Publications by authors named "Lubos Petruzelka"

66 Publications

Pembrolizumab as a first-line therapy in spinocellular esophageal cancer.

Klin Onkol 2021 ;34(1):59-61

Background: The treatment options in advanced stage of esophageal cancer are very limited. In recent years, a number of clinical trials have evaluated the effect of checkpoint inhibitors in this dia-gnosis.

Case: In our case report, we will demonstrate the administration of pembrolizumab in first-line therapy in generalized squamous cell carcinoma of the esophagus with PD-L1 expression > 70%. Complete remission of the disease was achieved by this approach.

Conclusion: Our case report shows the importance of investigating the expression of PD-L1 in advanced esophageal cancer. According to previous findings, immunotherapy, unlike chemotherapy, appears to have the potential to elicit a long-term response.
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http://dx.doi.org/10.48095/ccko202159DOI Listing
January 2021

Multicenter International Society for Immunotherapy of Cancer Study of the Consensus Immunoscore for the Prediction of Survival and Response to Chemotherapy in Stage III Colon Cancer.

J Clin Oncol 2020 11 8;38(31):3638-3651. Epub 2020 Sep 8.

Princess Margaret Cancer Centre, UHN, Toronto, Ontario, Canada.

Purpose: The purpose of this study was to evaluate the prognostic value of Immunoscore in patients with stage III colon cancer (CC) and to analyze its association with the effect of chemotherapy on time to recurrence (TTR).

Methods: An international study led by the Society for Immunotherapy of Cancer evaluated the predefined consensus Immunoscore in 763 patients with American Joint Committee on Cancer/Union for International Cancer Control TNM stage III CC from cohort 1 (Canada/United States) and cohort 2 (Europe/Asia). CD3+ and cytotoxic CD8+ T lymphocyte densities were quantified in the tumor and invasive margin by digital pathology. The primary end point was TTR. Secondary end points were overall survival (OS), disease-free survival (DFS), prognosis in microsatellite stable (MSS) status, and predictive value of efficacy of chemotherapy.

Results: Patients with a high Immunoscore presented with the lowest risk of recurrence, in both cohorts. Recurrence-free rates at 3 years were 56.9% (95% CI, 50.3% to 64.4%), 65.9% (95% CI, 60.8% to 71.4%), and 76.4% (95% CI, 69.3% to 84.3%) in patients with low, intermediate, and high immunoscores, respectively (hazard ratio [HR; high low], 0.48; 95% CI, 0.32 to 0.71; = .0003). Patients with high Immunoscore showed significant association with prolonged TTR, OS, and DFS (all < .001). In Cox multivariable analysis stratified by participating center, Immunoscore association with TTR was independent (HR [high low], 0.41; 95% CI, 0.25 to 0.67; .0003) of patient's sex, T stage, N stage, sidedness, and microsatellite instability status. Significant association of a high Immunoscore with prolonged TTR was also found among MSS patients (HR [high low], 0.36; 95% CI, 0.21 to 0.62; .0003). Immunoscore had the strongest contribution χ2 proportion for influencing survival (TTR and OS). Chemotherapy was significantly associated with survival in the high-Immunoscore group for both low-risk (HR [chemotherapy no chemotherapy], 0.42; 95% CI, 0.25 to 0.71; = .0011) and high-risk (HR [chemotherapy no chemotherapy], 0.5; 95% CI, 0.33 to 0.77; = .0015) patients, in contrast to the low-Immunoscore group ( > .12).

Conclusion: This study shows that a high Immunoscore significantly associated with prolonged survival in stage III CC. Our findings suggest that patients with a high Immunoscore will benefit the most from chemotherapy in terms of recurrence risk.
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http://dx.doi.org/10.1200/JCO.19.03205DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7605397PMC
November 2020

Regorafenib for Metastatic Colorectal Cancer: An Analysis of a Registry-Based Cohort of 555 Patients.

Cancer Manag Res 2020 3;12:5365-5372. Epub 2020 Jul 3.

Department of Oncology, First Faculty of Medicine and Thomayer Hospital, Charles University, Prague, Czech Republic.

Purpose: Regorafenib is an oral multikinase inhibitor approved for the therapy of previously treated metastatic colorectal carcinoma (mCRC). The aim of the present study was to analyze the outcomes of treatment with regorafenib in real-world clinical practice based on data from a national registry.

Methods: The CORECT registry, the Czech non-interventional database of patients with mCRC treated with targeted agents, searched for patients with metastatic CRC treated with regorafenib. In total, 555 evaluable patients were identified.

Results: The median age at diagnosis was 61.7 years. All patients had disease progression on or after previous systemic treatment. Most patients were treated with an initial dose of 160 mg daily (n = 463; 83.6%). The median duration of treatment was 2.7 months (range 0.0-23.4 months). By the data cut-off date, 472 patients (85%) had completed treatment with regorafenib and were evaluable for treatment response evaluation. Partial response was reported in 13 patients (2.8%) and disease stabilization in 130 patients (27.5%). Median progression-free survival (PFS) and overall survival (OS) were 3.5 months (95% confidence interval [CI] 3.2-3.7 months) and 9.3 months (95% CI 8.3-10.3 months), respectively. The 6-month OS rate was 67.7% (95% CI 63.4-72.1%). Multivariable analysis showed that female gender, longer interval from diagnosis of metastatic disease, M0 stage at diagnosis, and Eastern Cooperative Oncology Group performance status (ECOG PS) 0 were associated with longer PFS, while higher body-mass index (BMI), longer interval from diagnosis of metastatic disease, and ECOG PS of 0 were associated with longer OS.

Conclusion: OS of patients treated with regorafenib in the real-world clinical practice in this cohort exceeded that reported in randomized trials. Regorafenib is a safe and active treatment option for a subgroup of patients with mCRC who are progressing after other systemic therapies and maintain good performance status.
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http://dx.doi.org/10.2147/CMAR.S255332DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7342462PMC
July 2020

Care of patients with non-small-cell lung cancer stage III - the Central European real-world experience.

Radiol Oncol 2020 05 28;54(2):209-220. Epub 2020 May 28.

1st Faculty of Medicine of Charles University in Prague, Prague Czech Republic.

Background Management of non-small-cell lung cancer (NSCLC) is affected by regional specificities. The present study aimed at determining diagnostic and therapeutic procedures including outcome of patients with NSCLC stage III in the real-world setting in Central European countries to define areas for improvements. Patients and methods This multicentre, prospective and non-interventional study collected data of patients with NSCLC stage III in a web-based registry and analysed them centrally. Results Between March 2014 and March 2017, patients (n=583) with the following characteristics were entered: 32% females, 7% never-smokers; ECOG performance status (PS) 0, 1, 2 and 3 in 25%, 58%, 12% and 5%, respectively; 21% prior weight loss; 53% squamous carcinoma, 38% adenocarcinoma; 10% EGFR mutations. Staging procedures included chest X-ray (97% of patients), chest CT (96%), PET-CT (27%), brain imaging (20%), bronchoscopy (89%), endobronchial ultrasound (EBUS) (13%) and CT-guided biopsy (9%). Stages IIIA/IIIB were diagnosed in 55%/45% of patients, respectively. N2/N3 nodes were diagnosed in 60%/23% and pathologically confirmed in 29% of patients. Most patients (56%) were treated by combined modalities. Surgery plus chemotherapy was administered to 20%, definitive chemoradiotherapy to 34%, chemotherapy only to 26%, radiotherapy only to 12% and best supportive care (BSC) to 5% of patients. Median survival and progression-free survival times were 16.8 (15.3;18.5) and 11.2 (10.2;12.2) months, respectively. Stage IIIA, female gender, no weight loss, pathological mediastinal lymph node verification, surgery and combined modality therapy were associated with longer survival. Conclusions The real-world study demonstrated a broad heterogeneity in the management o f stage III NSCLC in Central European countries and suggested to increase the rates of PET-CT imaging, brain imaging and invasive mediastinal staging.
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http://dx.doi.org/10.2478/raon-2020-0026DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7276648PMC
May 2020

Sequential Treatment with Bevacizumab and Aflibercept for Metastatic Colorectal Cancer in Real-World Clinical Practice.

Target Oncol 2020 04;15(2):193-201

Department of Oncology, Palacky University Medical School and Teaching Hospital, I.P. Pavlova 6, 775 20, Olomouc, Czech Republic.

Background: Bevacizumab and aflibercept are currently the mainstay of antiangiogenic therapy for metastatic colorectal carcinoma (mCRC). They are often used in sequence with first- and second-line chemotherapy, especially in patients with RAS-mutated tumours.

Objective: The aim of the present study was to investigate the outcomes of patients with mCRC treated with the bevacizumab-aflibercept sequence in real-world clinical practice.

Patients And Methods: Data from a national clinical registry of targeted therapies for mCRC were analysed retrospectively. Overall, there were 366 patients with valid data who received first-line treatment with bevacizumab and chemotherapy followed by aflibercept with chemotherapy. The majority of the patients (n = 296, 80.8%) had RAS mutated tumours.

Results: Median cumulative progression-free survival (PFS) from the start of the bevacizumab-containing regimen to progression on aflibercept was 18.2 months (95% CI 16.8-19.5). Median PFS for bevacizumab and aflibercept was 10.6 months (95% CI 9.5-11.7) and 5.6 months (95% CI 5.1-6.1), respectively. Longer PFS on aflibercept was associated with metachronous metastatic disease and longer PFS on bevacizumab. Median overall survival (OS) from the start of first-line bevacizumab was 32.0 months (95% CI 26.6-37.5). The presence of metastatic disease at diagnosis was associated with worse OS.

Conclusions: Patients treated with aflibercept in real-world clinical practice achieved similar survival outcomes as those treated within randomised trials. Cumulative survival data provide a benchmark for future studies and enable indirect comparisons with other treatment sequences used in mCRC.
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http://dx.doi.org/10.1007/s11523-020-00705-1DOI Listing
April 2020

Practical instructions for testing and targeted therapy in adult patients with solid tumours with NTRK gene fusion in common clinical practice.

Klin Onkol 2020 ;33(6):414-419

Background: Tropomyosin receptor kinase inhibitors (TRKi) have been shown to produce a dramatic and long-lasting effect on tumours harbouring fusions of neurotrophic receptor tyrosine kinase (NTRK) genes. Due to the low incidence of these molecular aberrations in common types of solid adult tumours, the identification of patients eligible for the treatment with TRK inhibitors in routine clinical practice is a major challenge. The current methods for NTRK gene fusion testing include immunohistochemistry (IHC), fluorescence in situ hybridization (FISH), and several genomic assays using next-generation sequencing (NGS). After considering the characteristics of these tests, we recommend two-step testing for clinical practice in tumours with a low incidence of NTRK gene fusions. In the first step, a fresh or archival formalin fixed paraffin embedded (FFPE) sample is tested using a validated IHC method. If the IHC result is positive, verification using RNA-based should follow, preferably using fresh tissue sample. If fresh tissue bio-psy cannot be obtained, e.g. due to a disproportionate risk or discomfort for the patient, an archival FFPE sample may be used for testing. For tumours with high incidence of NTRK gene fusions, we recommend upfront NGS sequencing. Larotrektinib is currently the only TRK inhibitor registered in the EU. Although entrektinib, another TRK inhibitor, is not yet registered in the EU, it is currently available in the Czech Republic within an Early Access Programme.

Purpose: The aim of this paper is to provide concise and clear guidance on testing for the presence of NTRK gene fusions and indications for the treatment with TRK inhibitors in the routine clinical oncology practice.
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January 2020

Novel serum markers HSP60, CHI3L1, and IGFBP-2 in metastatic colorectal cancer.

Oncol Lett 2019 Dec 26;18(6):6284-6292. Epub 2019 Sep 26.

Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital in Prague, 128 08 Prague 2, Czech Republic.

Colorectal cancer (CRC) is the second leading tumor diagnosis in women and men in the Czech Republic. Patient outcome depends on tumor stage at the time of diagnosis and, in metastatic disease, on the localization and extent of distant metastases. The early detection of metastatic liver disease is an important indication for liver surgery. Therefore, novel biomarkers are urgently required. Serum samples were collected from 97 patients with histologically confirmed metastatic CRC at the time of diagnosis or at the time of progression during palliative treatment, and 79 samples from healthy controls. All patients exhibited adequate liver and renal function and signed informed consent was obtained from all patients included in the current study. The serum levels of Heat shock protein 60 (HSP60), Chitinase-3-like protein 1 (CHI3L1) and Insulin-like growth factor binding protein 2 (IGFBP-2) were measured using immunochemistry. The serum levels of HSP60, CHI3L1 and IGFBP-2 were significantly higher in patients with CRC compared with healthy controls. When compared with carcinoembryonic antigen (CEA), HSP60 exhibited the same sensitivity and specificity, while CHI3L1 and IGFBP-2 exhibited decreased sensitivity. Additionally, the serum levels of HSP60 and IGFBP-2 were indicated to be correlated with the presence of liver metastases, which is in contrast to CEA and Cancer antigen 19-9 (CA19-9). Patients with higher HSP60 and IGFBP-2 levels exhibited a significantly worse survival (P<0.001 and 0.007, respectively). The results of the current study indicate HSP60 to be an effective biomarker in patients with metastatic CRC, with it exhibiting an equal sensitivity to CEA. Additionally, HSP60 and IGFBP-2 levels also strongly correlated with extension of liver metastases and exhibited a prognostic value that contrasted that of CEA.
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http://dx.doi.org/10.3892/ol.2019.10925DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6864964PMC
December 2019

Beyond tissue biopsy: a diagnostic framework to address tumor heterogeneity in lung cancer.

Curr Opin Oncol 2020 01;32(1):68-77

Department of Biomedical Imaging and Image-Guided Therapy Medical University of Vienna, Austria.

Purpose Of Review: The objective of this review is to discuss the strength and limitations of tissue and liquid biopsy and functional imaging to capture spatial and temporal tumor heterogeneity either alone or as part of a diagnostic framework in non-small cell lung cancer (NSCLC).

Recent Findings: NSCLC displays genetic and phenotypic heterogeneity - a detailed knowledge of which is crucial to personalize treatment. Tissue biopsy often lacks spatial and temporal resolution. Thus, NSCLC needs to be characterized by complementary diagnostic methods to resolve heterogeneity. Liquid biopsy offers detection of tumor biomarkers and for example, the classification and monitoring of EGFR mutations in NSCLC. It allows repeated sampling, and therefore, appears promising to address temporal aspects of tumor heterogeneity. Functional imaging methods and emerging image analytic tools, such as radiomics capture temporal and spatial heterogeneity. Further standardization of radiomics is required to allow introduction into clinical routine.

Summary: To augment the potential of precision therapy, improved diagnostic characterization of tumors is pivotal. We suggest a comprehensive diagnostic framework combining tissue and liquid biopsy and functional imaging to address the known aspects of spatial and temporal tumor heterogeneity on the example of NSCLC. We envision how this framework might be implemented in clinical practice.
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http://dx.doi.org/10.1097/CCO.0000000000000598DOI Listing
January 2020

Serum levels of TIMP-1 and MMP-7 as potential biomarkers in patients with metastatic colorectal cancer.

Int J Biol Markers 2019 Sep 4;34(3):292-301. Epub 2019 Sep 4.

Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital in Prague, Czech Republic.

Objective: Tissue inhibitor of metalloproteinases 1 (TIMP-1) and matrix metalloproteinase 7 (MMP-7) were reported to have potent growth promoting activity. Lack of balance between MMPs and TIMPs is an important factor in the development of gastrointestinal malignancies.

Methods: We collected serum samples from 97 patients with metastatic colorectal cancer and 79 samples from healthy controls. Serum levels of TIMP-1 and MMP-7 were measured immunochemically and compared with standard tumor markers carcinoembryonic antigen and CA19-9.

Results: Serum levels of TIMP-1 and MMP-7 were significantly higher in patients with colorectal cancer compared to healthy controls (both, P < 0.001). TIMP-1 and MMP-7 correlate with the presence of colon involvement (P = 0.001; P = 0.012) and the presence of liver metastases (P = 0.002; P = 0.037), and negatively correlate with pulmonary metastases (P = 0.014; P = 0.005). MMP-7 had similar sensitivity and the same specificity as carcinoembryonic antigen. TIMP-1 and MMP-7 had better sensitivity than CA19-9. TIMP-1 and MMP-7 level correlate with worse outcome (P = 0.002).

Conclusion: The results indicate that TIMP-1 and MMP-7 are effective biomarkers in patients with metastatic colorectal cancer with good sensitivity. TIMP-1 and MMP-7 levels strongly correlate with the extent of liver disease and have prognostic value.
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http://dx.doi.org/10.1177/1724600819866202DOI Listing
September 2019

Estrogen Receptor Status Oppositely Modifies Breast Cancer Prognosis in Mutation Carriers Versus Non-Carriers.

Cancers (Basel) 2019 May 28;11(6). Epub 2019 May 28.

Institute of Biochemistry and Experimental Oncology, First Faculty of Medicine, Charles University, U Nemocnice 5, 128 00 Prague 2, Czech Republic.

Breast cancer (BC) prognosis in BRCA1 and BRCA2 mutation carriers has been reported contradictorily, and the significance of variables influencing prognosis in sporadic BC is not established in BC patients with hereditary BRCA1/BRCA2 mutations. In this retrospective cohort study, we analyzed the effect of clinicopathological characteristics on BC prognosis (disease-free survival [DFS] and disease-specific survival [DSS]) in hereditary BRCA1/BRCA2 mutation carriers. We enrolled 234 BRCA1/BRCA2 mutation carriers and 899 non-carriers, of whom 191 carriers and 680 non-carriers, with complete data, were available for survival analyses. We found that patients with ER-positive tumors developed disease recurrence 2.3-times more likely when they carried a BRCA1/BRCA2 mutation (23/60; 38.3% ER-positive carriers vs. 74/445; 16.6% ER-positive non-carriers; < 0.001). ER-positive mutation carriers also had a 3.4-times higher risk of death due to BC compared with ER-positive non-carriers (13/60; 21.7% vs. 28/445; 6.3%; < 0.001). Moreover, prognosis in ER-negative BRCA1/BRCA2 mutation carriers was comparable with that in ER-positive non-carriers. Our study demonstrates that ER-positivity worsens BC prognosis in BRCA1/BRCA2 mutation carriers, while prognosis for carriers with ER-negative tumors (including early-onset) is significantly better and comparable with that in ER-positive, older BC non-carriers. These observations indicate that BRCA1/BRCA2 mutation carriers with ER-positive BC represent high-risk patients.
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http://dx.doi.org/10.3390/cancers11060738DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6627684PMC
May 2019

Sequential therapy with bevacizumab and EGFR inhibitors for metastatic colorectal carcinoma: a national registry-based analysis.

Cancer Manag Res 2019 28;11:359-368. Epub 2018 Dec 28.

Department of Oncology, Palacky University Medical School and Teaching Hospital, 775 20 Olomouc, Czech Republic.

Purpose: Although inhibitors of vascular endothelial growth factor and inhibitors of epidermal growth factor receptor (EGFRi) are commonly used for the treatment of metastatic colorectal cancer (mCRC), the optimal sequencing of these agents is currently unclear.

Methods: A national registry of targeted therapies was used to analyze baseline characteristics and outcomes of patients with mCRC and wild-type exon 2 status who received bevacizumab and EGFRi (cetuximab or panitumumab) as a part of first- and second-line treatment in either sequence.

Results: The cohort included 490 patients (181 patients treated with first-line EGFRi and second-line bevacizumab and 309 patients treated with first-line bevacizumab and second-line EGFRi). Median overall survival (OS) from the initiation on first-line therapy was similar for patients treated with either sequence, reaching 31.8 (95% CI 27.5-36.1) vs 31.4 months (95% CI 27.8-35.0) for EGFRi → bevacizumab vs bevacizumab → EGFRi cohort, respectively. Time from first-line initiation to progression on the second-line therapy [progression-free survival (PFS)] was 21.1 (95% CI 19.3-23.0) vs 19.3 months (95% CI 17.3-21.3) for bevacizumab → EGFRi vs EGFRi → bevacizumab cohort, respectively (=0.016).

Conclusion: This retrospective analysis of real-world data of patients with wild-type exon 2 mCRC showed no differences in OS between cohorts treated with bevacizumab → EGFRi vs the reverse sequence while combined PFS favored the bevacizumab → EGFRi sequence.
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http://dx.doi.org/10.2147/CMAR.S183093DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6314050PMC
December 2018

Safe decontamination of cytostatics from the nitrogen mustards family. Part one: cyclophosphamide and ifosfamide.

Int J Nanomedicine 2018 26;13:7971-7985. Epub 2018 Nov 26.

Department of Oncology, 1st Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic,

Introduction: Macrocrystalline oxides of alkaline earth metals (Mg and Ca) or light metals (Al and Ti) can respond to standard warfare agents such as sulfur mustard, soman, or agent VX. In this paper, we compared the decontamination ability of sodium hydroxide (NaOH) and sodium hypochlorite (NaClO) for nitrogen mustards (cyclophosphamide [CP] and ifosfamide [IFOS]) with a new procedure using a destructive sorbent based on nanocrystalline and nanodispersive titanium dioxide (TiO) as a new efficient and cheap material for complete decontamination of surfaces.

Methods: Titanium (IV) dioxide nanoparticles were prepared by the homogeneous hydrolysis of titanium(IV) oxysulfate (TiOSO) with urea. The as-prepared TiO nanoparticles were used for the fast and safe decontamination of cytostatics from the nitrogen mustard family (CP and IFOS) in water. The adsorption-degradation process of cytostatics in the presence of TiO was compared with decontamination agents (0.01 M solution of sodium hydroxide and 5% solution of sodium hypochlorite). The mechanism of the decontamination process and the degradation efficiency were determined by high-performance liquid chromatography with mass spectrometry.

Results: It was demonstrated that a 0.01 M solution of sodium hydroxide (NaOH) decomposes CP to 3-((amino(bis(2-chloroethyl)amino)phosphoryl)oxy)propanoic acid and sodium hypochlorite formed two reaction products, namely, IFOS and 4-hydroxy-cyclophosphamide. IFOS is cytotoxic, and 4-hydroxy-cyclophosphamide is a known metabolite of CP after its partial metabolism by CYP/CYP450. IFOS degrades in the pres¬ence of NaOH to toxic IFOS mustard. Titanium(IV) dioxide nanoparticles adsorbed on its surface CP after 5 minutes and on IFOS after 10 minutes. The adsorption-degradation process of CP in water and in the presence of TiO led to 4-hydroxy-cyclophosphamide and IFOS, respectively, which decayed to oxidation product 4-hydroxy-ifosfamide.

Conclusion: Nanodispersive TiO is an effective degradation agent for decontamination of surfaces from cytostatics in medical facilities.
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http://dx.doi.org/10.2147/IJN.S159328DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6263216PMC
January 2019

Use of Trastuzumab for Neoadjuvant Therapy of HER2+ Breast Cancer - 5-Years of Experience in a Single Clinic.

Klin Onkol Spring 2018;31(3):191-199

Background: Trastuzumab (Herceptin® - H) has been the standard-of-care for patients with HER2+ breast cancer (BC) since 2009 in the Czech Republic. Neoadjuvant application of H increases the number of patients who achieve pathological complete remission (pCR) and improves patients' outcomes.

Aim: This study aimed to assess the effect of neoadjuvant therapy (NAT) with H in patients with early HER2+ BC and to correlate the therapeutic outcome with overall survival (OS). We defined pCR as no invasive carcinoma (ypT0) or in situ residual carcinoma (ypTis) in breast tissue and no invasive carcinoma in axillary lymphatic nodes (ypN0). To correlate pCR with the hormone dependency of BC, we compared the number of patients who achieved pCR between those with hormone-dependent (estrogen receptor (ER) +) BC and those with hormone-negative (ER-) BC.

Results: We evaluated data from 148 patients with HER2+ BC, most of whom were at stage II. Of these, 50.7% were premenopausal women and 45.9% had ER- BC. Most patients were treated with anthracyclines followed by taxanes and H. pCR was reported in 50% of patients (74/148). ER+ BC regressed more often to ypTis stage (24/35), ER- BC to ypT0ypN0 stage (26/39). The 1-year OS rate of patients who achieved pCR was significantly higher than that of patients who did not (100.0% vs. 95.3%, p = 0.009). Median OS was not achieved in pCR patients group.

Conclusion: Patients who achieved pCR had a better prognosis than patients who did not. Key words: neoadjuvant therapy - trastuzumab - early breast cancer - pathological complete remission - prognosis The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE recommendation for biomedical papers. Submitted: 14. 9. 2017 Accepted: 15. 2. 2018.
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http://dx.doi.org/10.14735/amko2018191DOI Listing
September 2019

Impact of Delayed Addition of Anti-EGFR Monoclonal Antibodies on the Outcome of First-Line Therapy in Metastatic Colorectal Cancer Patients: a Retrospective Registry-Based Analysis.

Target Oncol 2018 12;13(6):735-743

Department of Oncology, First Faculty of Medicine, Charles University and Thomayer University Hospital, Videnska 800, 140 59, Prague, Czech Republic.

Background: The addition of monoclonal antibodies targeting the epidermal growth factor receptor (anti-EGFR Abs) to chemotherapy for metastatic colorectal carcinoma (mCRC) is commonly delayed in the real-world clinical practice, usually because of late RAS testing results.

Objective: To determine whether delayed addition of anti-EGFR mAbs up to the fourth cycle of backbone chemotherapy adversely affected outcomes of mCRC patients treated with first-line regimens.

Patients And Methods: Clinical data of patients with histologically verified, RAS wild-type mCRC treated with first-line systemic therapy regimens containing anti-EGFR mAbs were retrospectively analysed from a national database. Patients were divided into three groups according to the timing of anti-EGFR mAbs addition to the chemotherapy backbone. Cohort A (n = 401) included patients in whom anti-EGFR mAbs were added to chemotherapy from the first cycle, cohort B (n = 71) patients with anti-EGFR mAbs added to chemotherapy from the second cycle, and cohort C (n = 101) patients who had anti-EGFR mAbs added to chemotherapy from the third or fourth cycle.

Results: Three hundred and thirty-six (58.6%) patients received panitumumab and 237 (41.4%) patients received cetuximab. The median progression-free survival (PFS) of the whole cohort was 12.2 months (95% confidence interval [CI] 10.9-13.5), and the median overall survival (OS) was 33.5 months (95% CI 27.6-39.4). The median PFS and OS for patients treated with anti-EGFR mAbs added to chemotherapy were 12.9 (95% CI 11.5-14.3) and 30.6 months (95% CI 25.2-36.1) for cohort A, 9.7 (95% CI 9.1-10.3) and not reached for cohort B, compared to 11.5 (95% CI 9.8-13.2) and 37.9 months (95% CI 28.6-47.3) for cohort C, respectively.

Conclusions: Delayed addition of anti-EGFR mAbs to first-line chemotherapy was not associated with inferior survival or response rates.
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http://dx.doi.org/10.1007/s11523-018-0597-7DOI Listing
December 2018

Immunological examination of peripheral blood in patients with colorectal cancer compared to healthy controls.

Immunol Invest 2018 Oct 20;47(7):643-653. Epub 2018 Jun 20.

a Department of Oncology, First Faculty of Medicine , Charles University , Prague , Czech Republic.

Background: The objective of this study was to investigate serum levels of immunosuppressive cytokines TGF beta 1 and VEGF and count of immune cells in peripheral blood in stage II and III colorectal cancer patients.

Methods: Blood samples were collected from 22 colorectal patients and 25 healthy controls before the start of treatment. All patients were examined by a clinical immunologist to exclude patients with immune disorders and autoimmune diseases. TGF beta 1 and VEGF were measured by ELISA, and anti-tumor cellular immunity cells (CD4, CD8, B cells, NK cells) were measured by flow cytometry.

Results: TGF beta 1 and VEGF plasma levels were significantly increased in stage II and III colorectal patients compared with control group (both p < 0.0001). A decrease in the cellular immunity was shown in the absolute numbers of cytotoxic T lymphocytes (CD8+ ; p = 0.0240), helper T lymphocytes (CD4+ ; p = 0.0019), and natural killer cells (CD16 + CD56+; p < 0.0001) in both stage II and stage III patients. On the contrary, B lymphocyte (CD19+) serum levels were increased in colon cancer patients (p < 0.0001) compared to the control group.

Conclusions: Our results show peripheral blood levels of TGF beta and VEGF were significantly increased in colorectal patients and changes in cellular anticancer immunity in comparison to control group. These results will be compared with results from Immunoscore.
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http://dx.doi.org/10.1080/08820139.2018.1480030DOI Listing
October 2018

International validation of the consensus Immunoscore for the classification of colon cancer: a prognostic and accuracy study.

Lancet 2018 05 10;391(10135):2128-2139. Epub 2018 May 10.

Department of Pathology and Laboratory Medicine, University Health Network, Toronto, ON, Canada.

Background: The estimation of risk of recurrence for patients with colon carcinoma must be improved. A robust immune score quantification is needed to introduce immune parameters into cancer classification. The aim of the study was to assess the prognostic value of total tumour-infiltrating T-cell counts and cytotoxic tumour-infiltrating T-cells counts with the consensus Immunoscore assay in patients with stage I-III colon cancer.

Methods: An international consortium of 14 centres in 13 countries, led by the Society for Immunotherapy of Cancer, assessed the Immunoscore assay in patients with TNM stage I-III colon cancer. Patients were randomly assigned to a training set, an internal validation set, or an external validation set. Paraffin sections of the colon tumour and invasive margin from each patient were processed by immunohistochemistry, and the densities of CD3+ and cytotoxic CD8+ T cells in the tumour and in the invasive margin were quantified by digital pathology. An Immunoscore for each patient was derived from the mean of four density percentiles. The primary endpoint was to evaluate the prognostic value of the Immunoscore for time to recurrence, defined as time from surgery to disease recurrence. Stratified multivariable Cox models were used to assess the associations between Immunoscore and outcomes, adjusting for potential confounders. Harrell's C-statistics was used to assess model performance.

Findings: Tissue samples from 3539 patients were processed, and samples from 2681 patients were included in the analyses after quality controls (700 patients in the training set, 636 patients in the internal validation set, and 1345 patients in the external validation set). The Immunoscore assay showed a high level of reproducibility between observers and centres (r=0·97 for colon tumour; r=0·97 for invasive margin; p<0·0001). In the training set, patients with a high Immunoscore had the lowest risk of recurrence at 5 years (14 [8%] patients with a high Immunoscore vs 65 (19%) patients with an intermediate Immunoscore vs 51 (32%) patients with a low Immunoscore; hazard ratio [HR] for high vs low Immunoscore 0·20, 95% CI 0·10-0·38; p<0·0001). The findings were confirmed in the two validation sets (n=1981). In the stratified Cox multivariable analysis, the Immunoscore association with time to recurrence was independent of patient age, sex, T stage, N stage, microsatellite instability, and existing prognostic factors (p<0·0001). Of 1434 patients with stage II cancer, the difference in risk of recurrence at 5 years was significant (HR for high vs low Immunoscore 0·33, 95% CI 0·21-0·52; p<0·0001), including in Cox multivariable analysis (p<0·0001). Immunoscore had the highest relative contribution to the risk of all clinical parameters, including the American Joint Committee on Cancer and Union for International Cancer Control TNM classification system.

Interpretation: The Immunoscore provides a reliable estimate of the risk of recurrence in patients with colon cancer. These results support the implementation of the consensus Immunoscore as a new component of a TNM-Immune classification of cancer.

Funding: French National Institute of Health and Medical Research, the LabEx Immuno-oncology, the Transcan ERAnet Immunoscore European project, Association pour la Recherche contre le Cancer, CARPEM, AP-HP, Institut National du Cancer, Italian Association for Cancer Research, national grants and the Society for Immunotherapy of Cancer.
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http://dx.doi.org/10.1016/S0140-6736(18)30789-XDOI Listing
May 2018

Anthracycline antibiotics derivate mitoxantrone-Destructive sorption and photocatalytic degradation.

PLoS One 2018 13;13(3):e0193116. Epub 2018 Mar 13.

Department of Oncology, 1st Faculty of Medicine, Charles University in Prague, Czech Republic.

Nanostructured titanium(IV) oxide was used for the destructive adsorption and photocatalytic degradation of mitoxantrone (MTX), a cytostatic drug from the group of anthracycline antibiotics. During adsorption on a titania dioxide surface, four degradation products of MTX, mitoxantrone dicarboxylic acid, 1,4-dihydroxy-5-((2-((2-hydroxyethyl)amino)ethyl)amino)-8-((2-(methylamino)ethyl)amino)anthracene-9,10-dione, 1,4-dihydroxy-5,8-diiminoanthracene-9,10(5H,8H)-dione and 1,4-dihydroxy-5-imino-8-(methyleneamino)anthracene-9,10(5H,8H)-dione, were identified. In the case of photocatalytic degradation, only one degradation product after 15 min at m/z 472 was identified. This degradation product corresponded to mitoxantrone dicarboxylic acid, and complete mineralization was attained in one hour. Destructive adsorbent manganese(IV) oxide, MnO2, was used only for the destructive adsorption of MTX. Destructive adsorption occurred only for one degradation product, mitoxantrone dicarboxylic acid, against anatase TiO2.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0193116PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5849306PMC
June 2018

Growth/differentiation factor 15 (GDF-15) as new potential serum marker in patients with metastatic colorectal cancer.

Cancer Biomark 2018 ;21(4):869-874

Department of Oncology, First Faculty of Medicine, Charles University, and General University Hospital in Prague, Prague 2, 128 08, Czech Republic.

Background: GDF-15 is a protein belonging to the transforming growth factor beta superfamily that has a role in regulating inflammatory and apoptotic pathways. High level GDF-15 in tumor tissues and plasma correlate with an increased risk of recurrence and reduced overall survival.

Objective: The aim of this study was to screen GDF-15 capacity to detecting metastatic CRC and compare it with standard tumor markers CEA and CA19-9.

Methods: We collected serum samples from 97 patients with metastatic colorectal cancer and 79 samples from healthy controls. Serum levels of GDF-15, CEA and CA19-9 were measured by immunochemically. A Kaplan-Meier curve was applied for analysis of survival rates, and a log-rank was used for univariate analysis.

Results: Serum levels of GDF-15 were significantly higher in patients with colorectal cancer compared to healthy controls (p< 0.001). In addition, serum levels of GDF-15 correlated with extent of liver involvement and patients with higher GDF-15 levels had significantly worse outcome (p< 0.0001).

Conclusions: Our results show GDF-15 as an effective biomarker in patients with metastatic colorectal cancer with the same sensitivity as CEA. In addition, GDF-15 levels strongly correlate with extension of liver involvement in contrast with CEA.
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http://dx.doi.org/10.3233/CBM-170792DOI Listing
August 2018

Molecular pathological predictive diagnostics in a patient with non-small cell lung cancer treated with crizotinib therapy: A case report.

Oncol Lett 2017 Dec 11;14(6):7545-7548. Epub 2017 Oct 11.

Institute of Biology and Medical Genetics, First Faculty of Medicine, Charles University in Prague and General University Hospital in Prague, 12808 Prague 2, Czech Republic.

Lung cancer is one of the most common malignant cancers in the Czech Republic in men, with the highest mortality rate of all the malignant diseases. The development of biological treatment enables study into novel personalized treatment options. This type of treatment is usually of high quality, and is often demanding of predictive and biopsy diagnostics, which is dependent on the quality of the collected material and close cooperation among particular departments. The present study describes the complete biopsy and predictive examinations performed in a male patient with lung adenocarcinoma, with an emphasis on the logistics of the whole process and the application of the tyrosine kinase inhibitors, crizotinib and LDK378. The patient experienced a long overall survival time of 28 months from diagnosis.
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http://dx.doi.org/10.3892/ol.2017.7167DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5755203PMC
December 2017

5-fluorouracil Toxicity Mechanism Determination in Human Keratinocytes: in vitro Study on HaCaT Cell Line.

Prague Med Rep 2017;118(4):128-138

Department of Oncology, First Faculty of Medicine, Charles University and General University Hospital in Prague, Prague, Czech Republic.

5-fluorouracil (5-FU) and capecitabine therapy is often accompanied by palmar-plantar erythrodysesthesia (PPE) which is manifestation of 5-FU toxicity in keratinocytes. The main mechanisms of 5-FU action are thymidylate synthase (TS) inhibition which can be abrogated by thymidine and strengthened by calciumfolinate (CF) and incorporation of fluorouridinetriphosphate into RNA which can be abrogated by uridine. For proper PPE treatment 5-FU mechanism of action in keratinocytes needs to be elucidated. We used the 5-FU toxicity modulators uridine, thymidine and CF to discover the mechanism of 5-FU action in human keratinocyte cell line HaCaT. To measure the cellular viability, we used MTT test and RTCA test. CF did not augment 5-FU toxicity and 5-FU toxicity was weakened by uridine. Therefore, the primary mechanism of 5-FU toxicity in keratinocytes is 5-FU incorporation into RNA. The uridine protective effect cannot fully develop in the presence of CF. Thymidine addition to 5-FU and uridine treated cells not only prevents the toxicity-augmenting CF effect but it also prolongs the 5-FU treated cells survival in comparison to uridine only. Therefore, it can be assumed that in the presence of uridine the 5-FU toxicity mechanism is switched from RNA incorporation to TS inhibition. Although particular 5-FU toxicity mechanisms were previously described in various cell types, this is the first time when various combinations of pyrimidine nucleosides and CF were used for 5-FU toxicity mechanism elucidation in human keratinocytes. We suggest that for PPE treatment ointment containing uridine and thymidine should be further clinically tested.
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http://dx.doi.org/10.14712/23362936.2017.14DOI Listing
April 2018

Molecular characterization and heterogeneity of circulating tumor cells in breast cancer.

Breast Cancer Res Treat 2017 Dec 16;166(3):695-700. Epub 2017 Aug 16.

Department of Laboratory Genetics, University Hospital Kralovske Vinohrady, Srobarova 50, 100 34, Prague, Czech Republic.

Introduction: This study analyzes peripheral blood samples from breast cancer (BC) patients. CTCs from peripheral blood were enriched by size-based separation and were then cultivated in vitro. The primary aim of this study was to demonstrate the antigen independent CTC separation method with high CTC recovery. Subsequently, CTCs enriched several times during the treatment were characterized molecularly.

Methods: Patients with different stages of BC (N = 167) were included into the study. All patients were candidates for surgery, surgical diagnostics, or were undergoing chemotherapy. In parallel, 20 patients were monitored regularly and in addition to CTC presence, also CTC character was examined by qPCR, with special focus on HER2 and ESR status.

Results: CTC positivity in the cohort was 76%. There was no significant difference between the tested groups, but the highest CTC occurrence was identified in the group undergoing surgery and similarly in the group before the start of neoadjuvant treatment. On the other hand, the lowest CTC frequencies were observed in the menopausal patient group (56%), ESR+ patient group (60%), and DCIS group (44.4%). It is worth noting that after completion of neoadjuvant therapy (NACT) CTCs were present in 77.7% of cases. On the other hand, patients under hormonal treatment were CTC positive only in 52% of cases.

Discussions: Interestingly, HER2 and ESR status of CTCs differs from the status of primary tumor. In 50% of patients HER2 status on CTCs changed not only from HER2+ to HER2-, but also from HER2- to HER2+ (33%). ESR status in CTCs changed only in one direction from ESR+ to ESR-.

Conclusions: Data obtained from the present study suggest that BC is a heterogeneous disease but CTCs may be detected independently of the disease characteristics in 76% of patients at any time point during the course of the disease. This relatively high CTC occurrence in BC should be considered when planning the long-term patient monitoring.
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http://dx.doi.org/10.1007/s10549-017-4452-9DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5680374PMC
December 2017

Migrastatics-Anti-metastatic and Anti-invasion Drugs: Promises and Challenges.

Trends Cancer 2017 06;3(6):391-406

Department of Cell Biology, Charles University, Viničná 7, Prague, Czech Republic; Biotechnology and Biomedicine Centre of the Academy of Sciences and Charles University (BIOCEV), Průmyslová 595, 25242, Vestec u Prahy, Czech Republic. Electronic address:

In solid cancers, invasion and metastasis account for more than 90% of mortality. However, in the current armory of anticancer therapies, a specific category of anti-invasion and antimetastatic drugs is missing. Here, we coin the term 'migrastatics' for drugs interfering with all modes of cancer cell invasion and metastasis, to distinguish this class from conventional cytostatic drugs, which are mainly directed against cell proliferation. We define actin polymerization and contractility as target mechanisms for migrastatics, and review candidate migrastatic drugs. Critical assessment of these antimetastatic agents is warranted, because they may define new options for the treatment of solid cancers.
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http://dx.doi.org/10.1016/j.trecan.2017.04.008DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5482322PMC
June 2017

MABp1 as a novel antibody treatment for advanced colorectal cancer: a randomised, double-blind, placebo-controlled, phase 3 study.

Lancet Oncol 2017 Feb 14;18(2):192-201. Epub 2017 Jan 14.

Oncology Department, Institut Hospitalier Franco-Britannique, Levallois-Perret, France.

Background: MABp1, an antibody that targets interleukin 1α, has been associated with antitumour activity and relief of debilitating symptoms in patients with advanced colorectal cancer. We sought to establish the effect of MABp1 with a new primary endpoint in patients with advanced colorectal cancer.

Methods: Eligible patients for the double-blind phase of this ongoing, placebo-controlled, randomised, phase 3 trial, had metastatic or unresectable disease, Eastern Cooperative Oncology Group performance status score 1 or 2, systemic inflammation, weight loss, and other disease-related morbidities associated with poor prognosis, and were refractory to oxaliplatin and irinotecan. Patients were randomly assigned 2:1 to receive either MABp1 or placebo. Randomisation codes were obtained from a centrally held list via an interactive web response system. Patients received an intravenous infusion of 7·5 mg/kg MABp1 or placebo given every 2 weeks for 8 weeks. The primary endpoint was assessed in patients who received at least one dose of MABp1 or placebo (modified intention-to-treat population), and was a composite of stable or increased lean body mass and stability or improvement in two of three symptoms (pain, fatigue, or anorexia) at week 8 compared with baseline measurements. This study is registered with ClinicalTrials.gov, number NCT02138422.

Findings: Patients were enrolled between May 20, 2014, and Sept 2, 2015. The double-blind phase of the study was completed on Nov 3, 2015. Of 333 patients randomly assigned treatment, 207 received at least one dose of MABp1 and 102 at least one dose of placebo. 68 (33%) and 19 (19%) patients, respectively, achieved the primary endpoint (relative risk 1·76, 95% CI 1·12-2·77, p=0·0045). The most common grade 3-4 adverse events in the MABp1 group compared with in the placebo group were anaemia (eight [4%] of 207 vs five [5%] of 102 patients), increased concentration of alkaline phosphatase (nine [4%] vs two [2%]), fatigue (six [3%] vs seven [7%]), and increased concentration of aspartate aminotransferase (six [3%] vs two [2%]). After 8 weeks, 17 (8%) patients in the MABp1 group and 11 (11%) in the placebo group had died, but no death was judged to be related to treatment. The incidence of serious adverse events was not significantly different in the MABp1 group and placebo groups (47 [23%] vs 33 [32%], p=0·07).

Interpretation: The primary endpoint was a useful means of measuring clinical performance in patients. MABp1 might represent a new standard in the management of advanced colorectal cancer.

Funding: XBiotech.
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http://dx.doi.org/10.1016/S1470-2045(17)30006-2DOI Listing
February 2017

Plasma Phosphatidylcholines Fatty Acids in Men with Squamous Cell Esophageal Cancer: Chemoradiotherapy Improves Abnormal Profile.

Med Sci Monit 2016 Oct 30;22:4092-4099. Epub 2016 Oct 30.

4th Department of Internal Medicine, 1st Faculty of Medicine of Charles University in Prague and General University Hospital, Prague, Czech Republic.

BACKGROUND Abnormal metabolism of fatty acids (FA) is considered to play a role in human cancers, including esophageal cancer (EC). Nevertheless, there have been only a few studies dealing with the influence of the chemotherapy or radiotherapy on the plasma FA profiles. In this work we compared FA in plasma phosphatidylcholine (PC) of the patients with squamous EC and healthy subjects and investigated changes in the FA spectrum during neoadjuvant chemoradiotherapy (CRT). MATERIAL AND METHODS Forty-two men with squamous EC were compared with age-matched healthy controls. The EC group was subjected to concurrent neoadjuvant CRT. We analyzed FA in plasma PC before and after CRT. RESULTS The EC group was characterized by increased levels of both saturated and monounsaturated FA, associated with an increased index of SCD1 (stearoyl-CoA desaturase-1). Moreover, decreased levels of linoleic acid and total polyunsaturated FA (PUFA) n-6 were found in EC patients. The CRT was accompanied by increased docosahexaenoic acid and total PUFA n-3 content in plasma PC, concurrently with the decrease of estimated activity of SCD1. CONCLUSIONS We found that patients with EC had altered FA profile in plasma PC, which could be related to abnormal FA metabolism in cancer (e.g., altered synthesis de novo, b-oxidation, desaturation, and elongation). The described changes in FA profiles during CRT could be involved in favorable functioning of CRT. Further studies investigating the plasma FA compositions and their changes due to CRT in EC patients are warranted.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5091214PMC
http://dx.doi.org/10.12659/msm.896799DOI Listing
October 2016

Regorafenib in the Real-Life Clinical Practice: Data from the Czech Registry.

Target Oncol 2017 02;12(1):89-95

Department of Oncology, University Hospital in Motol, Charles University, V Uvalu 84, 150 00, Prague, Czech Republic.

Objective: To describe the use of regorafenib for the treatment of metastatic colorectal cancer (mCRC) in clinical practice in the Czech Republic, and to describe the clinical outcomes of patients in terms of safety and survival.

Patients And Methods: The data of patients treated with regorafenib were extracted from the national CORECT registry. The CORECT registry is a non-interventional post-marketing database, gathering information about patients with CRC and treated with targeted agents. Twenty oncology centres in the Czech Republic contributed to this registry. Collected data included patients' characteristics, disease history, cancer treatments, response to treatments and safety.

Results: A total of 148 patients treated with regorafenib in clinical practice were analysed. At regorafenib initiation, almost all patients were fully active or slightly restricted in physical activity. Regorafenib was not administered as first-line treatment in any patient. Median progression-free survival was 3.5 months and median overall survival was 9.3 months. One-year survival rate was 44.6 %. Four partial responses were observed and 51 stable diseases. Progression was observed in 66 patients (44.6 %). The main reported adverse events were skin toxicity (5.4 %) and fatigue (2.0 %).

Conclusions: Regorafenib is a well-established treatment for pretreated patients with mCRC, however real-life data are scarce. Our results demonstrated slightly better efficacy of regorafenib and better safety profile in patients with mCRC compared to the randomised trials.
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http://dx.doi.org/10.1007/s11523-016-0458-1DOI Listing
February 2017

Bevacizumab plus paclitaxel versus bevacizumab plus capecitabine as first-line treatment for HER2-negative metastatic breast cancer (TURANDOT): primary endpoint results of a randomised, open-label, non-inferiority, phase 3 trial.

Lancet Oncol 2016 Sep 5;17(9):1230-9. Epub 2016 Aug 5.

Department of Medicine I and Comprehensive Cancer Center, Medical University Vienna, Vienna, Austria.

Background: The randomised phase 3 TURANDOT trial compared two approved bevacizumab-containing regimens for HER2-negative metastatic breast cancer in terms of efficacy, safety, and quality of life. The interim analysis did not confirm non-inferior overall survival (stratified hazard ratio [HR] 1·04; 97·5% repeated CI [RCI] -∞ to 1·69). Here we report final results of our study aiming to show non-inferior overall survival with first-line bevacizumab plus capecitabine versus bevacizumab plus paclitaxel for locally recurrent or metastatic breast cancer.

Methods: In this multinational, open-label, randomised phase 3 TURANDOT trial, patients aged 18 years or older who had an Eastern Cooperative Oncology Group performance status 0-2 and measurable or non-measurable HER2-negative locally recurrent or metastatic breast cancer who had received no previous chemotherapy for locally recurrent or metastatic breast cancer were stratified and randomly assigned (1:1) using permuted blocks of size six to either bevacizumab plus paclitaxel (bevacizumab 10 mg/kg on days 1 and 15 plus paclitaxel 90 mg/m(2) on days 1, 8, and 15 every 4 weeks) or bevacizumab plus capecitabine (bevacizumab 15 mg/kg on day 1 plus capecitabine 1000 mg/m(2) twice daily on days 1-14 every 3 weeks) until disease progression, unacceptable toxicity, or withdrawal of consent. Stratification factors were oestrogen or progesterone receptor status, country, and menopausal status. The primary objective was to show non-inferior overall survival with bevacizumab plus capecitabine versus bevacizumab plus paclitaxel in the per-protocol population by rejecting the null hypothesis of inferiority (HR ≥1·33) using a stratified Cox proportional hazard model. This trial is registered with ClinicalTrials.gov, number NCT00600340.

Findings: Between Sept 10, 2008, and Aug 30, 2010, 564 patients were randomised, representing the intent-to-treat population. The per-protocol population comprised 531 patients (266 in the bevacizumab plus paclitaxel group and 265 in the bevacizumab plus capecitabine group). At the final overall survival analysis after 183 deaths (69%) in 266 patients receiving bevacizumab plus paclitaxel and 201 (76%) in 265 receiving bevacizumab plus capecitabine in the per-protocol population, median overall survival was 30·2 months (95% CI 25·6-32·6 months) versus 26·1 months (22·3-29·0), respectively. The stratified HR was 1·02 (97·5% RCI -∞ to 1·26; repeated p=0·0070), indicating non-inferiority. The unstratified Cox model (HR 1·13 [97·5% RCI -∞ to 1·39]; repeated p=0·061) did not support the primary analysis. Intent-to-treat analyses were consistent with the per-protocol results. The most common grade 3 or worse adverse events were neutropenia (54 [19%] of 284 patients in the bevacizumab plus paclitaxel group vs 5 [2%] of 277 patients in the bevacizumab plus capecitabine group), hand-foot syndrome (1 [<1%] vs 43 [16%]), peripheral neuropathy (39 [14%] vs 1 [<1%]), leucopenia (20 [7%] vs 1 [<1%]), and hypertension (12 [4%] vs 16 [6%]). Serious adverse events were reported in 65 (23%) of 284 patients receiving bevacizumab plus paclitaxel and 68 (25%) of 277 receiving bevacizumab plus capecitabine. Deaths in two (1%) of 284 patients in the bevacizumab plus paclitaxel group were deemed by the investigator to be treatment-related. No treatment-related deaths occurred in the bevacizumab plus capecitabine group.

Interpretation: Bevacizumab plus capecitabine represents a valid first-line treatment option for HER2-negative locally recurrent or metastatic breast cancer, offering good tolerability without compromising overall survival compared with bevacizumab plus paclitaxel. Although progression-free survival with the bevacizumab plus capecitabine combination is inferior to that noted with bevacizumab plus paclitaxel, we suggest that physicians should consider possible predictive risk factors for overall survival, individual's treatment priorities, and the differing safety profiles.

Funding: Roche.
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http://dx.doi.org/10.1016/S1470-2045(16)30154-1DOI Listing
September 2016

Complete diagnostics and clinical approach for a female patient with unusual glioblastoma: A case study.

Mol Clin Oncol 2016 Jul 10;5(1):161-164. Epub 2016 May 10.

Institute of Medical Biochemistry and Laboratory Diagnostics, First Faculty of Medicine, Charles University and General University Hospital, 128 08 Prague 2, Czech Republic.

The present study reports a case of a 44-year-old female patient with a large frontal lobe tumor who underwent surgery using a modern navigation system SonoWand that combines the advantages of a non-frame navigation system with intraoperative real-time ultrasound imaging. The right frontal lobe tumor consisted of two morphologically different sections. A diffuse astrocytoma grade II and a glioblastoma grade IV were identified. These tumors were relatively substantially separated. A 17 p deletion, including , was detected in a diffuse astrocytoma but not in a glioblastoma. and amplifications were detected only in a glioblastoma. Detection of these amplifications is typical for primary glioblastomas. These findings support our assumption of two independent tumors. The , and gene mutations were also detected in a glioblastoma. Such an accumulation of molecular mutations is rare in one tumor. Following oncological treatment the patient was cared for in the oncological center and survived for 15 months after the surgery without any signs of a disease. This is an unusual case, and to the best of our knowledge, is not frequently published in literature.
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http://dx.doi.org/10.3892/mco.2016.891DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4906621PMC
July 2016

Phase II study on the efficacy and safety of Lapatinib administered beyond disease progression and combined with vinorelbine in HER-2/neu- positive advanced breast cancer: results of the CECOG LaVie trial.

BMC Cancer 2016 Feb 18;16:121. Epub 2016 Feb 18.

Department of Medicine I and Comprehensive Cancer Center, Clinical Division of Oncology, Medical University Vienna - General Hospital, Währinger Gürtel 18-20, 1090, Vienna, Austria.

Background: Vinorelbine constitutes effective chemotherapy for metastatic breast cancer (MBC) and acts synergistically with trastuzumab in HER-2/neu positive disease. The present study was set out to evaluate the efficacy and safety of vinorelbine when combined with lapatinib, an anti-HER2 tyrosine-kinase inhibitor, as late-line regimen administered beyond previous disease progression on prior lapatinib in patients with HER-2/neu- positive MBC.

Methods: The CECOG LaVie study was designed as open-labeled, single-arm, multicenter phase II trial. Patients had to be pretreated with lapatinib plus chemotherapy, and received lapatinib at a daily dose of 1250 mg in combination with vinorelbine 20 mg/m(2) i.v. on days 1 and 8 of a three-week cycle until disease progression, intolerable toxicity or withdrawal of consent. Progression-free survival (PFS) was defined as primary study endpoint; secondary endpoints included overall survival (OS), response rate according to RECIST 1.1, and safety. The study was terminated early due to poor accrual.

Results: A total number of nine patients were included; lapatinib administered beyond disease progression combined with vinorelbine resulted in a median PFS of 7.7 months (95% CI 0.56-14.91) and a median OS of 23.4 months (95% CI 16.61-30.13), respectively. Partial remission was seen in one of nine patients, three patients had stable disease of > six months, whereas the remaining five patients had primary disease progression. In two patients, modification of vinorelbine dose due to toxicity became necessary; no dose modification was needed for lapatinib. The majority of reported adverse events (AE) were grade 1 and 2 in severity with diarrhea being the most commonly observed AE CONCLUSION: In this heavily pretreated patient population, combination of vinorelbine plus lapatinib showed encouraging activity and was characterized by an acceptable safety profile. Despite the low patient number, lapatinib plus vinorelbine may constitute a potential treatment option in heavily pretreated patients with HER-2/neu-positive MBC previously exposed to lapatinib.

Trial Registration: EudraCT number 2009-016826-15, (15. 10.2009).
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http://dx.doi.org/10.1186/s12885-016-2171-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4758093PMC
February 2016

Bevacizumab with FOLFIRI or XELIRI in the First-line Therapy of Metastatic Colorectal Carcinoma: Results from Czech Observational Registry.

Anticancer Res 2015 Jun;35(6):3455-61

Masaryk Memorial Cancer Institute, Brno, Czech Republic.

Aim: To retrospectively compare the efficacy of two irinotecan-based chemotherapy regimens combined with bevacizumab in first-line therapy of metastatic colorectal cancer (mCRC).

Patients And Methods: The data of 558 patients with mCRC treated with first-line bevacizumab plus irinotecan-containing regimen were obtained from the national CORECT registry that collects data of all patients with mCRC treated with targeted-agents. The treatment outcomes of patients treated with bevacizumab plus irinotecan, 5-fluorouracil and folinic acid (FOLFIRI) were compared to patients treated with bevacizumab plus irinotecan and capecitabine (XELIRI).

Results: Among 4,312 patients with CRC treated with bevacizumab, only 13% (558) received irinotecan-based chemotherapy. No significant differences were observed in terms of progression-free survival and overall survival between FOLFIRI and XELIRI groups. Moreover, the toxicity of both regimens was also comparable.

Conclusion: This retrospective analysis confirms the comparable activity of FOLFIRI and XELIRI regimens when combined with bevacizumab.
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June 2015

The protective effect of pyrimidine nucleosides on human HaCaT keratinocytes treated with 5-FU.

Anticancer Res 2015 Mar;35(3):1303-10

First Faculty of Medicine, Charles University, Prague, Czech Republic Department of Oncology, General Teaching Hospital, Prague, Czech Republic.

Background: Therapy with 5-fluorouracil (5-FU) and capecitabine is often complicated by skin toxicity (hand-foot syndrome, HFS). Topical application of uridine ointment is beneficial for alleviating HFS and other pyrimidine nucleosides have been described as 5-FU toxicity modulators. We tested pyrimidine nucleosides and their combinations to find the best combination for topical therapy of HFS.

Materials And Methods: Cellular viability was measured by the real-time cell analyser and methyl thiazol tetrazolium (MTT) assay in order to evaluate the effect of pyrimidine nucleosides on HaCaT keratinocytes treated with 5-FU. The results were confirmed by evaluation of the cellular colonization by microphotography.

Results: Cytidine and uridine protected keratinocytes to the same extent. Thymidine enhanced the protective effect when added to cytidine or uridine. Deoxycytidine did not have any protective effect.

Conclusion: Our findings support the rationale for using uridine or cytidine in combination with thymidine in ointment for HFS treatment.
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March 2015