Publications by authors named "Karel Cwiertka"

17 Publications

  • Page 1 of 1

Targeting genotoxic and proteotoxic stress-response pathways in human prostate cancer by clinically available PARP inhibitors, vorinostat and disulfiram.

Prostate 2019 03 29;79(4):352-362. Epub 2018 Nov 29.

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

Background: Castration-resistant prostate cancer (PCa) represents a serious health challenge. Based on mechanistically-supported rationale we explored new therapeutic options based on clinically available drugs with anticancer effects, including inhibitors of PARP1 enzyme (PARPi), and histone deacetylases (vorinostat), respectively, and disulfiram (DSF, known as alcohol-abuse drug Antabuse) and its copper-chelating metabolite CuET that inhibit protein turnover.

Methods: Drugs and their combination with ionizing radiation (IR) were tested in various cytotoxicity assays in three human PCa cell lines including radio-resistant stem-cell like derived cells. Mechanistically, DNA damage repair, heat shock and unfolded protein response (UPR) pathways were assessed by immunofluorescence and immunoblotting.

Results: We observed enhanced sensitivity to PARPi/IR in PC3 cells consistent with lower homologous recombination (HR) repair. Vorinostat sensitized DU145 cells to PARPi/IR and decreased mutant p53. Vorinostat also impaired HR-mediated DNA repair, as determined by Rad51 foci formation and downregulation of TOPBP1 protein, and overcame radio-resistance of stem-cell like DU145-derived cells. All PCa models responded well to CuET or DSF combined with copper. We demonstrated that DSF interacts with copper in the culture media and forms adequate levels of CuET indicating that DSF/copper and CuET may be considered as comparable treatments. Both DSF/copper and CuET evoked hallmarks of UPR in PCa cells, documented by upregulation of ATF4, CHOP and phospho-eIF2α, with ensuing heat shock response encompassing activation of HSF1 and HSP70. Further enhancing the cytotoxicity of CuET, combination with an inhibitor of the anti-apoptotic protein survivin (YM155, currently undergoing clinical trials) promoted the UPR-induced toxicity, yielding synergistic effects of CuET and YM155.

Conclusions: We propose that targeting genotoxic and proteotoxic stress responses by combinations of available drugs could inspire innovative strategies to treat castration-resistant PCa.
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http://dx.doi.org/10.1002/pros.23741DOI Listing
March 2019

Risks and protective factors for triple negative breast cancer with a focus on micronutrients and infections.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2018 Jun 15;162(2):83-89. Epub 2018 May 15.

Department of Preventive Medicine, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.

Triple negative breast cancer (TNBC) is an aggressive form of breast cancer (BC) with a poor prognosis. Second, patients cannot benefit from targeted therapy, except for those with BRCA1/2 mutations, for whom poly (ADP-ribose) polymerase (PARP) inhibition therapy using olaparib has recently been approved. As global priorities continue to be epidemiological analysis of BC risk factors and early diagnosis, this review focuses on the risks and protective factors associated with TNBC. A PubMed keyword search for new knowledge on the risks and protective factors for TNBC was carried out. We also found statistical information from current online databases concerning the estimated incidence, prevalence and mortality worldwide of this cancer. Traditional risk factors for BC and TNBC are those related to reproduction such as the age of menarche, age of first birth, parity, breastfeeding and age at menopause. Attention needs to be paid to familial BC, weight control, alcohol consumption and regular physical activity. Epidemiological studies on TNBC provide evidence for protective factors such as regular consumption of soya, seafood, green tea, folic acid and vitamin D. Potential risk factors may include night work and viral infectious agents like human papillomavirus (HPV) and Epstein-Barr virus (EBV). Droplet digital methylation-specific PCR (ddMSP) is a possible new screening method for detection of BC including TNBC. Further research is necessary to validate these new factors.
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http://dx.doi.org/10.5507/bp.2018.014DOI Listing
June 2018

Radiotherapy management of brain metastases using conventional linear accelerator.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2016 Sep 13;160(3):412-6. Epub 2016 Sep 13.

Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.

Background And Aims: As treatments for primary cancers continue to improve life expectancy, unfortunately, brain metastases also appear to be constantly increasing and life expectancy for patients with brain metastases is low. Longer survival and improved quality of life may be achieved using localised radiological and surgical approaches in addition to low dose corticosteroids. Stereotactic brain radiotherapy is one rapidly evolving localized radiation treatment. This article describes our experience with stereotactic radiotherapy using a linear accelerator.

Methods: We reviewed patients treated with stereotactic radiotherapy, from the time of its introduction into daily practice in our Department of Oncology in 2014. We collected the data on patient treatment and predicted survival based on prognostic indices and actual patient outcome.

Results: A total of 10 patients were treated by stereotactic radiotherapy, in one case in combination with whole brain radiotherapy and hippocampal sparing. There was no significant treatment related toxicity during the treatment or follow-up and due to the small number of fractions, the overall tolerance of the treatment was excellent. The patient intrafractional movement in all cases was under 1 mm suggesting that 1 mm margin around the CTV to create the PTV is sufficient and also that patient immobilization using the thermoplastic mask compared with invasive techniques, is feasible. We also found that prognostic indices such as the Graded Prognostic Assessment provide accurate predictions of patient survival.

Conclusions: Based on our current evidence, patients with brain metastases fit enough, should be considered for stereotactic radiotherapy treatment.
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http://dx.doi.org/10.5507/bp.2016.043DOI Listing
September 2016

Treatment of brain metastases of renal cell cancer with combined hypofractionated stereotactic radiotherapy and whole brain radiotherapy with hippocampal sparing.

Oncol Lett 2016 Jun 15;11(6):3777-3781. Epub 2016 Apr 15.

Department of Neurosurgery, Faculty of Medicine and Dentistry, Palacky University, Olomouc 77900, Czech Republic.

Renal cell cancer patients with brain metastatic disease generally have poor prognosis. Treatment options include surgery, radiotherapy, targeted therapy or best supportive care with respect to disease burden, patient preference and performance status. In the present case report the radiotherapy technique combining whole brain radiotherapy with hippocampal sparing (hippocampal avoidance whole brain radiotherapy HA-WBRT) and hypofractionated stereotactic radiotherapy (SRT) of the brain metastases is performed in a patient with metastatic renal cell carcinoma. HA-WBRT was administered to 30 Gy in 10 fractions with sparing of the hippocampal structures and SRT of 21 Gy in 3 fractions to brain metastases which has preceded the HA-WBRT. Two single arc volumetric modulated arc radiotherapy (VMAT) plans were prepared using Monaco planning software. The HA-WBRT treatment plan achieved the following results: D2=33.91 Gy, D98=25.20 Gy, D100=14.18 Gy, D50=31.26 Gy. The homogeneity index was calculated as a deduction of the minimum dose in 2% and 98% of the planning target volume (PTV), divided by the minimum dose in 50% of the PTV. The maximum dose to the hippocampus was 17.50 Gy and mean dose was 11.59 Gy. The following doses to organs at risk (OAR) were achieved: Right opticus Dmax, 31.96 Gy; left opticus Dmax, 30.96 Gy; chiasma D max, 32,76 Gy. The volume of PTV for stereotactic radiotherapy was 3,736 cm3, with coverage D100=20.95 Gy and with only 0.11% of the PTV being irradiated to dose below the prescribed dose. HA-WBRT with SRT represents a feasible technique for radiotherapy of brain metastatic disease, however this technique is considerably demanding on departmental equipment and staff time/experience.
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http://dx.doi.org/10.3892/ol.2016.4440DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4888132PMC
June 2016

Prognostic Significance of Serum and Urinary Neopterin Concentrations in Patients with Rectal Carcinoma Treated with Chemoradiation.

Anticancer Res 2016 Jan;36(1):287-92

Department of Oncology, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic Institute of Molecular and Translational Medicine, Palacký University Medical School and Teaching Hospital, Olomouc, Czech Republic.

Aim: To analyze the prognostic significance of serum and urinary neopterin concentrations in patients with rectal adenocarcinoma treated with (chemo)radiation.

Patients And Methods: Urinary and serum neopterin and peripheral blood cell count were determined in 49 patients with rectal carcinoma before the start of (chemo)radiation.

Results: Neopterin concentrations exhibited a significant inverse correlation with hemoglobin and positive correlation with leukocyte count, platelet count and platelet-to-lymphocyte ratio. Increased serum neopterin concentration was associated with significantly inferior relapse-free survival (RFS) and overall survival. However, a significant association was observed only in 28 patients treated in the neoadjuvant setting. Although increased urinary neopterin was also associated with inferior RFS and overall survival, this was not statistically significant. The neutrophil-to-lymphocyte ratio was also associated with poor prognosis.

Conclusion: The data presented herein indicate a prognostic significance of serum neopterin concentrations in patients with rectal cancer treated with neoadjuvant chemoradiation.
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January 2016

Citrulline as a biomarker of gastrointestinal toxicity in patients with rectal carcinoma treated with chemoradiation.

Clin Chem Lab Med 2016 Feb;54(2):305-14

Background: Gastrointestinal toxicity is the principal toxicity of chemoradiation in the treatment of rectal carcinoma. The assessment of this toxicity still relies mostly on the symptoms reported by the patient.

Methods: Plasma citrulline, serum neopterin and urinary neopterin were followed weekly in 49 patients with rectal carcinoma during chemoradiation.

Results: Citrulline significantly (p<0.05) decreased while serum and urinary neopterin concentrations increased during therapy. Irradiated gut volume correlated significantly inversely with citrulline and positively with urinary neopterin. Statistically significant inverse correlations were also observed between urinary neopterin and plasma citrulline concentrations during the treatment. Urinary neopterin concentrations were significantly higher and citrulline concentrations were lower in patients who experienced grade ≥3 gastrointestinal toxicity.

Conclusions: Citrulline represents a promising biomarker of gastrointestinal toxicity. Moreover, the volume of irradiated gut correlated with urinary neopterin concentrations and an association was observed between gastrointestinal toxicity evidenced by lower citrulline concentrations and systemic immune activation reflected in increased concentrations of urinary neopterin.
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http://dx.doi.org/10.1515/cclm-2015-0326DOI Listing
February 2016

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

Predictive parameters for internal mammary node drainage in patients with early breast cancer.

Tumori 2014 May-Jun;100(3):254-8

Introduction: Breast cancer treatment currently represents one of the biggest challenges in clinical oncology. The gold standard for axillary lymph node management is to perform sentinel node biopsy to avoid axillary dissection and its sequelae. The detection of radiocolloid flow outside the axillary nodes is a diagnostic and therapeutic challenge.

Methods: A database search at the Department of Oncology of Palacky University, Olomouc, Czech Republic, identified 127 patients who underwent breast cancer resection with a sentinel node procedure and had radiocolloid flow into the internal mammary nodes. Sentinel node lymphoscintigraphy was performed after intraparenchymal injection. Clinical and pathological data were collected to identify possible risk factors.

Results: Ten clinical and pathological parameters including age, tumor histology, axillary lymph node status, estrogen receptor expression, progesterone receptor expression, tumor grade, Ki-67 expression, Her-2 status, tumor size and tumor location were analyzed with regard to internal mammary node drainage. A cohort of 127 patients with detected drainage into the internal mammary nodes was compared with 135 patients without such drainage. Six significant risk factors, including age <50 years ( P <0.0313), tumor location in central and inner quadrants (P <0.012), larger tumor size (P <0.017), positive Her-2 status (P <0.025), progesterone receptor expression (P <10-4) and axillary lymph node involvement (P <0.01) were found to predict radiocolloid flow into the internal mammary nodes.

Conclusion: Six parameters (patient age, tumor location, hormone receptor status, tumor size, Her-2 status and axillary lymph node status) should be considered in the management of breast cancer patients and help in the selection of patients for locoregional procedures encompassing the internal mammary nodes.
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http://dx.doi.org/10.1700/1578.17194DOI Listing
November 2014

Internal mammary node management in breast cancer. A review.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2013 Sep 13;157(3):261-5. Epub 2013 Sep 13.

Department of Oncology, Faculty of Medicine and Dentistry, Palacky University Olomouc, Czech Republic.

Background: Internal mammary nodes visualized during sentinel node biopsy for breast cancer, remain an unresolved management issue. Further, both internal mammary node (IMN) radiotherapy and biopsy have attendant risks and hence should be used with caution. The purpose of this review is to highlight the available data and evidence.

Methods And Results: A PubMed database from 1960 to 2012 using key words: internal mammary nodes, breast cancer radiotherapy planning, adjuvant radiotherapy, sentinel node biopsy in breast cancer and selected publications on the significance of internal mammary nodes in breast cancer treatment, published data and approaches used. We found 14513 relevant papers and we selected 30 that clearly investigated the management of internal mammary nodes during sentinel node search. We focused on the incidence of IMN metastasis (6 papers), risk factors associated with IMN drainage (9 reports), management of IMN and the impact on disease free and overall patient survival (15 papers).

Conclusions: The evidence for breast cancer axillary nodes management is good but the data for other draining nodes such as internal mammary nodes are far less conclusive and further research is needed.
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http://dx.doi.org/10.5507/bp.2013.068DOI Listing
September 2013

Abagovomab as maintenance therapy in patients with epithelial ovarian cancer: a phase III trial of the AGO OVAR, COGI, GINECO, and GEICO--the MIMOSA study.

J Clin Oncol 2013 Apr 11;31(12):1554-61. Epub 2013 Mar 11.

Kliniken Essen-Mitte, Germany.

Purpose: To determine whether abagovomab maintenance therapy prolongs recurrence-free (RFS) and overall survival (OS) in patients with ovarian cancer in first clinical remission.

Patients And Methods: Patients with International Federation of Gynecology and Obstetrics stage III to IV ovarian cancer in complete clinical remission after primary surgery and platinum- and taxane-based chemotherapy were randomly assigned at a ratio of 2:1 in a phase III, double-blind, placebo-controlled, multicenter study. Abagovomab 2 mg or placebo was administered as 1-mL suspension once every 2 weeks for 6 weeks (induction phase) and then once every 4 weeks (maintenance phase) until recurrence or up to 21 months after random assignment of the last patient. The primary end point was RFS; secondary end points were OS and immunologic response.

Results: Characteristics of the 888 patients included: mean age, 56.3 years; Eastern Cooperative Oncology Group performance status, ≤ 1 in > 99% of patients; serous papillary subtype, 81.5%; stage III, 85.9%; and cancer antigen 125 ≤ 35 U/mL after third cycle, 80.9%. Mean exposure to study treatment (± standard deviation) was 449.7 ± 333.08 days. Hazard ratio (HR) of RFS for the treatment group using tumor size categorization (≤ 1 cm, > 1 cm) was 1.099 (95% CI, 0.919 to 1.315; P = .301). HR of OS using tumor size categorization (≤ 1 cm, > 1 cm) was 1.150 (95% CI, 0.872 to 1.518; P = .322). The most frequently reported type of adverse event was an injection site reaction in 445 patients (50.2%), followed by injection site erythema and fatigue in 227 (25.6%) and 212 patients (23.9%), respectively. By the final visit, median anti-anti-idiotypic antibody level was 493,000.0 ng/mL, indicating a robust response.

Conclusion: Abagovomab administered as repeated monthly injections is safe and induces a measurable immune response. Administration as maintenance therapy for patients with ovarian cancer in first remission does not prolong RFS or OS.
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http://dx.doi.org/10.1200/JCO.2012.46.4057DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5795662PMC
April 2013

Metastases of esophageal carcinoma to skeletal muscle: single center experience.

World J Gastroenterol 2012 Sep;18(35):4962-6

Department of Oncology, Palacký University Medical School and Teaching Hospital, 77520 Olomouc, Czech Republic.

Metastases of esophageal carcinoma to the skeletal muscle are rare, but the incidence may be increasing because of better diagnosis resulting from widespread use of positron emission tomography/computed tomography (PET/CT). A cohort of 205 patients with esophageal carcinoma treated at our center who had PET/CT between 2006 and 2010 was retrospectively evaluated for the presence of skeletal muscle metastases. Four patients had skeletal muscle metastases of esophageal carcinoma, including two patients with squamous cell carcinoma. In another patient with squamous cell carcinoma of the esophagus and synchronous skeletal muscle metastases, muscle metastases were subsequently shown to be related to second primary pancreatic adenocarcinoma. In all cases, skeletal muscle metastases were the first manifestation of systemic disease. In three patients palliation was obtained with the combination of external beam radiation therapy, systemic chemotherapy or surgical resection. Skeletal muscle metastases are a rare complication of esophageal carcinoma.
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http://dx.doi.org/10.3748/wjg.v18.i35.4962DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3447280PMC
September 2012

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

Combination therapy of lapatinib and Capecitabine for ErbB2-positive metastatic or locally advanced breast cancer: results from the Lapatinib Expanded Access Program (LEAP) in Central and Eastern Europe.

Onkologie 2011 26;34(5):233-8. Epub 2011 Apr 26.

IIIrd Medical Department of Hematology and Medical Oncology, Private Medical University Hospital, Salzburg, Austria.

Background: The Lapatinib Expanded Access Program (LEAP) was initiated in 45 countries to provide lapatinib in combination with capecitabine to patients with ErbB2 (HER2)-positive breast cancer already treated with anthracyclines, taxanes and trastuzumab. We report the results from 12 Central and Eastern European countries.

Patients And Methods: By 30 September 2008, 293 patients were enrolled. Patients were monitored for serious adverse events (SAEs) and for any decrease in left ventricular ejection fraction (LVEF). Overall survival and progression-free survival were also assessed.

Results: Mean treatment duration was 30 weeks; 107 patients (36.5%) discontinued therapy during the study, mainly due to disease progression (n = 86; 29.4%). A total of 78 SAEs were reported from 47 patients; the most frequently reported was diarrhoea (13 reports). Treatment had a relatively small effect on LVEF. Decreases were minor (0 to < 20%) in 61% of patients at the end of the study. During the study, 3 patients had decreased LVEF meeting the definition of an SAE; these events all resolved. Median overall and median progression-free survival were 37.6 and 21.1 weeks, respectively.

Conclusions: Heavily pretreated patients with ErbB2-positive locally advanced or metastatic breast cancer may benefit from treatment with lapatinib and capecitabine, with a low risk of cardiac toxicity.
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http://dx.doi.org/10.1159/000327710DOI Listing
September 2011

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

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

Pseudoangiomatous stromal hyperplasia of breast: a case report.

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2008 Jun;152(1):117-20

Department of Radiology, Faculty of Medicine and Dentistry, Palacky University, Olomouc, Czech Republic.

Aim: To present a case of pseudoangiomatous stromal hyperplasia (PASH) and its findings under 1. mammography - MG, 2. ultrasonography - USG and 3. magnetic resonance imaging - MRI.

Materials And Methods: A woman 39 years of age with a history of mass in her right breast of 3 months duration was subjected to a routine examination of the mass using MG & USG. According to the modality findings a core cut biopsy was done following which the samples were send for histological analysis. Later, MRI was done as advocated by the surgeon to get a better picture of the extent of the lesion prior to surgery.

Results: Bilateral mammogram views revealed in the patient's right breast a huge well-bordered tumour of lobulated contour without halo sign. Sonography revealed a big well-demarcated tumour in the central part of the right breast which was cystic and lobulated in shape. Histological analysis of the sample confirmed pseudoangiomatous stromal hyperplasia (PASH). MRI under a breast array coil revealed a mass of 85 x 75 x 35mm in the right breast. Finally, based on the clinical, radiological and histological report the mass was diagnosed as benign and despite the massive size of the mass, tumour excision alone was done and not mastectomy. The right breast after the huge tumour excision was almost normal in size compared to the left.

Conclusion: PASH should be included in the differential diagnosis of a circumscribed or partially circumscribed mass, especially in the pre-menopausal female population. These benign masses often grow over time and can recur locally. Radiological diagnosis of PASH is usually done by MG and USG followed by core cut biopsy for histological analysis. However great the mass is, excision only of the tumor mass is recommended and not mastectomy.
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http://dx.doi.org/10.5507/bp.2008.018DOI Listing
June 2008

Technetium-99m-MIBI scintimammography by planar and SPECT imaging in the diagnosis of breast carcinoma and axillary lymph node involvement.

Nucl Med Rev Cent East Eur 2004 ;7(2):151-5

Department of Nuclear Medicine, University Hospital Olomouc, Czech Republic.

Background: We compared SPECT and planar (99m)Tc-MIBI scintimammography (SMM) in the detection of primary breast cancer and metastatic axillary lymph node involvement, and the scintigraphic results with the histopathological/cytological findings.

Material And Methods: 303 consecutive patients with 308 suspicious or indeterminate lesions observed in mammographies were entered in this study. After an intravenous injection of 740 MBq of (99m)Tc-MIBI, anterior supine, right and left lateral planar images in a prone position and a SPECT study were acquired.

Results: 85 malignant and 223 benign breast lesions were confirmed by histopathology/cytology. The overall sensitivity in the detection of breast cancer was 92% (78/85) for SPECT and 82% (70/85) for planar imaging (p = NS), respectively; overall specificity was 91% (204/223) for SPECT and 91% (202/223) for planar scans (p = NS), respectively. Metastatic axillary lymph node involvement was seen in 35 patients; per-axilla overall sensitivity was 66% (23/35) for SPECT and 54% (19/35) for planar images (NS), respectively; overall specificity was 76% (38/50) and 86% (43/50), respectively (NS).

Conclusions: Our results confirm the high diagnostic accuracy of (99m)Tc-MIBI scintimammography in the diagnosis of breast cancer, and show SPECT to be slightly more sensitive than planar imaging, especially in detecting malignant breast lesions. We found the sensitivity of both imaging modalities to be quite low in the detection of metastatic axillary lymph node involvement. SPECT provides additional information to planar SMM with respect to the localization of (99m)Tc-MIBI uptake and tumour extent and improves diagnostic certainty. Our experience suggests that SPECT combined with planar SMM should be used more widely.
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August 2005
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