding mRNA that is highly overexpressed in prostate tumor cells. The aim of the present study was to evaluate the potential of DD3(PCA3) for mRNA in PCa diagnosis., Patients and Methods: A total of 186 patients were examined. In a group of patients with suspected PCa, one tissue specimen core was collected for testing DD3(PCA3) expression. According to the histological verification there were 100 patients with benign prostatic hyperplasia, 12 patients with prostatic intraepithelial neoplasia and 74 patients with PCa. The total RNA was isolated and DD3(PCA3) and PSA expressions were quantified using quantitative RT real-time PCR method. The DD3(PCA3)/PSA mRNA ratio was determined for all groups., Results: It was found that the levels of the mRNA expression of DD3(PCA3) were significantly higher (p<0.045) in patients with PCa than in patients with benign prostatic hyperplasia. No statistically significant differences in levels of mRNA expression of DD3(PCA3) between patients with organ-confined and those with advanced or metastatic disease, nor according to Gleason score, were found., Conclusion: DD3(PCA3) appears to be a promising marker for early detection of PCa and also for differential diagnosis between patients with benign prostate hyperplasia and those with PCa.

Objectives: RECK (reversion-inducing cysteine-rich protein with Kazal motifs) is a glycoprotein which negatively regulates the activity of matrix metalloproteinases (MMPs). We analyzed differences in RECK mRNA expression in histological types of non-small cell lung cancer (NSCLC) and the relationship between promoter methylation status of RECK gene, level of RECK mRNA expression and clinicopathological values of patients with NSCLC., Patients and Methods: Methylation status of the promoter and the expression of RECK mRNA were analyzed in paired tissue samples (tumor and control) of 50 patients with NSCLC. The methylation status of the RECK promoter was assessed using methylation-specific PCR. The level of RECK mRNA expression was measured using an RT real-time PCR method., Results: Lower expression of RECK mRNA in NSCLC tissue was recorded compared to normal tissue (p=0.0032). Significantly lower expression of RECK in squamous cell carcinoma (SCC) tissue was observed in comparison with adenocarcinoma tissue (p=0.0051). Significant differences in expression of RECK in stages IB-IIIA were found in comparison with stage IA (p=0.0455). There was a significantly lower expression of RECK mRNA in NSCLC tissue in samples with positive RECK promoter methylation status in comparison with samples with negative promoter methylation status (p=0.0400)., Conclusion: We showed that there were differences in expression between histological types of NSCLC (SCC, adenocarcinoma). There was a higher expression of RECK in stage IA in comparison with stages IB-IIIA. Our results indicate that RECK could be classified as a tumor suppressor gene and is an interesting target for further investigation of MMP inhibitors.

Unlabelled: The expression of matrix metallo-proteinases (MMP-7 and MMP-9) and tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2), which are involved in the degradation of the extracellular matrix (ECM) and tumor growth, was investigated in normal lung tissue, tissue of benign pulmonary diseases and non-small cell lung cancer (NSCLC) tissue., Patients and Methods: Tumor tissue and surrounding carcinoma-free lung tissue samples were obtained from 91 patients with NSCLC who had undergone surgery in the years 2005-2007 as well as lung tissue from 12 patients operated on for 'benign' bullous emphysema or interstitial lung disease. The mRNA was isolated from the tissues and the expression of mRNA was assessed using a real-time RT PCR method., Results: Significantly higher expression of MMP-7, MMP-9 and TIMP-1 mRNA was demonstrated in the NSCLC tissue in comparison with the normal lung tissue from the same patients (p=0.0003, p<0.0001 and p=0.0018, respectively). Similar results for MMP-7, MMP-9 and TIMP-1 were found in the histological subgroups: squamous cell lung cancer vs. normal tissue (p=0.0198, p=0.0015 and p=0.0366, respectively), and adenocarcinoma vs. normal tissue (p=0.0045, p<0.0001 and p=0.0140, respectively). The expression of MMP-7 was found to be significantly higher in tumor tissue vs. lung tissue of the benign diseases (p=0.0086) and similar results were also recorded in the histological subgroups: squamous cell lung cancer vs. benign tissue (p=0.0171) and adenocarcinoma vs. benign tissue (p=0.0135). The expression of MMP-9 was significantly higher only in the adenocarcinoma subgroup vs. the benign tissue (p=0.0412). No differences in the expression of mRNA between stage IA and stages IB-IIIB of NSCLC were recorded., Conclusion: Significantly higher expression of MMP-7 and MMP-9 in tumor tissue than in the surrounding tissue or in benign lung disease tissue supports the notion of an important role of these metalloproteinases in the growth of lung carcinoma. TIMP-1 expression is increased only in carcinoma, but not in benign lung disease.

Background: Portal vein ligation (PVL) could multiply the future liver remnant volume (FLRV). Interuleukin-6 (IL-6) is a pleiotropic cytokine that is associated with an initial phase of liver regeneration. The aim of this study was to accelerate the regeneration of liver parenchyma after PVL by intraportal cytokine application., Materials and Methods: After ligation of portal branches of caudate and right lateral and right medial liver lobes, recombinant porcine IL-6 (IL-6 group) or physiological solution (control group) were applied into non-occluded portal vein branches. The biochemical and immunoanalytical parameters were assessed. The compensatory hypertrophy was evaluated by periodic ultrasonography. The histological examination of liver was performed., Results: The acceleration of growth of hypertrophic liver lobes was maximal at the 7th postoperative day in comparison with the control group (p<0.05), nevertheless, this stimulating effect was lost at the end of the experiment. Important differences in biochemical or histological studied parametres were not proved., Conclusion: The presented study describes the use of IL-6 for stimulation of the first phase of liver regeneration. The achieved acceleration of growth of hypertrophic liver lobes after application of IL-6 confirmed the key role of the studied cytokine in priming regenerating liver parenchyma after portal vein ligation.

Unlabelled: Portal vein embolization (PVE) can be used prior to liver surgery to increase the volume of the remaining liver tissue after an extensive resection. However, the application of PVE is limited and new strategies to augment liver regeneration by cellular therapy are promising alternatives., Materials and Methods: The influence of syngeneic multipotent mesenchymal stromal cells (MSC) on liver regeneration was analysed after the ligation of the right portal vein branches in a porcine model, closely mimicking the situation of human surgery. Liver regeneration was monitored by ultrasonography, immunohistological analysis and serum biochemistry., Results: The volume of the contra-lateral, non-ligated liver lobe increased in all piglets after portal vein ligation. This hyperplasia occurred earlier and was more pronounced in those piglets receiving MSC infusions as compared to non-treated controls. Biochemical liver function was stable in all pigs. Only solitary transplanted MSC were detected in recipient livers two weeks after the infusion., Conclusion: The infusion of porcine MSC into the portal vein in a setting of liver regeneration after surgical resection leads to accelerated and augmented hyperplasia. This effect is most likely due to bystander effects of the transplanted MSC.

Background: An ovarian cancer marker panel including leptin, prolactin, osteopontin, insulin-like growth factor II (IGFII), macrophage migration inhibitory factor and CA125 was tested for multiplex marker measurement. Multiplex was compared to single assayed tumour markers: CA125, TPS, thymidine kinase, monototal and HE4., Patients and Methods: The serum marker levels in ovarian cancer patients were compared to controls with benign ovarian disease. xMAP technology was used for multiplex panel and routine immunoanalytic methods for other markers., Results: Considering the multiplexed markers, only CA125(Luminex), osteopontin and IGF-II differed significantly between groups. Levels of all non-multiplexed tumour markers were significantly higher in the cancer group compare to the control., Conclusion: Multiplex is a powerful tool for multiparametric studies, but we are still in the era of looking for the right marker combinations for cancer diagnostics and monitoring. The panel will be tested on a larger ovarian cancer cohort and in patients with other cancer and non-cancerous diseases.

Background: Optimal chemotherapy (CT) for advanced breast treatment should be effective, well tolerated and convenient. In this study the efficacy and safety of the fully oral combination of oral vinorelbine (Navelbine Oral) plus capecitabine (Xeloda) in metastatic breast cancer (MBC) patients pretreated with anthracycline, was evaluated., Patients and Methods: In this phase II multicenter study, this combination CT was given as a first- or second-line therapy for MBC. The treatment schedule was: oral vinorelbine 60 mg/m2 day 1 and day 8 plus capecitabine 1,000 mg/m2 twice daily from day 1 to day 14, every 21 days., Results: One hundred and fifteen patients were included in this trial. The median age was 58 years (range: 40-75). All the patients had received prior anthracycline-based chemotherapy. The combination was well tolerated, with, in particular, only 0.8% of patients presenting with febrile neutropenia. In the intention-to-treat (ITT) population, an objective response was achieved in 65 patients (56.5%). A complete response was achieved in 22 patients (19.1%); partial response in 43 patients (37.4%); stable disease in 36 patients (31.3%), and progressive disease was observed in 14 patients (12.2%). After a median follow-up of 10.0 months, the median progression-free survival (PFS) was 10.5 months and the median survival was 17.5 months., Conclusion: Oral vinorelbine-capecitabine shows very promising activity and low toxicity in MBC treatment, with high compliance of the patients.

The Aim of Study: The limits of liver surgery are restricted today by the functional reserves of remnant parenchyma. The aim of this article was to acquaint the general surgical and medical public with the results of experimental liver regeneration stimulated by cytokines and thus to enhance their effort to carry on with implementing the research results in clinical practice., Methods: Authors present their experimental model of liver regeneration after ligation of portal branches for caudate and right lateral, and right medial liver lobes. The regeneration was induced by application of TNF-alpha and IL-6 into the non-occluded portal branches, and compared with the results of other experimental teams., Results and Conclusion: The absolute volume of hypertrophic lobes increases after application of TNF-alpha more rapidly, whereas in the control group, practically no changes were recorded in hypertrophic liver lobes volumes in first three days. The achieved acceleration of growth of hypertrophic liver lobes after application of TNF-alpha and IL-6 confirmed the key role of studied pleiotropic cytokines in the priming of liver parenchyma regeneration after portal vein ligation (Fig. 3, Ref. 26).

The family of human matrix metalloproteinases (MMPs) comprises several tightly regulated classes of proteases. These enzymes and their specific inhibitors play important roles in tumour progression and the metastatic process by facilitating extracellular matrix degradation. As scientific understanding of the MMPs has advanced, therapeutic strategies focusing on blocking these enzymes by matrix metalloproteinase inhibitors have rapidly developed. Low molecular weight tissue inhibitors of matrix metalloproteinase (TIMPs) represent a new therapeutic approach for the treatment of individual types of cancer. This paper aims to briefly summarize current knowledge about the role of MMPs in select non- tumorous lesions, tumor invasion and metastasis. The perspectives in therapeutic intervention in cancer are also mentioned. The role of MMPs in diagnosis and prognosis of colorectal and thyroid cancer is discussed in detail.

Background: Thymidine kinase (TK) is involved in nucleic acid synthesis and is therefore considered to be an important proliferation tumor marker. Our main goal was to determine the significance of elevated TK levels as a relapse marker during follow-up with child patients suffering from acute leukemia., Patients and Methods: TK serum levels in 38 children with acute leukemia (34 lymphoblastic, 4 myeloblastic) were determined using radio-receptor analysis (RRA, Immunotech, Prague, USA). All patients included in this study had had TK examined before the start of the treatment and at least twice during the follow-up., Results: Our results showed that TK serum levels at the time of diagnosis were extremely high (78-5826 U/l, median value 403 U/l, normal < 8 U/l), while in remission TK serum levels were much lower (5-80 U/l, median value 31 U/l). During relapse of acute leukemia (5 cases), TK levels increased considerably to measurements between 120-800 U/l (median value 324 U/l). The study showed that the elevation of TK serum levels during follow-up was a helpful marker for the recognition of an early stage of relapse and in some cases occurred as early as one month before the appearance of clinical signs. Sensitivity in this case was 87% and thus TK serum levels seem to be a very good parameter during follow-up because of acceptable sensitivity, low cost (4 $/sample) and the elimination of a requirement for screening of bone marrow samples., Conclusion: While TK serum levels were helpful in predicting relapse during follow-up, it is necessary to note that they did not correlate with prognosis in our group of patients during the time of the initial diagnosis of acute leukemia.