Publications by authors named "Radek Trojanec"

21 Publications

  • Page 1 of 1

The Influence of Gene Aberrations on Survival in Resected Wildtype Glioblastoma Patients: A Single-Institution Study.

Curr Oncol 2021 03 21;28(2):1280-1293. Epub 2021 Mar 21.

Department of Neurosurgery, University Hospital Olomouc, I.P. Pavlova 6, 779 00 Olomouc, Czech Republic.

This prospective population-based study on a group of 132 resected IDH-wildtype (IDH-wt) glioblastoma (GBM) patients assesses the prognostic and predictive value of selected genetic biomarkers and clinical factors for GBM as well as the dependence of these values on the applied therapeutic modalities. The patients were treated in our hospital between June 2006 and June 2015. Clinical data and tumor samples were analyzed to determine the frequencies of TP53, MDM2, EGFR, RB1, BCR, and CCND1 gene aberrations and the duplication/deletion statuses of the 9p21.3, 1p36.3, 19q13.32, and 10p11.1 chromosome regions. Cut-off values distinguishing low (LCN) and high (HCN) copy number status for each marker were defined. Additionally, MGMT promoter methylation and IDH1/2 mutation status were investigated retrospectively. Young age, female gender, Karnofsky scores (KS) above 80, chemoradiotherapy, TP53 HCN, and CCND1 HCN were identified as positive prognostic factors, and smoking was identified as a negative prognostic factor. Cox proportional regression models of the chemoradiotherapy patient group revealed TP53 HCN and CCND1 HCN to be positive prognostic factors for both progression-free survival and overall survival. These results confirmed the influence of key clinical factors (age, KS, adjuvant oncotherapy, and smoking) on survival in GBM IDH-wt patients and demonstrated the prognostic and/or predictive importance of CCND1, MDM2, and 22q12.2 aberrations.
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http://dx.doi.org/10.3390/curroncol28020122DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8025822PMC
March 2021

Tumor-Infiltrating Lymphocytes/Plasmocytes in Chemotherapeutically Non-Influenced Triple-Negative Breast Cancers - Correlation with Morphological and Clinico-Pathological Parameters.

Klin Onkol 2019 ;32(5):380-387

Background: Triple-negative breast cancers (TNBCs) are considered a morphologically heterogeneous group of breast carcinomas characterized by the absence or low protein expression of hormone receptors and HER2/neu/ERBB2 with a specific biological behavior and therapeutic response. This study aimed to evaluate correlations of the density of tumor-infiltrating lymphocytes/plasmocytes (TILs) in the tumor parenchyma, stroma, and invasive margins with tumor morphology, the proliferation rate, Bcl-2 expression, and selected clinical and pathological parameters in early breast cancer patients prior to mastectomy who had not received initial chemotherapy.

Materials And Methods: Samples of 3,544 breast cancer patients investigated in our department between 2007 and 2017 were re-examined. In total, 413 (11.65%) patients were diagnosed with TNBC. Only 61 cases did not undergo neoadjuvant therapy prior to mastectomy. Correlations between the density of TILs and tumor morphology, Bcl-2 expression, proliferative activity measured by Ki-67, patient age at diagnosis, tumor grade, and metastases were investigated.

Results: The samples were predominantly relatively well-localized invasive carcinomas of no special type with medullary features (80.32%) that measured on average 13.4mm (range 5-20mm, median 15mm) and exhibited central necrosis or fibrosis, a tendency to undergo spindle cell and/or apocrine-like differentiation, and intensive infiltration of TILs. There were significant positive correlations between TILs and premenopausal status (p=0.003), Ki-67 expression (p=0.015), and tumor grade (p=0.002), a marginal positive correlation between TILs and tumor size (p=0.065), and a significant negative correlation between TILs and Bcl-2 expression (p=0.035). In younger patients (< 50 years) with tumor size less than or equal to 20 mm (pT1a-pT1c) we recorded a lower number of women with metastatic lymph node involvement (p=0.001).

Conclusion: The density and location of TILs in non-therapeutically influenced TNBCs, evaluated in the context of morphological changes and other clinicopathological parameters, may have prognostic significance and assist effective therapy planning.
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http://dx.doi.org/10.14735/amko2019380DOI Listing
March 2020

Genetic Markers in Triple-Negative Breast Cancer.

Clin Breast Cancer 2018 10 4;18(5):e841-e850. Epub 2018 Aug 4.

Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic.

Triple-negative breast cancer (TNBC) accounts for 15% to 20% of breast cancer cases and is characterized by the absence of estrogen, progesterone, and human epidermal growth factor 2 receptors. Though TNBC is a highly heterogenic and aggressive disease, TNBC patients have better response to neoadjuvant therapy compared to other breast cancer subtypes. Nevertheless, patients with residual disease have a very poor prognosis, with higher probability of relapse and lower overall survival in the first years after diagnosis. TNBC has 6 subtypes with distinct molecular signatures with different prognoses and probably different responses to therapy. The precise stratification of TNBC is therefore crucial for the development of potent standardized and targeted therapies. In spite of intensive research into finding new molecular biomarkers and designing personalized therapeutic approaches, BRCA mutational status is the only clinically validated biomarker for personalized therapy in TNBC. Recent studies have reported several promising biomarkers that are currently being validated through clinical trials. The objective of this review was to summarize the clinically relevant genetic markers for TNBC that could serve as diagnostic, prognostic, or predictive or could improve personalized therapeutic strategies.
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http://dx.doi.org/10.1016/j.clbc.2018.07.023DOI Listing
October 2018

Age-associated prognostic and predictive biomarkers in patients with breast cancer.

Oncol Lett 2017 Jun 6;13(6):4201-4207. Epub 2017 Apr 6.

Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, CZ-775 15 Olomouc, Czech Republic.

To date, no comprehensive prognostic or predictive marker profiling analysis has been performed in association with the age of patients with breast cancer. In the present study, 632 breast cancer tissue samples were analyzed for expression of estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), B-cell lymphoma (Bcl)-2 protein, HER2 gene amplification, proliferation [as evaluated by proliferating cell nuclear antigen (PCNA) and Ki-67 index], tumor grade, histological type and molecular subtype. The data revealed correlations with the age of patients. A statistically significant positive correlation was identified between patient age and expression of ER (P<0.0001). There was no significant association between patient age and PR, HER2 protein expression, HER2 gene amplification or PCNA. A significant negative correlation between age and Ki-67 expression (P<0.0001) as well as grade of tumor (P=0.007) was identified. The spectrum of molecular subtypes differed according to age (P=0.0003). The highest incidence of aggressive triple-negative and HER2-positive breast cancer was present in patients aged between 20 and 39 years. Luminal A subtype was the most frequent cancer subtype in patients from age 40 onwards, where proliferation activity declined with age and expression of hormone receptors increased along with Bcl-2 expression. Aggressive forms of breast cancer were more common in younger patients. Prognostic and predictive markers have a complex age-specific distribution. The findings of less aggressive luminal A and B subtypes in older patients, and the positive correlation with ER, PR and Bcl-2 expression reveal the potential efficacy of Bcl-2 as a marker of hormone responsiveness in these patients.
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http://dx.doi.org/10.3892/ol.2017.6000DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5452934PMC
June 2017

Frequency of chromosome 17 polysomy in relation to CEP17 copy number in a large breast cancer cohort.

Genes Chromosomes Cancer 2016 May 5;55(5):409-17. Epub 2016 Feb 5.

Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Hnevotinska 5, 775 15 Olomouc, the Czech Republic.

Eligibility to anti-HER2 therapy for breast tumors strictly depends on demonstrating HER2 overexpression (by immunohistochemistry) or HER2 gene amplification by in situ hybridization (ISH), usually defined by the ratio of HER2 gene to chromosome 17 centromere (CEP17) copies. However, the CEP17 copy number increase (CNI) has been proven responsible for misleading HER2 FISH results and recent small cohort studies suggest that chromosome 17 polysomy is actually very rare. Here we investigated by FISH the frequency of true chromosome 17 polysomy in a consecutive cohort of 5,477 invasive breast cancer patients. We evaluated and selected the LSI 17p11.2 probe for chromosome 17 enumeration on a training cohort of 67 breast cancer samples (CEP17 ≥ 2.5). LSI 17p11.2 was used in the 297/5,477 patients from the validation cohort displaying CEP17 CNI (CEP17 ≥ 3.0). Using HER2/17p11.2 scoring criteria, 37.3%/1.5% patients initially classified as equivocal/non-amplified were reclassified as amplified. For a more accurate assessment of chromosome 17 and ploidy in the samples, we tested six markers located on chromosome 17 and centromeric regions of chromosome 8 (CEP8) and 11 (CEP11) in 67 patients with CEP17 and LSI 17p11.2 CNI. True polysomy (hyperdiploidy) according to these markers was found in 0.48% of cases (24/5,020). CEP8 and CEP11 CNI (≥3.0) was more frequent in the hyperdiploid than CEP17 non-polysomic group (55.6% vs. 6.1% and 25% vs. 2.3%, respectively). Our results suggest that chromosome 17 polysomy is a rare event found in <1% breast cancer cases and that polysomy of other chromosomes frequently occurs with chromosome 17 polysomy.
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http://dx.doi.org/10.1002/gcc.22337DOI Listing
May 2016

Evaluation of HER2 Gene Status in Breast Cancer Samples with Indeterminate Fluorescence in Situ Hybridization by Quantitative Real-Time PCR.

J Mol Diagn 2015 Jul 5;17(4):446-55. Epub 2015 May 5.

Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University and University Hospital in Olomouc, Olomouc, Czech Republic. Electronic address:

Administration of drugs targeting HER2 (official symbol ERBB2) is an important component of therapy for breast cancer patients with HER2 amplification/overexpression as determined by in situ hybridization (ISH) and immunohistochemistry (IHC). In approximately 5% of breast cancers, ISH assays fail. In these cases, HER2 protein expression is evaluated by IHC alone that may yield false negatives/positives for poor-quality samples. Therefore, we developed a method that was based on quantitative real-time PCR applicable for DNA from formalin-fixed, paraffin-embedded tissue samples. Its limit of detection was determined with breast cancer cell lines and validated with 223 breast cancer patient samples. On the basis of comparisons with fluorescent ISH (FISH) and IHC data, the sensitivity of the new method was 94.2% and 95.1%, its specificity was 100% and 99.1%, and overall concordance between results obtained with the quantitative real-time PCR method and FISH/IHC was 97.6% for both methods. The quantitative real-time PCR method was then used to evaluate the HER2 status of 198 of 3696 breast cancer tissues that yielded indeterminate FISH results. The HER2 copy number was successfully determined in 69.2% of these indeterminate samples. Thus, the DNA-based technique appears to be a specific, sensitive method for determining HER2 copy numbers when the FISH assay fails, which may complement IHC tests.
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http://dx.doi.org/10.1016/j.jmoldx.2015.03.007DOI Listing
July 2015

BCL2 is an independent predictor of outcome in basal-like triple-negative breast cancers treated with adjuvant anthracycline-based chemotherapy.

Tumour Biol 2015 Jun 24;36(6):4243-52. Epub 2015 Jan 24.

Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University, Hnevotinska 5, 775 15, Olomouc, Czech Republic,

Neither targeted therapies nor predictors for chemotherapy sensitivity are available for triple-negative breast cancer (TNBC). Our study included 187 patients with TNBC, 164 of whom were treated with anthracycline-based adjuvant chemotherapy. Eleven molecular biomarkers were analyzed. BCL2, epidermal growth factor receptor (EGFR), MYC, TOP2A, and Ki-67 protein expression was evaluated by immunohistochemistry. The status of the EGFR, MYC, and TOP2A genes and chromosomes 7, 8, and 17 was assessed using fluorescence in situ hybridization. High BCL2 expression predicted poor relapse-free survival (RFS) in patients treated with anthracycline-based adjuvant chemotherapy (p = 0.035), poor breast cancer-specific survival (BCSS) (p = 0.048), and a trend to poor overall survival (OS) (p = 0.085). High levels of BCL2 expression predicted poor OS in basal-like (BL) TNBC patients treated with adjuvant anthracycline-based regimens (log-rank p = 0.033, hazard ratio (HR) 3.04, 95 % confidence interval (CI) 1.04-8.91) and a trend to poor RFS (log-rank p = 0.079) and poor BCSS (log-rank p = 0.056). Multivariate analysis showed that BCL2 status, tumor size, and nodal status all had independent predictive significance for RFS (p = 0.005, p = 0.091, p = 0.003, respectively; likelihood ratio test for the whole model, p = 0.003), BCSS (p = 0.012, p = 0.077, p = 0.01, respectively; likelihood ratio test for the whole model, p = 0.016), and OS (p = 0.008, p = 0.004, p = 0.004, respectively; likelihood ratio test for the whole model, p = 0.0006). Similarly, multivariate analysis for BL TNBC showed BCL2, tumor size, and nodal status all had independent predictive significance for RFS (likelihood ratio test for the whole model, p = 0.00125), BCSS (p = 0.00035), and OS (p = 0.00063). High EGFR expression was associated with poor BCSS (p = 0.039) in patients treated with anthracycline-based adjuvant chemotherapy. Patients who underwent anthracycline-based adjuvant chemotherapy and exhibited CMYC amplification had a trend to worse BCSS (p = 0.066). In conclusion, high BCL2 expression is a significant independent predictor of poor outcome in TNBC patients treated with anthracycline-based adjuvant chemotherapy, and this is the first study showing the BCL2 prediction in BL TNBC. BCL2 expression analysis could facilitate decision making on adjuvant treatment in TNBC patients.
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http://dx.doi.org/10.1007/s13277-015-3061-7DOI Listing
June 2015

Primitive neuroectodermal tumor (PNET) of the lung in an adult woman.

World J Surg Oncol 2014 Dec 5;12:374. Epub 2014 Dec 5.

Department of Clinical and Molecular Pathology and Institute of Molecular and Translational Medicine (IMTM), Faculty of Medicine and Dentistry, Palacky University, Hněvotínská 3, 775 15 Olomouc, Czech Republic.

Primary primitive neuroectodermal tumors (PNETs) are extremely rare in the lung and especially in adult women. We describe a case of PNET of the lung with aggressive behavior in 31-year-old woman. Diagnosis was based on histopathological and immunohistochemical studies, and confirmed by molecular genetic analysis of chromosome rearrangements in the EWSR1 gene region. Clinical follow-up, post-mortem findings, and differential diagnosis are also discussed.
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http://dx.doi.org/10.1186/1477-7819-12-374DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4289161PMC
December 2014

Isocitrate dehydrogenase 1 and 2 mutations in gliomas.

J Neurosci Res 2014 Dec 31;92(12):1611-20. Epub 2014 Jul 31.

Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital in Olomouc, Olomouc, Czech Republic.

Over the past few years, new biomarkers have allowed a deeper insight into gliomagenesis and facilitated the identification of possible targets for glioma therapy. Isocitrate dehydrogenase (IDH) 1 and IDH2 mutations have been shown to be promising biomarkers for monitoring disease prognosis and predicting the response to treatment. This review summarizes recent findings in this field. Web of Science, Science Direct, and PubMed online databases were used to search for publications investigating the role of IDH in glioma. References were identified by searching for the keywords "IDH1 or IDH2 and glioma and diagnostic or predictive or prognostic" in papers published from January, 2008, to April, 2014. Only papers in English were reviewed. Publications available only as an abstract were not included. IDH1/2 mutations are tightly associated with grade II and III gliomas and secondary glioblastomas, with better prognosis and production of a recently described oncometabolite, 2-hydroxyglutarate (2HG). Although the contradictory positive effect of IDH mutation on prognosis and negative role of 2HG in tumor transformation remain unresolved, the future direction of personalized treatment strategies targeted to glioma development is likely to focus on IDH1/2 mutations.
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http://dx.doi.org/10.1002/jnr.23456DOI Listing
December 2014

An adult multifocal medulloblastoma with diffuse acute postoperative cerebellar swelling: immunohistochemical and molecular genetics analysis.

Neurosurg Rev 2015 Jan 10;38(1):1-10; discussion 10. Epub 2014 Jun 10.

Department of Neurosurgery, University Hospital Olomouc and Faculty of Medicine and Dentistry, University Hospital Olomouc and Palacky University, Olomouc, Czech Republic,

Medulloblastoma (MB), the most common malignant tumor typically affecting children, occurs only exceptionally in adults. Multifocal presentation of this malignancy in adulthood is even much rarer—only four cases with favorable postoperative course have been reported, so far. The study illustrates a very rare rapid postoperative clinical deterioration due to diffuse cerebellar swelling (DCS) in an adult multifocal MB (MMB). To the best of their knowledge, authors for the first time performed genetic analysis of MMB and demonstrated expression patterns of selected markers that put the patient within the sonic hedgehog (SHH) molecular subgroup and at least partially explain her unsatisfactory clinical course. Herein, authors summarized the relevant literature concerning this issue with the aim to determine features that would facilitate diagnosis and therapy of such a scarce clinical entity.
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http://dx.doi.org/10.1007/s10143-014-0556-4DOI Listing
January 2015

Non-small cell lung cancer--genetic predictors.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013 Jun 29;157(2):125-36. Epub 2013 May 29.

Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic.

Background: Non-small cell lung cancer (NSCLC) accounts for approximately 85% of all lung cancer that is the leading cause of cancer-related mortality worldwide. Several predictive markers have been found in NSCLC patients to date but only a few are currently used for tailored therapy.

Methods And Results: PubMed and Web of Science online databases were used to search review and original articles on the most important predictive markers in NSCLC.

Conclusion: EGFR activating mutations (exons 18 to 21) and EML4-ALK rearrangement are clinically important markers able to select NSCLC patients which benefit from EGFR or ALK tyrosine kinase inhibitors (gefitinib, erlotinib, crizotinib). Other markers, such as KRAS mutation, EGFR T790M mutation and C-MET amplification, are responsible for resistance to these inhibitors. Overcoming of this resistance as well as discovery of new potential markers and inhibitors is the main goal of ongoing research and clinical trials in NSCLC.
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http://dx.doi.org/10.5507/bp.2013.034DOI Listing
June 2013

High lapatinib plasma levels in breast cancer patients: risk or benefit?

Tumori 2012 Jan-Feb;98(1):162-5

Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Palacky University and University Hospital Olomouc, Olomouc, Czech Republic.

Aims And Background: Lapatinib is a tyrosine kinase inhibitor targeting epidermal growth factor receptors 1 (EGFR/HER1) and 2 (HER2) used in the treatment of patients with HER2-positive breast cancer. The aim of the present study was to determine lapatinib plasma levels in breast cancer patients treated with lapatinib plus capecitabine.

Patients And Methods: We assessed lapatinib plasma levels in blood samples from 21 breast cancer patients treated with lapatinib plus capecitabine using the standard regimen in an expanded access program. Liquid chromatography tandem mass spectrometry was used for measuring lapatinib plasma concentrations. The validated method was applied for measurement of 55 plasma samples.

Results: The median lapatinib plasma level was 5.09 μg/mL, with large interindividual differences. Patients of lower weight tended to have higher lapatinib plasma levels (Spearman correlation coefficient R = -0.435, P = 0.055). One patient's lapatinib plasma levels were markedly higher than those of the others, with a median level of 11.25 μg/mL and repeatedly exceeding 7.80 μg/mL. The treatment was terminated after 8 months when hyperbilirubinemia occurred.

Conclusions: The lapatinib plasma levels reported here are twice as high as the clinically effective steady-state geometric mean maximum concentration. We conclude that increased lapatinib body levels occur when patients are in a nonfasting state at the time of drug intake and when lapatinib doses are not adjusted to low body weight or weight loss during treatment. In Europe, dose adjustments are not recommended in the case of hepatic function impairment. Thus, attention should be paid to changes in liver function test results in clinical practice, especially in patients of small stature and weight, given the risk of high plasma concentrations. Prospective lapatinib plasma level assessment in treated patients might be useful to confirm or refute the possible correlation of high lapatinib plasma levels with hepatic and/or other toxicities.
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http://dx.doi.org/10.1700/1053.11516DOI Listing
July 2012

Lapatinib in breast cancer - the predictive significance of HER1 (EGFR), HER2, PTEN and PIK3CA genes and lapatinib plasma level assessment.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2010 Dec;154(4):281-8

Laboratory of Experimental Medicine, Institute of Molecular and Translational Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc and University Hospital Olomouc, Czech Republic.

Background: Breast cancer treatment trends are currently based on tailored therapies using tumor and patient biomarkers. Lapatinib is the first dual inhibitor of HER1 (EGFR, ErbB1) and HER2 (ErbB2, Neu) tyrosine kinases to be used in clinical practice. However, only HER2 is currently used for therapy indications and new predictors for the treatment with lapatinib are sought.

Methods And Results: This minireview focuses on lapatinib and its role in breast cancer treatment. Preclinical and clinical studies as well as pharmacological characteristics are briefly reviewed while the focus is on efficacy assessment including predictive factors for therapy outcome.

Conclusion: Lapatinib (Tykerb/Tyverb) was Food and Drug Administration (FDA) approved in 2007 for use in combination with capecitabine for the treatment of HER2-positive advanced or metastatic breast cancer in patients who had received previous treatment (including anthracycline, taxane and trastuzumab containing regimens) and in 2010 for use in combination with letrozole for postmenopausal women with hormonal receptor positive and HER2- positive metastatic breast cancer. In contrast to trastuzumab (Herceptin), lapatinib is orally administered and it targets both HER2 and HER1 receptors. As a synthetic and oral tyrosine kinase inhibitor (TKI), it is convenient, cheaper and easier to produce than monoclonal antibodies. The recommended dosage is not dependent on body weight either. Lapatinib plasma level measurement could be an approach to tailored therapy for further optimizing the dose and prolonging this efficient therapy. New lapatinib response predictors are being evaluated. At this time, only HER2 amplification/overexpression is used to choose lapatinib therapy candidates. Further studies on concurrent HER1 fluorescent in situ hybridization (FISH)/immunohistochemistry (IHC) assessment and/or microarray analyses may produce new data on the predictive role of the HER1 (EGFR) gene/protein. PTEN loss and PIK3CA gene mutations are other markers that may predict lapatinib poor response.
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http://dx.doi.org/10.5507/bp.2010.043DOI Listing
December 2010

Merkel cell carcinoma of the gluteal region with ipsilateral metastasis into the pancreatic graft of a patient after combined kidney-pancreas transplantation.

Onkologie 2010 20;33(10):520-4. Epub 2010 Sep 20.

3rd Department of Internal Medicine and Nephrology, University Hospital Olomouc, Czech Republic.

Background: Merkel cell carcinoma (MCC) is a rare tumour of the skin that predominantly affects elderly or immunocompromised patients. The malignant transformation of Merkel cells is currently considered to be related to an infection with Merkel cell polyomavirus.

Case Report: We present the case of a 62-year-old man who developed a Merkel cell polyomavirus-positive MCC in a non-UV-exposed part of the right gluteal region 8 years after combined kidney-pancreas transplantation. Following excision and radical re-excision of the tumour, no adjuvant radiotherapy was indicated because of the risk of adjacent pancreatic graft failure. Despite adjustment of the immunosuppressive therapy with conversion to sirolimus, the tumour generalised and metastasised into the pancreatic graft, leading to its failure. Subsequent chemotherapy did not affect the course of the disease, and the patient died 9 months after diagnosis.

Conclusions: To our knowledge, we present the first case of MCC associated with metastatic involvement of the transplanted pancreas followed by its subsequent failure. Given the highly aggressive course of the disease in patients after organ transplantation, MCC therapy should be sufficiently aggressive from the time of diagnosis and should not be influenced by attempts to preserve graft function.
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http://dx.doi.org/10.1159/000319694DOI Listing
February 2011

Intramedullary spinal cord and cauda equina metastasis of breast carcinoma: case report.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2010 Jun;154(2):175-7

Department of Neurosurgery, Palacky University and University Hospital Olomouc, Czech Republic.

Aim: We present a case report of a female patient with metastasis of breast carcinoma to the medullary conus and cauda equina.

Methods: A 48-year-old woman with a history of breast tumor, suddenly felt severe weakness and numbness of the lower extremities. MRI of the spine disclosed a mass lesion within the medullary conus, with leptomeningeal involvement of cauda equina at the spinal level L1. Laminectomy was performed and partial resection of the medullary conus tumor and especially release of nerve roots of cauda equina was achieved using microsurgical techniques.

Results: Her clinical status, especially right leg weakness and sensory loss in the lower extremities have immediately improved but bladder dysfunction remained and she was unable to walk. The histological picture and immunophenotype indicates the presence of metastatic ductal adenocarcinoma of the mammary gland. Patient died 4 months after the spinal cord and cauda equina surgery.

Conclusion: To our knowledge, this is the first report of successful surgical treatment of metastatic leptomeningeal infiltration of breast carcinoma.
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http://dx.doi.org/10.5507/bp.2010.027DOI Listing
June 2010

Fetal colon cell line FHC exhibits tumorigenic phenotype, complex karyotype, and TP53 gene mutation.

Cancer Genet Cytogenet 2010 Mar;197(2):107-16

Department of Cytokinetics, Institute of Biophysics, Academy of Sciences of the Czech Republic, Brno, Czech Republic.

Stable cell lines obtained by spontaneous immortalization might represent early stages of malignant transformation and be useful experimental models for studies of mechanisms of cancer development. The FHC (fetal human cells) cell line has been established from normal fetal colonic mucosa. Detailed characterization of this cell line and mechanism of spontaneously acquired immortality have not been described yet. Therefore, we characterized the FHC cell line in terms of its tumorigenicity, cytogenetics, and TP53 gene mutation analysis. FHC cells displayed capability for anchorage-independent growth in semisolid media in vitro and formed solid tumors after transplantation into SCID (severe combined immunodeficiency) mice. This tumorigenic phenotype was associated with hypotriploidy and chromosome number ranging from 66 to 69. Results of comparative genetic hybridization arrays showed that most chromosomes included regions of copy number gains or losses. Region 8q23 approximately 8q24.3 (containing, e.g., MYC proto-oncogene) was present in more than 20 copies per nucleus. Moreover, we identified mutation of TP53 gene in codon 273; triplet CGT coding Arg was changed to CAG coding His. Expression of Pro codon 72 polymorphic variant of p53 was also detected. Mutation of TP53 gene was associated with abolished induction of p21(Waf1/Cip1) and MDM-2 proteins and resistance to apoptosis after genotoxic treatment. Because of their origin from normal fetal colon and their relative resistance to the induction of apoptosis, FHC cells can be considered a valuable experimental model for various studies.
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http://dx.doi.org/10.1016/j.cancergencyto.2009.11.009DOI Listing
March 2010

Triple negative breast cancer--current status and prospective targeted treatment based on HER1 (EGFR), TOP2A and C-MYC gene assessment.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2009 Mar;153(1):13-7

Department of Paediatrics, Faculty of Medicine and Dentistry, Laboratory of Experimental Medicine, Palacky University and University Hospital, Olomouc, Czech Republic.

Background: Every year about one million women worldwide are diagnosed with breast cancer which is the most common malignancy in female. Of these, triple negative breast carcinoma represents 10-17 %. Triple negative breast carcinomas, characterized by estrogen, progesterone and HER2 receptor negativity are very aggressive tumours with poor prognosis. Individualized treatment (tailored therapy) based on molecular biology markers of tumor and patient is the trend in clinical practice these days. However, molecular targets and predictors for the treatment of triple negative breast carcinoma do not currently exist.

Methods And Results: This minireview focuses on biomarkers (HER1/EGFR, TOP2A and C-MYC genes) that may predict the response of triple negative breast carcinoma patients to chemotherapy and/or targeted biological treatment with a summary of current knowledge about them.

Conclusion: HER1 belonging to the HER family of receptors plays an important role in cell proliferation, migration and protection against apoptosis. HER1 protein could be targeted by monoclonal antibodies and/or tyrosine kinase inhibitors (TKIs). Given signal pathway complexity and HER family member cooperation, it may be better to simultaneously target a number of these receptors (e.g. HER1/HER2 by lapatinib). Thus, HER1 assessment could reveal a particular breast cancer patient group with probably good response to HER1 targeted therapy. TOP2A gene, encoding topoisomerase II alpha (target for anthracyclines) is predictive of response to anthracycline therapy. TOP2A aberrations (amplification, deletion) are found in up to approximately 30-90 % of HER2 amplified breast cancer and amplifications are more common than deletions. Recent publications describe TOP2A amplification also in 2.7-8.8 % HER2 nonamplified breast cancers. Patients with a pathologic complete response to anthracycline based neoadjuvant chemotherapy had a good overall prognosis regardless of molecular subtype of breast cancer. These results suggest that particularly tumors with a complete pathological response to anthracyclines could have TOP2A amplification. C-MYC encodes nuclear DNA binding proteins that regulate proliferation and apoptosis; amplification is associated with poor prognosis and hormonally negative breast carcinoma.
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http://dx.doi.org/10.5507/bp.2009.002DOI Listing
March 2009

Dumbbell-shaped peripheral primitive neuroectodermal tumor of the spine--case report and review of the literature.

J Neurooncol 2009 Apr 3;92(2):211-7. Epub 2008 Dec 3.

University Hospital Olomouc, Olomouc, Czech Republic.

Primary spinal peripheral primitive neuroectodermal tumors (pPNETs) are extremely rare. Here, we present a case study of a 29-year-old male with a dumbbell-shaped pPNET at the T9-10 spine level, including details of his examination, surgical procedures applied, histological and genetic findings, and his subsequent treatment. We discuss the clinical course, the pathology and treatment for this disease, the surgical approach to thoracic dumbbell tumors and we review the literature. To our knowledge, this is the first report of a case of a dumbbell-shaped intradural and spinal peripheral PNET.
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http://dx.doi.org/10.1007/s11060-008-9744-9DOI Listing
April 2009

Glioblastoma multiforme with an abscess: case report and literature review.

J Neurooncol 2008 Jun;88(2):221-5

Neurosurgical Department, University Hospital, Olomouc 77520, Czech Republic.

An intratumoral or peritumoral microbial intracranial abscess is an infrequent diagnosis. The development of this complication may not be preceded by apparent local or general infection in all cases. To identify this diagnosis by radiological (MRI) or laboratory investigations is very intricate. Nevertheless, the recommended life-saving strategy is early surgery with resolution of both the tumor and infection. If subsequent oncological treatment is required, it has to be adjusted for prevention of re-inflammation. The described patient suffered from an intracranial abscess superimposed on a Glioblastoma Multiforme. The confirmed etiological agent was Staphylococcus aureus. The suspected route of microbial migration and colonization in this tumor was bacteremia via agents from thrombophlebitis. The patient is in a good condition following surgery, antimicrobial treatment, and radiotherapy.
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http://dx.doi.org/10.1007/s11060-008-9557-xDOI Listing
June 2008

[A retrospective analysis of trastuzumab-based therapy in metastatic breast cancer patients at Masaryk Memorial Cancer Institute. Identification of predictive factors].

Klin Onkol 2008 ;21(6):348-58

Klinika komplexní onkologické péce, Masarykův onkologický ústav, Brno.

Introduction: Trastuzumab is a humanized monoclonal antibody directed against the HER-2 receptor. Trastuzumab-based therapy significantly improves response rate (RR), time to progression (TTP) and overall survival (OS) for women with HER-2 positive metastatic breast cancer. Despite its initial efficacy, acquired resistance to trastuzumab develops in a majority of patients with MBC, and a large subset never responds, demonstrating primary resistance. The purpose of this retrospective study was to determine prognostic factors applicable to clinical practice.

Methods: We enrolled 112 women with metastatic breast cancer, who started the trastuzumab-based therapy at Masaryk Memorial Cancer Institute until January 2007. Clinical and laboratory factors, such as: patients conditions, character ofmetastatic spread, histology, estrogen, progesterone and Her-2 receptor status, Her-2/neu gene amplification, and serum tumor markers CEA, CA 15-3 and extracellular domain of Her-2 receptor (S-HER-2 ECD) were monitored. The association of all factors to response to therapy, time to progression (TTP) and overall survival (OS) was assessed.

Results: In 95% patients, the trastuzumab was combined with cytostatics (83% taxanes), 88,4% of patients started the trastuzumab as the first or second-line anticancer treatment. The median TTP was 284 days (9,3 months) and the median OS was 612 days (20,1 months) for all patients, RR was 54,5%. The highest RR was associated with the first-line treatment (p<0.0001) and with HER-2 gene/Chromosome 17 ratio > 2,2 (p=0,0092). Eleven patients (9,8%) discontinued the treatment because of toxicity, 7 patients did it as a result of cardiotoxicity (6,2%). CNS metastases occurred in 31 patients (27,7%). The S-HER-2 ECD was the most frequently elevated serum marker at the time of the treatment initialization (72,5%) and at the time of the progression (55,9%). Cox regression analysis identified S-HER-2 ECD levels at the beginning and between day 90 and 130 of the trastuzumab therapy as the best predictors of TTP. On the other hand the best predictor of OS was level of CEA before the treatment started and level of S-HER-2 ECD between day 90 and 130 of the trastuzumab therapy.

Conclusions: We confirmed that the only one predictive marker for response to trastuzumab therapy is a proof of HER-2 tumor positivity.The highest prevalence of S-HER-2 ECD positivity among serum tumor markers and the strong association between initial and subsequent S-HER-2 ECD serum concentrations and time to progression and overall survival make the S-HER-2 ECD the most significant prognostic marker.
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May 2009

A duplication dup(4)(q28q35.2) de novo in a newborn.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2006 Jul;150(1):113-6

Institute of Biology and Medical Genetics, General Faculty Hospital and The 1st Faculty of Medicine, Charles University, Prague 2, Czech Republic.

We report here a case of a newborn with hypotrophy and somatic stigmatization: microcephaly, facial dysmorphism, heart defect and immunodeficiency syndrome. The proband's karyotype was 46,XY,dup(4)(q28q35.2) de novo with chromosomal breaks in 4% of metaphases. We demonstrate the usefulness of a combination of physical examination, classical cytogenetics, FISH and PCR techniques in order to establish correct diagnosis because of overlap of some clinical and cytogenetic features of Nijmegen breakage syndrome (NBS) and duplication 4q in our patient. Although FISH technique detected translocation t(14q;21q) in 4 metaphases, deletion 657del5 in exon 6 of the NBS1 gene associated with NBS in Slavic population was not confirmed. We compare in this report similarity of the clinical picture of our patient, NBS cases and other patients carrying a duplication of the distal part of 4q as described in the literature.
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http://dx.doi.org/10.5507/bp.2006.016DOI Listing
July 2006
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